EvasayilTM : A Placebo-controlled Trial to Evaluate the Efficacy and Safety of Spesolimab in the Treatment of Patients With Netherton Syndrome
Phase: PHASE2
Conditions: Netherton Syndrome
Sponsor: Boehringer Ingelheim

Clinical Trial Protocol
TITLE PAGE
Document Number:
c38465777-03
EU Trial No.
2022-501104-10-00
BI Trial No.
1368-0104
UTN
U1111-1289-6825
BI Investigational
Medicinal Product
Spesolimab, BI 655130
Title
EvasayilTM : A placebo-controlled trial to evaluate the efficacy 
and safety of spesolimab in the treatment of patients with 
Netherton syndrome
Lay Title
A study to test whether spesolimab helps people with skin 
disease called Netherton syndrome
Clinical Phase
II/III
Clinical Trial 
Leader
Phone: 
Coordinating 
Investigator
Phone:
Current Version 
and Date
Version: 3.0, 24 Sep 2024
Original Protocol 
Date
22 Nov 2022
Page 1 of 131
Proprietary confidential information.
2024 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.
Boehringer 
~1lll1v lngelheim 

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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim 
Original Protocol 
date
22 Nov 2022
Revision date
24 Sep 2024
BI trial number
1368-0104 
EU Trial No.
2022-501104-10-00
UTN
U1111-1289-6825
Title of trial
EvasayilTM : A placebo-controlled trial to evaluate the efficacy and 
safety of spesolimab in the treatment of patients with Netherton 
syndrome
Coordinating 
Investigator
Phone:
Trial site(s)
Multi-center trial conducted globally
Clinical phase
II/III
Trial rationale
IL-36 is an upstream driver of barrier dysfunction and activator of 
pathogenic responses in NS. As for GPP, dysregulated 
IL-36 signaling causes a chronic inflammatory loop and pustule 
formation and treatment with spesolimab showed efficacy in patients 
with GPP. Netherton syndrome and GPP have overlaps with respect 
to the pathobiology involving IL-36R pathway and associated 
neutrophil mediated skin disease by promoting a feed forward loop 
of pro-inflammatory mediators.
Trial objective(s)
The primary objective is to evaluate the treatment response of 
spesolimab (determined by 50% improvement at Week 16 in IASI 
score). 
The secondary objectives are to evaluate reduction in other skin 
severity assessments, improvement in quality-of-life assessments, 
improvement in sleep, itch and scalp hair assessments and describe 
safety descriptively, with incidence of AEs. 
Trial endpoints
Primary endpoint:
The primary endpoint is IASI response, defined as a decrease of at 
least 50% absolute change in IASI score from baseline at Week 16 
(Yes/No).
Key secondary endpoint:
The key secondary endpoint is IGA response, defined as a decrease 
of at least 1-grade absolute change in IGA score from baseline at 
Week 16 (Yes/No).

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Efficacy
o
IGA score of 0 or 1 at Weeks 4, 8, 12, and 16 (Yes/No)
o
IASI response, defined as a decrease of at least 50%
absolute change in IASI score from baseline at Weeks 4, 
8, and 12 (Yes/No)
o
IASI-E subscore response, defined as a decrease of at 
least 50% absolute change in IASI-E subscore at 
Weeks 4, 8, 12, and 16 (Yes/No)
o
IASI-S subscore response, defined as a decrease of at 
least 50% absolute change in IASI-S subscore from 
baseline at Weeks 4, 8, 12, and 16 (Yes/No)
o
Percent change from baseline in IASI score at Weeks 4, 
8, 12 and 16
o
Absolute change from baseline in NRS pain at Weeks 4, 
8, 12 and 16
o
Absolute change from baseline in NRS itch at Weeks 4, 
8, 12 and 16
o
Absolute change from baseline in DLQI score at 
Weeks 8 and 16
o
Absolute change from baseline in CDLQI score at 
Weeks 8 and 16
Safety
o
The occurrence of treatment emergent adverse events
including serious and/or opportunistic infections
Trial design
Multi-center, randomised, double blind, placebo-controlled 
Phase II/III to evaluate the efficacy and safety of spesolimab 
compared with placebo in the treatment of patients with Netherton 
syndrome
Total number of 
patients randomised 
Approximately 39
Including at least 6 adolescent patients, randomisation ratio 2:1
(active: placebo)
Number of patients 
per treatment group
Approximately 26 patients in the active group
Approximately 13 patients in placebo group
Diagnosis
Adolescents ≥12 years old and adult patients with Netherton 
syndrome
Main inclusion and 
exclusion criteria
Inclusion criteria

Male or female patients, aged 12 years and older (weight 
minimum is 35 kg)

Confirmed diagnosis of NS (SPINK5 causative mutations) at 
baseline

At least moderate severity of erythema at baseline (IASI 
score ≥16 and IASI-E score ≥8) and ≥3 on IGA score

Signed and dated written informed consent and assent in 
accordance with ICH-GCP and local legislation prior to 
admission in the trial

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
Women of childbearing potential (WOCBP)1 must be ready 
and able to use highly effective methods of birth control per 
ICH M3 (R2) that result in a low failure rate of less than 1% 
per year when used consistently and correctly. A list of 
contraception methods meeting these criteria is provided in 
the CTP as well as in the patient, parent(s) (or patient’s legal 
guardian) information.
1A woman is considered of childbearing potential (WOCBP), 
i.e. fertile, following menarche and until becoming 
postmenopausal unless permanently sterile. Permanent 
sterilization methods include hysterectomy, bilateral 
salpingectomy and bilateral oophorectomy. Tubal ligation is 
not a method of permanent sterilization. A postmenopausal 
state is defined as no menses for 12 months without an 
alternative medical cause.
Exclusion criteria

Patients who have used topical corticosteroids (medium to 
high, US class I-V), topical retinoids, topical calcineurin 
inhibitors or keratolytics within 1 week prior to 
randomisation

Patients who have used emollient on the area to be biopsied 
in the previous 24 h

Patients who have used systemic retinoids, other systemic 
immunosuppressants, systemic corticosteroids or 
phototherapy within 4 weeks prior to randomisation

Patients who have used systemic antibiotics within 2 weeks 
prior to randomisation

Patients who have received live vaccines within 4 weeks 
prior to randomisation

Patients who have received investigational products, 
biologics or immunoglobulins within 4 weeks or 5 half-lives 
(whichever is longer) prior to randomisation

Relevant chronic or acute infections including active 
tuberculosis, human immunodeficiency virus (HIV) infection 
or viral hepatitis at the time of randomisation. A patient can 
be re-screened if the patient was treated and is cured from the 
acute infection.
Test product(s)
BI 655130 (spesolimab)
Dose
 doses at Week 0 (Day1) followed by 
 
 
Mode of 
administration
Comparator 
product(s)
Placebo

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Dose
Matching placebo
 placebo at Week 0 (Day 1) followed by every 
 
placebo 
Mode of
administration
 
Duration of 
treatment
Statistical methods
Suissa-Shuster Z-pooled test will be used to test if spesolimab is 
different from placebo regarding the primary binary endpoint 
variable (the proportions of IASI response at Week 16).

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FLOW CHART 1 (WHOLE TRIAL)
Flowchart
Screening
Randomised Treatment 
Period
CO
*
Open Label Treatment period
Extended Treatment 
Period
From 
up to 
**
FUP
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16 to 40
41/EoT2
EoS3
Visit location19- C: visits at 
clinic; C/R: Clinic or 
Remote visits
C
C
C
C
2C
C
C
C
C
C
C
C
C
C
C
C/R
C
C
Week
Day
Visit Window (days)
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
+/-14
+/-14
+7
Informed consent
X
Confirmation NS 
diagnosis4
X
Infection testing5
X
X
Visit 29
X
Demographics
X
Medical History 
X
Vital signs6
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination 19
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Height20
X
X
X
Weight
X
X
X
X
X
X
Pregnancy tests7
Xs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Every
weeks
X
X
Safety laboratory tests8
X
X
X
X
X
X
X
X
X
X
X
Every 
weeks
X
X
12 lead-ECG 9
X
X
X
X
X
X
X
X
Every 
weeks
X
Review of in/-exclusion 
criteria
X
X
IASI (E & S)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Every 
weeks
X
X

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FLOW CHART 1 (WHOLE TRIAL) cont’d
Screening
Randomised Treatment 
Period
CO
*
Open Label Treatment period
Extended Treatment 
Period
From 
 up to 
**
FUP
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16 to 40
41/EoT2
EoS3
Visit location19- C: visits at 
clinic; C/R: Clinic or 
Remote visits 
C
C
C
C
2C
C
C
C
C
C
C
C
C
C
C
C/R
C
C
Week
Day
Visit Window (days)
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
+/-14
+/-14
+7
IGA
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Every 
weeks
X
X
NASA
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Every 
weeks
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Itch, Pain NRS
X
X
X
X
X
X
X
X
X
X
X
Every 
weeks
X
X
DLQI/CDLQI
X
X
X
X
X
X
Every 
weeks
X
X
5-D Itch scale
X
X
X
X
X
X
HADS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Itchy Qol
X
X
X
X
X
X
PGIS-E
X
X
X
X
X
X
X
X
X
PGIS-S
X
X
X
X
X
X
X
X
X
PGIC
X
X
X
X
X
X
X
X
In- trial interviews (sub 
study-optional)21
X
Local tolerability 10
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X

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FLOW CHART 1 (WHOLE TRIAL) cont’d
Screening
Randomised Treatment 
Period
CO
*
Open Label Treatment period
Extended Treatment 
Period
From W56 up to 
W156**
FUP
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16 to 40
41/EoT2
EoS3
Visit location19- C: visits at 
clinic; C/R: Clinic or 
Remote visits 
C
C
C
C
2C
C
C
C
C
C
C
C
C
C
C
C/R
C
C
Week
Day
Visit Window (days)
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
+/-14
+/-14
+7
ADA/Nab Sampling11
X
X
X
X
X
X
X
X
X
X
X
Every 
weeks
X
PK sampling11
X
X
X
X
X
X
X
X
X
X
X
Every 
weeks
X
Photographs of skin 
lesions12
X
X
X
X
X
X
X
X
X
X
X
Skin Biopsies -Lesional 
(L) and non
lesional (NL)13
X 
(L;
NL)
X(L
)
Microbiome sample -
Lesional (L) and non
lesional (NL)14
X 
(L;
NL)
X
(L)
X(L
)
Soluble serum biomarkers
X
X
X
X
X
X
X
Blood sample (gene 
expression analysis)
X
X
X
X
X
X
X
Sampling for biobanking15
X
Randomisation
X
Administration trial drug17
Every 
weeks
Issue patient diary18
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Every 
weeks

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FLOW CHART 1 (WHOLE TRIAL) cont’d
Screening
Randomised Treatment 
Period
CO
*
Open Label Treatment period
Extended Treatment 
Period
From W56 up to 
W156**
FUP
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16 to 40
41/EoT2
EoS3
Visit location19- C: visits at 
clinic; C/R: Clinic or 
Remote visits 
C
C
C
C
2C
C
C
C
C
C
C
C
C
C
C
C/R
C
C
Week
 after 
last dose
Day
Visit Window (days)
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
+/-14
+/-14
+7
Review patient diary
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Every 
weeks
X
All AEs/SAEs/ AESIs16
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant therapy
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Completion of patient 
participation
X
* CO: Crossover, **: For detailed overview of assessments per individual visit for the extended treatment period, please see “Flow Chart 2".
S: serum
Footnotes to Flow Chart 1:
1 Day of Randomisation / Day of first intake of randomised medication
2 After Visit 15 (Week
), each individual patient may continue receiving the trial drug up to Week
 (approximately additional
years). EoT will be at Week
. 
All patients who stop treatment prior to Week
 will be considered early discontinued. Timepoint of early EoT will be considered the visit when the last dose of 
IMP was administered. In case of early discontinuation from trial treatment, every effort should be made to keep the patient in the trial and complete all of the 
remaining visits up to Week
(without IMP administration in that case). At a minimum, patients should come to an End-of-study Visit (EoS),
weeks after the 
last dose to cover full REP. 
3 End of Study (EoS), synonym for End of Trial. Regularly, EoS is 
weeks after last dose of trial medication. If a patient discontinues early from trial treatment and
continues with original visit schedule (without receiving treatment), EoS could also take place beyond
weeks after last treatment dose. EoS visit would be 
performed as the last patient visit in that case.
4 SPINK5 causative mutations to be confirmed by the investigator.
5 Infection testing at screening includes tuberculosis (QuantiFERON® or T-Spot®), hepatitis B, hepatitis C, and HIV assessments. See Section 5.2.3 for complete list 
of testing required. For patients who sign the informed consent ≥4 weeks prior to V2, infection testing must be repeated 2 to 4 weeks prior to V2. For patients who 
continue in the extended treatment period, tuberculosis test is to be repeated at Week
, Week
 and at EOS.

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6 Measurements of vital signs should precede blood sampling. In addition, at dosing visits, vital signs will be assessed pre dose, prior to blood sampling,
approximately 10 minutes after the end of trial drug administration 
 and approximately 60 minutes after the end of the trial drug administration
 (see 
Section 5.2.2) 
7 Pregnancy test: Only applicable for women of childbearing potential. Serum pregnancy test (performed at screening). Urine pregnancy tests will be performed at all 
other visits indicated, and every 4 weeks in the extended treatment period. Urine pregnancy testing should be done prior to trial drug administration. Trial drug should 
only be administered in case of a negative test result. In case of a positive urine pregnancy test, a serum pregnancy test will be done (via central laboratory) and trial 
drug administration will be postponed until negative result of serum pregnancy test is available.
8 Safety lab test: Laboratory tests will be performed at a central laboratory. Patient is not required to be fasting prior to blood collection. Please refer to Section 5.2.3
for further details.
9 ECG measurements should always precede blood sampling and drug administration.
10 Local tolerability at the administration site of spesolimab or placebo will be assessed during the trial drug administration on site or by questioning retrospectively 
since the last visit, if local tolerability related to AEs was observed. Any observed local tolerability reaction, e.g. swelling induration, heat, redness, pain, and other 
findings should be reported as an AE. 
11 PK/ADA/Nab samples will be obtained predose at all indicated visits. In addition, post-dose PK samples will be collected right after the 
 at Visit
and
Visit
12 Photographs of skin lesions are to precede skin biopsies and trial drug administration. In addition to photographs of skin lesions, biopsy site photographs will also be 
taken at Visit 2 and Visit 6.
13 Skin biopsy is mandatory.  
 
) prior to trial dug administration. Each skin biopsy should be collected prior to trial drug infusion. After approval of protocol amendment v2.0, skin 
biopsies will be obtained only from adult patients.
14
 samples must be taken before biopsies are taken and before trial drug administration. Patients should be instructed to not bathe, shower, or apply any 
topical product to the area that will be tested 24 h before Visit 2, Visit 3, and Visit 6.
15 DNA biobanking requires only one blood sample, preferably at Visit 2 or later during the trial, if not obtained at Visit 2.
16 After the EoS visit (individual patient’s end of the trial) the investigator should report only any cancers of new histology and exacerbations of existing cancer, trial 
drug related SAEs and trial drug related AESIs, of which the investigator may become aware of and only via the BI SAE form, please see Section 5.2.6.2.1.
17 At Week
 (Visit 6) each patient will receive 
 spesolimab 
mg)/placebo plus
 spesolimab 
mg)/placebo.
18 A patient diary will be given to the patient to collect daily information about NRS Pain score and NRS Itch score during the past 7 days prior to the scheduled visit. 
Changes in the use of concomitant therapies for NS (e.g. emollients, corticosteroids, antibiotics and analgesics use to manage pain) should be documented in the diary 
and eCRF throughout the trial. The diary should be given to the patient every weeks until Visit
 and every 
weeks starting Visit
. The diary should be 
reviewed by the trial staff during the visit.
19 During extension treatment phase, visits with reduced number of assessments (i.e every second visit starting Visit 16 and up to Visit 40) could be either performed 
at the investigational site or remotely by a trained Health Care Professional (HCP) at the patient’s home During remote visits, an abbreviated body system assessment 

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will be conducted by the trained HCP instead of a physical exam. This abbreviated body system assessment will include evaluation of organ systems associated with 
AE(s) symptoms and is only observational and conversational with patient.
20 At Visit 15, and at EOT visit, height will be measured only for adolescent patients.
21 Interviews should occur within 4 weeks after the Week
visit. They can also be at early termination visit if this visit occurs between Week
and Week
. 
Interviews will be conducted by 
. Consent to participate in the in-trial interviews can be collected at any visit up to Week
visit included.

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FLOW CHART 2 (EXTENDED TREATMENT PERIOD, ASSESSMENTS PER INDIVIDUAL VISITS)
From 
 up to 
FUP
Visit
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
EoT1
EoS2
Visit location12 (C: 
visits at clinic; 
C/R: Clinic or 
Remote visits)
C/
R
C
C/
R
C
C/
R
C
C/
R
C
C/
R
C
C/
R
C
C/
R
C
C/
R
C
C/
R
C
C/
R
C
C/
R
C
C/
R
C
C/
R
C
C
Week
 wks 
after
last 
dose
Day
Visit Window 
(days)
±14
±14
±14
±14
±14
±14
±14
±14
±14
±14
±14
±14
±14
±14
±14
±14
±14
±14
±14
±14
±14
±14
±14
±14
±14
±14
±7
Infection testing3
X
X
Vital signs4, 
Physical 
examination12
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Height13
X
Weight
X
Pregnancy tests5
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Safety laboratory 
tests6
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12 lead-ECG7
X
X
X
X
X
X
X
IASI (E & S), IGA, 
NASA
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ISS
X
Itch, Pain NRS 
X
X
X
X
X
X
X
X
X

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FLOW CHART 2 (EXTENDED TREATMENT PERIOD, ASSESSMENTS PER INDIVIDUAL VISITS) cont’d
From 
 up to 
FUP
Visit
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
EoT1
EoS2
Visit location12 (C: 
visits at clinic; 
C/R: Clinic or 
Remote visits) 
C/
R
C
C/
R
C
C/
R
C
C/
R
C
C/
R
C
C/
R
C
C/
R
C
C/
R
C
C/
R
C
C/
R
C
C/
R
C
C/
R
C
C/
R
C
C
Week
 wks 
after
last 
dose
Day
DLQI/CDLQI
X
X
X
X
X
X
5-D Itch scale, 
HADS, MOS Sleep, 
HADS, Itch QoL, 
PGIS-E, PGIS-S, 
PGIC, Scalp Hair 
Assessment
X
Local tolerability8
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PK/ADA/Nab 
Sampling9
X
X
X
X
X
Photographs of skin 
lesions
X
Administration trial 
drug
Issue patient diary11
X
X
X
X
X
X
X
X
X
Review patient diary
X
X
X
X
X
X
X
X
X
All AEs, SAEs, 
AESIs10
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant therapy
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X

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FLOW CHART 2 (EXTENDED TREATMENT PERIOD, ASSESSMENTS PER INDIVIDUAL VISITS) cont’d
From 
 up to 
FUP
Visit
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
EoT1
EoS2
Visit location12 (C: 
visits at clinic; 
C/R: Clinic or 
Remote visits) 
C/
R
C
C/
R
C
C/
R
C
C/
R
C
C/
R
C
C/
R
C
C/
R
C
C/
R
C
C/
R
C
C/
R
C
C/
R
C
C/
R
C
C/
R
C
C
Week
 wks 
after
last 
dose
Completion of 
patient participation
X
Footnotes to Flow Chart 2:
1 After Visit 15 (
), each individual patient may continue receiving the trial drug up to Week
 (approximately additional 
). EoT will be at Week
. 
All patients who stop treatment prior to Week
 will be considered early discontinued. Timepoint of early EoT will be considered the visit when the last dose of 
IMP was administered. In case of early discontinuation from trial treatment, every effort should be made to keep the patient in the trial and complete all of the 
remaining visits up to Week
 (without IMP administration in that case). At a minimum, patients should come to an End-of-study Visit (EoS),
weeks after the 
last dose to cover full REP.
2 End of Study (EoS), synonym for End of Trial. Regularly, EoS is 
weeks after last dose of trial medication. If a patient discontinues early from trial treatment and 
continues with original visit schedule (without receiving treatment), EoS could also take place beyond
weeks after last treatment dose. EoS visit would be 
performed as the last patient visit in that case.
3 Tuberculosis test has to be repeated at Week
 (Visit 29) and EoS. See Section 5.2.3 for complete list of testing required. 
4 Measurements of vital signs should precede blood sampling. At dosing visits, vital signs will be assessed pre dose, prior to blood sampling and approximately 
10 min after the end of trial drug administration (see Section 5.2.2) 
5 Pregnancy test: Only applicable for women of childbearing potential. Urine pregnancy tests will be performed every weeks in the extended treatment period. Urine 
pregnancy testing should be done prior to trial drug administration. Trial drug should only be administered in case of a negative test result. In case of a positive urine 
pregnancy test, a serum pregnancy test will be done (via central laboratory) and trial drug administration will be postponed until negative result of serum pregnancy 
test is available.
6 Safety lab test: Laboratory tests will be performed at a central laboratory. Patient is not required to be fasting prior to blood collection. Please refer to Section 5.2.3
for further details.
7 ECG measurements should always precede blood sampling and drug administration.

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8 Local tolerability at the administration site of spesolimab or placebo will be assessed during the trial drug administration on site or by questioning retrospectively 
since the last visit, if local tolerability related to AEs was observed. Any observed local tolerability reaction, e.g. swelling induration, heat, redness, pain, and other 
findings should be reported as an AE. 
9 PK/ADA/Nab samples will be obtained predose at all indicated visits. 
10 After the EoS visit (individual patient’s end of the trial) the investigator should report only any cancers of new histology and exacerbations of existing cancer, trial 
drug related SAEs and trial drug related AESIs, of which the investigator may become aware of and only via the BI SAE form, please see Section 5.2.6.2.1.
11 A patient diary will be given to the patient to collect daily information about NRS Pain score and NRS Itch score during the past 7 days prior to the scheduled visit. 
Changes in the use of concomitant therapies for NS (e.g. emollients, corticosteroids, antibiotics and analgesics use to manage pain) should be documented in the diary 
and eCRF throughout the trial. During extended treatment phase, the diary should be given to the patient every 
weeks. The diary should be reviewed by the trial 
staff during the visit.
12 During extension treatment phase, visits with reduced number of assessments (i.e. every second visit starting Visit 16 and up to Visit 40) could be either performed 
at the investigational site or remotely by a trained Health Care Professional (HCP) at the patient’s home. During remote visits, an abbreviated body system assessment 
will be conducted by the trained HCP instead of a physical exam. This abbreviated body system assessment will include evaluation of organ systems associated with 
AE(s) symptoms and is only observational and conversational with patient.
13 At EoT visit, height will be measured only for adolescent patients.

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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART 1 (WHOLE TRIAL)....................................................................................6
FLOW CHART 2 (EXTENDED TREATMENT PERIOD, ASSESSMENTS PER 
INDIVIDUAL VISITS).......................................................................................12
TABLE OF CONTENTS ......................................................................................................16
ABBREVIATIONS AND DEFINITIONS...........................................................................20
1.
INTRODUCTION...............................................................................................23
1.1
MEDICAL BACKGROUND.............................................................................23
1.2
DRUG PROFILE................................................................................................23
1.3
RATIONALE FOR PERFORMING THE TRIAL.........................................29
1.4
BENEFIT - RISK ASSESSMENT.....................................................................30
1.4.1
Benefits.................................................................................................................30
1.4.2
Risks .....................................................................................................................30
1.4.3
Discussion.............................................................................................................35
2.
TRIAL OBJECTIVES AND ENDPOINTS......................................................35
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........35
2.1.1
Main objectives....................................................................................................35
2.1.2
Primary endpoint(s)............................................................................................35
2.1.3
Key secondary endpoint(s).................................................................................35
2.1.4
Secondary endpoint(s) ........................................................................................35
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................37
3.1
OVERALL TRIAL DESIGN.............................................................................37
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)......................................................................................39
3.3
SELECTION OF TRIAL POPULATION .......................................................40
3.3.1
Main diagnosis for trial entry ............................................................................40
3.3.2
Inclusion criteria .................................................................................................40
3.3.3
Exclusion criteria ................................................................................................41
3.3.4
Discontinuation of patients from treatment or assessments ...........................42
3.3.4.1
Discontinuation of trial treatment .........................................................................43
3.3.4.2
Withdrawal of consent to trial participation .........................................................44
3.3.4.3
Discontinuation of the trial by the sponsor...........................................................44
4.
TREATMENTS...................................................................................................45
4.1
INVESTIGATIONAL TREATMENTS ...........................................................45
4.1.1
Identity of the Investigational Medicinal Products..........................................45
4.1.2
Selection of doses in the trial and dose modifications......................................46

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4.1.3
Method of assigning patients to treatment groups...........................................48
4.1.4
Drug assignment and administration of doses for each patient......................49
4.1.5
Blinding and procedures for unblinding...........................................................50
4.1.5.1
Blinding.................................................................................................................50
4.1.5.2
Unblinding and breaking the code ........................................................................50
4.1.6
Packaging, labelling, and re-supply...................................................................51
4.1.7
Storage conditions...............................................................................................51
4.1.8
Drug accountability.............................................................................................51
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ................................................................................................52
4.2.1
Other treatments and emergency procedures..................................................52
4.2.1.1
Other treatments....................................................................................................52
4.2.1.2
Emergency procedures..........................................................................................53
4.2.2
Restrictions ..........................................................................................................54
4.2.2.1
Restrictions regarding concomitant treatment ......................................................54
4.2.2.2
Restrictions on diet and lifestyle...........................................................................54
4.2.2.3
Contraception requirements..................................................................................54
4.3
TREATMENT COMPLIANCE........................................................................55
5.
ASSESSMENTS..................................................................................................55
5.1
ASSESSMENT OF EFFICACY........................................................................55
5.2
ASSESSMENT OF SAFETY.............................................................................58
5.2.1
Physical examination ..........................................................................................58
5.2.2
Vital signs.............................................................................................................59
5.2.3
Safety laboratory parameters ............................................................................59
5.2.4
Electrocardiogram ..............................................................................................62
5.2.5
Other safety parameters.....................................................................................62
5.2.6
Assessment of adverse events.............................................................................62
5.2.6.1
Definitions of AEs ................................................................................................63
5.2.6.1.1
Adverse event........................................................................................................63
5.2.6.1.2
Serious adverse event............................................................................................63
5.2.6.1.3
AEs considered “Always Serious”........................................................................63
5.2.6.1.4
Adverse events of special interest.........................................................................64
5.2.6.1.5
Intensity (severity) of AEs....................................................................................65
5.2.6.1.6
Causal relationship of AEs....................................................................................65
5.2.6.2
Adverse event collection and reporting ................................................................66
5.2.6.2.1
AE Collection........................................................................................................66
5.2.6.2.2
AE reporting to the sponsor and timelines............................................................66
5.2.6.2.3
Pregnancy..............................................................................................................67
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS...................................................................................67
5.3.1
Assessment of pharmacokinetics .......................................................................67
5.3.2
Methods of sample collection .............................................................................68
5.3.2.1
Plasma sampling for PK analysis..........................................................................68
5.3.2.2
Sampling for ADA/Nab assessment .....................................................................68
5.3.4
Pharmacokinetic - pharmacodynamic relationship.........................................68

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5.5.1
Methods and timing of sample collection..........................................................70
5.6
OTHER ASSESSMENTS...................................................................................70
5.7
APPROPRIATENESS OF MEASUREMENTS..............................................70
6.
INVESTIGATIONAL PLAN.............................................................................70
6.1
VISIT SCHEDULE.............................................................................................71
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................71
6.2.1
Screening and run-in period(s)..........................................................................71
6.2.2
Treatment period(s)............................................................................................72
6.2.3
Follow-up period and trial completion..............................................................73
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE 
SIZE......................................................................................................................74
7.1
NULL AND ALTERNATIVE HYPOTHESES ...............................................74
7.2
PLANNED ANALYSES.....................................................................................74
7.2.1
General considerations .......................................................................................74
7.2.2
Handling of Intercurrent Events .......................................................................75
7.2.3
Primary objective analyses.................................................................................75
7.2.3.1
Sensitivity Analyses..............................................................................................76
7.2.3.2
Subgroup Analyses ...............................................................................................76
7.2.3.3
Supplementary Analyses.......................................................................................76
7.2.4
Secondary objective analyses.............................................................................76
7.2.6
Safety analyses.....................................................................................................77
7.2.7
Other Analyses ....................................................................................................78
7.2.8
Interim Analyses .................................................................................................78
7.3
HANDLING OF MISSING DATA ...................................................................78
7.4
RANDOMISATION ...........................................................................................79
7.5
DETERMINATION OF SAMPLE SIZE .........................................................79
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY, AND ADMINISTRATIVE STRUCTURE ........80
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT ...........................................................................................................81
8.2
DATA QUALITY ASSURANCE ......................................................................81
8.3
RECORDS...........................................................................................................82
8.3.1
Source documents ...............................................................................................82
8.3.2
Direct access to source data and documents.....................................................83
8.3.3
Storage period of records ...................................................................................83
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS ..................................83
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY........83
8.5.1
Collection, storage and future use of biological samples and 
corresponding data .............................................................................................84
8.6
TRIAL MILESTONES.......................................................................................84

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8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ...................................85
9.
REFERENCES....................................................................................................86
9.1
PUBLISHED REFERENCES............................................................................86
9.2
UNPUBLISHED REFERENCES......................................................................88
10.
APPENDICES.....................................................................................................89
10.1
SCALES...............................................................................................................89
10.1.1
IASI- Ichtyosis Area Severity Index..................................................................89
10.1.2
IGA.......................................................................................................................89
10.1.3
NASA- Netherton Area Severity Assessment Score.........................................90
10.1.4
NRS Pain..............................................................................................................90
10.1.5
NRS Itch...............................................................................................................91
10.1.6
Dermatology Life Quality Index (DLQI) / Children’s Dermatology Life 
Quality Index (CDLQI) ......................................................................................92
10.1.7
5D-Itch-scale........................................................................................................94
10.1.8
Hospital Anxiety and Depression Scale (HADS)..............................................95
10.1.12
Diagnosis of Anaphylaxis....................................................................................99
10.1.13
Itchy QOL..........................................................................................................101
10.1.14
Patient Global Impression of Severity for Erythema (PGIS-E) ...................102
10.1.15
Patient Global Impression of Severity for Scaling (PGIS-S) ........................102
10.1.16
Patient Global Impression of Change for Netherton Syndrome Skin 
Symptoms (PGIC).............................................................................................102
10.2
TRIAL PARTICIPANT FEEDBACK............................................................103
10.3
MAXIMUM ALLOWABLE RESEARCH-RELATED BLOOD SAMPLE 
VOLUMES FOR ADOLESCENTS IN EU COUNTRIES ...........................103
11.
DESCRIPTION OF GLOBAL AMENDMENT............................................104
11.1
GLOBAL AMENDMENT 1 ............................................................................104
11.2
GLOBAL AMENDMENT 2 ............................................................................117

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ABBREVIATIONS AND DEFINITIONS
ADA
Anti-Drug Antibodies
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALCOA
Attributable, Legible, Contemporaneous, Original, Accurate 
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
AUC
Area under the Curve
BI
Boehringer Ingelheim
CA
Competent Authority
CD
Crohn’s disease
CDLQI
Children’s Dermatology Life Quality Index
CI
Confidence Interval
Cmax
Maximum Plasma Concentration
CO
Cross over
Cmin
Minimum Plasma Concentration
CRA
Clinical Research Associate
CRF
Case Report Form, paper or electronic (sometimes referred to as “eCRF”)
CRO
Contract Research Organisation
CTCAE
Common Terminology Criteria for Adverse Events
CT Leader
Clinical Trial Leader
CT Manager
Clinical Trial Manager
CTP
Clinical Trial Protocol
DBL
Database Lock
DILI
Drug Induced Liver Injury
DLQI
Dermatology Life Quality Index
EC
Ethics Committee
ECG
Electrocardiogram
(e)COA
(electronic) Clinical Outcome Assessment
eCRF
Electronic Case Report Form
eDC
Electronic Data Capture
EoS
End of Study (corresponds with End of Trial)

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ADA
Anti-Drug Antibodies
EoT
End of Treatment
FC
Flow Chart
FUP
Follow-up
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
GPP
Generalized pustular psoriasis
IGA
Investigator Global Assessment
HA
Health Authority
HADS
Hospital Anxiety and Depression Scale
HCP
Health Care Professional
HS
Hidradenitis suppurativa
IASI
Ichthyosis Area Severity Index
IB
Investigator’s Brochure
IBD
Inflammatory bowel disease
ICH
International Council on Harmonisation
IEC
Independent Ethics Committee
INN
International Non-Proprietary Name
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
IUD
Intrauterine Device
IUS
Intrauterine Hormone-Releasing System
LPLT
Last patient last treatment
LPLV
Last patient last visit
MedDRA
Medical Dictionary for Drug Regulatory Activities
nAb
Neutralizing Anti-Drug Antibodies
NASA
Netherton Area Severity Assessment Score
NS
Netherton syndrome
OPU
Operative Unit
PBO
Placebo
PGI
Patient Global Impression

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ADA
Anti-Drug Antibodies
PK
Pharmacokinetics
PPP
Palmoplantar pustulosis
PV
Pharmacovigilance
RA
Regulatory Authority
QoL
Quality of life
REP
Residual effect period
SAE
Serious Adverse Event
SD
Standard deviation
SC
Steering Committee
SMC
Safety Monitoring Committee
SoC
Standard of care
SOP
Standard Operating Procedure
SUSAR
Suspected Unexpected Serious Adverse Reactions
t1/2
Half-life time
tmax
Timepoint of maximum plasma concentration
TEAE
Treatment-emergent adverse event
TMF
Trial Master File
TSAP
Trial statistical analysis plan
ULN
Upper limit of normal
UTN
Universal Trial Number
WHO
World Health Organisation
WOCBP
Woman of childbearing potential

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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Netherton syndrome (NS) is an ultra-rare and severe autosomal recessive ichthyosis 
syndrome, which manifests at birth or shortly thereafter. There is marked variability in 
disease expression from patient to patient and over time. The severity of the skin condition
may lessen somewhat as patients grow into adulthood; however, it remains a serious and
debilitating condition. Patients with NS are characterized by 3 main signs: ichthyosis linearis 
circumflexa or congenital ichthyosis, trichorrhexis invaginata (“bamboo hair”), and atopic 
predisposition. The pathogenesis of NS lay in the mutations in the SPINK5 gene, which result 
in a deficiency or lack of lympho-epithelial Kazal-type-related inhibitor (LEKTI) and lead to 
unregulated desquamation resulting in a profound skin barrier defect and triggers the 
activation of inflammatory pathways. 
Spesolimab is a humanized antagonistic monoclonal IgG1 antibody blocking IL36α-, IL36β-
and IL36γ-induced IL36R activation. The IL-36 pathway has been associated with the 
pathogenesis of several inflammatory diseases, including pustular psoriasis (generalized 
pustular psoriasis [GPP] and palmoplantar pustulosis [PPP]), hidradenitis suppurativa (HS), 
and inflammatory bowel disease (IBD and Crohn`s disease [CD]). 
In NS, IL-36γ isoform, which is normally not expressed in healthy skin, is significantly 
increased in skin biopsies from lesional and non-lesional skin [R22-0746]. Immunostaining 
of IL-36R was also upregulated in the skin sections from NS patients [R22-0856]. 
Transcriptomic analysis performed in lesional and non-lesional skin biopsy samples obtained 
from NS patients and healthy donors showed that genes involved in IL-36 pathway 
(S100A7/8/9, IL-36, IL-36β, IL-36and CCL20) were among the highest expressed in 
lesional as well as non-lesional skin biopsies from NS patients [R22-0856; R22-0746]. 
Highly significant Pearson correlation was found between the clinical erythema/inflammation 
severity scores (IASI-E) and IL36gene expression on the skin from patients with NS 
[R22-1085].
1.2
DRUG PROFILE
Mode of action
BI 655130 (INN: spesolimab) is a humanized antagonistic monoclonal IgG1 antibody that
blocks human IL36R signalling. Binding of spesolimab to IL36R is anticipated to prevent the
subsequent activation of IL36R by cognate ligands (IL36α, β and γ) and downstream
activation of pro-inflammatory and pro-fibrotic pathways in inflammatory skin and bowel
diseases such as generalized pustular psoriasis (GPP), palmoplantar pustulosis (PPP), atopic
dermatitis (AD), hidradenitis suppurativa (HS), and inflammatory bowel disease (IBD). Thus,

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spesolimab may be unique in directly suppressing not only pro-inflammatory but also 
profibrotic mechanisms in these diseases.
Data from non-clinical studies
Preclinical Studies
BI 655130 binds to human IL36R with a binding avidity of less than 1 pM. BI 655130
inhibits IL36 ligand-stimulated NF-B activation in HT29 and transformed epithelial cells
and in primary human dermal fibroblasts or intestinal myofibroblasts with IC90 values in a
consistent range of 0.7 to 3.7 nM. BI 655130 also inhibits IL8 release in primary human
intestinal myofibroblasts and IFNγ secretion in human PBMC stimulated with IL36α, IL36β,
or IL36γ combined with IL12. Mutations of two key residues (L234 and L235) to alanine
were made to BI 655130 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 BI 655130 will be a non-depleting therapy in vivo.
Toxicology studies
BI 655130 does not bind to IL-36R from common toxicology species. Therefore, meaningful
toxicity studies of the molecule cannot be performed in any animal species with BI 655130.
However, hazard identification studies of the mode-of-action (MoA) of IL-36R inhibition
were performed in mice using a mouse specific anti-IL-36R monoclonal antibody 
(BI 674304), which is a mouse IgG2a monoclonal antibody with rat variable regions. In a 
13-week intravenous toxicity study of BI 674304 in mice, no adverse effects of IL-36R
antagonism was seen at a dose (50 mg/kg, twice weekly) that was 5-fold higher than the dose
that was protective in an experimental mouse colonic inflammation model. In the 26-Week
toxicity study, male and female mice (20- 30/sex/group at 0, 10 and 50 mg/kg/day) were
administered BI 674304 twice Weekly for 26 weeks by intravenous injection via the caudal
vein. There were no BI 674304-related changes in clinical observations, body weights, food
consumption, ophthalmology, clinical pathology parameters (hematology, 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

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cross-reactivity assays demonstrate that the risk of transient cytokine release in humans is
low and that, as expected, BI 655130 stains epithelium in a variety of tissues. There were no
signs of local irritation after single, 1 mL injections of the subcutaneous formulation in
rabbits. These preclinical toxicology data support chronic BI 655130 dosing in humans.
Data from clinical studies
For a more detailed description of the BI 655130 profile, please refer to the current 
Investigator’s Brochure (c03320877).
In the First-in-Human (FIH) study, BI 655130 or placebo (PBO) was administered to 78
healthy 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 were good. There were no SAEs. AEs categorized 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 BI 655130. The most frequent treatment-emergent AEs were nasopharyngitis 
(BI 655130: 20.7%; PBO: 15.0%), headache (BI 655130: 8.6%; PBO: 15.0%), influenza like
illness (BI 655130: 6.9%; PBO: 10.0%), and diarrhea (BI 655130: 3.4%; PBO: 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.
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 dosedependency
was observed.
PK analysis showed that exposure (AUC0-tz and Cmax) to BI 655130 increased with
increasing dose in an approximately dose-proportional manner from 0.3 to 10 mg/kg. The
effective half-life of BI 655130 is approximately 4 weeks in the linear dose range. PK data
suggests target-mediated drug disposition (TMDD) kinetics for BI 655130 below 0.3 mg/kg
dose. Anti-drug antibodies (ADA) were detected in 9 subjects (8 subjects on BI 655130 and 
1 subject on placebo), 3 of those had pre-existing levels. 
 
In a multiple rising dose trial, BI 655130 or placebo have been administered to healthy
volunteers at multiple ascending i.v. doses of 3, 6,10 and 20 mg/kg given Weekly for 4 weeks
(i.e. 4 administrations) or a single dose of 20 mg/kg (8 subjects each, 3:1 on active or PBO).
Overall, 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 BI 655130 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 BI 655130 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. For further details refer to the
current Investigator`s Brochure.

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Study 1368.3 explored pharmacokinetics as well as safety and tolerability of a subcutaneous
formulation of BI 655130 at two different dose strengths of 150 mg (1 mL) and 300 mg
(2 mL) using an open-label, single dose, parallel group, matched pair design to determine the
relative bioavailability of the 300 mg s.c. compared with one single 300 mg i.v. dose of
BI 655130. In this study, 36 healthy male and female subjects have been treated with
BI 655130, with 12 subjects per dose group. 35 subjects completed the study per protocol,
one subject discontinued for logistical reasons (work-related issues).
No important protocol violations occurred. Pharmacokinetic data from 34 subjects (94.4%)
were analysed for the primary and secondary endpoints. The minimum number of 11 subjects
per treatment group was considered sufficient for the exploratory assessment of the primary
objective. The precision and accuracy of the analytic methods used for the determination of
PK parameters were adequate to achieve the trial aims. Matching was only performed for the
300 mg BI 655130 IV and 300 mg BI 655130 SC groups; however, the demographics were
comparable across all treatment groups.
In a double-blind, randomised, and placebo-controlled trial in patient with GPP (study 
1368.13), patients were randomised in a 2:1 ratio to receive a single dose of spesolimab 
900 mg i.v. (35 patients) or placebo (18 patients) on Day 1. All randomised patients were 
treated. Patients could qualify to receive an open-label treatment with spesolimab on Day 8
(27 patients overall) and/or rescue treatment with spesolimab after Day 8 (6 patients overall; 
of those, 3 patients received both an open-label and a rescue dose).
The proportion of patients achieving a GPPGA pustulation subscore of 0 at Week 1 was 
higher in the spesolimab group (54.3%) than in the placebo group (5.6%). The risk difference 
between spesolimab and placebo of 48.7% was statistically significant (p = 0.0004). 
Similarly, the proportion of patients achieving a GPPGA total score of 0 or 1 at Week 1 was 
higher in the spesolimab group (42.9%) than in the placebo group (11.1%). The risk 
difference between spesolimab and placebo of 31.7% was statistically significant 
(p = 0.0118).
The effect of spesolimab on clearing pustules and achieving clear or almost clear skin for all 
skin manifestations seen in the primary analysis was consistent across prespecified sensitivity 
analyses and the prespecified subgroups, thereby demonstrating the robustness of the efficacy 
of spesolimab over placebo for treating a GPP flare.
A GPPASI 75 at Week 4 was achieved by a higher proportion of patients in the spesolimab 
group (45.7%) than in the placebo group (11.1%), with a risk difference of 34.6% in favour 
of spesolimab (p = 0.0081). The results of the sensitivity and subgroup analyses were 
generally consistent with the primary analyses for the GPPASI 75, and treatment effects seen 
at Week 4 were maintained until Week 12.
Pharmacokinetics
Statistical analysis of relative bioavailability showed that on average, the value of the AUCs
of the 300 mg BI 655130 SC dose group was two-thirds of the value of the AUCs of the 
300 mg BI 655130 IV dose group. The Cmax of 300 mg BI 655130 SC dose group was one-
third of the value of 300 mg BI 655130 IV dose group. The inter-individual variability of 
exposure parameters ranged from 23.7 to 26.6%. Exposures following the 300 mg BI 655130 
IV dose were comparable with those observed in the SRD study 1368.1. At least for a 300 mg
655130 SC dose, exposure following this dose is expected to result in a sustained >90% 
MIP-1 β inhibition.

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The relative bioavailability of the 300 mg BI 655130 SC dose group was more than double
the bioavailability of the 150 mg BI 655130 SC dose group. For all parameters, the value of
the 300 mg BI 655130 SC dose group was 2.7 times higher (on average) than the value of the
150 mg BI 655130 SC dose group. The 90% CI was above the expected value of 200%. The
inter-individual variability of exposure parameters ranged from 34.8 to 38.7%.
The assessment of dose normalised PK parameters of 300 mg BI 655130 IV compared with
150 mg BI 655130 SC is consistent with the other two assessments: the gMean ratios of
Cmax, norm (21%) and AUCnorm (50%) were even smaller than the comparison of 300 mg
BI 655130 SC vs. 300 mg BI 655130 IV.
The geometric mean terminal elimination half-life for BI 655130 after IV administration of
300 mg was 27.1 d. After SC administration of 150 mg and 300 mg, the geometric mean
terminal elimination half-life for BI 655130 was 20.6 d and 25.6 d, respectively.
Safety
In study 1368.3, single doses of BI 655130 given as SC injection or IV infusion were safe 
and well tolerated by the healthy subjects included in this trial. no AEs of severe intensity, 
protocol-specified AESIs, deaths, or other serious AEs were reported. One subject 
discontinued trial medication due to an AE (panic attack) beginning shortly after the start of 
the infusion, which was considered possibly related to trial drug administration. The overall 
incidence of AEs was higher in the 300 mg dose groups (both IV and SC) than the 150 mg
SC group (300 mg BI IV: 11 subjects, 91.7%; 300 mg BI SC: 11 subjects, 91.7%; 150 mg BI 
SC: 8 subjects, 66.7%). This difference was mainly driven by the AE dermatitis acneiform. 
Since AUC and Cmax were substantially lower for 300 mg BI SC than for 300 mg BI IV, 
there was no clear exposure /AE relationship. The incidence of AEs assessed as possibly 
drug-related by the investigator was higher in the SC groups than in the IV group (150 mg BI 
SC: 5 subjects, 41.7%; 300 mg BI SC: 5 subjects, 41.7%; 300 mg BI IV: 3 subjects, 25.0%).
Safety laboratory tests and the evaluation of vital signs, oral body temperature, local
tolerability, and electrocardiogram recordings revealed no clinically relevant findings.
In study 1368.13, The proportions and incidence rates of patients with any AE, as well as 
severe, serious, and investigator-defined drug-related AEs were comparable between the 
placebo and the spesolimab treatment group during Week 1 (i.e. following 1 dose of trial 
medication). Around two-thirds of patients reported any AE and a third of patients were 
reported with investigator-defined drug-related AEs. Serious adverse events were reported for 
3 patients in the placebo group (16.7%) and 5 patients in the spesolimab group (14.3%). no 
AEs leading to death occurred in this study.
Regarding safety laboratory values, the number of patients who were within normal range at 
baseline and then shifted to either below or above limits of normal was generally low. With 
the exception of parameters such as CRP which may be related to the GPP flare, no marked 
increases or decreases of mean values from baseline to end-of-treatment were observed for 
any parameter. For none of the vital signs, marked increases or decreases of mean values 
were observed over time. The overall frequency of patients with local tolerability symptoms 
at the infusion site was lower in the placebo group than in the spesolimab group. No clear 
pattern of symptoms was observed.
Overall, spesolimab showed an acceptable safety profile. The overall rates of adverse events 
were generally comparable between treatment groups during Week 1. There was no increase 

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in the incidence rates of adverse events after longer observation time (12 weeks) or higher 
exposure to spesolimab (2 to 3 doses).
Overall conclusions:
The relative bioavailability comparison showed that the 300 mg BI 655130 SC formulation
obtained approximately two-thirds of the 300 mg IV total exposure (AUC0-tz and AUC0-∞)
and approximately one-third of the peak exposure (Cmax). Single IV and SC doses of 
BI 655130 were safe and well tolerated by the healthy subjects in this trial.
In 1368.9 trial, 32 healthy Japanese male subjects were enrolled in 4 dose groups comprising
8 subjects per group. The study consisted of three dose groups receiving single rising
intravenous doses of BI 655130 (300 mg, 600 mg, and 1200 mg) and one dose group
receiving single subcutaneous doses of BI 655130 (300 mg). In each dose group, 6 subjects
received BI 655130 and 2 subjects, placebo.
Treatments were administered in a double-blind fashion within dose groups. In total,
24 subjects received BI 655130 and 8 subjects, placebo. Three subjects in the 600 mg i.v.
group (1 of them allocate to placebo) and 1 subject in the 1200 mg i.v. group discontinued the
trial prematurely due to personal reasons.
A total of 3 out of 18 subjects (16.7%) on intravenous doses of BI 655130 (1 subject per i.v.
dose level) were reported with an AE compared with 2 out of 8 subjects (25%) on placebo.
No subject was reported with an AE following subcutaneous administration of BI 655130.
Adverse events by preferred term reported on placebo were vomiting, chest discomfort, and
allergic rhinitis, while AEs reported on BI 655130 were upper respiratory infection (300 mg
i.v.), contusion (600 mg i.v.), gastroenteritis (1200 mg i.v.), and temporomandibular joint
syndrome (1200 mg i.v.). None of the observed AEs were judged by the investigator as
related to the trial medication.
The open-label, single group Phase I study (1368.11) was conducted to investigate the safety, 
tolerability, pharmacokinetics, pharmacogenomics, and efficacy of a single intravenous dose 
of BI 655130 (10 mg/kg) in 7 patients with acute flare of generalized pustular psoriasis. 
Based on the PK results in GPP patients, the elimination half-life of BI 655130 was 
approximately 3 weeks in GPP patients. The proof-of-concept (PoC) for IL36R inhibition in 
GPP was achieved in these patients who showed rapid clinical responses to single 
administrations of BI 655130. Five of these 7 patients became clear or almost clear of GPP 
1 week after the infusion, and all of them reached this status by 4 weeks after treatment.
Within 48 h of treatment, pustules were completely cleared in 3 patients; pustules were
cleared by Week 1 in 5 patients, and by Week 2 in 6 patients. The early response in the skin
was also accompanied by an early response in systemic components (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 to 79.8% (15.6), 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. For further details and most recent results refer to 
the current IB and published letter in the New England Journal of Medicine [P19-01888].
A placebo-controlled Phase II study (1368-0015) has also been conducted in 59 patients with
palmoplantar pustulosis (PPP), 38 of whom received infusions of BI 655130 at doses up to
900 mg every 4 weeks (0, 4, 8 and 12 weeks) and were followed-up through Week 32. Two

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Serious AEs (SAEs) were reported (one patient each in the 300 mg BI 655130 and placebo
arm). While the majority of AEs were mild or moderate and expected for the population, a
severe AE was reported in 2 patients for each of the three study arms (300 mg BI 655130,
900 mg BI 655130 and placebo). Four AEs (10.5%) in patients treated with BI 655130 and
three AEs (14.3%) in patients treated with placebo led to discontinuation of trial medication.
Three patients in the 900 mg BI 655130 arm and two in the placebo arm experienced a
significant AE. no AEs of special interest (AESI) were reported. No clinically relevant
abnormalities with respect to safety laboratory and vital signs were observed.
While the proportion of patients who achieved ppPASI50 at Week 16 in the total population
was similar in all treatment groups (6 of 19 in 900 mg BI 655130 arm, 6 of 19 in 300 mg
BI 655130 arm, and 5 of 21 in placebo arm) the baseline disease severity within the trial
population was lower than expected, with half of the patients having a baseline ppPASI total
score ≤16.70. In the overall population, the proportion of patients achieving ppPASI50 at
Week 16 was not statistically different between the BI 655130 groups (900 mg and 300 mg:
each 31.6% [95% CI 15.4%, 54.0%]) and the placebo group (23.8% [95% CI 10.6%,
45.1%]). Thus, the primary endpoint was not met. In patients with baseline disease scores 
>16.7, post hoc subgroup analyses indicated efficacy for both doses of BI 655130 relative to
placebo. The mean percent reduction from baseline in ppPASI total score was 40%, 24% and
8%, at Week 16 for BI 655130 900 mg, BI 655130 300 mg, and placebo respectively in this
subgroup. The mean percent reduction from baseline in pustular severity was 57%, 30% and
5% for the 900 mg BI 655130, 300 mg BI 655130 and placebo groups respectively at 
Week 16 of this subgroup, indicating a pronounced reduction in pustule severity.
Summary
BI 655130 is an anti-IL36R antibody with a high clinical activity to block IL36R signaling as
demonstrated in patients with Generalized Pustular Psoriasis, a severe inflammatory skin
disease driven by uncontrolled IL36 activity. BI 655130 has been tested in healthy volunteers
who received multiple doses every week for 4 weeks. These Weekly doses of up to 20 mg/kg
i.v. were all found to be safe in the subjects treated. In addition, IL36R inhibition shows a
favorable nonclinical safety profile. BI 655130 has also been tested in acute flare of GPP
patients. In these patients, BI 655130 was well tolerated, with no serious adverse events or
other clinically notable safety concerns. In a larger trial investigating patients with PPP no
safety signals have been identified for BI 655130.
For further details and most recent results refer to the current IB (c03320877).
1.3
RATIONALE FOR PERFORMING THE TRIAL
It has been shown that IL-36 is an upstream driver of barrier dysfunction and activator of 
pathogenic responses in NS. As for GPP, dysregulated IL-36 signaling causes a chronic 
inflammatory loop and pustule formation and treatment with spesolimab showed efficacy in 
patients with GPP [P22-00345]. Altogether, NS and GPP have overlaps with respect to the 
pathobiology involving IL-36R pathway and associated neutrophil mediated skin disease by 
promoting a feed forward loop of pro-inflammatory mediators.
Currently, there are no established treatment guidelines for NS. Topical corticosteroids are 
the main treatment option for NS, but treatment is limited to a short duration and body area 
due to potential side effects associated with prolonged use of corticosteroids (e.g. Cushing 

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syndrome). Additionally, daily application of topicals can be time-consuming, impacting 
patient and caregiver QoL [R22-0760]. Thus, there is an unmet need for an effective therapy 
that targets the NS pathophysiology with a tolerable and long-term safety profile.
Based on the current knowledge about the mechanism of action, and disease similarity 
between adults and paediatric subjects, BI expects that similar exposure (i.e. plasma 
concentrations) will result in similar efficacy and safety in adults and paediatrics with NS.
 
 
The same pharmaceutical forms and formulations are 
planned to be used in adults and adolescents 12 to <18 years based on the similarity of 
disease pathophysiology between adolescents and adults in this genetic disorder.
1.4
BENEFIT - RISK ASSESSMENT
1.4.1
Benefits
Preclinical profiles of BI 655130 and clinical data from healthy volunteer trials suggest that
BI 655130 is safe, tolerable and may address an unmet medical need in NS patients.
We hypothesize that in NS, due to the increase activation of different proteases, inactive 
IL-36 cytokines are cleaved and activated. These cytokines can target different types of cells, 
from keratinocytes to immune cells, promoting the production of pro-inflammatory 
cytokines, including IL-36, thus establishing an autocrine loop which further amplifies 
inflammation. IL-36 cytokines also have a strong ability to recruit neutrophils to the skin and, 
in turn, neutrophil-derived proteases process IL-36 cytokines, enhancing their biological 
activity. Altogether, data are supportive of a pivotal role of the IL-36 pathway in 
orchestrating the skin inflammatory cascades implicated in the pathogenesis of NS and define 
the therapeutic potential for IL-36 pathway inhibition in NS. Please refer to IB (c03320877).
for additional details.
No relevant animal species is available for toxicology testing of the highly human specific
antibody BI 655130. However, preclinical toxicology studies with a mouse surrogate
antibody have demonstrated the safety of IL-36R inhibition in mice (c03320877). As of 
September 2023, an estimated 863 subjects have been exposed to spesolimab, out of a total of 
966 subjects in the clinical development programme. For additional details please refer to IB 
(c03320877). 
 
1.4.2
Risks
There are no identified risks for BI 655130, based on the toxicology program or any clinical 
trials conducted for this product to date. No other IL-36 receptor antagonist is currently 
approved, providing information on identified risks in molecules of this class.
There are 4 important potential risks identified for BI 655130, as shown in the table below. 
The first 3, including hypersensitivity reaction, infections, and malignancies are generally 
hypothetical in nature; these are derived from general safety considerations of 
immunomodulatory drugs. The 4th, peripheral neuropathy, is based on clinical trial 

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experience, in which observed cases showed a heterogenous pattern. A causal association to 
spesolimab to any of the reported cases was assessed to be unlikely.
Blood volumes for safety analysis will be reduced for adolescent patients in this trial. In EU
countries, the total blood volume collected will be in line with the EU recommendations for 
clinical trials on medicinal products conducted with minors across the study [R23-1267].
Table 1.4.2:1 
Overview of trial related risks 
Possible or 
known risks of 
clinical 
relevance for 
this trial
Summary of data, rationale for 
the risk
Mitigation strategy
Investigational Medicinal Product
Hypersensitivity 
reaction
After administration of any 
biologic agent or protein, there is a 
possibility of occurrence of 
immediate adverse immune 
reactions (such as anaphylaxis) or 
delayed (such as drug reaction with 
eosinophilia and systemic 
symptoms)
Patients with a history of 
allergy/hypersensibility to the 
systemically administered trial 
medication agent or its excipients 
are excluded from the trial
Infections
Inhibition of the immune 
response with an immune-
modulating biologic may increase 
the risk of infections
Screening procedures for 
infections are defined for the trial. 
Patients with any relevant chronic 
or acute infections including 
human immunodeficiency virus 
(HIV), viral hepatitis or 
tuberculosis are excluded from 
the trial. Treatment of infections 
should be initiated promptly 
according to standards of care

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Table 1.4.2:1 (cont’d) Overview of trial related risks 
Possible or 
known risks 
of clinical 
relevance for 
this trial
Summary of data, rationale for the risk
Mitigation strategy
Investigational Medicinal Product
Malignancies
Inhibition of the immune response with 
an immunomodulatory drug may 
potentially impair immune defences and 
thus theoretically decrease immune 
defense against malignancies
Patients with a recent history 
of malignancy within 5 years 
will be excluded from 
participation in this trial. In 
case of occurrence of 
malignant neoplasm other than 
appropriately treated basal cell 
carcinoma or squamous cell 
carcinoma of the skin or in 
situ carcinoma of uterine 
cervix, the investigator should 
discontinue treatment with 
spesolimab. Diagnostics and 
treatment have to be initiated 
according to the local standard 
of care. Malignancies 
represent always serious 
adverse events 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 
showed a heterogenous pattern. A causal 
association to spesolimab to any of the 
reported cases was assessed to be 
unlikely.
As per assessment by the panel of 
external neurologists the nonspecific 
symptoms and findings in all three cases 
may best be referred to as peripheral 
neuropathy.
Timely detection, evaluation, 
and follow-up of suspected 
peripheral neuropathies to 
ensure patients´ safety.
Use of dedicated questions to 
elicit neurologic history 
during screening and 
exclusion criteria to avoid 
selection of patients with 
acute demyelinating 
neuropathy. Targeted Follow 
up questions to gather detailed 
information in case of any 
event during trial to ensure 
proper decision making.
Trial treatment continuation 
criteria as well as criteria for 
trial treatment restart are 
implemented for relevant 
cases.

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Table 1.4.2:1 (cont’d) Overview of trial related risks 
Possible or 
known risks of 
clinical relevance 
for this trial
Summary of data, rationale for the 
risk
Mitigation strategy
Investigational Medicinal Product
Drug-induced 
liver injury
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.
Timely detection, evaluation, 
and follow-up of laboratory
alterations in selected liver 
laboratory parameters to 
ensure patients’ safety. Trial
treatment discontinuation 
criteria as well as criteria for 
trial treatment restart are 
implemented for relevant 
cases.
Blood sampling
As with all blood sampling, there is a 
risk of mild pain, local irritation, or 
bruising at the puncture site. 
Furthermore, there is a small risk of 
light-headness and/or fainting. In 
rare cases, the puncture site can also 
become infected, or nerves may be 
damaged, inducing long-lasting 
abnormal sensations (paresthesia), 
impaired sensations of touch and 
persistent pain
The risks will be addressed by 
careful safety monitoring for 
AEs, selection of experienced 
sites and staff and training.
Skin biopsy
Skin biopsy can cause local bruising, 
inflammation, nerve damage and 
pain
These risks will be addressed 
by careful monitoring and risk 
mitigation measures such as: 
close clinical monitoring for 
AEs, selection of sites with 
experienced staff, training
Based on the findings in the nonclinical studies conducted to date and in accordance with 
international regulatory guidelines, the inclusion of Women of Childbearing Potential 
(WOCBP) in this study is justified. To minimize the risk of unintentional exposure of an 
embryo or fetus to the investigational drug, WOCBP must agree to the requirements for the 
pregnancy testing and contraceptive methods described in the protocol.
Benefit-Risk Assessment in context of COVID-19 pandemic for patients participating in
clinical trials investigating Spesolimab:
A thorough assessment based on the data available as of 31 May 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

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underlying disease and common co-morbidities was assessed. The key aspects of the
assessment are summarized below.
Spesolimab is an immune-modulating humanized monoclonal antibody that blocks the human
IL-36 receptor and thereby the pro-inflammatory IL-36 pathway. Available non-clinical and
clinical data in 
subjects (see c03320877) have not shown an increased risk of infections 
with spesolimab. However, as reflected in Table 1.4.2:1 above and the patient informed 
consent form, similar to other immune modulating biological treatments, spesolimab may 
hypothetically increase the risk of infections. Therefore, risk mitigation measures, such as 
exclusion of patients with increased risk of infections, close monitoring of adverse events, as 
well as guidance on treatment and handling of acute infections occurring during the trial have 
been included within this clinical trial protocol.
As any other acute infection, a suspected or diagnosed COVID-19 infection should be treated
according to the standard of care and interruption of study medication should be considered.
Currently, information about the immune response in patients with COVID-19 is sparse and
inconclusive. There are some reports suggesting high-levels of pro-inflammatory cytokines in
the severe cases, with much of the morbidity associated with coronavirus infection,
potentially related to immune activation and inflammation. To date, there is no reliable
evidence suggesting a link between SARS-CoV-2 infections and the IL-36 pathway targeted
by spesolimab. Considering the current knowledge of COVID-19 and the implemented risk
mitigation measures addressing the potential risk of infections, patients studied in trials with
spesolimab are not believed to be at higher risk of COVID-19 due to their background or
concomitant diseases. Protocol-defined procedures do not impose undue risk to study
participants.
The benefit-risk assessment of spesolimab remains favourable in the context of the 
COVID-19 pandemics. Patients participating in trials with spesolimab are expected to benefit 
from trial treatment and interruption of treatment may worsen their disease. Published 
guidance for the use of biologics during the COVID-19 pandemic recommends to continue 
treatment with biologics (e.g. NICE COVID-19 rapid guideline: severe asthma [R20-2257], 
American College of Allergy, Asthma&Immunology [R20-2258], and National Psoriasis 
Foundation [R20-2256]. In line with this guidance no systematic testing for SARS-CoV-2 is 
required to be performed on the trial. However, the investigator may choose to perform the 
testing as per his/her discretion if useful based on individual medical consideration and in the 
case of suspected COVID-19 infection. Patients may receive COVID-19 vaccination in line 
with local recommendations/guidance and approved labels. However, it is not known whether
there is any negative impact of spesolimab on the protective effect of COVID-19 vaccines.
To address potential risks associated with operational aspects related to the participation in
this clinical trial in context of COVID-19 pandemic, the following risk mitigation measures
are to be considered based on local requirements and development of pandemic.
The investigators will take the totality of information related to each single patient and the
local COVID-19 situation into consideration when performing the individual benefit-risk
assessment on a case-by-case basis. Considering all aspects, the investigator will decide upon
each patient’s (continued) participation in the planned trials. BI as the sponsor, where

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required, will support the investigator in their decision finding. It is acknowledged that the
investigator may decide to implement protocol deviations where this protects the safety,
wellbeing, and/or is in the best interest of the patient.
1.4.3
Discussion
In the context of the unmet medical need and anticipated benefit of spesolimab, the benefit 
risk evaluation of the compound, based upon the available preclinical and clinical 
information, is favourable.
Considering the medical need for the development of a better tolerated and more effective 
treatment for patients with NS, the expected benefit outweighs the potential risks.
2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
This trial will assess the efficacy, safety, PK and the tolerability of 
 
followed by 
 of spesolimab compared with placebo in patients 
≥12 years old with confirmed diagnosis of NS (SPINK5 causative mutations). The primary 
objective is to evaluate the treatment response of spesolimab (determined by 50% 
improvement at Week 16 in IASI score). The secondary objectives are to evaluate reduction 
in other skin severity assessments, improvement in quality-of-life assessments, improvement 
in sleep, itch and scalp hair assessments and describe safety descriptively, with incidence of 
AEs.
2.1.2
Primary endpoint(s)
The primary endpoint of the trial is:
o
IASI response, defined as a decrease of at least 50% absolute change in IASI 
score from baseline at Week 16 (Yes/No)
2.1.3
Key secondary endpoint(s)
The key secondary endpoint of this trial is:
o
IGA response, defined as a decrease of at least 1-grade absolute change in IGA 
score from baseline at Week 16 (Yes/No)
2.1.4
Secondary endpoint(s)
Secondary endpoints of the trial are:
Efficacy:
o
IGA score of 0 or 1 at Weeks 4, 8, 12 and 16 (Yes/No)
o
IASI response, defined as a decrease of at least 50% absolute change in IASI 
score from baseline at Weeks 4, 8, and 12 (Yes/No)

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o
IASI-E subscore response, defined as a decrease of at least 50% absolute change 
in IASI-E subscore at Weeks 4, 8, 12, and 16 (Yes/No)
o
IASI-S subscore response, defined as a decrease of at least 50% absolute change 
in IASI-S subscore from baseline at Weeks 4, 8, 12, and 16 (Yes/No)
o
Percent change from baseline in IASI score at Weeks 4, 8, 12 and 16
o
Absolute change from baseline in NRS pain at Weeks 4, 8, 12 and 16
o
Absolute change from baseline in NRS itch at Weeks 4, 8, 12 and 16
o
Absolute change from baseline in DLQI score at Weeks 8 and 16
o
Absolute change from baseline in CDLQI score at Weeks 8 and 16
Safety
o
The occurrence of treatment emergent adverse events including serious and/or 
opportunistic infections

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
Safety
o
Intensity of adverse events will be assessed by Common Terminology Criteria for 
Adverse Events (CTCAE) version 5.0
o
Safety laboratory tests
o
Physical examination
o
Vital signs (blood pressure, pulse rate, body temperature, respiratory rate)
o
12-lead Electrocardiogram (ECG)
o
Local tolerability
o
Immunogenicity (ADA/Nab)
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN 
This is a multicentre, randomised double blind, placebo-controlled Phase II/III trial 
comprising a spesolimab treatment group compared with placebo in 2:1 ratio in patients with 
moderate to severe NS.
Randomised period
After providing informed consent, patients will enter the screening period for up to 
days. 
Eligible patients will be randomised either in the active treatment arm to receive spesolimab 
at Week 0 plus spesolimab 
 every weeks
starting from Week
 or in the placebo arm to receive placebo

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Crossover period
There will be a crossover period when patients reach Week
where patients initially in 
placebo arm will receive spesolimab 
 and patients 
initially in spesolimab arm will receive 
 at Week
and continue receiving 
spesolimab 
.
To maintain the blinding during the crossover, each patient will receive
at Week
in addition to the 
Therefore, neither the patient nor the investigator (or the trial staff) will 
know if the patient had received spesolimab or placebo in the double-blind portion.
Patients will be evaluated for the primary endpoint defined as 50% improvement in IASI 
score at Week 16.
The primary analysis of this trial is planned to be performed once all randomised patients 
have completed the 16 weeks or early discontinued from the trial, to support an early 
submission; a database lock for the primary analysis will then be performed. 
Final analysis is planned to be performed at the end of the trial once all patients have 
completed the trial (including any follow-up period if applicable). 
Open label period
At Week
, all patients will enter the open label period to receive spesolimab 
 
. At Week
, patients will be evaluated for response to 
treatment. 
Patients who have responded (responders), defined as having more than or equal to 
 at Week
 compared with baseline will receive a 
 dose of 
spesolimab, 
every weeks. Patients who have not responded (non- responders), 
defined as having less than 
 in IASI score at Week
 compared with baseline 
will continue receiving 
of spesolimab every 4 weeks until Week
.
For patients who were responders at Week
 and were 
 
can be conducted if the patients, based on the 
investigator’s judgement, experience
 of less than 
 response. The dose 
escalation should be applicable only once. 
 Period (from Week
to Week
)
After completing the first 
weeks of treatment, the patients are offered to continue 
receiving their assigned treatment at Visit 16 (i.e. Spesolimab 
 
) in the extended treatment period up to additional 
weeks. 
Starting Week 56:

Patients receiving
of spesolimab and experiencing a reduction of less than 
 on 
IASI compared with Visit 2 for two consecutive visits should be discontinued from the trial 
treatment.  These two consecutive visits should be at least 4 weeks apart.
 from 
will not be permitted during the extended treatment period.

Patients who are receiving spesolimab 
and experience a 
 
on IASI should not be discontinued, but 
first. Only if the patient still 

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shows reduction of less than 50% on IASI on 
for two consecutive visits, patient 
should be discontinued.
Patients will then enter the 
 follow up period for ongoing safety data collection. The 
patient’s trial participation is complete when they have completed the last planned visit (EoS) 
weeks after the EoT visit.
Patients who prematurely discontinue from the trial drug will be encouraged to continue with 
the original visit schedule up to Week
 (without IMP administration in that case). EoS 
(End of Study) visit will be performed as the last patient visit in that case. At a minimum, 
patients should come to an EoS Visit
weeks after the last dose to cover full REP (see 
Figure 3.1:1 ).
DB: double blind
OL: open label
CO: Cross over (
):

Placebo patients receive spesolimab

Spesolimab patients receive placebo
Figure 3.1:1 Trial design
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
The placebo control is required to control for investigator bias and/or beneficial effects of 
being in a clinical trial. The 2:1 randomisation (active: placebo) is warranted in order to 
maximize the number of patients receiving active treatment and is being controlled for a 
statistical standpoint. The rationale for switching placebo patients to active treatment at 
Week
 is to allow patients who have not received active treatment at baseline and during 
the double-blind portion of the trial to have the opportunity to receive active treatment during 
open label portion of the trial. In addition, the extended treatment period after Week
is 
included to provide trial patients with continued treatment and assessments, and to collect 
further efficacy and safety evaluations.
As part of the trial, patients may participate to the Qualitative Interview sub-study to 
understand their experience with the received treatment during the clinical trial. Participation 
in the interview is optional and details will be described in an optional informed consent 
form/Assent. The interview will be conducted after a separate patient interview informed 
consent has been given in accordance with local ethical and regulatory requirements. Further 
details will be provided in a separate In-trial interview Manual.
OB 
 
D 
D 
OL: spesolimab 
 
D 
Responder 
 
 continue 600mg a& 
spesolimab i.v./H?" 
llll:31flll 
spesolimab ,.e, 
S!l.l~9Jimab s.c. 
placebo i.v./s,c, 
IIE!.li!IIIII 
spesolimab ,.e. 
w... 
0 
~----~ 
1' 
,o ~
~ 
'2 
I
II 
G4 II ~t I I
I 
" 
Extended 
Treatment Period 
(104w additional) 
"' 
E£! (EOS: I Im afte, last dose) 

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This trial will also include an option for adult participants to complete anonymized 
questionnaires to provide feedback on their clinical trial experience. Providing
this feedback is not required for trial participation, and information collected from these
questionnaires will not be analysed as part of the clinical data for the trial (see
Appendix 10.2).
3.3
SELECTION OF TRIAL POPULATION
The trial will be conducted worldwide in approximately 20-25 countries, at sites experienced 
in the management of dermatologic diseases, including rare dermatological conditions like 
GPP and NS.
The regions and clinical sites will be selected based on availability of patients with NS and 
experience in the conduct of clinical trials and use of the clinical assessments.
A total of approximately 39 patients with NS including at least  adolescent patients will be 
randomised. It is planned to enrol at least 1-2 patients per site due to the rareness of the 
disease. A sufficient number of patients will be screened to meet the randomised goal.
Screening of patients for this trial is competitive, i.e. screening for the trial will stop at all 
sites at the same time once a sufficient number of patients has been screened. Investigators 
will be notified about screening completion and will then not be allowed to screen additional 
patients for this trial. Patients already in screening at this time will be allowed to continue to 
randomisation if eligible.
A log of all patients enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the Investigator Site File (ISF) irrespective of whether they have been treated 
with investigational drug or not.
If retrospectively it is found that a patient has been in error (=did not meet all inclusion 
criteria or met one or more exclusion criteria), the sponsor or delegate should be contacted 
immediately. Based on an individual benefit-risk assessment a decision will be made whether 
continued trial participation is possible or not.
3.3.1
Main diagnosis for trial entry
This trial will assess treatment of patients with history of NS.
The patient eligibility will be based on a confirmed causative SPINK5 mutations, and at least 
moderate severity of erythema defined as (IASI score ≥16 and IASI-E score ≥8) at baseline
(Visit 2) and ≥3 on IGA score.
Please refer to Section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the in- and exclusion criteria.
3.3.2
Inclusion criteria
1. Male or female patients, aged 12 years and older (weight minimum is 35 kg)
2. Confirmed diagnosis of NS (causative SPINK5 mutations) at baseline (Visit 2)

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3. At least moderate severity of erythema at baseline (Visit 2) (IASI score ≥16 and IASI-E 
score ≥8) and ≥3 on IGA score.
4. Signed and dated written informed consent and assent in accordance with ICH-GCP and 
local legislation prior to admission in the trial.
5. Women of childbearing potential (WOCBP)1 must be ready and able to use highly 
effective methods of birth control per ICH M3 (R2) that result in a low failure rate of less 
than 1% per year when used consistently and correctly. A list of contraception methods 
meeting these criteria is provided in the CTP as well as in the patient, parent(s) (or 
patient’s legal guardian) information.
1 A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming 
postmenopausal unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy and bilateral oophorectomy. Tubal ligation is not a method of permanent sterilization. A postmenopausal 
state is defined as no menses for 12 months without an alternative medical cause.
3.3.3
Exclusion criteria
1. Patients who have used topical corticosteroids (medium to high, US class I-V), topical 
retinoids, topical calcineurin inhibitors or keratolytics within 1 week prior to 
randomisation
2. Patients who have used emollient on the area to be biopsied in the previous 24 h
3. Patients who have used systemic retinoids, other systemic immunosuppressants, systemic 
corticosteroids or phototherapy within 4 weeks prior to randomisation
4. Patients who have used systemic antibiotics within 2 weeks prior to randomisation
5. Patients who have received live vaccines within 4 weeks prior to randomisation
6. Patients who have received investigational products, biologics or immunoglobulins within 
4 weeks or 5 half-lives (whichever is longer) prior to randomisation
7. Severe, progressive, or uncontrolled hepatic disease, defined as >3-fold Upper Limit of 
Normal (ULN) elevation in AST or ALT or alkaline phosphatase, or >2x ULN elevation 
in total bilirubin
8. Patients who have any prior exposure to BI 655130 or another IL-36R inhibitor biologics
9. Increased risk of infectious complications (e.g. recent pyogenic infection, any congenital 
or acquired immunodeficiency (e.g. HIV), past organ or stem cell transplantation), as 
assessed by the investigator
10. Relevant chronic or acute infections including active tuberculosis, human 
immunodeficiency virus (HIV) infection or viral hepatitis at the time of randomisation. A 
patient can be re-screened if the patient was treated and is cured from the acute infection
11. Active or Latent TB:
o
Patients with active tuberculosis should be excluded
o
Patients with a positive QuantiFERON® (or if applicable, T-Spot®) TB test 
during screening are excluded, unless the patient had previous diagnosis of active 
or latent TB and has completed appropriate treatment per the discretion of the 
local investigator within the last 3 years and at the latest at the time of screening 

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(i.e. 2 to 4 weeks before study drug administration); patients may be re-screened 
once to meet this criterion)
o
Patients with suspected false positive or indeterminate QuantiFERON® (or if 
applicable, T-Spot®) TB result may be re-tested once
o
If QuantiFERON® (or if applicable, T-Spot®) TB testing is not available or 
provides indeterminate results after repeat testing, a tuberculin skin test (TST) or 
any alternative test/procedure (as per local standards) to rule out TB can be 
performed: a TST reaction of ≥10 mm (≥5 mm if receiving ≥15 mg/d prednisone 
or its equivalent) is considered positive.
12. Active skin infection requiring the use of a systemic therapy within 2 weeks
13. History of allergy/hypersensitivity to the systemically administered trial medication agent 
or its excipients
14. Currently enrolled in another investigational device or drug study, or less than 30 days 
since ending another investigational device or drug study(s) or receiving other 
investigational treatment(s)
15. Women who are pregnant, nursing, or who plan to become pregnant while in the trial. 
Women who stop nursing before the trial drug administration do not need to be excluded 
from participating; they should refrain from breastfeeding for 
weeks after the last trial
drug administration
16. Major surgery (major according to the investigator’s assessment) performed within 
12 weeks prior to receiving first dose of trial drug or planned during the trial, e.g. hip 
replacement, aneurysm removal, stomach ligation, as assessed by the investigator
17. Evidence of a current or previous disease, medical condition (including chronic alcohol or 
drug abuse or congestive heart disease or any condition) other than NS, surgical 
procedure, psychiatric or social problems, medical examination finding (including vital 
signs and electrocardiogram (ECG), or laboratory value at the screening outside the 
reference range that in the opinion of the investigator is clinically significant and would 
make the trial participant unreliable to adhere to the protocol, comply with all trial 
visits/procedures or to complete the trial, compromise the safety of the patient or 
compromise the quality of the data.
18. Any other condition that according to the investigator will impair the ability to evaluate 
treatment effect.
19. Any documented active or suspected malignancy or history of malignancy within 5 years 
prior to screening, except appropriately treated basal cell carcinoma of the skin or in situ
carcinoma of uterine cervix.
20. Previous enrolment in this trial (re-screening is allowed).
21. Presence of acute demyelinating neuropathy.
3.3.4
Discontinuation of patients from treatment or assessments
Patients may discontinue trial treatment or withdraw consent to trial participation as a whole
(“withdrawal of consent”) with very different implications; please see Sections 3.3.4.1 and 
3.3.4.2 below.

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However, if the patients agree, they should stay in the trial. Even if continued trial treatment 
is not possible, they should attend further trial visits to ensure their safety and to collect 
important trial data.
Measures to control the withdrawal rate include careful patient selection, appropriate 
explanation of the trial requirements and procedures prior to trial enrolment, as well as the
explanation of the consequences of withdrawal. 
The decision to discontinue trial treatment or withdraw consent to trial participation and the 
reason must be documented in the patient files and CRF. If applicable, consider the 
requirements for Adverse Event collection reporting (please see Section 5.2.6.2).
3.3.4.1
Discontinuation of trial treatment
An individual patient will discontinue trial treatment if:

The patient wants to discontinue trial treatment. The patient will be asked to explain the 
reasons but has the right to refuse to answer.

The patient has repeatedly shown to be non-compliant with important trial procedures 
and, in the opinion of the investigator, the safety of the patient cannot be guaranteed as 
he / she is not willing or able to adhere to the trial requirements in the future. 

The patient needs to take concomitant medication that interferes with the safety of the 
investigational medicinal product or other trial treatment

The patient can no longer receive trial treatment for medical reasons as per physician’s 
discretion (such as surgery, adverse events, other diseases, or pregnancy

If a hepatic injury alert is detected without identification of an alternative cause in the 
work-up according to the “DILI checklist” (see Section 5.2.6.1.4), the patient should not 
receive subsequent doses of trial medication

For individual stopping rules related to specific adverse events, please see 

Section 4.2.1 “Other treatments and emergency procedures.”

Worsening of clinical status or symptoms requiring treatment with restricted medication 
in the investigator’s opinion

In case of a temporary reason, trial treatment should be restarted if medically justified, 
please see Section 4.1.4.
In case the study drug administration is permanently discontinued before EoT visit, all
effortsshould be made to keep the patient in observation for the remaining trial visits up to the 
regular EoT visit at Week
, according to Flowchart. EoS visit will be performed as the last 
patient visit in that case. As a minimum, the patient should come back to an EoS 
Visit
weeks after the last dose ofthe study drug. 
If new efficacy/safety information becomes available, Boehringer Ingelheim will review the 
benefit-risk-assessment and, if needed, pause or discontinue the trial treatment for all patients 
or take any other appropriate action to guarantee the safety of the trial patients. 
Even if the trial treatment is discontinued, the patients remain in the trial and, given their
agreement, will undergo the procedures for early treatment discontinuation and follow-up as 
outlined in the Flowchart and Section 6.2.3.

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3.3.4.2
Withdrawal of consent to trial participation
Patients may withdraw their consent to trial participation at any time without the need to 
justify the decision.
If a patient wants to withdraw consent, the investigator should be involved in the discussion 
with the patient and explain the difference between trial treatment discontinuation and 
withdrawal of consent to trial participation, as well as explain the options for continued 
follow-up after trial treatment discontinuation, please see Section 3.3.4.1 above.
3.3.4.3
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial
site at any time for the following reasons:
1. Failure to meet expected enrolment goals overall or at a particular trial site.
2. New efficacy or safety information invalidating the earlier positive benefit-risk-
assessment, please see Section 3.3.4.1.
3. Deviations from GCP, the trial protocol, or the contract impairing the appropriate conduct 
of the trial.
4. Termination of development of compound in this indication
Further treatment and follow up of patients affected will occur as described in section 3.3.4.1.
The investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).

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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
4.1.1
Identity of the Investigational Medicinal Products
Table 4.1.1:1 
Test product 1: BI 655130 (spesolimab)
Substance:
BI 655130 (spesolimab)
Pharmaceutical formulation:
Solution for infusion
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
BI 655130
Posology:
Spesolimab arm:
 at Week 0
Placebo arm:
 spesolimab
at Week
 
Mode of administration:
 
Table 4.1.1:2 
Test product 1: BI 655130 (spesolimab) 
Substance:
BI 655130 (spesolimab)
Pharmaceutical formulation:
Solution for injection
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
BI 655130 
Posology:
Spesolimab arm:
weeks
 
Placebo arm:
weeks
Mode of administration:

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Table 4.1.1:3 
Placebo comparator 
Substance:
Placebo matching to spesolimab
Pharmaceutical formulation:
Solution for infusion
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
Placebo matching to spesolimab
 
Posology:
Placebo arm:
Spesolimab arm:
 
Mode of administration:
Table 4.1.1:4 
Placebo comparator
Substance:
Placebo matching to spesolimab
Pharmaceutical formulation:
Solution for injection
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
Placebo matching to spesolimab
 
Posology:
Placebo arm:
Placebo 
 
Mode of administration:
4.1.2
Selection of doses in the trial and dose modifications
As dose ranging is not feasible in this extremely rare disease, a high yet safe dosing regimen 
is proposed in the NS trial 1368-0104:
 spesolimab 
 on Day 1
followed by 
 starting from Week . In responders, the dose 
is reduced to 
 to explore the efficacy of a lower dose. 

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In the on-going GPP prevention trial 1368-0027, spesolimab s.c. up to 300 mg q4w is being 
evaluated. To account for potential difference in the dose-response relationship between NS 
and GPP, 600 mg s.c. q4w is proposed as maintenance dose for NS patients considering the 
chronic nature of the disease and the potential need for persistent inhibition of IL-36. A dose 
regimen of 600 mg q4w is expected to be safe (see below) and considered to provide an 
appropriate balance between efficacy and patient burden in the administration of required 
injections per visit (2 shots for 600 mg). The dose reduction (to 300 mg q4w) in responders at 
Week 32 provides opportunity to explore the dose-response in this rare disease population. 
Based on the similarity of disease pathophysiology between adolescents and adults as an 
underlying genetic disorder, the same dose is proposed for adolescents in trial 1368-0104.  
Adolescents have been included in GPP trial 1368-0027 up to 300 mg spesolimab s.c. q4w 
and no safety signals have been identified specific to this subpopulation. The proposed dosing 
regimen in adults and adolescents is expected to be safe.
Spesolimab has been generally well tolerated throughout the clinical development
(c03320877), 
 
 
 As there is no PK data in NS population, typical parameters were 
used from a popPK model developed from other indications, 
 
(c34990476). 

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Table 4.1.2:1 
Observed exposures or exposures predicted from a Population PK 
model 
 
2. Observed geometric mean exposures (gCV%) for 1368.2 (HV)
* Mean (SD)
4.1.3
Method of assigning patients to treatment groups
An Interactive Response Technology (IRT) will be used to screen eligible patients, perform 
drug assignment, manage initial/re-supply ordering of drug supplies and handle emergency 
un-blinding. The investigator will receive all necessary instructions to access the IRT from 
the Sponsor. Detailed IRT functions and procedures will be documented in the user 
requirement specifications mutually agreed to by the sponsor and the IRT vendor.
After the assessment of all in- and exclusion criteria, each eligible patient will be randomised 
to a treatment group according to a randomisation plan in a 2:1 ratio at Visit 2 via Interactive 
Response Technology (IRT). Note that the medication number is different from the patient 
Study
Population
Dose 
Regimen
Body 
weight 
(kg)
Cmax, 
overall 
(mcg/mL)
AUC over last 
4 weeks 
(mcg/mL*day)
Predicted exposure metrics for NS
Predicted or observed exposure metrics from other populations 
1368.2
Healthy
20 mg/kg 
i.v., q1w, 
x4 doses, 
until 
Week 4
75.6 
(8.2)*
826 
(15.8%)
2  
13400 (9.3%) 
2

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number (the latter is generated during screening via the IRT System). Each syringe and vial 
will have an individual medication number for dispensation. 
4.1.4
Drug assignment and administration of doses for each patient
Prior to each administration of trial drug, a urine pregnancy test will be performed on site. If 
this test has positive result, the administration of trial drug should not proceed, and this urine 
test should be confirmed by a serum pregnancy test.
The trial drug will be prepared and handled according to the ‘clinical supplies handling 
instruction’ which will be filed in the ISF.
Upon randomisation, patients will receive a 
or 
placebo
). Throughout the randomised portion of trial, patients will 
receive either speoslimab
or placebo 
s at Week
.
The administration of the trial medication
will be done under the supervision of 
the investigating physician or designee.
To maintain the treatment blind during the
, all patients will 
receive
placebo at Week
. 
During the open label period starting at Week
, all patients will receive spesolimab 
. 
every weeks. During the visits with reduced number of assessments e.g. Weeks
, and extended treatment period, patients will be offered to receive spesolimab s.c. at 
home or closer to the patient’s home, administered by a specialized vendor/HCP if 
applicable. However, if preferable for the patient and the investigational site, all s.c. 
injections will be performed at the trial site. Patient self-administration is not permitted.
Detailed instructions for administration of the s.c. injections are provided in the ISF.
The 
 will be administered over a period of 
min. In case of safety concerns, 
e.g. due to systemic hypersensitivity including infusion reactions, it is at the discretion of the 
investigator or his/her designee to adapt the infusion scheme, including but not limited to 
slowing down the infusion rate, stopping the infusion, and provided no further safety concern 
exists, restarting at a slower rate. Regardless, the total duration of infusion should not exceed 
180 min (3 h). Patients should be closely monitored for signs and symptoms of 
hypersensitivity reactions for approximately 1 hour after the i.v. dose of trial drug 
administered at Visit 2 and Visit 6. Hypersensitivity reactions should be treated according to 
medical standards. Further based on his/her medical judgment the investigator will provide 
medications as needed.
 
 
personnel should observe the injection site for signs of redness, 
swelling or hardness. They should also ask patients about itching, dizziness or shortness of 
breath. Patients should be advised that if they experience redness, swelling or other changes 
at the injection site, they should notify site personnel. They should further be advised that if 

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they experience itching all over or a feeling of being swollen, dizzy or short of breath, they 
should notify site personnel or their own healthcare provider immediately. Pre-medications 
for further injections might be considered upon discussion with the sponsor.
In exceptional cases of missed or delayed visits, if any of these visits has to be rescheduled, 
the date of subsequent visit should be calculated from Visit 2/Day 1.
During the COVID-19 pandemic, physical visits to the trial sites may need to be restricted to 
ensure patient safety. Based on a thorough assessment of the benefits and risks, the 
investigator may still decide to continue the trial treatment and trial medication 
 may be administered at patient’s home if acceptable according to local law and 
regulations.
4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding 
The primary analysis of this trial is planned to be performed once all randomized patients 
have completed the 
weeks or early discontinued from the trial, to support an early 
submission; a database lock for the primary analysis will then be performed and treatment 
will be unblinded to the sponsor.
Patients, investigators and central reviewers involved in trial conduct in this double-blind trial
will remain blinded regarding the randomised treatment assignments until the database is 
declared ready for final analysis according to the sponsor’s SOPs. Further details regarding 
the timepoint of unblinding the database for analysis is documented in the TSAP.
The access to the randomisation code will be kept restricted until its release for analysis.
The randomisation codes may be provided to bioanalytics before the last patient completed 
the trial for the PK and ADA analysis. Bioanalytics will not disclose the randomisation code 
or the results of their measurements until the trial has been officially un-blinded to the 
sponsor.
A fully external DMC will perform an unblinded safety and efficacy assessment at specified 
intervals in order to ensure that patients are protected from potential harm, please refer to 
Section 8.7 for further details.
4.1.5.2
Unblinding and breaking the code
Emergency unblinding will be available to the investigator via IRT. It must only be used in
an emergency situation when the identity of the trial drug must be known to the investigator
in order to provide appropriate medical treatment or otherwise assure safety of trial
participants. The reason for unblinding must be documented in the source documents and/or 
appropriate CRF page.
Due to the requirements to report Suspected Unexpected Serious Adverse Reactions 
(SUSARs), it may be necessary for a representative from BI’s Pharmacovigilance group to 
access the randomisation code for individual patients during trial conduct. The access to the 

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code will only be given to authorised Pharmacovigilance representatives for processing in the 
PV database system and not be shared further. 
4.1.6
Packaging, labelling, and re-supply
The investigational medicinal products will be provided by BI or a designated CRO. They 
will be packaged and labelled in accordance with the principles of Good Manufacturing 
Practice (GMP). Re-supply to the sites will be managed via an IRT system, which will also 
monitor expiry dates of supplies available at the sites.
In accordance with the Clinical Trial regulation (EU) No 536/2014 and the corresponding 
Annex VI, omitting of label content with the following justifications:

the translation of country specific label text may differ from the Master Label Text based 
on specific local requirements. This could include the omission, addition or revision of 
some text per local regulation compliance.

the Investigator name was omitted from the label due to IRT System.
For details of packaging and the description of the label, refer to the ISF.
4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area according to the recommended storage conditions on the medication label. A
temperature log must be maintained for documentation.
If the storage conditions are found to be outside the specified range, the Clinical Research 
Associate CRA (as provided in the list of contacts) must be contacted immediately.
The trial medication will be prepared for infusion just prior to infusion, for further details 
please refer to preparation instructions in the ISF.
4.1.8
Drug accountability
The investigator or designee will receive the investigational drugs delivered by the sponsor or 
delegate when the following requirements are fulfilled:

Approval of the clinical trial protocol by the IRB / ethics committee,

Availability of a signed and dated clinical trial contract between the sponsor or delegate
and the investigational site,

Approval / notification of the regulatory authority, e.g. competent authority,

Availability of the curriculum vitae of the Principal Investigator,

Availability of a signed and dated clinical trial protocol,

Availability of the proof of a medical license for the Principal Investigator (if 
applicable),

Availability of FDA Form 1572 (if applicable).
Investigational drugs are not allowed to be used outside the context of this protocol. They 
must not be forwarded to other investigators or clinics. 
The investigator or designee must maintain records of the product’s delivery to the trial site, 
the inventory at the site, the use by each patient, and the return to the sponsor or warehouse / 
drug distribution centre or alternative disposal of unused products. If applicable, the sponsor 
or warehouse / drug distribution centre will maintain records of the disposal. 

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These records will include dates, quantities, batch / serial numbers, expiry (‘use- by’) dates, 
and the unique code numbers assigned to the investigational medicinal product and trial
patients. The investigator or designee will maintain records that document adequately that the 
patients were provided the doses specified by the Clinical Trial Protocol (CTP) and reconcile 
all investigational medicinal products received from the sponsor. At the time of return to the 
sponsor or appointed CRO, the investigator or designee must verify that all unused or 
partially used drug supplies have been returned by the clinical trial patient and that no 
remaining supplies are in the investigator’s possession.
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
4.2.1.1
Other treatments
Overall, the choice of Standard of Care (SoC) treatment will be left at the discretion of the 
investigator. 
All concomitant treatment(s) taken during the trial must be recorded in the source documents 
(e.g. patient files) and on the CRF.
Skin Care
Emollients will be used throughout the trial. The use is at least twice a day. Emollients must 
not include urea or salicylic acid, should not be keratolytics and
should not be medicinal products (i.e. no treatment indications).
The use of emollients will be documented in a patient diary and eCRF. 
Supporting medications
Low potency topical corticosteroids (US class VI and VII) for treatment of NS are allowed
according to investigator’s judgement. The use of topical corticosteroids will help retention 
of patients in the study. Patients who experience skin infection requiring antibiotics during 
the trial will not be discontinued from trial drug or withdrawn from the trial. 
Supporting medications will be documented in a patient diary and eCRF.
Restricted medications and treatments for NS
If the patient experiences an intolerable worsening of NS during the course of the trial, the 
patient will be discontinued from trial treatment to receive alternative medication or the 
patient will receive treatment for NS (including restricted medications with the exception of 
biologics,immunoglobulins and investigational products, in which case the patientneeds to be 
discontinued from trial treatment) as deemed appropriate by the investigator.
In case of early discontinuation from trial treatment, the patient will be followed up as 
described in the Flowchart 1 (Footnote 2) for early EoT. 
Supporting medications and alternative treatments will not be provided by BI.

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4.2.1.2
Emergency procedures
Systemic hypersensitivity including infusion reaction and anaphylactic reaction
In case of systemic hypersensitivity including infusion reaction and anaphylactic reaction
emerging during or after infusion(s) / injection(s) of trial medication, the investigator should
consider in accordance with severity of the reaction and local standard of care to:

Immediately interrupt the infusion (i.v) or stop further injections (s.c.).

Treat with systemic antihistamines, i.v. steroids, and in case of a severe allergic reaction 
(e.g. anaphylactic reaction) epinephrine.
Also draw a plasma sample for IgE and ADA as detailed in the Lab Manual in the ISF. Please
initiate the evaluation of histamine, serum tryptase, and complement components.
In case of infusion reaction/systemic hypersensitivity, based on patient’s clinical course and 
medical judgment, the infusion may be re-initiated in case of mild or moderate infusion 
reactions/systemic hypersensitivity (according to CTCAE grading) at lower speed with 
gradual increase to complete the infusion as detailed in the Instructions for Preparation and 
Handling of spesolimab/placebo in the Investigator Site File.
In any case, the 
. 
In case of anaphylactic reaction based on the criteria discussed in the statement paper from 
Sampson HA (Appendix 10.1.12, R11-4890) suspected to be caused by the trial medication, 
the investigator should permanently discontinue treatment with spesolimab/placebo. 
When a delayed hypersensitivity reaction is suspected, please draw a blood sample for 
laboratory assessment and evaluate for signs of extra-cutaneous organ involvement. The 
decision to discontinue treatment and/or restart treatment after resolution of the reaction 
should be based on reaction type and severity. 
Severe infections (according to CTCAE Version 5.0), serious infections, opportunistic or 
mycobacterium tuberculosis infections.
Treatment of the infection should be initiated promptly according to local standard of care. No 
further trial medication should be administered until the active infection has resolved. Treatment 
with spesolimab may be restarted when the patient has recovered according to investigator’s 
assessment. 
Malignancies 
In case of occurrence of malignant neoplasm other than appropriately treated basal cell carcinoma 
or squamous cell carcinoma of the skin or in situ carcinoma of uterine cervix, the investigator 
should discontinue treatment with BI 655130. Diagnostics and treatment must be initiated 
according to local standard of care. 
Peripheral Neuropathy
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.

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4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
The medications (or classes of medications) listed in Table 4.2.2.1:1 must not be taken for
the time periods as specified.
Table 4.2.2.1:1
Restricted medications and treatments
1 No restriction on inhaled corticosteroids to treat asthma, intranasal corticosteroids to treat allergic rhinitis, or 
corticosteroid drops administered in the eye or ear.
2 To treat non−NS-related conditions such as asthma or allergy/anaphylaxis allowed according to Investigator’s 
judgment.
3 Allowed in case of skin infection of NS, emergency or other indication than NS.
4.2.2.2
Restrictions on diet and lifestyle
No specific restrictions on diet or lifestyle of the patients are required
4.2.2.3
Contraception requirements
Women of childbearing potential must use highly effective methods of birth control per ICH 
M3 (R2) that result in a low failure rate of less than 1% per year when used consistently and 
correctly. A list of contraception methods meeting these criteria is provided in the patient, 
parent(s) (or patient’s legal guardian) information.
Acceptable methods of birth control for this trial are:

Combined (estrogen and progestogen containing) hormonal birth control that prevents 
ovulation (oral, intravaginal, transdermal).

Progestogen-only hormonal birth control that prevents ovulation (oral, injectable, 
implantable).
Medication or class of medications
or treatment
Restriction duration 
Topical retinoids,
Topical calcineurin inhibitors, 
keratolytics (including urea)
1 week prior to Visit 2 and until EoT visit
Medium and high potency topical 
corticosteroids (US class I-V)1
1 week prior to Visit 2 and until EoT visit
Systemic immunosuppressants
(e.g. cyclosporine, methotrexate, 
azathioprine, mycophenolate mofetil, 
JAK inhibitors),
Systemic retinoids (e.g. acitretin, 
alitretinoin, isotretinoin, etretinate),
Systemic corticosteroids2 or 
phototherapy
4 weeks prior to Visit 2 and until EoT visit
Systemic antibiotics3
2 weeks prior to Visit 2 and until EoT visit
Live vaccines
4 weeks prior to Visit 2 and until EoS visit
Investigational products, biologics 
(e.g. secukinumab), immunoglobins
4 weeks or 5 half-lives (whichever is longer) prior to Visit 2
and until EoS visit

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
Intrauterine device (IUD) or intrauterine hormone-releasing system (IUS).

Bilateral tubal occlusion

Vasectomised sexual partner with documented absence of sperm.

Complete sexual abstinence (not to have male-female vaginal sex).
As monoclonal antibodies can be secreted in milk, women should refrain from breastfeeding 
once they receive the study drug and up to 
weeks after, i.e. until BI 655130 is eliminated. 
They can start nursing again after this period.
Male Patients:
Contraception of male trial participants and female partners of male trial participants are not 
required.
4.3
TREATMENT COMPLIANCE
The trial drug will be administered at the clinic site under the supervision of trained site 
personnel. For the visits with reduced number of assessments (e.g. Weeks
 
the trial drug may be administered by the specialized HCP in accordance with the protocol. 
The measured plasma concentration will provide additional confirmation of compliance.
5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
The primary, secondary and further endpoints of the study are specified in Sections 2.1.2 and, 
2.1.3 and 2.2.2, respectively.
IASI
IASI is a composite score based on the global Congenital Ichthyosis Severity Instrument 
(CISI) score that captures differences in severity in different body regions as a function of 
their body surface area, and also standardizes the number of choices within the Likert scales 
for erythema and scaling. IASI measures erythema and scaling as 0-4+ in severity at each of 
4 locations: head and neck (including scalp); arms (including palms); legs (including soles); 
and trunk, prorated based on body surface area in these sites and the percentage of 
involvement in each of these sites. The scale has a range of 0-48 (sum of a max score of 24 
for erythema and 24 for scaling). A higher score means worse clinical severity [R22-1085].
IGA
IGA for NS will assess the global severity of erythema and scaling in NS using 5-point Likert 
scale ranging from 0=clear, to 4=severe.
NASA
The NASA represents a modification of the standard Eczema Area and Severity Index 
(EASI) and assesses the severity of dermatitis over 4 body areas (head and neck, trunk, upper 
extremities, and lower extremities [R22-0826]. It assigns proportionate body surface areas to 
the head and neck (10%), trunk (30%), upper extremities (20%), and lower extremities 
(40%). The area of involvement (affected by inflammation, not including dry skin) of each of 

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the 4 body regions is represented by a 7-point numeric coded value (0-6). The investigator is 
required to record the percentage area (0-100%) and suggested to record to nearest 5%.
Score
Area of involvement, %
0
No eruption
1
<10
2
10-29
3
30-49
4
50-69
5
70-89
6
90-100
The head, trunk, upper limbs and lower limbs are assessed separately for erythema (E), 
infiltration/ papulation (I), lichenification (L), and scaling (S). The average degree of severity 
of each sign in each of the 4 body parts is assigned a score of 0 to 3 indicating no 
involvement (0) or mild (1), moderate (2), or severe (3) expression of the clinical sign. A 
higher score means worse clinical severity.
NRS Pain
The Numeric Pain Rating Scale is a unidimensional measure of pain intensity, including 
those with chronic pain. The 11-point numeric scale ranges from ‘0’ representing ‘no pain’ to 
‘10’ representing worst pain imaginable.
NRS Itch
The NRS itch is comprised of one item to measure intensity of itch. The scale ranges from ‘0’ 
representing ‘no itch’ to 10 ‘worst imaginable itch’.
DLQI/CDLQI
DLQI is the most commonly used and first dermatology-specific quality of life assessment 
tool to assess various dermatologic conditions and has been a reliable measure of quality of 
life. It contains 10 questions and scores from 0 to 30 in total. Response categories include 
“not relevant” (score of 0), “not at all” (score of 0), “a little” (score of 1), “a lot” (score of 2) 
and “very much” (score of 3). Question 7 is a “yes”/ “no” question where “yes” is scored as 
3. DLQI total score is calculated by summing the scores of each question resulting in a range 
of 0 to 30. Interpretation can be done by cut points: 0 (score of 0–1), no effect;1 (score of 2–
5), small effect; 2 (score of 6–10), moderate effect;3 (score 11–20), very large effect;4 (score 
21–30), extremely large effect [R22-1982].
For adolescents, an adapted version of this tool is used, called the Children’s Dermatology 
Life Quality Index (CDLQI).  The CDLQI is a questionnaire designed to measure the impact 
of skin disease on the lives of children and young people. The CDLQI has been developed to 
resemble the DLQI, with responses ranging from not at all to very much.  Data from the two 
cannot be combined, because the items and score meaning bands are different. CDLQI total 
score is calculated by summing the scores of each question resulting in a range of 0 to 30. 
Interpretation can be done by cut points: 0 (scores of 0–1), no effect;1 (scores of 2–6), small 
effect; 2 (scores of 7–12), moderate effect;3 (scores 13–18), very large effect;4 (scores 19–
30), extremely large effect [R24-3537].

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5D-Itch-scale
The 5-D itch scale is a multidimensional questionnaire designed to assess itching in clinical 
trials. The five domains of the questionnaire include: degree, duration, direction, disability,
and distribution. The duration, degree and direction domains include one item each, and the 
disability domain had four items. All items of the first four domains were measured on a five-
point Likert scale. The distribution domain includes 16 potential locations of itch, including 
15 body part items and one point of contact with clothing or bandages. For the distribution 
domain, the number of affected body parts is tallied (potential sum 0–16) and the sum is 
sorted into five scoring bins: sum of 0–2 = score of 1, sum of 3– 5 = score of 2, sum of 6–10 
= score of 3, sum of 11–13 = score of 4, and sum of 14–16 = score of 5. [R22-1980].
HADS
HADS is a widely used scale for assessing anxiety and depression in general hospital setting. 
It has 14 items in total (scoring from 0 to 3), which constitute the overall distress scale 
(HADS-S), and it groups 7 items each to anxiety subscale (HADS-A) and depression 
subscale (HADS-D), respectively. The categorisation of severity for both HADS-A and 
HADS-D subscales are mild (scores 8-11), moderate (scores 12-15), severe (scores 16-21, 21 
is the highest score for each subscale). The highest score for HADS-S is 42, and a score over 
9 is considered as distress [R22-2030].
Itchy-Qol
Itchy QoL is a pruritus-specific quality-of-life (QOL) instrument that consists of 22 pruritus-
specific items (each score from 1 to 5; the sum ranges from 22 to 110) regarding symptoms, 
functions and emotions [R24-3478].

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Patient Global Impression of Severity for Erythema
The Patient Global Impression of Severity for Erythema (PGIS-E) is a single item 
questionnaire that describes the severity of erythema over the past 24 h when considering 
skin area affected by NS. Participants will rate how his/her severity of erythema over the past 
24 h can be described using a 5-point scale ranging from "None" to "Very Severe".
Patient Global Impression of Severity for Scaling
The Patient Global Impression of Severity for Scaling (PGIS-S) is a single item questionnaire 
that describes the severity of scaling over the past 24 h when considering skin area affected 
by NS. Participants will rate how his/her severity of scaling over the past 24 h can be 
described using a 5-point scale ranging from "None" to "Very Severe".
Patient Global Impression of Change for Netherton Syndrome Skin Symptoms
The Patient Global Impression of Change (PGIC) for Netherton syndrome skin symptoms is a 
single item questionnaire that describes the change (improvement or deterioration) in skin 
symptoms overall related to NS since the medication of this study has started. Participants 
will rate how his/her NS has changed since the beginning of the study using a 5-point scale 
ranging from "Much better" to "Much worse" with "no change" indicating neither better nor
worse.
5.2
ASSESSMENT OF SAFETY
Safety will be assessed descriptively based on:

Treatment Emergent Adverse events

Adverse events of special interest (AESIs)

Serious adverse events (SAEs)

Safety lab tests

Intensity of adverse events will be assessed according to Common Terminology Criteria 
for Adverse Events (CTCAE) version 5.0 (refer to ISF for details)

Physical examination

Vital signs (blood pressure, pulse rate, body temperature)

12-lead ECG

Infusion reaction

Immunogenicity (ADA)

Injection site reactions
5.2.1
Physical examination
A complete physical examination will be performed at the time points specified in the
Flowchart It includes at a minimum general appearance, neck, lungs, cardiovascular system, 
abdomen, extremities, and skin.
Measurement of height and body weight will be performed at the time points specified in the
Flowchart.
During remote visits, an abbreviated body system assessment will be conducted by the 
trained HCP instead of a physical exam. This abbreviated body system assessment will 
include evaluation of organ systems associated with AE(s) symptoms and is only 
observational and conversational with patient.

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The results must be included in the source documents available at the site. 
5.2.2
Vital signs
Vital signs will be evaluated at the time points specified in the Flowchart, prior to blood 
sampling. This includes temperature, respiratory rate, systolic and diastolic blood pressure,
and pulse rate (electronically or by palpation count for 1 minute) in a seated position after 
5 min of rest. The results must be included in the source documents available at the site.
At dosing visits for 
At dosing visits, for 
 
 
The investigator should evaluate the clinical significance of the results. Clinically abnormal 
findings will be reported as baseline condition or AEs. 
Monitoring for hypersensitivity reactions: 
Patients should be closely monitored for signs and symptoms of hypersensitivity reactions for 
approximately 1 hour after the i.v. drug administration at Visit 2 and Visit 6. Hypersensitivity 
reactions should be treated according to medical standards. 
Pre-medications for further infusions might be considered and will be agreed on between 
investigator and BI clinical monitor. 
5.2.3
Safety laboratory parameters
Safety laboratory parameters to be assessed are listed in Table 5.2.3:1. For the sampling time 
points please see the Flowchart.
All analyses will be performed by a central laboratory, the respective reference ranges will be 
provided in the ISF. 
Patients do not have to be fasted for the blood sampling for the safety laboratory. 
Instructions regarding sample collection, sample handling / processing and sample shipping 
are provided in the Laboratory Manual in the ISF. 
According to the EU recommendation [R23-1267], the following applies for adolescent 
patients in EU countries:
It needs to be assured that the research related blood loss (including any waste) does not 
exceed 3% of the total blood volume over a period of four weeks, and does not exceed 1% at 
any single time. This recommendation leads to the allowable sample volumes, indicated in 
the Appendix 10.3. Total blood volume is approximately 80-90 mL/kg body weight.
With the minimum weight of 35 kg allowed in this study, the maximum blood volume 
allowed would be 28 mL – 31.5 mL (1%) at a single visit and 84 mL – 94.5 mL (3%) over 
4 weeks. 

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For EU countries, the central laboratory has been set up specifically for adolescents to 
minimize the blood volume and to not exceed the limits considering a weight of 35 kg. In 
case additional blood collections are needed, e.g. for DILI, investigators have to take care to 
stay within the accepted range of blood volume, according to the EU recommendation. Step-
wise collection of samples at separate days / visits may be considered, if needed.
For non-EU countries, central laboratory has been set up for adolescents to minimize the 
blood volumes in a similar way. Step-wise collection of samples at separate days / visits may 
be considered, if larger volumes of blood need to be collected (e.g. for DILI).
The central laboratory will send reports to the investigator. It is the responsibility of the 
investigator to evaluate the laboratory reports. Clinically relevant abnormal findings as 
judged by the investigator will be reported as adverse events (please refer to Section 5.2.6).
In case the criteria for hepatic injury are fulfilled, a number of additional measures will be 
performed (please see Section 5.2.6.1 and the DILI Checklist provided in the ISF and eCRF
system. The amount of blood taken from the patient concerned will be increased due to this 
additional sampling.
The central laboratory will transfer the results of the analysis to the sponsor or delegate.
Table 5.2.3:1 
Safety laboratory tests (central lab Assessment)
Category
Test name
Infection testing
Hepatitis B Surface Antigen (qualitative)
Hepatitis B core Antibody (qualitative)
HBV-DNA PCR (quantitative) at screening and EoS Visit1
Hepatitis C Antibodies (qualitative)*
HIV-1, and HIV-2 Antibody (qualitative)
QuantiFERON® (or if applicable, T-Spot®) TB2,3,4
Specific gamma-globulin 
quantification IgE
IgE5
Urine-Sediment (only
if urine analysis abnormal)
Microscopic examination
Urine Pregnancy test6. At the drug 
administration
visits, the test will be performed prior 
to the
administration of study drug
Human Chorionic Gonadotropin in urine
Serum Pregnancy test6 (only for 
female
patients of childbearing potential)
Human Serum Chorionic Gonadotropin

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Table 5.2.3:1 (cont’d) Safety laboratory tests (central lab Assessment) 
Category
Test name
Haematology
Haematocrit
Haemoglobin
Red blood cell count (RBC)
White blood cell count (WBC)
Platelet count
Automatic WBC differential 
(relative and absolute)
Neutrophils, eosinophils, basophils, monocytes, lymphocytes
Manual differential WBC (if automatic 
differential WBC is abnormal)
Neutrophils (stabs), eosinophils, basophils, monocytes, lymphocytes 
Coagulation
Activated partial thromboplastin time (aPTT)
Prothrombin time (Quick’s test and International Normalized Ratio [INR])
Fibrinogen
Enzymes
Aspartate transaminase (AST/GOT)
Alanine transaminase (ALT/GPT)
Alkaline phosphatase (AP)
Gamma-glutamyl transferase (GGT)
Creatine kinase (CK)
CK-MB, only if CK is elevated 
Lactate dehydrogenase (LDH)
Serum tryptase7
Amylase
Lipase
Substrates
C-Reactive Protein (CRP) 
Serum albumin 
Creatinine 
Total bilirubin 
Direct bilirubin
Total protein
Total cholesterol 
Triglycerides 
Glucose
BUN (blood urea nitrogen)
Uric acid
eGFR (estimated by CKD-EPI formula) (only at screening)
Bilirubin Indirect (if total is elevated)
Troponin (Reflex, in case of elevated CK)
LDL-Cholesterol
HDL-Cholesterol
Electrolytes
Sodium
Potassium
Chloride
Calcium
Urinalysis (dipstick)
Urine nitrite
Urine protein
Urine glucose 
Urine ketone 
Urobilinogen 
Urine bilirubin
Urine erythrocytes 
Urine leukocytes 
Urine pH
1 An HBV-DNA should be conducted at screening if Hepatitis B core Antibody is positive and Hepatitis B Surface Antigen 
is negative. If at screening, Hepatitis B core Antibody is positive and Hepatitis B Surface Antigen is negative, HBV-DNA 
should be repeated at the EOS visit. 
* A positive Hep C Antibodies test result should be confirmed by PCR. 

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2 There is a trial site option to perform a tuberculin skin test (i.e. PPD skin test) or any alternative test/procedure (as per local 
standards) to rule out TB if the retest QuantiFERON®-TB test result is indeterminate (see footnote 4 below for details).
3 If the 1 st QuantiFERON® (or if applicable, T-Spot®) -TB test result is indeterminate, a retest should be performed. If the 
retest QuantiFERON-TB test result is indeterminate, a tuberculin skin test (i.e. PPD skin test) or any alternative 
test/procedure (as per local standards) to rule out TB should be performed at the site.
<For Japan> T-Spot® TB test may be performed at local labs instead of QuantiFERON®-TB test.
4 In patients with a negative QuantiFERON®-TB or tuberculin skin test (i.e. PPD skin test) or alternative test/procedure (as 
per local standards), the test should be repeated on a yearly basis (see Flowchart) and at EoS.
<For Japan> T-Spot® TB test may be performed at local labs instead of QuantiFERON®-TB test
5 IgE will be taken in case of systemic hypersensitivity including infusion reaction together with ADA (anti-drug antibodies)
sample.
6 Urine and serum pregnancy testing will be performed as indicated in the Flowchart. In case a remote visit is performed by 
the HCP, the HCP should be provided with urine pregnancy test kits. The kits may be supplied by the trial site or by the 
sponsor.
7 Serum tryptase will be assessed only in the event of suspected hypersensitivity reaction. 
5.2.4
Electrocardiogram
The 12-lead ECGs must be administered by a qualified technologist and results will be 
recorded as scheduled in the Flowchart. The investigator or a designee will evaluate whether 
the ECG is normal or abnormal and assess clinical relevance. ECGs may be repeated for 
quality reasons and a repeated recording used for analysis. 
Additional ECGs may be recorded for safety reasons. Dated and signed printouts of ECG 
with findings should be documented in patient’s medical record.
Clinically relevant abnormal findings will be reported either as baseline condition (if 
identified at the screening visit) or otherwise as AEs and will be followed up and / or treated 
as medically appropriate.
Clinically relevant abnormal findings will be reported either as baseline condition (if 
identified at the screening visit) or otherwise as AEs and will be followed up and/or treated as 
medically appropriate.
5.2.5
Other safety parameters
Local Tolerability
Local tolerability at the administration site of spesolimab or placebo will be assessed by the 
investigator during the trial drug administration visit and at time of AE assessment by 
questioning retrospectively since the last visit. Any observed local tolerability reaction, e.g.
‘swelling’, ‘induration’, ‘heat’, ‘redness’, pain’, and other findings’ should be reported as an 
adverse event.
All cases of malignancies, sepsis or other serious infections that are detected during the trial 
will be reported as SAEs. 
5.2.6
Assessment of adverse events
Data and information necessary for the thorough assessment of AEs, SAEs, and AESIs will 
be reported to the sponsor via eCRF. This may include specific data and information not 
prospectively specified in this protocol.

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5.2.6.1
Definitions of AEs 
5.2.6.1.1
Adverse event
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a medicinal product and which does not necessarily have to have a 
causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether considered related or not.
The following should also be recorded as an AE in the CRF and BI SAE form (if applicable):
Worsening of the underlying disease or of other pre-existing conditions 
Changes in vital signs, ECG, physical examination, and laboratory test results, if they 
are judged clinically relevant by the investigator.
If such abnormalities already exist prior to trial inclusion, they will be considered as baseline 
conditions and should be collected in the eCRF only.
5.2.6.1.2
Serious adverse event
A serious adverse event (SAE) is defined as any AE, which fulfils at least one of the 
following criteria:
-
results in death,
-
is life-threatening, which refers to an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe,
-
requires inpatient hospitalisation or prolongation of existing hospitalisation
-
results in persistent or significant disability or incapacity,
-
is a congenital anomaly / birth defect,
-
is deemed serious for any other reason if it is an important medical event when based 
on appropriate medical judgement which may jeopardise the patient and may require 
medical or surgical intervention to prevent one of the other outcomes listed in the 
above definitions. Examples of such events are intensive treatment in an emergency 
room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalisation or development of dependency or abuse. 
For Japan only: An event that possibly leads to disability will be handled as ‘deemed serious 
for any other reason’ and, therefore, reported as an SAE.
5.2.6.1.3
AEs considered “Always Serious”
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of AEs, which by their nature, can always be 
considered to be “serious” even though they may not have met the criteria of an SAE as 
defined above.

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The latest list of “Always Serious AEs” can be found in the eDC system. A copy of the latest 
list of “Always Serious AEs” will be provided upon request. These events should always be 
reported as SAEs as described in Section 5.2.6.2.
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the time since discontinuation of the drug and must be reported as 
described in Section 5.2.6.2, subsections “AE Collection” and “AE reporting to sponsor and 
timelines”.
5.2.6.1.4
Adverse events of special interest
The term adverse events of special interest (AESI) relate to any specific AE that has been 
identified at the project level as being of particular concern for prospective safety monitoring 
and safety assessment within this trial, e.g. the potential for AEs based on knowledge from 
other compounds in the same class. AESIs need to be reported to the sponsor’s 
Pharmacovigilance Department within the same timeframe that applies to SAEs, please see 
Section 5.2.6.1.2. 
The following are considered as AESIs:
Potential Severe DILI
A potential severe Drug Induced Liver Injury (DILI) that requires follow-up is defined by the 
following alterations of hepatic laboratory parameters: 

An elevation of AST (Aspartate Aminotransferase) and / or ALT (Alanine 
Aminotransferase) ≥3x ULN combined with an elevation of total bilirubin ≥2x ULN
measured in the same blood sample, or in samples drawn within 30 days of each other, or

ALT and / or AST elevations ≥10x ULN.
These lab findings constitute a hepatic injury alert and the patients showing these lab 
abnormalities need to be followed up according to the “DILI checklist” provided in the ISF.
In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without lab results 
(ALT, AST, total bilirubin) available, the investigator should make sure these parameters are 
analysed, if necessary, in an unscheduled blood test. Should the results meet the criteria of 
hepatic injury alert, the procedures described in the DILI checklist should be followed.
Systemic hypersensitivity including infusion reaction and anaphylactic reaction 
Any suspicion of severe infusion reaction systemic / hypersensitivity reaction and of any 
potential cases of anaphylaxis should be defined and assessed using the criteria discussed in 
the statement paper from Sampson HA (Appendix 10.1.12; R11-4890). (See Section 4.2.1 for 
“Other treatments and emergency procedures”) 
Severe infections (according to CTCAE version 5.0)
Opportunistic and mycobacterium tuberculosis infections
These include pneumocystis jirovecii, BK virus disease including PVAN, CMV, post-
transplant lymphoproliferative disorder (EBV), progressive multifocal leucoencephalopathy, 
bartonellosis (disseminated only), blastomycosis, toxoplasmosis, coccidioidomycosis,
histoplasmosis, aspergillosis (invasive only), candidiasis (invasive or pharyngeal), 

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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 would be considered as an AESI.
For the treatment interruption rules, please see Section 3.3.4.3 Discontinuation of the trial by 
sponsor.
5.2.6.1.5
Intensity (severity) of AEs
The intensity (severity) of adverse events should be classified and recorded in the CRF
according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0
[R18-1357] and judged based on the following:
Grade 1
Mild
Grade 2
Moderate
Grade 3
Severe
Grade 4
Life-threatening
Grade 5
Death
5.2.6.1.6
Causal relationship of AEs
Medical judgement should be used to determine the relationship between the adverse event 
and the BI investigational compound, considering all relevant factors, including pattern of 
reaction, temporal relationship, de-challenge or re-challenge, confounding factors such as 
concomitant medication, concomitant diseases and relevant history. 
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:

The event is consistent with the known pharmacology of the trial drug.

The event is known to be caused by or attributed to the drug class.

A plausible time to onset of the event relative to the time of drug exposure.

Evidence that the event is reproducible when the drug is re-introduced.

No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications).

The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome).

An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is reduced).

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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 trial 
drug concerned).

Continuation of the event despite the withdrawal of the medication, considering the 
pharmacological properties of the compound (e.g. after 5 half-lives).
Of note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger.

There is an alternative explanation, e.g. situations where other drugs or underlying 
diseases appear to provide a more likely explanation for the observed event than the 
drug concerned.

Disappearance of the event even though the trial drug treatment continues or remains 
unchanged.
5.2.6.2
Adverse event collection and reporting
5.2.6.2.1
AE Collection
The investigator shall maintain and keep detailed records of all AEs in the patient files.
Per default SAEs/AESIs should be reported via the eCRF in the EDC system. If the EDC 
system is not or no longer available (e.g. after data base lock), the BI paper SAE form should 
be used, please see Section 5.2.6.2.2. 
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 trial (= 
the End of Study (EoS) visit): 
all AEs (serious and non-serious) and all AESIs.

After the individual patient’s end of trial: 
the investigator does not need to actively monitor the patient for new AEs but should 
only report any occurrence of cancer and trial drug related SAEs and trial drug related 
AESIs of which the investigator may become aware of by any means of communication, 
e.g. phone call.
5.2.6.2.2
AE reporting to the sponsor and timelines
The investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the AE or SAE eCRF pages, to the sponsor’s unique entry point
immediately (within 24 h of becoming aware of the event). The country specific process will 
be specified in the ISF. The same timeline applies if follow-up information becomes 
available. In specific occasions, the investigator could inform the sponsor upfront via 
telephone in addition. 
With receipt of any further information to these events, a follow-up report has to be provided. 
For follow-up information the same rules and timeline apply as for initial information. All
(S)AEs, including those persisting after individual patient’s end of trial must be followed up 

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until they have resolved, have been assessed as “chronic” or “stable”, or no further 
information can be obtained.
Should the EDC system not be available for more than 24 h, reporting must occur via the BI 
paper SAE forms.
5.2.6.2.3
Pregnancy
Urine pregnancy testing should be done prior to trial drug administration. Trial drug should
only be administered in case of a negative test result. In case of a positive urine pregnancy
test, a serum pregnancy test will be done. Women who underwent tubal ligation are still 
considered of childbearing potential and pregnancy testing is necessary as well. The testing
schedule is specified in the Flowchart.
In rare cases, pregnancy might occur in a clinical trial. Once a patient has been enrolled in the 
clinical trial and has taken trial medication, the investigator must report any drug exposure 
during pregnancy in a trial participant immediately (within 24 h) 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.
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
5.3.1
Assessment of pharmacokinetics
Spesolimab concentrations will be reported descriptively. No PK parameters will be
calculated. PK data will be incorporated into a larger pharmacometric analysis with other
trials of the spesolimab project. Also, ADAs will be measured and their impact on PK will be 
assessed. The relationship between PK and selected efficacy endpoints, biomarkers and AEs 
may be assessed. PK and demographic data together with treatment assignments and dosing 
information may be made available to individuals outside of the trial team for the purpose of 
PK dataset generation in accordance with sponsor’s standard procedures.
Refer to the Flowchart for the time points of PK and ADA/Nab sample collection. Date and
exact time of drug administration and PK and ADA/Nab sampling will be recorded on CRFs.
On visits with trial medication dosing, PK and ADA/Nab samples should be collected prior to 
administration of trial drug.

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5.3.2
Methods of sample collection
After completion of the trial the plasma/serum samples may be used for further 
methodological investigations, (e.g. for stability testing, for further investigations to 
characterize ADA response or to address Health Authority questions regarding the 
results/methodology). However, only data related to the analyte and / or anti-drug antibodies 
(if applicable) will be generated by these additional investigations. The samples will be 
discarded after completion of the additional investigations but not later than 5 years upon the 
final trial report has been signed.
5.3.2.1
Plasma sampling for PK analysis
For quantification of spesolimab plasma concentrations, blood will be taken from a 
forearmvein into a K2EDTA (ethylendiaminetetraacetic acid) anticoagulant blood-drawing 
tube at the time points listed in the Flowchart under plasma PK. Handling procedures can be 
found in the laboratory manual.
5.3.2.2
Sampling for ADA/Nab assessment
For ADA assessment, blood will be taken from a forearm vein into a K2EDTA anticoagulant 
blood-drawing tube at the time points listed in the Flowchart under ADA/Nab. For Nab
assessment, blood will be taken from a forearm vein into a serum blood-drawing tube at the 
time points listed in the Flowchart under ADA/Nab. Handling procedures can be found in the 
laboratory manual.
5.3.4
Pharmacokinetic - pharmacodynamic relationship
No formal analysis of pharmacokinetic/pharmacodynamic relationships is planned. If the data 
suggest a pharmacokinetic/pharmacodynamic relationship of special parameters, e.g. an 
exploratory analysis may be performed.
Correlation between drug concentration and response may be made if adequate data are
available. In addition, exploratory correlations may also be made between drug concentration
and AEs.
Data may also be used to develop pharmacokinetic/pharmacodynamic models using nonlinear
mixed effect modeling techniques, if feasible. For this purpose, data may also be combined
with data from other trials. Modeling activities will be planned and documented separately
according to internal and external guidelines and Standard Operating Procedures (SOP).
This trial is also intended to contribute to modelling of the dose-exposure relationship in 
children from 12 years to less than 18 years of age (and adults) with Netherton syndrome.

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5.5.1
Methods and timing of sample collection
Detailed instructions on sampling, preparation, processing, shipment and storage are provided 
in the laboratory manual. For sampling timepoints see Flowchart.
5.6
OTHER ASSESSMENTS
Photography of skin will be performed in all patients. Front and back trunk, legs and arms, as 
well as target lesions photographs will be taken preferably at the time points specified in the
Flowchart. Instrcutions for taking the photos will be provided in the ISF. Patients must be 
unrecognizable on the photos (refer to the procedure in the ISF).
5.7
APPROPRIATENESS OF MEASUREMENTS
The safety assessments are standard, are accepted for evaluation of safety and tolerability of 
both subcutaneous and intravenously administered drug and are widely used in clinical trials. 
The pharmacokinetic parameters and measurements outlined in Section 5.3 are generally used 
assessments of drug exposure. The biomarkers and pharmacogenomic parameters outlined in 
Section 5.4 are of exploratory nature only.
Information about race should be obtained from study participants as allowed by local 
regulations. This is because the prevalence and characteristics of NS may differ between 
patients of different racial origin. It will thus be worthwhile to assess if patients of different 
race will respond differently to the study treatment.
6.
INVESTIGATIONAL PLAN
In the event of force majeure or other disruptive circumstances (e.g. pandemic, war) the 
investigational plan as per this clinical trial protocol may not be feasible at a site. With the 
consent of the patient, sponsor and investigator may agree on alternative, back-up or rescue 
methodology which may include but will not be limited to virtual patient visits and
assessments, home healthcare nurse visits, and direct-to-patient shipments of trial treatment. 
The implementation of these measures will depend on patient’s consent, operational 
feasibility, local law and regulations. If alternative methodology is implemented, the 
deviations from the original plan will be precisely documented.

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6.1
VISIT SCHEDULE
All patients should adhere to the visit schedule specified in the Flowchart. If any visit has to 
be rescheduled, subsequent visits should follow the original visit date schedule calculated 
from randomisation visit (Visit 2).
will be 
instructed to not bath, shower, or apply any topical product to the area that will be tested, 
24 h before the visit. Vigorous activity will also be minimized for several hours prior to the 
visit.
In addition to the scheduled assessments, unscheduled assessments for safety reasons may be 
performed at any time according to the clinical need.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
Study procedures to be performed as specified in the Flowchart. All efforts should be made to 
perform the most critical visits e.g. randomisation at Visit 2, primary endpoint at Week 16 
and end of treatment at Week
. These and other visits requiring i.v. administration should 
always be performed at the investigator site facility whenever possible. The visits with 
reduced number of assessments and no routine lab sampling, e.g. every second visit during 
the extended treatment period could be performed remotely or using hybrid approach 
(assessments performed at home by the specialized vendor/HCP, if applicable) or performed 
in the investigator site facility, if this is preferable for the patient and the investigational site. 
Note: 
. drug administration should be performed by the HCP. Patient self-administration is 
not allowed. 
The patients’ questionnaires are to be completed by the patient him/herself in quiet area/room 
without any interpretation by other people, and if possible, before any interaction with the 
investigator or other member of the trial team. For adolescent patients or if the patient is too 
sick to complete the questionnaires by him/herself or is illiterate, but is able to reply verbally, 
a parent/legal guardian or a member of the trial team should read the instructions, questions, 
and response options aloud to the patient and collect the patient’s verbal response in as 
neutral and unbiased a manner as possible. If this is not possible either, the questionnaires are 
not to be completed. There is no order of completion.
Whenever possible, the evaluation of efficacy assessments (IASI, IGA, IASI-E, IASI-S,
NASA, ISS) are to be conducted by the same investigator throughout the trial.
6.2.1
Screening and run-in period(s)
Screening Period
All patients will need to sign the informed consent form in accordance with the GCP and the 
local legislation prior to performing any trial related procedures. Only patients with 
confirmation of NS diagnosis are eligible. The diagnosis of NS is to be done and confirmed 
by the clinical investigator (either genetic test available in the past or confirmation during the 
screening).
Demographics:
During the screening visit, demographics information will be collected. This includes:

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
Age on the day of informed consent (in years) 

Sex (male, female in order to describe the patient`s sex at birth), 

Ethnicity and race (if allowed by local regulations) will be collected and reported in 
the eCRF
Screening visit (visit1) is to be performed within 84 days before Visit 2. Screening 
assessments may be repeated as long as they fall within the Screening visit window. If more 
than one screening assessment is available, the latest assessment prior to the start of treatment 
must be used to assess eligibility.
Baseline Conditions
Chronic diseases, current observable conditions, any new clinically relevant findings 
discovered from the physical examination, ECG, safety labs, and any condition requiring 
therapy will be reported on the baseline condition eCRF page.
Infections testing will include tuberculosis, hepatitis B, hepatitis C, and HIV assessments (see 
Table 5.2.3:1)
Medical History:
Medical history of NS, including previous and concomitant treatment will be reported in the 
eCRF. 
Mutation status:
Information on the genetic testing for SPINK5 causative mutations to confirm the diagnosis 
of NS will be collected in patient’s historical data and reported in the eCRF.
Re screening:
If a patient results in a screen failure, the patient must be registered as a screen failure in IRT 
system. However, re-screening of patient who has previously failed screening will be 
permitted. In this situation patient will be allocated a new patient number which will be 
linked to the previous patient number in the IRT system. Details of IRT procedures can be 
found in the IRT manual located in the ISF.
Is a patient enrolled in error (does not meet all inclusion criteria or meets one or more 
exclusion criteria on the day of enrolment or misdiagnosed), the sponsor should be contacted 
immediately.
6.2.2
Treatment period(s)
The investigator must perform a final assessment of eligibility when the results of all
screening assessments are available. If the patient does not meet the eligibility criteria, the 
patient must be recorded as a screen failure.
The eligible patient will be randomised at Visit 2 (Day1) using IRT. Subsequent visits during 
the treatment period are performed as described in the Flowchart.
Patients may decide to continue receiving the Open Label Extended trial treatment until 
Week 156.
Physical examination, vital signs Laboratory tests, ECG, local tolerability See Section 5.2.

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Blood sampling should be done prior to trial drug administration. Fasting is not required for 
blood sampling.
Pregnancy test will be conducted for women of childbearing potential only. Serum pregnancy 
test will be performed at screening and urine pregnancy tests will be performed at all other 
visits indicated in the Flowchart. Urine pregnancy test should be done prior to study drug 
administration and trial drug should only be administered in case of a negative test result. In 
case of a positive urine pregnancy test, a serum pregnancy test will be done (via central lab) 
and study drug administration will be postponed until negative result of serum pregnancy test 
is available.
Concomitant medication review
Data concerning concomitant medications will be collected throughout the trial as specified 
in the Flowchart.
For more details on PK, ADA and Nab, and biomarkers samples collection please refer to 
Sections 5.3 and 5.4.
Unscheduled visits
The unscheduled visit may include additional collection of blood samples for safety reasons. 
The unscheduled visit may also include additional assessments deemed necessary by the
investigator such as laboratory samples, ECGs, or other procedures which were missed at a
previous visit. All unscheduled visits should be described (including the reason for the visit)
and documented in the medical/source record, and in the eCRF.
6.2.3
Follow-up period and trial completion
For patients completing the full treatment period up to Week
, a Follow-up Visit should 
be performed 
weeks after the last administration of trial medication (EoS). Termination of 
trial medication (EoT) and trial completion (EoS) must be recorded on the corresponding 
eCRF.
The information collected at the EoS visit should include all follow up of AEs ongoing at 
EoT and new AEs that occurred after EoT.
Abnormal assessments or lab values judged clinically relevant by the investigator will be 
monitored until they returned to a medically acceptable level. 
Early treatment discontinuation
Patients who discontinue the trial treatment early (prior to Week
). These patients should 
be registered as withdrawn from randomized treatment in IRT and the eCRF accordingly.
Timepoint of early EoT will be considered the visit when the last dose of IMP was 
administered. In case of early discontinuation from trial treatment, every effort should be 
made to keep the patient in the trial and complete all of the remaining visits up to Week
 
(without IMP administration in that case). At a minimum, patients should come to an End-of-
study Visit (EoS),
weeks after the last dose to cover full REP.

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Early trial discontinuation
The patients who have not reached the End-of-trial Visit (EoS) within the specified window 
per protocol (e.g. due to withdrawal of consent, administrative reason, lost to follow-up, 
death etc.).
7.
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE
The study design is described in Section 3.1 and trial objectives are described in Section 2.
7.1
NULL AND ALTERNATIVE HYPOTHESES
Statistical hypothese to be tested for the primary endpoint are: 
H01: There is no difference regarding the proportion of the primary endpoint (IASI response, 
defined as a decrease of at least 50% absolute change in IASI score from baseline at 
Week 16) between spesolimab versus placebo against H11: There is a difference regarding 
the proportion of the primary endpoint (IASI response, defined as a decrease of at least 50%
absolute change in IASI score from baseline at Week 16) between spesolimab versus placebo. 
The trial is considered positive, if the null hypothesis of the primary endpoint can be rejected 
and the result is more favorable for spesolimab versus placebo (proportion in spesolimab 
group ≥proportion in placebo group).
Further hypothesis will be tested on the key secondary endpoint in a hierarchical manner if
the null hypothesis of the primary endpoint H01 has been previously rejected.
Statistical hypothese to be tested for the key secondary endpoint are:
H02: There is no difference regarding the proportion of the key secondary endpoint (IGA 
response, defined as a decrease of at least 1-grade absolute change in IGA score from 
baseline at Week 16) between spesolimab versus placebo against H12: There is a difference 
regarding the proportion of the key secondary endpoint (IGA response, defined as a decrease 
of at least 1-grade absolute change in IGA score from baseline at Week 16) between 
spesolimab versus placebo.
No adjustment of the two-sided alpha level of 0.05 is necessary.
7.2
PLANNED ANALYSES
7.2.1
General considerations
The primary analysis of this trial is planned to be performed once all randomized patients 
have completed the 16 weeks or early discontinued from the trial, to support an early 
submission; a database lock for the primary analysis will then be performed. 
Final analysis is planned to be performed at the end of the trial once all patients have 
completed the trial (including any follow-up period if applicable). 
Details of treatment unblinding for the primary analysis and final analysis are described in

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Section 4.1.5. Details of the analysis to be performed will be described in the TSAP.
In general, baseline refers to the last non-missing value prior to first treatment in this study.
There will be two main patient sets in this trial for analyses:
Full analyses set (FAS) 
This patient set includes all patients who were randomised and received at least one study 
treatment in this trial. 
Per-Protocol Set (PPS)
This patient set includes all patients in FAS who adhered to the CTP without any important 
protocol deviations (iPDs) which lead to exclusion from the PPS. This set will be used for 
sensitivity analysis on the primary endpoint and key secondary endpoint. 
Further analysis sets will be defined in the trial statistical plan (TSAP) if necessary.
Important deviations of the protocol will include deviations of the key inclusion and
exclusion criteria, concomitant use of restricted medications, and any other deviations of the
protocol deemed important by the study team. All decisions concerning important protocol
deviations will be made prior to unblinding of the database for the final trial analysis.
Standard statistical parameters (number of non-missing values, mean, standard deviation 
(SD), median, quartiles, minimum and maximum) or frequency tables (including patient 
frequencies and percentages) will be calculated where appropriate.
7.2.2
Handling of Intercurrent Events
The expected intercurrent events of interest in this trial are:

Restricted medications and treatments for NS (see Section 4.2.1)

Treatment discontinuation due to AE/lack of efficacy/other reasons
The strategy for handling intercurrent events is as follows:
Composite strategy: This is the effect of spesolimab, where intercurrent events of use of 
restricted medications and treatments for NS will be considered as treatment failure. 
Treatment policy strategy: treatment discontinuation will be handled by a treatment policy 
approach, i.e. the value of the variable regardless of the occurrence of the intercurrent event 
will be used.
Each analysis will reference the strategy for handling intercurrent events that it will be 
estimating. The estimand for each main analysis in this protocol is the combination of the 
relevant detailed clinical objective from Section 2.1 and this strategy.
7.2.3
Primary objective analyses
The analysis for the primary endpoint will be on the FAS, including calculating the 
proportion of patients achieving IASI response at Week 16 (defined as a decrease of at least 
50% absolute change in IASI score from baseline at Week 16). For the estimand concept on 

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the primary binary endpoint, composite strategy will be applied that occurrence of use of 
restricted medications and treatments for NS prior to Week 16 will be considered to represent 
a non-response at the Week 16 timepoint.
Comparisons between treatment groups regarding the binary endpoint variable, the 
proportions of IASI response at Week 16 will be performed using the exact unconditional 
Suissa-Shuster Z-pooled test. The risk difference together with 95% confidence intervals will 
be used to quantify the treatment, comparing spesolimab to placebo. 
The patients will be analysed according to the stratum to which they belong (regardless of
any mis-assignment to treatment based on identification of the wrong stratum), as such an
error occurs before randomization and is therefore consistent with regulatory guidance.
7.2.3.1
Sensitivity Analyses
Sensitivity analyses of the primary endpoint will include:

A sensitivity analysis utilizing the PPS;

A sensitivity analysis which utilizes alternative methods for the handling of missing 
data as described in Section 7.3.

A sensitivity analysis to adjust for covariates of age group (adult vs. adolescent) and 
baseline IASI group (classified into 2 equally sized groups by median) using logistic 
regression model.
Further sensitivity analyses, if any, will be defined in the TSAP.
7.2.3.2
Subgroup Analyses
Subgroup analyses are planned for primary endpoint regarding age (adult vs. adolesent), sex 
(female/male). Further subgroup analyses, if any, will be defined in the TSAP.
7.2.3.3
Supplementary Analyses
Not applicable.
7.2.4
Secondary objective analyses
For key secondary endpoint, the analyses will be performed on the FAS in the same manner 
as described for the analysis of the primary endpoint in Section 7.2.3.
For binary secondary endpoints, the analyses will be performed on the FAS in the same 
manner as described for the analysis of the primary endpoint in Section 7.2.3.
Analyses for the continuous secondary endpoints will be analysed by a restricted maximum 
likelihood (REML) estimation-based approach using a mixed-effect model with repeated 
measurements (MMRM) analysis, including calculating the adjusted means and 95% CIs (if 
applicable) based on FAS. The analysis will include the fixed, categorical effects of treatment 
at each visit, age group and the fixed continuous effects of baseline at each visit.
Analysis of treatment emergent AEs will be described in Section 7.2.6.

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7.2.6
Safety analyses
Adverse events will be coded using the Medical Dictionary for Drug Regulatory Activities
(MedDRA). Standard BI summary tables and listings will be produced. All adverse events 
with an onset between start of treatment and end of the REP, defined as 16 weeks after the 
last dose of trial medication, will be assigned to the on-treatment period for evaluation.
All treated patients will be included in the safety analysis. In general, safety analyses will be 
descriptive in nature and will be based on BI standards. No hypothesis testing is planned.
Statistical analysis and reporting of adverse events will concentrate on treatment-emergent 
adverse events, i.e. all adverse events occurring between start of treatment and end of the 
REP. Adverse events that start before first drug intake and deteriorate under treatment will 
also be considered as ‘treatment-emergent’.
Frequency, severity, and causal relationship of adverse events will be tabulated by system 
organ class and preferred term after coding according to the current version of the Medical 
Dictionary for Drug Regulatory Activities (MedDRA) at database lock.
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), where:
Time at risk [patient-years] = (date of onset of TEAE – study drug start date + 1) /365.25
If, for a patient, the selected treatment emergent adverse event didn’t occur then the time at 
risk will be censored at min (date of death, last contact date per EoS page, drug stop date + 
112 days). 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].
Laboratory data will be analysed both quantitatively as well as qualitatively. The latter will 
be done via comparison of laboratory data to their reference ranges. Values outside the 

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reference range as well as values defined as clinically relevant will be summarised. Treatment 
groups will be compared descriptively with regard to distribution parameters as well as with 
regard to frequency and percentage of patients with abnormal values or clinically relevant 
abnormal values.
Vital signs, physical examinations, or other safety-relevant data observed at screening, 
baseline, during the course of the trial and at the end-of-trial evaluation will be assessed with 
regard to possible changes compared with findings before start of treatment.
7.2.7
Other Analyses
Not applicable
7.2.8
Interim Analyses
A Data Monitoring Committee (DMC) will be in place with tasks as described in Section 8.7.
The primary analysis of this trial is planned to be performed once all randomized patients 
have completed the 16 weeks or early discontinued from the trial, to support an early 
submission; a database lock for the primary analysis will then be performed. Further interim
analyses may be conducted during the open label treatment period to support, for example, 
regulatory interactions and/or regulatory filing. Final analysis is planned to be performed at 
the end of the trial once all patients have completed the trial (including any follow-up period 
if applicable). 
7.3
HANDLING OF MISSING DATA
For handling missing data on the primary, key secondary and secondary binary efficacy 
endpoints, a Non-Response Imputation (NRI) will be applied as the primary imputation 
approach, that is, imputing as a failure to achieve a response, however:

If there are available data at the visits both before and after the visit with a missing 
outcome, then impute as a success only if both the preceding and the following 
observations also represent a success.

Otherwise, impute as a failure to achieve a response (i.e. no response imputation 
[NRI]).
NRI is a conservative imputation scheme because it assumes that withdrawal (or missing data
due to any other reason) is related to treatment failure. A Best-Response Imputation (BRI)
will also be considered, i.e. to impute all missing values based on the best response observed 
at visits prior to occurrence of intercurrent events/missing data. If there is no non-missing 
data available, then the missing value will be imputed as a failure.
Missing data will not be imputed for secondary continuous endpoints. The mixed effect
model will handle missing data based on a likelihood method under the ‘missing at random
assumption’. 
For further endpoints, rules for handling of missing data will be specified in the TSAP if 
necessary. With respect to safety evaluations, it is not planned to impute missing values. 

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7.4
RANDOMISATION
The trial will be performed as a double-blind design for the randomized treatment period with 
respect to two blinded treatment groups. Randomisation to the treatment groups of 
Spesolimab and placebo will be 2:1 and will be stratified by the following factor:

Adults versus adolecents

Japan versus China versus other regions 
Stratification for Japan versus China versus other regions will be done in order to assure that 
sufficient patients per treatment group are recruited specifically to support individual country
submission in Japan and China; these strata will be treated as operational strata and will not 
be included into the analyses of efficacy endpoints.
The adolescent patients will be randomised in a 2:1 ratio to two treatment groups (spesolimab 
and placebo) regardless of blocking factor of Japan versus China versus other regions.
BI will arrange for the randomisation and the packaging and labelling of trial medication. The 
randomisation list will be generated using a validated system, which involves a pseudo-
random number generator so that the resulting treatment will be both reproducible and non-
predictable. The block size will be documented in the Clinical Trial Report. Access to the 
codes will be controlled and documented.
7.5
DETERMINATION OF SAMPLE SIZE
The sample size is determined as 39 patients based on feasibility and practical considerations
due to the rareness of this disease.
As there is no experience in this ultra-rare disease, the main assumptions for the primary 
endpoint and key secondary endpoint are, that there is a treatment difference (delta) of 50% 
between placebo and spesolimab in both endpoints. In addition, the correlation of the two 
endpoints are assumed to range from 0.3 to 0.7. The power estimates below are derived using 
R version 4.0.2 with 2-sided type I error of 0.05 when considering 39 patients.

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Table 7.5: 1
Power to achieve statistical significance for primary endpoint and key 
secondary endpoint on spesolimab versus placebo under various 
scenarios for N=39 (2:1)
Sample size: 
spesolimab vs. 
placebo
Placebo/Spesolimab 
response rate in 
primary endpoint 
and key secondary 
endpoint  
Correlation 
between 
primary 
and key 
secondary 
endpoint 
Power to 
achieve primary 
endpoint
Power to achieve 
primary and key 
secondary 
endpoint
26:13
15%, 65%
0.3
89.0%
80.6%
0.5
81.8%
0.7
83.3%
26:13
20%, 70%
0.3
88.0%
78.9%
0.5
80.2%
0.7
81.9%
26:13
30%, 80%
0.3
88.5%
79.7%
0.5
80.9%
0.7
82.6%
8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND
ADMINISTRATIVE STRUCTURE
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Guideline for Good 
Clinical Practice (GCP), relevant BI Standard Operating Procedures (SOPs), the EU 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. Deviation from the protocol, the principles of ICH 
GCP or applicable regulations as will be treated as “protocol deviation”.
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains the 
responsibility of the treating physician of the patient.
The investigator will inform the sponsor or delegate immediately of any urgent safety 
measures taken to protect the trial patients against any immediate hazard, as well as of any 
serious breaches of the protocol or of ICH GCP.
The Boehringer Ingelheim transparency and publication policy can be found on the following 
web page: trials.boehringer-ingelheim.com. The rights of the investigator and of the sponsor
with regard to publication of the results of this trial are described in the investigator contract. 
As a rule, no trial results should be published prior to finalisation of the Clinical Trial Report.
The certificate of insurance cover is made available to the investigator and the patients and is
stored in the ISF.

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8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB) / Independent Ethics Committee 
(IEC) and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to patient participation in the trial, written informed consent must be obtained from each 
patient (or the patient’s legally accepted representative) according to ICH-GCP and to the 
regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent, and any additional patient-
information form retained by the investigator as part of the trial records. A signed copy of the 
informed consent and any additional patient information must be given to each patient or the 
patient’s legally accepted representative.
For adolescents, the patient will be provided with an age-adapted information sheet 
wherehis/her assent will be collected according to the regulatory and legal requirements of 
the participating country. The refusal of an adolescent to participate must be 
acceptedindependently of the consent of his/her parent(s)/legal guardian.
For patients who may legally consent during the trial participation (turning to the age of legal
consent in the participating country), written informed consent must be obtained to confirm
the patient’s willingness to pursue trial participation. The patient will continue with the 
assessments for which he/she consented at the beginning of the trial (as an adolescent).
The investigator or delegate must give a full explanation to trial patients based on the patient
information form. A language understandable to the patient should be chosen, technical terms 
and expressions avoided, if possible. 
The patient (or patient’s parents (s) /legal guardian) must be given sufficient time to consider 
participation in the trial. The investigator or delegate obtains written consent/assent of the 
patient’s (or patient’s parent(s)/legal guardian) own free will with the informed consent form 
after confirming that the patient understands the contents. The investigator or 
 delegate
must sign (or place a seal on) and date the informed consent form. If a trial collaborator has 
given a supplementary explanation, the trial collaborator also signs (or places a seal on) and 
dates the informed consent/assent.
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.
The consent and re-consenting process should be properly documented in the source 
documentation.
8.2
DATA QUALITY ASSURANCE
A risk-based approach is used for trial quality management. It is initiated by the assessment 
of critical data and processes for trial patient 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 

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ICH-GCP E6, for fully outsourced trials, documents the rationale and strategies for risk 
management during trial conduct including monitoring approaches, vendor management and 
other processes focusing on areas of greatest risk.
Continuous risk review and assessment may lead to adjustments in trial conduct, trial design 
or monitoring approaches. 
A quality assurance audit / inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
8.3
RECORDS
CRFs for individual patients will be provided by the sponsor. See Section 4.1.5.2 for rules 
about emergency code breaks. For drug accountability, refer to Section 4.1.8.
8.3.1
Source documents
In accordance with regulatory requirements, the investigator should prepare and maintain 
adequate and accurate source documents and trial records that include all observations and 
other data pertinent to the investigation on each trial patient. Source data as well as reported 
data should follow the “ALCOA principles” and be attributable, legible, contemporaneous, 
original and accurate. Changes to the data should be traceable (audit trail).
Data reported on the CRF must be consistent with the source data or the discrepancies must 
be explained.
The current medical history of the patient may not be sufficient to confirm eligibility for the 
trial and the investigator may need to request previous medical histories and evidence of any 
diagnostic tests. In this case, the investigator must make at least one documented attempt to 
retrieve previous medical records. If this fails, a verbal history from the patient, documented 
in their medical records, would be acceptable.
If the patient is not compliant with the protocol, any corrective action e.g. re-training must be 
documented in the patient file.
For the CRF, data must be derived from source documents, for example:

Patient identification: gender, year of birth (in accordance with local laws and 
regulations)

Patient participation in the trial (substance, trial number, patient number, date patient was 
informed)

Dates of patient’s visits, including dispensing of trial medication

Medical history (including trial indication and concomitant diseases, if applicable)

Medication history

Adverse events and outcome events (onset date (mandatory), and end date (if available))

Serious adverse events (onset date (mandatory), and end date (if available))

Concomitant therapy (start date, changes)

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
Originals or copies of laboratory results and other imaging or testing results, with proper 
documented medical evaluation (in validated electronic format, if available)

Completion of patient’s participation in the trial” (end date; in case of premature 
discontinuation document the reason for it).

Prior to allocation of a patient to a treatment into a clinical trial, there must be 
documented evidence in the source data (e.g. medical records) that the trial participant 
meets all inclusion criteria and does not meet any exclusion criteria. The absence of 
records (either medical records, verbal documented feedback of the patient or testing 
conducted specific for a protocol) to support inclusion / exclusion criteria does not make 
the patient eligible for the clinical trial.
8.3.2
Direct access to source data and documents
The investigator / institution will allow site trial-related monitoring, audits, IRB / IEC review 
and regulatory inspections. Direct access must be provided to the CRF and all source 
documents / data, including progress notes, copies of laboratory and medical test results, 
which must always be available for review by the CRA, auditor and regulatory inspector 
(e.g. FDA). They may review all CRFs and informed consents. The accuracy of the data will 
be verified by direct comparison with the source documents described in Section 8.3.1. The 
sponsor or delegate will also monitor compliance with the protocol and GCP.
8.3.3
Storage period of records
Trial site(s):
The trial site(s) must retain the source and essential documents (including ISF) according to 
contract or the local requirements valid at the time of the end of the trial (whatever is longer).
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with
regulatory requirements. 
SAE/AESI are processed in the global Safety Database and assessed for the company causal 
relationship as well as the expectedness of the event according to the reference safety 
information. Individual Case Safety Reports (ICSR) are subsequently reported according to local 
Regulations. 
Reporting to the EMA will be done via E2B transmission of ICSRs to the Eudravigilance CT 
Module.
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY
Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principles 7 and 12 of the WHO GCP 
handbook. 

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To ensure confidentiality of records and personal data, only pseudonymised data will be 
transferred to the sponsor by using a patient identification number instead of the patient’s 
name. The code is only available at the site and must not be forwarded to the sponsor. In case 
patient’s records will be forwarded e.g. for SAE processing or adjudication committees, 
personal data that can identify the patient will be redacted by the site prior to forwarding. 
Access to the patient files and clinical data is strictly limited: personalised treatment data may 
be given to the patient’s personal physician or to other appropriate medical personnel 
responsible for the patient’s welfare. Data generated at the site as a result of the trial need to 
be available for inspection on request by the participating physicians, the sponsor’s 
representatives, by the IRB / IEC and the regulatory authorities.
A potential data security breach will be assessed regarding the implications for rights and 
privacy of the affected person(s). Immediate actions as well as corrective and preventive 
actions will be implemented. Respective regulatory authorities, IRBs / IECs and patients will 
be informed as appropriate.
8.5.1
Collection, storage and future use of biological samples and corresponding 
data 
Measures are in place to comply with the applicable rules for the collection, biobanking and 
future use of biological samples and clinical data, in particular

Sample and data usage have to be in accordance with the separate biobanking 
informed consent

The BI-internal facilities storing biological samples from clinical trial participants as 
well as the external banking facility are qualified for the storage of biological samples 
collected in clinical trials

An appropriate sample and data management system, incl. audit trail for clinical data 
and samples to identify and destroy such samples according to ICF is in place

A fit for the purpose documentation (biomarker proposal, analysis plan and report) 
ensures compliant usage

A fit for purpose approach will be used for assay / equipment validation depending on 
the intended use of the biomarker data

Samples and / or data may be transferred to third parties and other countries as 
specified in the biobanking ICF
8.6
TRIAL MILESTONES
The start of the trial is defined as the date when the first patient in the whole trial signs 
informed consent.
The end of the trial is defined as the date of the last visit of the last patient in the whole trial
(“Last Patient Completed”).
The “Last Patient Last Treatment” (LPLT) date is defined as the date on which the last 
patient in the whole trial is administered the last dose of trial treatment (as scheduled per 
protocol or prematurely). Individual investigators will be notified of SUSARs occurring with 
the trial medication until 30 days after LPLT at their site.

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Early termination of the trial is defined as the premature termination of the trial due to any 
reason before the end of the trial as specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the 
sponsor with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.
The IEC / competent authority in each participating EU member state will be notified about 
the trial milestones according to the respective laws.
A final report of the clinical trial data will be written only after all patients have completed 
the trial in all countries (EU or non-EU) to incorporate and consider all data in the report.
The sponsor will submit to the EU database a summary of the final trial results within one 
year from the end of a clinical trial as a whole, regardless of the country of the last patient
(EU or non-EU).
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim (BI).
A Coordinating Investigator is responsible to coordinate investigators at the different sites 
participating in this trial. Tasks and responsibilities are defined in a contract. 
A
 will be established. Members of the 
 are independent of BI, they are physicians 
experienced in the treatment of the disease under investigation and a statistician. 
The 
 will evaluate safety and efficacy data. The 
 will receive urgent significant 
safety concerns, for immediate evaluation. While 
 members may be unblinded, 
measures are in place to ensure the blinding for everyone else involved in the trial. Regular 
 meetings will be held at specified intervals. The 
 will recommend continuation, 
modification or termination of the trial as detailed in the 
 charter. 
 
recommendations as well as the final BI decision will be reported to the appropriate 
Regulatory Authorities (RAs) / Health Authorities (HAs), IrBs / ECs, and to investigators as 
requested by local law. The tasks and responsibilities of the 
 are specified in a charter.
Relevant documentation on the participating (Principal) Investigators (e.g. their curricula 
vitae) will be filed in the ISF.
The investigators will have access to the BI web portal Clinergize to access documents 
provided by the sponsor.
BI has appointed a Clinical Trial Leader responsible for coordinating all required activities, in 
order to 
-
manage the trial in accordance with applicable regulations and internal SOPs,
-
direct the clinical trial team in the preparation, conduct, and reporting of the trial,
-
ensure appropriate training and information of Clinical Trial Managers (CT 
Managers), Clinical Research Associates (CRAs), and investigators of participating 
countries.

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In the participating countries the trial 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) based on a contract. The CRO will 
perform project management, clinical field monitoring, medical monitoring, and reporting.
Data Management and Statistical Evaluation will be done by BI according to BI SOPs.
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF.
A central laboratory service, vendor for photo documentation, and an IRT vendor will be 
used in this trial. Details will be provided in the IRT Manual and Central Laboratory Manual, 
available in the ISF.
9.
REFERENCES
9.1
PUBLISHED REFERENCES
P19-01888
Bachelez H, Choon SE, Marrakchi S, et al. Inhibition of the 
interleukin-36 pathway for the treatment of generalized pustular psoriasis. 
N Engl J Med; 2019; 380(10); 981-983.
P22-00345
Nielsen VW, Thomsen SF. Filling the gaps in generalized pustular 
psoriasis: role of IL-36R antibodies. Drugs Future; 2021; 46(12); 
995-1002.
P22-00835
Sugiura K. Role of interleukin 36 in generalised pustular psoriasis and 
beyond. Dermatology and Therapy, Published online: 21 January 2022. 
P22-03177
Hwang J, Rick J, Hsiao J, Shi VY. A review of IL-36: an emerging 
therapeutic target for inflammatory dermatoses. J Dermatolog Treat. 
Published online: 2022;1-12.
R11-4890
Sampson HA, et al. Second symposium on the definition and 
management of anaphylaxis: summary –report - second National Institute 
of Allergy and Infectious Disease/Food Allergy and Anaphylaxis 
Network symposium. 2nd Symp of the National Institute of Allergy and 
Infectious Disease (NIAID)/Food Allergy and Anaphylaxis (FAA) 
Network on the Definition and Management of Anaphylaxis; J Allergy 
Clin Immunol; 2006; 117(2); 391-397. 
R17-2617
Winthrop KL, Novosad SA, Baddley JW, 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; 74; 2107-2116.
R18-1357
U.S. Department of Health and Human Services. Common terminology 
criteria for adverse events (CTCAE) version 5.0 (published: 
November 27, 2017).

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R20-2256
National Psoriasis Foundation (NPF) COVID-19 Task Force. Updated: 
COVID-19 recommendations. National Psoriasis Foundation (NPF); 
2020.
R20-2257
National Institute for Health and Care Excellence (NICE). COVID-19
rapid guideline: severe asthma (NICE guideline, published: 3 April 2020). 
National Institute for Health and Care Excellence (NICE); 2020.
R20-2258
American Academy of Allergy Asthma & Immunology (AAAA). An 
update on COVID-19 for the practicing allergist/immunologist (July 9, 
2020). American Academy of Allergy Asthma & Immunology (AAAA); 
2020.
R22-0746
Barbieux C, Bonnet des Claustres M, Fahrner M, et al. Netherton 
syndrome subtypes share IL-17/IL-36 signature with distinct IFN-α and 
allergic responses. J Allergy Clin Immunol. 2022;149(4):1358-1372.
R22-0760
Versteegh JJWM, Dulfer K, Stuvel K, et al. Netherton syndrome; 
neuropsychological and psychosocial functioning of child and adult 
patients and their parents. J Health Psychol; 2020; 25(13/14); 2296-2316.
R22-0826
Yan AC, Honig PJ, Ming E, The safety and efficacy of pimecrolimus, 
1%, cream for the treatment of Netherton syndrome: results from an 
exploratory study. Arch Dermatol; 2010; 146(1); 57-62.
R22-0856
Malik K, He H, Huynh TN, et al. Ichthyosis molecular fingerprinting 
shows profound TH17 skewing and a unique barrier genomic signature. J 
Allergy Clin Immuno l. 2019 ;143(2):604-618.
R22-1085
Paller AS, Renert-Yuval Y, Suprun M, et al. An IL-17-dominant immune 
profile is shared across the major orphan forms of ichthyosis. J Allergy 
Clin Immunol. 2017;139(1):152-165.
R22-1980
Elman S, Hynan LS, Gabriel V, Mayo MJ. The 5-D itch scale: a new 
measure of pruritus. Br J Dermatol; 2010; 162(3); 587-593.
R22-1982
Rider LG, Werth VP, Huber AM, Alexanderson H, Rao AP, Ruperto N, 
Herbelin L, Barohn R, Isenberg D, Miller FW: Measures for adult and 
juvenile dermatomyositis, polymyositis, and inclusion body myositis. 
Arthritis Care Res (Hoboken); 2011; 63(11); S118-S157.
R22-1983
Akcay BD, Akcay D, Yetkin S. Turkish reliability and validity study of 
the medical outcomes study (MOS) sleep scale in patients with 
obstructive sleep apnea. Turk J Med Sci; 2021; 51; 268-279.
R22-2030
Garaiman A, Mihai C, Dobrota R, et al. The Hospital Anxiety and 
Depression Scale in patients with systemic sclerosis: a psychometric and 
factor analysis in a monocentric cohort. Clin Exp Rheumatol. 2021;39 
Suppl 131(4):34-42.
R22-2031
Desai NS, Poindexter GB, Monthrope YM, Bendeck SE, Swerlick RA, 
Chen SC. A pilot quality-of-life instrument for pruritus. J Am Acad 
Dermatol. 2008;59(2):234–44.

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R22-2286
Sun Q, Asch S, Bayart C, et al. Development and initial validation of a 
novel system to assess ichthyosis severity. JAMA Dermatol; 2022; 
158(4); 359-365.
R23-1267
Ethical considerations for clinical trials on medicinal products conducted 
with minors: recommendations of the expert group on clinical trials for 
the implementation of Regulation (EU) No 536/2014 on clinical trials on 
medicinal products for human use (revision 1, 18 September 2017
R24-3478
Desai NS, Poindexter GB, Monthrope YM, Bendeck SE, Swerlick RA, 
Chen SC. A pilot quality-of-life instrument for pruritus. J Am Acad 
Dermatol; 2008; 59(2); 234-244.
R24-3537
Lewis-Jones MS, Finlay AY. The children's dermatology life quality 
index (CDLQI): initial validation and practical use. Br J Dermatol; 1995; 
132(6); 942-949.
9.2
UNPUBLISHED REFERENCES
c03320877
Investigator’s Brochure, BI 655130 (spesolimab), version 11, dated 04 
October 2022.
c09985235
Randomized, double-blind, placebo-controlled, study of spesolimab in 
patients with moderate to severe hidradenitis suppurativa. 
c31523813
Effisayil™ 1: Multi-center, double-blind, randomized, placebo-
controlled, Phase II study to evaluate efficacy, safety and tolerability of a 
single intravenous dose of BI 655130 in patients with Generalized 
Pustular Psoriasis (GPP) presenting with an acute flare of moderate to 
severe intensity. 
c34990476
TMCP List of Analyses for BI 655130 (Spesolimab)

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10.
APPENDICES
10.1
SCALES
10.1.1
IASI- Ichtyosis Area Severity Index
10.1.2
IGA
The Final score for each intensity measure (IASI-E or IASI-S) is thus the 
composite of:
IASI-E: Ichthyosis Area Severity Index – Erythema
(A1 erythema x B1 x C1) + (A2 erythema x B2 x C2) + (A3 erythema x B3 
x C3) + (A4 erythema x B4 x C4)
IASI-S: Ichthyosis Area Severity Index – Scaling
(A1 scaling x B1 x C1) + (A2 scaling x B2 x C2) + (A3 scaling x B3 x C3) 
+ (A4 scaling x B4 x C4)
The composite score IASI (max potential 48) = IASI-E (max potential = 
24) + IASI S (max potential) = 24
BODY REGION
Erythema 
(A)
X
Region 
score (B)
X
Multiplier 
(C)
Score per body 
region
Head/Neck (1)
X
X
0.1
Trunk (2)
X
X
0.3
Upper 
extremities (3)
X
X
0.2
Lower 
extremities (4)
X
X
0.4
TOTAL (Sum Score per Region): IASI-E =
BODY REGION
Scaling 
(A)
X
Region 
score (B)
X
Multiplier 
(C)
Score per body 
region
Head/Neck (1)
X
X
0.1
Trunk (2)
X
X
0.3
Upper 
extremities (3)
X
X
0.2
Lower 
extremities (4)
X
X
0.4
TOTAL (Sum Score per Region): IASI-S =
IASI = IASI-E + 
IASI-S
a) Determine mean INTENSITY of erythema or scaling in a body region (A1 = head and 
neck; A2 = upper limbs; A3 = trunk; A4 = lower limbs) through either selecting a 
representative area of ichthyosis or averaging the intensity within a body region. The 
intensity of redness/ erythema and scaling of the ichthyosis is assessed as none (0), 
mild (1), moderate (2), severe (3) or very severe (4). 
0 
None 
1 
Mild 
2 
Moderate 
3 
Severe 
4 
Very Severe 
b) Determine what percentage of AREA within a body region is affected by ichthyosis. In 
each region, the area is expressed as nil (0), 1-9% (1 ), 13-29% (2). 30-49% (3). 50-69% 
(4), 70-89% (5) or 90-100% (6). Many with ichthyosis have generalized involvement with 
100% of area affected (e.g., score of 6), but it is possible that areas may be spared (e.g., 
palms or soles). The mean intensity score (A 1-A4 for each site) is multiplied by the 
number correlating with the percentage within a region with ichthyosis (B1-4). 
% involvement 
Re ion score 
1·9% 
10 • 
29% 
30 • 
49% 
50-
69% 
70-
89% 
90 • 
100% 
c) Determine TOTAL EXTENT by using a multiplier that takes into account the percentage 
of the total body surface area represented by each body region (C1 = 0.1 for head and 
neck; C2 = 0.2 for upper limbs; C3 = 0.3 for trunk; C4 = 0.4 for lower limbs). 
The IASI (lchthyosis Area and Severity Index) is a modification of the 
global GISI score that incorporates extent through the techniques used 
for assessment in the EASI and PASI scores for eczema (AD) and 
psoriasis, respectively. IASI takes only a few minutes to assess, and the 
totals are calculated automatically in spreadsheets. 
Score 
Morphological Descriptors 
Clear (0) 
Almost clear (1) 
Mild (2) 
Moderate (3) 
Severe (4) 
Normal skin 
Light pink erythema and/or minimal scaling 
Pink erythema and/or localized scaling 
Red erythema and/or generalized fine scaling 
Deep red erythema and/or generalized coarse scaling 

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10.1.3
NASA- Netherton Area Severity Assessment Score
10.1.4
NRS Pain
• Netherton-specific modification of the EASI 
score that substitutes scaling for excoriation 
• NASA score con theoretically vary from Oto 72 
scor 
0 
2 
3 
5 
6 
The calculation of ASA score for children 8 years or 
older is performed as follows ( where the area is defined 
on the 7-point ordinal scale): 
Location 
Head/Neck 
Trunk 
Upper limbs 
Lower limbs 
NASA score equals: 
(E +I+ L +S) xArea x0.1 
(E+ I +L +S) xArea x0.3 
(E +I+ L +S) xArea x0.2 
(E +I+ L +S) xArea x0.4 
Sum of the above 4 body areas 
el able. Scoring Signs of Netherto Area 
Severity Assessment 
(E) 
0-
1-
2-
3-
ln • 
papul 
(I) 
0-
(l) 
(S) 
1-
2-
Please rate the severity of your Netherton Syndrome (NS) pain in the past 24 hours at its worst? 
Please mark the number on the Oto 10 scale below. 
0 
1 
2 
3 
4 
5 
No pain 
6 
7 
8 
9 
10 
Worst 
possible 
pain 

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10.1.5
NRS Itch
Please rate the severity of your Netherton Syndrome (NS) itch in the past 24 hours at its worst? 
Please mark the number on the Oto 10 scale below. 
0 
1 
2 
3 
4 
5 
6 
7 
8 
No itch 
9 
10 
Worst 
possible 
itch 

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10.1.6
Dermatology Life Quality Index (DLQI) / Children’s Dermatology Life 
Quality Index (CDLQI)
D E RMATOLOGY LIFE Q UALITY INDEX 
DLQI 
Hospital No: 
Nanie: 
Address: 
Date: 
Score: 
Dia~osis : 
D 
The aim o f t his quest ionnaire is to measure how much your skin p roble m has affected your We 
OVER THE LAST WEEK. P lease t:ick • one box for each question. 
1 . 
Over the ls.st week, how itchy, sore, 
p ainful or atinl!inl! has your skin 
1oeen? 
2. 
Over the ls.st we.e.k, how embarrassed 
3. 
or self conscious have you been be<:ause 
of your s kin? 
Over the 
s week, how much has y our 
skin interfered with you going 
shoppinl! or looking after your home or 
j!arden? 
4. 
Over the 
st week, how much has your 
skin influenced the clothes 
you ~ear? 
5. 
Over the ls.st week, how much has your 
skin affected any social or 
leisure activities? 
6. 
Over the 
st we.e.k, how much has your 
skin made it difficult for 
7. 
8. 
you to do any s p ort? 
Over the last week, has your skin prevented 
you from workinl! or studyinj!? 
If "No", over the ls.st we.e.k how xnuch has 
your skin been a pro blern at 
"Work or studyini!? 
Over the ls.st week, how much has your 
skin created pro blenis with your 
p artner or any of ;your close friends 
or relatives? 
9 . 
Over the ls.st week, how much has your 
skin caused any sexual 
d ifficul t ies? 
V ery much 
A lot 
A little 
ot at all 
V ery xnuch 
A lot 
A little 
·otatall 
ery ,:nuch 
A lot 
A little 
ot at all 
V ery ,:nuch 
A lot 
A little 
ot at all 
Very ,:nuch 
A lot 
A little 
Ot at all 
ery much 
A lot 
A little 
Ot at all 
Yes 
0 
A lot 
A little 
Ot at all 
Very much 
A lot 
A little 
Ot at all 
ery much 
A lot 
A little 
-ot at all 
1 0 . 
Over the 
st week, how much of a 
V ery :much 
problem has the treatment for your 
A lot 
skin been, for exainple by making 
A little 
Not relevant 
Not relevant CJ 
ot relevant a 
ot relevant a 
• ot relevant CJ 
• ot relevant CJ 
'ot relevant CJ 
your home ,:nessy, or by taking up time? 
'ot at all 
·ot relevant CJ 
P lease che ck you have answere d E VER Y quest.ion. Thank you. 
AX F'icl.:,.y, GK Kb=, April 199:? .....-a,.~
-ar&-uk, tl::i,; ==< 001: be cop;.d. "Ori<bou~ u:,, penai.:,ao:, ohhe "''-'-tho=. 

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CHILDREN'S DERMATOLOGY LIFE QUALITY INDEX
Hospital No
Name:
Diagnosis:
CDLQI
Age:
SCORE:
Address:
Date:
The aim of this questionnaire is to measure how much your skin problem has
affected you OVER THE LAST WEEK.  Please tick one box for each question.
1.
Over the last week, how itchy, "scratchy",
             Very much
□
sore or painful has your skin been?
             Quite a lot
□
Only a little
□
Not at all
□
2.
Over the last week, how embarrassed
            Very much
□
or self conscious, upset or sad have you 
            Quite a lot
□
been because of your skin?
Only a little
□
Not at all
□
3.
Over the last week, how much has your 
            Very much
□
skin affected your friendships?
            Quite a lot
□
Only a little
□
Not at all
□
4.
Over the last week, how much have you changed
             Very much
□
or worn different or special clothes/shoes
             Quite a lot
□
because of your skin?
             Only a little
□
Not at all
□
5.
Over the last week, how much has your 
           Very much
□
skin trouble affected going out, playing,
            Quite a lot
□
or doing hobbies?
Only a little
□
Not at all
□
6.
Over the last week, how much have you
         
Very much
□
avoided swimming or other sports because
                          Quite a lot
□
of your skin trouble?
Only a little
□
Not at all
□
7.
Last week,

If school time: Over the
          
Prevented school            □  


last week, how much did
              Very much
□
school time?  
            your skin problem affect your
            Quite a lot
□




school work?
Only a little
□
   OR
Not at all
□
was it
  
If holiday time: How much
Very much

□
holiday time?
  
              over the last week, has your
Quite a lot

□
skin problem interfered with
Only a little

□
your enjoyment of the holiday?
             Not at all

□
8.
Over the last week, how much trouble 
            Very much
□
have you had because of your skin with
            Quite a lot
□
other people calling you names, teasing,
           Only a little
□
bullying, asking questions or avoiding you?
            Not at all
□
9.
Over the last week, how much has your sleep
            Very much
□
been affected by your skin problem?
             Quite a lot
□
Only a little
□
Not at all
□
10.
Over the last week, how much of a 
            Very much
□
problem has the treatment for your 
             Quite a lot
□
skin been?
Only a little
□
Not at all
□
Please check that you have answered EVERY question. Thank you.
M.S. Lewis-Jones, A.Y. Finlay, May 1993, This must not be copied without the permission of the authors.
was it
D 

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10.1.7
5D-Itch-scale
5-D Pruritus Scale 
1. Duration: During the last 2 weeks, how many hours a day have you been itching? 
Less than 6hrs/day 6-12 hrs/day 
12-18 hrs/day 
18-23 hrs/day 
1 
2 
3 
4 
2. Degree: Please rate the intensity of your itching over the past 2 weeks 
Not present 
1 
Mild 
2 
Moderate 
Severe 
3 
4 
All day 
5 
Unbearable 
5 
3. Direction: Over the past 2 weeks has your itching gotten better or worse compared to the 
previous month? 
Completely 
resolved 
1 
Much better, but 
Little bit better, 
still present 
but still present 
2 
3 
Unchanged 
Getting worse 
4 
5 
4. 
Disability: Rate the impact of your itching on the following activities over the last 2 
weeks 
Sleep 
Never 
affects sleep 
1 
N/A 
Leisure/Social 
D 
Housework/ 
D 
Errands 
Work/School 
Occasionally 
delays 
falling asleep 
2 
Frequently 
delays 
falling asleep 
3 
Delays falling asleep 
and occasionally 
wakes me up 
at night 
4 
Delays falling 
asleep and frequently 
wakes me up 
at night 
5 
Never 
affects 
this activity 
Rarely 
affects 
this activity 
Occasionally 
affects 
this activity 
Frequently 
affects 
this activity 
Always 
affects 
this activity 
2 
2 
1 
2 
3 
3 
4 
4 
5 
5 
5. 
Distribution: Mark whether itching has been present in the following parts of your body 
over the last 2 weeks. If a body part is not listed, choose the one that is closest 
anatomically. 
Head/Scalp 
Face 
Chest 
Abdomen 
Back 
Buttocks 
Thighs 
Lower legs 
Tops of Feet/Toes 
Present 
Soles 
Palms 
Tops of Hands/Fingers 
Forearms 
Upper Arms 
Points of Contact w/ Clothing 
(e.g waistband, undergarment) 
Groin 
Present 

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10.1.8
Hospital Anxiety and Depression Scale (HADS)
Name: _______________ _ 
Date: ____ _ 
C ·rum are aware that emotiom la 
imp01 
m DJOst illnes~. If your clini • knov.'5 a 
the.,e eeJin .. • he or she will be able to help ·ou mo 
:: Thi, que. ·onnaire i; de:; gned to help ·our clime m to know how you feel Read e.ach item 
ow and 
11.Dderline thtrepl}· v.mch c 
• closest to how you 
:e 
feeling · 
;t ;eek. 
re the 
numbm printed at the 
g e of 
que,ilomiau 
Don't 
e too o g o :er your replie· your immedia reacti 
o e.ach tem will proba I be more 
a long. thought-out rupocse. 
:\ D 
.-\ D 
I feel tense or 1wo11.Dd up" 
I feel as ifl 
3 
1o5t of the time 
N 
. lotof 
tune 
rom tune to time occaionall ' 
0 
. ot at all 
0 
I ;till enjo)· the thing· I u ed to t11jor 
I get a ort of frightened f eeli.ng like 
0 
• ely as much 
"butterflie-" in the omach 
. ot quite so much 
ot a all 
0 
a little 
1 
3 
Hardl a 
I get 
ort of frightened feeling 
if 
3 
' 
:ful i about to happt11 
I hare lost intemt in ~ -apptarme 
s 
3 
ely and quite bi y 
Definitei 
too bad! 
as I 
d 
1t doe;n • t worry me 
0 
care as e\'er 
0 
I C1\n laugh ruid ee the funny side of tbiob 
I fe+I re;de 
s i£ I bare to be on the more 
0 
mu as I always could 
ery mucli indeed 
3 
choow 
Qmtea ot 
so 
ch ow 
ot\'e! 1mu 
1 
3 
ot a all 
0 
go through ~ -mind 
Iloo forn-ard uitb enjorment to thing· 
3 
tune 
muc as I ever di 
0 
Ra 
e;s than I used o 
Defimtel '. ·s than I used to 
0 
Hardly at all 
3 
I feel cheerful 
I get sudden feeling, of panic 
3 
. e ·er 
oftw indeed 
3 
Qweo 
Notrn ·o 
1 
0 
time 
ot a all 
0 
I C1tn it t me and fe-el relaxed 
I crui en.joy, good boo or radio or 
0 
• ly 
telen,ion progr:unme 
0 
0 
Some 
3 
Noto 
3 
:\'on- check that i·ou hare answered all the gue lions 
:\ D 
TOBL [I] 

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10.1.12
Diagnosis of 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 (eg, generalized hives, pruritus or flushing, swollen lips-tongue-
uvula)
AND AT LEAST ONE OF THE FOLLOWING
a. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced PEF, 
hypoxemia)
b. Reduced BP or associated symptoms of end-organ dysfunction (eg, hypotonia [collapse], 
syncope, incontinence)
2. Two or more of the following that occur rapidly after exposure to a likely allergen for 
that patient (minutes to several hours):
a. Involvement of the skin-mucosal tissue (eg, generalized hives, itch-flush, swollen lips-
tongue-uvula)
b. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced PEF, 
hypoxemia)
c. Reduced BP or associated symptoms (eg, hypotonia [collapse], syncope, incontinence)
d. Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting)
3. Reduced BP after exposure to known allergen for that patient (minutes to several hours):
a. Infants and children: low systolic BP (age specific) or greater than 30% decrease in 
systolic BP*
b. Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from that 
person’s baseline 
PEF, Peak expiratory flow; BP, blood pressure.

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*Low systolic blood pressure for children is defined as less than 70 mm Hg from 1 month to 
1 year, less than (70 mm Hg +[2 x age] from 1 to 10 years, and less than 90 mm Hg from 11 
to 17 years

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10.1.13
Itchy QOL
ITCHING QUALITY OF LIFE SURVEY 
The rono"ving ques t:ions concern y our feelings about your itc h y s kin 
condition. Please check the ans\.ver that b est describes y our experience. 
--r:-M y itchy skin conditio n bleeds. 
2 . M y skin hurts because of" 1ny ilchy skin condition. 
3 . M y itchy skin condition bums or stings. 
4
-:--1 get scars frorn ,ny itc h y skin conditi o n . 
S . I need to scratch 1ny itchy s k i n condi t ion. 
6 . Te,nperaturc or seasonal changes aggrav ate ,ny itchy s kin conditio n . 
- 7. I spend a lot of"1noncy treating m y itchy s kin condi tion. 
8. M y itc h y skin condi t ion makes it hard to work or do ... vhat I enjoy. 
1-lo,v~ durin g I.h e ~ 
d o lhese 
s 1a1e 1ne nu apply lo yo u ? 
-f-
D , 
D , 
-f-
D , 
D , 
--
D , 
D , 
D , 
D , 
D , 
D , 
D , 
D , 
D , 
D , 
-I----+---·-
+ 
-
D , 
D , 
D , 
D , 
9 . M y itchy skin condition a .ITccts m y interaction =ith o thers . (For example: f"an1ily. friends. close 
relations hips. etc.) 
D , 
D , 
D , 
D , 
D , 
D , 
C 2004. 2012 Emory University. All righ&:s reserved. 
Page, I / 3 
The rollo"ving questions concern y our feelings about y our itc h y skin 
condition. Please check the ans\.vcr that bes t 
d escribes your experie nce . 
I 0 . My itchy s kin conditio n affects how well I sleep. 
I I . My itchy s kin conditio n often 1nakcs it difficult to conccnnutc . 
12 . My itchy s kin conditio n lirn i ts the types of"clothcs I can ,venr. 
- i 3 . My itc h y skin condition f"orccs me to buy special soaps. detergents. and lotions. 
14 . I am frustrated by 1ny itchy s kin condition. 
15 . I 1un e n1barrnsscd b y my itchy ski n conditio n . 
C 
2 004. 2012 En10ry Univcrsi ty . All righua rcsc,,...,,c,d_ 
Pagc 2/3 
1 6 . M y it·chy s kin conditio n drives me ernzy/ nuts. 
17 . My itchy s kin conditio n 1nakcs 111e angry o r irritable. 
I 8 . M y itchy s kin condition nU!okes 1ne f"eel depressed or sad. 
19. I worry about =ha t other people think about rTIC becaus e o f" m y itchy ski n condition. 
20. I worry that the itching will last f"orevcr . 
21. I f"ee l self"-consc io u s because of" n1y itc h y s kin condition. 
22. My personality has changed because of"my itchy skin condition. 
Subject s ignature 
C 2004. 2012 Emory Univcrsity. All righ1s rc:,sc,...,•cd. 
Pagc 3 /3 
H o 1vJl!l.s::.u. during the~ 
d o these 
s lalemen l.s a ppl y lo y ou? 
D , 
D , 
I D , 
D , 
D , 
D , 
D , 
D , 
D , 
D , 
D , 
D , 
D , 
D , 
D , 
D , 
D , 
D , 
Ho,.,-...Jl!l.rn c.Juring 1he p ·Jst »·eek do these 
s1a1en:1enls apply IO yo u ? 
D , 
D , 
D , 
--D , 
I D , 
D , 
D , 
I D , 
D , 
D , 
I D , 
D , 
D , 
D , 
D , 
D , 
I D , 
D , 
D , 
I D , 
::-:!"L H-
D , 
D--'----
D , 

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10.1.14
Patient Global Impression of Severity for Erythema (PGIS-E)
Please note that erythema refers to the change in the color of your skin, 
typically turning red or purple, due to Netherton Syndrome. 
When considering the skin area (or areas) affected by your disease, 
please choose the response below that best describes the severity of 
erythema on your skin over the past 24 h:
□None
□Mild
□Moderate
□Severe
□Very Severe
10.1.15
Patient Global Impression of Severity for Scaling (PGIS-S)
When considering the skin area (or areas) affected by your disease, 
please choose the response below that best describes the severity of the 
scaling of your skin over the past 24 h:
□None
□Mild
□Moderate
□Severe
□Very Severe
10.1.16
Patient Global Impression of Change for Netherton Syndrome Skin 
Symptoms (PGIC)
Please choose the response below that best describes the change in the skin 
symptoms overall related to your Netherton Syndrome since you started 
taking the medication of this study:
□Much better
□A little better
□No change
□A little worse
□Much worse

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10.2
TRIAL PARTICIPANT FEEDBACK
Optional Trial Participant Feedback Questionnaires:
This trial will include an option for adult participants to complete anonymized 
questionnaires,‘Trial Participant Feedback Questionnaire’, to provide feedback on their 
clinical trial experience. Individual participant level responses will not be reviewed by 
investigators.
Responses will be used by the sponsor to understand where improvements can be made in the
clinical trial process. These questionnaires will not collect data about the participant’s
disease, symptoms, treatment effect, or AEs and therefore will not be part of the trial data or
clinical trial report. The questionnaires will be implemented after local regulatory approval
and after consent of the trial participant. Providing feedback is optional and not required for
participation in the trial.
10.3
MAXIMUM ALLOWABLE RESEARCH-RELATED BLOOD SAMPLE 
VOLUMES FOR ADOLESCENTS IN EU COUNTRIES
Body weight (kg)
Circulating total 
blood volume (ml)
Maximum 
allowable sample 
volume over 
4 weeks (ml) - 3% 
of total blood 
volume
Maximum 
allowable sample 
volume at single 
time (ml) - 1% of 
total blood volume
30 - 70
2400 - 5600
48 – 168
24 – 56

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11.
DESCRIPTION OF GLOBAL AMENDMENT
11.1
GLOBAL AMENDMENT 1
Date of amendment
10 JAN 2024
EU number
2022-501104-10-00
UTN
U1111-1289-6825
BI Trial number
1368-0104
BI Investigational 
Medicinal Product
Spesolimab, BI 655130
Title of protocol
EvasayilTM : A placebo-controlled trial to evaluate the efficacy 
and safety of spesolimab in the treatment of patients with 
Netherton syndrome
Global Amendment due to urgent safety reasons
Global Amendment
X
Section to be changed
Title page
Description of change
The Universal Trial Number (UTN) was added
Rational of change
Updated information
Section to be changed
Several sections
Description of change
Corrected typos and spelling errors
Rationale for change
Administrative change
Section to be changed
Flow Chart, footnote#5 and Section 6.2.1
Description of change
Updated the screening period to 
week
Updated the screening period to
days
Footnote#5 was updated as follows: 
Infection testing at screening includes tuberculosis 
(QuantiFERON® or T-Spot®), hepatitis B, hepatitis C, and 
HIV assessments. See Section 5.2.3 for complete list of testing 
required. For patients who sign the informed consent 
≥4 weeks prior to V2, infection testing must be repeated 2 to 
4 weeks prior to V2. For patients who continue in the 
extended treatment period,  tuberculosis test is to be repeated  
at Week
, Week
, and at EOS.
Section 6.2.1 was updated with the following added text: 
Screening visit (visit1) is to be performed within
days 
before Visit 2. Screening assessments may be repeated as long 
as they fall within the Screening visit window. If more than 
one screening assessment is available, the latest assessment 
prior to the start of treatment must be used to assess eligibility.
Rationale for change
Updated to account the availability of Spink5 genetic test 
results and to clarify that tuberculosis test will be repeated
during the extended treatment period.
Section to be changed
Flow Chart and footnote#2
I 
I 

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Description of change
Footnote # 2 was updated accordingly to include the following 
text:
After Visit 15 (Week
 each individual patient may 
continue receiving the trial drug up to 
weeks 
(approximately 2 years). Patients who do not agree to continue 
should have their EoT visit at Week
. If the patients 
continue in the extended treatment period, then the EoT visit 
will occur at Week
.
Rationale for change
To allow the patients benefiting from the trial drug to continue 
receiving Spesolimab after Week
 and for the duration of 
approxiametely 
weeks
Section to be changed
Flow Chart and footnote#21
Description of change
Added assessments of Itchy Qol, PGIS-E, PGIS-S
PGIC, In- trial interviews (sub study-optional). 
Footnote#21 regarding in-trial interviews was added as 
follows: 
Interviews should occur within 4 weeks after the 
Week
visit. They can also be at early termination visit if 
this visit occurs between Week 8 and Week 16. Interviews 
will be conducted by 
. Consent to participate in the in-
trial interviews can be collected at any visit up to 
Week
visit included.
Rationale for change
Addition of assessment tools to further capture the pruritus-
specific quality of life and patient’s experience.
Section to be changed
Flow Chart and footnote #11
Description of change
Footnote #11 collection of ADA and Nab post-dose have been 
removed and changed to:
PK/ADA/Nab samples will be obtained predose at all 
indicated visits. In addition, post-dose PK samples will be 
collected right after the
 at Visit 2 and Visit 6.
Rationale for change
To reduce the amount of blood samples collected thoughout 
the trial.
Section to be changed
Flow Chart and footnote #12 
Description of change
Added timepoints for photographies at remote visits V9; V11; 
V12; V14 
Rationale for change
To clarify that during the remote visits, photographies will be 
taken by the HCP
Section to be changed
Flow Chart footnote#13, footnote#18 and footnote#19
Description of change
Footnote#13: added “After approval of protocol amendment 
v2.0, skin biopsies will be obtained only from adult patients.”

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Footnote#18: added “and every 12 weeks starting Visit 15.” 
After sentence “The diary should be given to the patient every 
4 weeks until Visit 14”. 
Footnote#19: added “During extension treatment phase, visits 
without clinical efficacy assessments (i.e every second visit 
starting V16) could be performed at the investigating site or 
remotely.”
Rationale for change
Skin biopsies will not be collected for adolescents to lower the 
burden associated with trial assessments. Updates about the 
assessments during extention treatment phase were added.  
Section to be changed
Flow Chart footnote #20
Description of change
Added footnote#20: 
At Visit 15, and at EOT visit, height will be measured only for 
adolescent patients.
Section to be changed 
Flow Chart and footnote#7
Description of change
An extended treatment period from 
 up to 
 was 
added to the flow chart.
Description about frequency of pregnancy test 
106andomizteneded treatment period was added to footnote#7
Rationale for change
Update according to extension of trial
Rationale for change
To monitor growth in adolescent patients
Section to be changed 
Section 1.4.1 Benefits
Description of change
As of September 2022 2023, an estimated 734 863 subjects 
have been exposed to spesolimab, out of a total of 936
966 subjects in the clinical development programme.
Rationale for change
Number of subjects exposed to spesolimab has increased since 
the original CTP
Section to be changed
Section 1.4.2 Risks
Description of change
Added “Blood volumes for safety analysis will be reduced for 
adolescent patients in this trial. In EU, the total blood volume 
collected will be in line with the EU recommendations for 
clinical trials on medicinal products conducted with minors 
across the study (R23-1267).
Rationale for change
Added for according to the EU recommendations
Section to be changed
Section 2.1.4 Secondary endpoint-Efficacy
Description of change
Moved the original secondary efficacy endpoint “Occurrence 
of bacterial or fungal mucocutaneous infection through 
Week 16” to further endpoint
Rationale for change
Number of bacterial or fungal mucocutaneous infection
occurrences might end up being so small which could make 
interpretation of results or conclusions difficult. Also, 
distribution of these occurrences between the arms might end 

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Date of amendment
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up being disproportionate, purely by chance, which also could
make any interpretation of results or conclusions difficult.
Section to be changed
Section 2.1.4 Secondary endpoint-Efficacy
Description of change
Moved the original secondary efficacy endpoint “Percent 
change from baseline in NASA score at Weeks 4, 8, 12 and
16” to further endpoint, and changed it to “Percent change 
from baseline in NASA score up to Week
 and by visit up to 
Week
”
Rationale for change
Update of endpoint
Section to be changed
Section 2.1.4 Secondary endpoint-Efficacy
Description of change
The original secondary efficacy endpoint “IASI subscore 
response, defined as a decrease of at least 50% absolute 
change in IASI-E subscore AND a decrease of at least 50%
absolute change in IASI-S subscore from baseline at Weeks 4, 
8, 12 (Yes/No)” was splited to two endpoints “IASI-E 
subscore response, defined as a decrease of at least 50%
absolute change in IASI-E subscore at Weeks 4, 8, 12, 16 
(Yes/No)” and “IASI-S subscore response, defined as a 
decrease of at least 50% absolute change in IASI-S subscore 
from baseline at Weeks 4, 8, 12, 16 (Yes/No)”
Rationale for change
Clarification to separately evaluate the IASI subscore response 
Section to be changed
Section 2.1.4 Secondary endpoint-Safety
Description of change
“The occurrence of treatment emergent adverse events” was 
change to “The occurrence of treatment emergent adverse 
events including serious and/or opportunistic infections”
Rationale for change
As per PDCO recommendation, opportunistic infection should 
be added as a secondary endpoint for all studies involving 
pediatric subjects
Section to be changed
Description of change
Rationale for change
Section to be changed

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Description of change
Rationale for change
Section to be changed
Section 3.1 Overall Trial Design
Description of change
Contents (texts and Figure 3.1:1) were updated due to the 
implementation of the extended treatment period after 
Week 52
Rationale for change
Update according to the extended trial duration
Section to be changed
Section 3.2 Discussion of Trial Design including the choice of 
control group(s)
Description of change
The following texts were added:
In addition, the extended treatment period after Week
is 
included to provide trial patients with continued treatment and 
assessments, and to collect further efficacy and safety 
evaluation.
As part of the trial, patients may participate to the Qualitative 
Interview sub-study to understand their experience with the 
received treatment during the clinical trial. Participation in the 
interview is optional and details will be described in an 
optional informed consent form/Assent. The interview will be 
conducted after a separate patient interview informed consent 
has been given in accordance with local ethical and regulatory 
requirements. Further details will be provided in a separate In-
trial interview Manual.
This trial will also include an option for participants and/or 
participant caregivers to complete anonymized questionnaires 
to provide feedback on their clinical trial experience. 
Providing this feedback is not required for trial participation, 
and information collected from these questionnaires will not 
be analysed as part of the clinical data for the trial (see 
Appendix 10.2).
Rationale for change
Update of trial design
Section to be changed
Section 3.3.4.1 Discontinuation of trial
Description of change
Wording amended (second bullet point)
The patient has repeatedly shown to be non-compliant with 
important trial procedures
and, in the opinion of both the investigator and sponsor 
representative, the safety of the

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patient cannot be guaranteed as he / she is not willing or able 
to adhere to the trial
requirements in the future.
Rationale for change
Request by the Competent Authorities to change the wording 
from “the opinion of both the investigator and sponsor 
representative to “the opinion of the investigator”.
Section to be changed
Section 4.1.4 Drug assignment and admistration of doses for 
each patient
Description of change
The bolded text is added to sentence “During the visits with 
reduced number of assessments e.g. Weeks
, 
and extended treatment period, patients will be offered to 
receive spesolimab s.c. at home or closer to the patient’s 
home, administered by a specialized vendor/HCP if 
applicable.”
Rationale for change
Updated according to change in trial design
Section to be changed
Section 4.1.5.1 Blinding
Description of change
The primary analysis of this trial is planned to be performed 
once all randomized patients have completed the 16 weeks or 
early discontinued from the trial, to support an early 
submission: a database lock for the primary analysis will then 
be performed and treatment will be unblinded to the sponsor.
Patients, investigators and central reviewers, and everyone
involved in trial conduct or analysis or with any other interest
in this double-blind trial will remain blinded regarding the
randomised treatment assignments until the database is 
declared ready for final analysis according to the sponsor’s 
SOPs. Further details regarding the timepoint of unblinding 
the database for analysis is documented in the TSAP.
If the primary analysis and the final analysis are performed 
separately (see Section 7.2.1),
then a database lock for the primary analysis will be done and 
treatment will be unblinded to
trial and project team members. Details will be described in 
the primary analysis logistics
plan.
… 
The randomisation codes will may be provided to bioanalytics 
before the last patient completed the trial to exclude placebo 
samples from for the PK and ADA analysis. Bioanalytics will 
not disclose the randomisation code or the results of their 
measurements until the trial has been officially un-blinded to 
the sponsor.

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Rationale for change
Clarified the unblinding at primary analysis and final analysis
Section to be changed
4.1.6 Packaging, labelling, and re-supply
Description of change
Added:
In accordance with the Clinical Trial regulation (EU) No 
536/2014 and the corresponding Annex VI, omitting of label 
content with the following justifications:
-the translation of country specific label text may differ from 
the Master Label Text based on specific local requirements. 
This could include the omission, addition or revision of some 
text per local regulation compliance
- the Investigator name was omitted from the label due to IRT 
System
Rationale for change
Clarification added to comply with EU regulation on labels 
content in Clinical trials
Section to be changed
Section 4.2.1.1 Other treatments
Description of change
The following text were added: 
For skin care: 
Emollients must not include urea or salicylic 
acid, should not be keratolytics and 
should not be medicinal products (i.e. 
no treatment indications).
Rationale for change
To clarify the type of emollients allowed 
Section to be changed
Section 4.2.2 Restrictions
Description of change
Table 4.2.2.1: 1 Restricted medications and treatments
Include urea as one of the Topical retinoids, topical 
calcineurin inhibitors, keratolytics for the restricted mediation 
usage.
Rationale for change
Clarification
Section to be changed
Section 5.1 Assessment of Efficacy
Description of change
Added the following text for DLQI/CDLQI assessment: 
Response categories include “not relevant” (score of 0), “not 
at all” (score of 0), “a little” (score of 1), “a lot” (score of 2) 
and “very much” (score of 3). Question 7 is a “yes”/ “no” 
question where “yes” is scored as 3. DLQI total score is 
calculated by summing the scores of each question resulting in 
a range of 0 to 30.
Added the following text for the 5D-Itch-scale assessment: 
For the distribution domain, the number of affected body parts 
is tallied (potential sum 0–16) and the sum is sorted into five 
scoring bins: sum of 0–2 = score of 1, sum of 3– 5 = score of 

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2, sum of 6–10 = score of 3, sum of 11–13 = score of 4, and 
sum of 14–16 = score of 5. 
Added the following assessment: 
Itchy-Qol
Itchy QoL is a pruritus-specific quality-of-life (QoL) 
instrument that consists of 22 pruritus-specific items (each 
score from 1 to 5; the sum ranges from 22 to 110) regarding 
symptoms, functions, emotions, and self-perception 
[R22-2031]. 
Patient Global Impression of Severity for Erythema
The Patient Global Impression of Severity for Erythema 
(PGIS-E) is a single item questionnaire that describes the 
severity of erythema over the past 24 h when considering skin 
area affected by NS. Participants will rate how his/her severity 
of erythema over the past 24 h can be described using a 
5-point scale ranging from "None" to "Very Severe".
Patient Global Impression of Severity for Scaling
The Patient Global Impression of Severity for Scaling (PGIS-
S) is a single item questionnaire that describes the severity of 
scaling over the past 24 h when considering skin area affected 
by NS. Participants will rate how his/her severity of scaling 
over the past 24 h can be described using a 5-point scale 
ranging from "None" to "Very Severe".
Patient Global Impression of Change for Netherton 
Syndrome Skin Symptoms

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The Patient Global Impression of Change (PGI-C) for 
Netherton syndrome skin symptoms is a single item 
questionnaire that describes the change (improvement or 
deterioration) in skin symptoms overall related to NS since the 
medication of this study has started. Participants will rate how 
his/her NS has changed since the beginning of the study using 
a 5-point scale ranging from "Much better" to "Much worse" 
with "no change" indicating neither better nor worse.
Rationale for change
Updated the assessment
Section to be changed
Section 5.2.3 Safety laboratory parameters and Appendix 10.3
Description of change
Contents (texts and Appendix 10.3) were added to include 
blood collection instructions for adolescent patients according 
to EU recommendation [R23-1267]. 
Footnotes of Table 5.2.3.1 were updated.
Added Appendix 10.3 maximum allowable research-related 
blood volumes for adolescents in EU countries
Rationale for change
Clarification
Section to be changed
Section 5.2.6.2.2 AE reporting to the sponsor and timelines
Description of change
The following texts were modified: 
The investigator must report SAEs, AESIs, and non-serious 
AEs which are relevant for the reported SAE or AESI, on the 
AE or SAE eCRF pages, according to the process used, 
EDC/eCRF or paper, to the sponsor’s unique entry point 
immediately (within 24 h of becoming aware of the event). 
The country specific process will be specified in the ISF. 
With receipt of any further information to these events, a 
follow-up SAE form reports have to be provided.
Rationale for change
Typos corrections
Section to be changed
Section 5.3.4: Pharmacok–netic - pharmacodynamic 
relationship
Description of change
The following texts were added: 
This trial is also intended to contribute to modelling of the 
dose-exposure relationship in children from 12 years to less 
than 18 years of age (and adults) with Netherton syndrome.
Rationale for change
Text updated to align the wording with other submission 
documents
Section to be changed
Section 5.4.3 Methods of sample collection
Description of change
The following text was added: After approval of protocol 
amendment v2.0, skin biopsies will be obtained only from 
adult patients.
Rationale for change
To lower the burden associated with the trial assessments for 
adolescent patients

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Section to be changed
5.4 Assessment of Biomarker(s)
Description of change
The following text was added:
Rationale for change
To clarify how long biomarker samples will the be stored
Section to be changed
Section 6.2 Details of trial procedures at selected visits
Description of change
Updated texts due to the inclusion of extended treatment 
period. 
Updated texts to specify assistance from other people is 
applicable during the questionnaires collection. The following 
texts were added: 
For adolescent patients or if the patient is too sick to complete 
the questionnaires by him/herself but is able to reply verbally, 
a parent/legal guardian or a member of the trial team should 
read the instructions, questions, and response options aloud to 
the patient and collect the patient’s verbal response in as 
neutral and unbiased a manner as possible. If this is not
possible either, the questionnaires are not to be completed.
Rationale for change
Updated texts due to the inclusion of extended treatment 
period and specify assistance from other people is applicable 
during the questionnaires collection.
Section to be changed
Section 6.2.1: Screening and run-in period (s)
Description of change
The following text was updated: 
Screening visit (visit1) is to be performed within 
days 
before Visit 2. Screening assessments may be repeated as 
long as they fall within the Screening visit window. If more 
than one screening assessment is available, the latest 
assessment prior to the start of treatment must be used to 
assess eligibility.
Rationale for change
Clarification to reflect the extension of the screening period
Section to be changed
6.2.2 Treatment period(s)
Description of change
The following text was updated:
Patients may decide to continue receiving the Open Label 
Extended trial treatment until 
.
Similar edits regarding inclusion of open label extension were 
also applied in Section 6.2.3 for updated definitions of EoT 
and early treatment discontinuation.
Rationale for change
Update according to change in trial design
Section to be changed
7.1 Null and Alternative Hypotheses
Description of change
Wording was corrected:

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H02: There is no difference regarding the odds proportion of 
patients of the key secondary
endpoint (IGA score of 0 or 1 at Week 16) between 
spesolimab versus placebo against H12:
There is a difference regarding the proportion of patients odds
of the key secondary endpoint
(IGA score of 0 or 1 at Week 16) between spesolimab versus 
placebo
Rationale for change
correction
Section to be changed
Section 7.2.2 Handling of Intercurrent Events
Description of change
Updated one of the expected intercurrent events of interest as: 
Treatment discontinuation (due to AE/ or due to lack of 
efficacy/)other reasons.
Updated was made to clarify treatment discontinuation will be 
handled by treatment policy, but not composite strategy. See 
updated text below: 
Composite strategy: This is the effect of spesolimab, where 
intercurrent events of use of restricted medications and 
treatments for NS and treatment discontinuation will be 
considered as treatment failure.
Treatment policy strategy: treatment discontinuation will 
be handled by a treatment policy approach, i.e. the value 
of the variable regardless of the occurrence of the 
intercurrent event will be used. All intercurrent events will
be handled using the composite approach and handled as 
treatment failure.
Rationale for change
Update of intercurrent event and clarification. Update of 
policy and clarification based on health authority feedback 
and spesolimab experience.
Section ot be changed
Section 7.2.3 Primary objective analyses
Description of change
The following text was added:
For the estimand concept on the primary binary endpoint, 
composite strategy will be applied that occurrence of any 
intercurrent events (i.e. use of restricted medications and 
treatments for NS, treatment discontinuation prior to Week 16 
will be considered to represent a non-response at the Week 16 
timepoint.
Additional updates in Section 7.2.3: 
Comparisons between treatment groups regarding the binary 
endpoint variable, the proportions of IASI response at 

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Week 16 will be performed using a logistic regression model 
adjusting for the categorical covariate age group (adult vs. 
adolescent) and the categorical covariate baseline IASI score 
(classified into 4 2 equally sized quartiles groups by median). 
The likelihood-ratio test will be used to test for difference 
between treatments. Adjusted odds ratio and risk differences 
together with 95% confidence intervals will be used to 
quantify the effect of treatment, comparing spesolimab to 
placebo as the reference. Procedures to follow if the analysis 
fails to converge will be described in the TSAP. 
Rationale for change
Update of analysis and clarification.
Section ot be changed
Section 7.2.4 Secondary objective analyses
Description of change
The following texts were updated:
For key secondary endpoint, the analyses will be performed 
on the FAS in the same manner as described for the analysis 
of the primary endpoint in Section 7.2.3 but excluding 
baseline IASI score and including baseline IGA as covariate.
Analyses for the continuous secondary endpoints will be 
evaluated descriptively, including calculating the means and 
95% CIs (if applicable) based on FAS.
Analyses for the continuous secondary endpoints will be 
analysed by a restricted maximum likelihood (REML) 
estimation-based approach using a mixed-effect model with 
repeated measurements (MMRM) analysis, including 
calculating the adjusted means and 95% CIs (if applicable) 
based on FAS. The analysis will include the fixed, categorical 
effects of treatment at each visit, age group and the fixed 
continuous effects of baseline at each visit.
Rationale for change
Added the clarification
Section ot be changed
7.2.6 Safety analyses
Description of change
Was corrected:
If, for a patient, the selected treatment emergent adverse event 
didn’t occur then the time at
risk will be censored at min (date of death, last contact date 
per EoS page, drug stop date +
112 days, date of rescue medication if spesolimab 900 mg i.v. 
is given). 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].

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Rationale for change
Correction
Section to be changed
7.2.8 Interim analyses
Description of change
Was added:
The primary analysis of this trial is planned to be performed 
once all randomized patients have completed the 16 weeks or 
early discontinued from the trial, to support an early
submission; a database lock for the primary analysis will then 
be performed. Multiple analyses may be conducted during the 
open label treatment period to support, for example, 
regulatory interactions. Final analysis is planned to be 
performed at the end of the trial once all patients have 
completed the trial (including any follow-up period if 
applicable).
Rationale for change
The primary analysis to be consistent with the description 
from Section 7.2.1
Section to be changed
Section 7.3 Handling of missing data
Description of change
The following texts were updated: 
For handling missing data on the primary, key secondary and 
secondary binary efficacy endpoints, a Non-Response 
Imputation (NRI) will be applied as the primary imputation 
approach,
The primary imputation strategy of missing values of 
secondary continuous endpoints is LOCF, i.e. impute the 
missing outcome as the last available value (including 
baseline) prior to the missing outcome. Missing data will not 
be imputed for secondary continuous endpoints. The mixed 
effect model will handle missing data based on a likelihood 
method under the ‘missing at random assumption’. 
Rationale for change
Update of analysis. 
Section to be changed
Section 7.4 Randomisation
Description of change
The following text was added:
The adolescent patients will be randomized in a 2:1 ratio to 
two treatment groups (spesolimab and placebo) regardless of 
blocking factor of Japan versus China versus other regions. 
Rationale for change
To apply PIP requirement.
Section to be changed
Section 8.4 Expedited reporting of adverse events
Description of change
Was added:
SAE/AESI are processed in the global Safety Database and 
assessed for the company causal relationship as well as the 
expectedness of the event according to the reference safety
information. Individual Case Safety Reports (ICSR) are 
subsequently reported according to local Regulations. 

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Reporting to the EMA will be done via E2B transmission of 
ICSRs to the Eudravigilance CT Module
Rationale for change
Request by the Competent Authorities to describe the 
procedures for reporting of suspected unexpected serious 
adverse reactions to the Eudravigilance database as set out in 
CTR Annex I paragraph D, subsection 20c.
Section to be changed
Section 10.1 Scales
Description of change
Updated the assessment according to the change in main text
Rationale for change
Adaption to the change in main text
Section to be changed
Section 10.2 Trial Participant Feedback
Description of change
Added the whole section
Rationale for change
To align with BI standards for Clinical Trial Protocols
Section to be changed
Section 9.1 pubished references
Description of change
Added reference R23-1267
Rationale for change
Admistrative
Section to be changed
Protocol synopsis
Description of change
The synopsis was updated according to the main text changes 
in the protocol
Rationale for change
Admistrative
11.2
GLOBAL AMENDMENT 2
Date of 
amendment
24 Sep 2024
EU trial no.
2022-501104-10-00
UTN
U1111-1289-6825
BI Trial 
number
1368-0104
BI 
Investigational 
Medicinal 
Product
Spesolimab, BI 655130
Title of 
protocol
EvasayilTM : A placebo-controlled trial to evaluate the efficacy and 
safety of spesolimab in the treatment of patients with Netherton 
syndrome
Global Amendment due to urgent safety reasons
Global Amendment
X
Section to be 
changed
Title page
Description of 
change
I 
I 

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Phone: 
Rationale of 
change
To update clinical trial leader’s name and contact information.
Section to be 
changed
Clinical Trial Protocol Synopsis, Trial Endpoints
Description of 
change
Updated key secondary endpoint as follows:
The key secondary endpoint is IGA response, defined as a decrease of 
at least 1-grade absolute change in IGA score from baseline IGA 
score of 0 or 1 at Week 16 (Yes/No).
Rationale for 
change
Due to new learnings from experts, case report from dupilumab and 
IGA development report, 0 or 1 on IGA is most likely not achievable. 
This was also mentioned in the FDA Written feedback from 2022 -
FDA would be open to 1 or 2 grade improvement (if it is clinically 
meaningful to patients).
Section to be 
changed
Clinical Trial Protocol Synopsis, Trial Endpoints
Description of 
change
Text was updated as follows:
o
IGA response, defined as IGA score of 0 or 1 at Weeks 4, 8, 12,
and 16 (Yes/No)
Rationale for 
change
To update secondary endpoint.
Section to be 
changed
Clinical Trial Protocol Synopsis, Trial Endpoints 
Description of 
change
Text was updated as follows:
o
Absolute change from baseline in DLQI/CDLQI score at Weeks 8
and 16
o
Absolute change from baseline in CDLQI score at Weeks 8
and 16
Rationale for 
change
To split DLQI and CDLQI score into two endpoints.
Section to be 
changed
Clinical Trial Protocol Synopsis, Statistical methods
Description of 
change
Text was updated from:
Logistic regression will be used to test if there is a difference between 
treatments regarding the binary primary endpoint variable, adjusting 
for the categorical covariate age and categorical baseline IASI score.  
To:
Suissa-Shuster Z-pooled test will be used to test if spesolimab is 
different from placebo regarding the binary endpoint variable 
(the proportions of IASI response at Week 16).

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Rationale for 
change
Due to the small number of patients in this trial for an ultra rare 
disease and fewer responses observed so far than assumed, the original 
primary analysis logistic regression model has a higher risk of non-
convergence, i.e. cannot be fitted to the data. The primary analysis 
model is changed to an exact test (Suissa-Shuster Z-pooled test) which 
is an appropriate method for small sample size. The original primary 
analysis model will be run as a sensitivity analysis if it converges. 
Section to be 
changed
Flow chart, photographs
Description of 
change
Crosses at Visits 9, 11, 12, 14 were removed.
Rationale for 
change
The possibility to conduct Visits 9, 11, 12 and 14 remotely was 
removed. Therefore, no photos will be taken by the home care nurse at 
these visits.
Section to be 
changed
Flow Chart
Description of 
change
Flow chart 1, Footnote #2 was updated as follows:
2 After Visit
), each individual patient may continue receiving the trial 
drug up to Week
). EoT will be at Week
. 
All patients who stop treatment prior to Week 156 will be considered early 
discontinued. Timepoint of early EoT will be considered the visit when the last 
dose of IMP was administered. Patients who do not agree to continue should have 
their EoT visit at Week 52. If the patients continue in the extended treatment period, 
then the EoT visit will occur at Week 156.
Should a patient prematurely discontinue from the trial treatment before scheduled 
EoT visit, In case of early discontinuation from trial treatment, every effort 
should be made to keep the patient in the trial and complete all of the remaining 
visits up to Week
 (without IMP administration in that case). At a minimum, 
patients should come to or at a minimum, an End-of-study Visit (EoS),
weeks 
after the last dose to cover full REP.
Rationale for 
change
To clarify wording regarding EoT and early EoT.
Section to be 
changed
Flow Chart
Description of 
change
In Flow chart 1, Footnote #3, the following text was added:
Regularly, EoS is 
weeks after last dose of trial medication to cover REP. If a 
patient discontinues early from trial treatment and continues with original visit 
schedule (without receiving treatment), EoS could also take place beyond 
weeks after last treatment dose. EoS visit would be performed as the last 
patient visit in that case.
Rationale for 
change
To clarify timepoint of EoS in case of early EoT.
Section to be 
changed
Flow chart
Description of 
change
Flow chart 1, Footnote #12 was updated as follows:

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12Photographs of skin lesions are to precede skin biopsies and trial drug 
administration. In addition to photographs of skin lesions, biopsy site photographs 
will also be taken at Visit 2 and Visit 6. If a remote visit is performed at visits 9, 11, 
12 and 14, photographies of skin lesions will be taken by the Health Care Personnel 
(HCP) and transmitted electronically to the Investigator for skin assessments. If 
these visits are performed at the clinic then collection of photographs is not needed. 
Rationale for 
change
To remove wording related to remote visits 9, 11 12 and 14, as these 
were not set-up due to lack of interest by sites, as well as logistical 
constraints.
Section to be 
changed
Flow chart
Description of 
change
Flow chart 1, Footnote #19 was updated as follows:
19VisitsDuring extension treatment phase, visits with reduced number of 
assessments (i.e Visits 9, 11, 12 and 14 every second visit starting Visit 16 and up 
to Visit 40) could be either performed at the investigational site or remotely by a 
trained Health Care Personnel Professional (HCP) at the patient’s home or at a 
facility closer to the patient’s home. During extension treatment phase. During 
extension treatment phase, visits without clinical efficacy assessments (i.e. every 
second visit starting V16) could be performed at the investigating site or remotely.  
During remote visits, an abbreviated body system assessment will be conducted 
by the trained HCP instead of a physical exam. This abbreviated body system 
assessment will include evaluation of organ systems associated with AE(s) 
symptoms and is only observational and conversational with patient.
Rational for 
change
To remove option to perform visits 9, 11, 12, 14 remotely; clarify that 
trained HCP will do an abbreviated body system assessment instead of 
a complete physical exam during remote visits.
Section to be 
changed
Flow chart 
Description of 
change
Flow chart 2 was added.
Rationale for 
change
To provide detailed overview of assessments per individual visits 
during extension treatment phase.
Section to be 
changed
Section 2.1.3 Key secondary endpoint(s)
Description of 
change
In efficacy section, text was updated as follows: 
The key secondary endpoint of this trial is:
o
IGA response, defined as a decrease of at least 1-grade absolute 
change in IGA score from baseline IGA score of 0 or 1 at 
Week 16 (Yes/No)
Rationale for 
change
Due to new learnings from experts, case report from dupilumab and 
IGA development report, 0 or 1 on IGA is most likely not achievable. 
This was also mentioned in the FDA Written feedback from 2022 -
FDA would be open to 1 or 2 grade improvement (if it is clinically 
meaningful to patients).

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Section to be 
changed
Section 2.1.4 Secondary endpoint(s)
Description of 
change
IGA response, defined as IGA score of 0 or 1 at Weeks 4, 8, 12 and 
16 (Yes/No)
Rationale for 
change
To update description of secondary endpoint. 
Section to be 
changed
Section 2.1.4 Secondary endpoint(s)
Description of 
change
Text was changed as follows:
o
Absolute change from baseline in DLQI/CDLQI at Weeks 8 and 
16
o
Absolute change from baseline in CDLQI score at Weeks 8
and 16
Rationle for 
change
To split DLQI and CDLQI score into two endpoints
Section to be 
changed
Description of 
change
Rationale for 
change
Section to be 
changed
Section 3.1 Overall Trial Design
Description of 
change
In section “open label period”, the following sentences were updated 
as follows: 
Patients who have responded (responders), defined as having more 
than or equal to 50% reduction in IASI score at Week 32 compared 
with baseline will receive a reduced dose of spesolimab, 
every 
4 weeks 
.

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…
The dose escalation should be applicable only once 
 
The beginning of the section "extended treatment period" updated as 
follows:
(from Week
).
In section “extended treatment period” the text was modified as 
follows:
After completing the first 
weeks of treatment, the patients may be 
are offered to continue their assigned treatment at Visit 165 (i.e. 
Spesolimab 
) in the extended 
treatment period up to
weeks.
Starting Week 56:
o
Patients receiving 600 mg of spesolimab and experiencing a 
reduction of less than 50% on IASI compared with Visit 2 for 
two consecutive visits should be discontinued from the trial 
treatment. These two consecutive visits should be at least 
4 weeks apart. Down-titration from 600 mg to 300 mg
spesolimab will not be permitted during extended treatment 
period.
o
Patients who are receiving spesolimab 300 mg and experience 
a reduction of less than 50% on IASI should not be 
discontinued, but up-titrated to 600 mg first. Only if the 
patient still shows reduction of less than 50% on IASI on 
600 mg for two consecutive visits, patient should be 
discontinued.
During the extended treatment period, dose escalation to 
will 
be permitted once for patients who were receiving spesolimab 
and experience a reduction of less than 50% on IASI. 
 
of spesolimab will not be permitted.
Patients receiving 
of spesolimab and experience a reduction of 
less than 50% on IASI for two consecutive visits should be 
discontinued from the trial treatment.  These two consecutive visits 
should be at least 4 weeks apart.
Patients who prematurely discontinue from the trial drug will be 
encouraged to complete all of the remaining visits up to Week
 
(without IMP administration in that case). At a minimum, 
patients should come to an End-of-study Visit (EoS), 
weeks 

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after the last dose to cover full REP. perform an unscheduled visit 
and will then enter the 16-week follow-up period (see Figure 3.1: 1).
…
Patients who prematurely discontinue from the trial drug will be 
encouraged to continue with the original visit schedule up to 
Week
 (without IMP administration in that case). EoS (End of 
Study) visit will be performed as the last patient visit in that case. 
At a minimum, patients should come to an EoS Visit
weeks 
after the last dose to cover full REP perform an unscheduled visit 
and will then enter the 
 follow-up period (see Figure 3.1:1 ).
Rationale for 
change
To clarify information related to open-label and extended treatment 
period, as well as to the follow-up period. 
Section to be 
changed
Section 3.2 Discussion on trial design, incl. the choice of control 
group(s)
Description of 
change
Text was updated as follows: 
This trial will also include an option for adult participants and/or 
participant caregivers to complete anonymized questionnaires to 
provide feedback on their clinical trial experience.
Rationale for 
change
To clarify that the questionnaires are only available for adult trial 
participants.
Section to be 
changed
Section 3.3.4.1 Discontinuation of trial treatment
Description of 
change
Text was updated as follows:
In case the infusion of trial drug is permanently discontinued before 
the whole amount of the prepared solution has been administered to 
the patient, every effort should be made to complete all remaining 
study assessment.
In case the study drug administration is permanently discontinued 
before EoT visit, all efforts should be made to keep the patient in 
observation for the remaining trial visits up to regular EoT visit at 
Week
, according to flow chart. EoS visit will be performed as 
the last patient visit in that case. As a minimum for at least, the 
patient should come back for an EoS Visit
weeks after the last 
dose of the study drug.
Rationale for 
change
To clarify the follow-up of patients with early treatment 
discontinuation 
Section to be 
changed 
Section 3.3.4.3 Discontinuation of the trial by the sponsor
Description of 
change
The following reason was added:
4. Termination of development of compound in this indication

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Rationale for 
change
To add termination of development of compound in NS as a possible 
reason for trial discontinuation by the sponsor, as this is part of 
standard CTP template.
Section to be 
changed 
Section 4.1.4 Drug assignment and administration of doses for each 
patient
Description of 
change
The following text was removed:
For the remote visits, if applicable the HCP, will be provided with at 
home urine pregnancy test kits.
The s.c. injection should avoid sites where the skin is tender, bruised, 
erythematous, or indurated, and should be alternated to other areas for 
subsequent doses. If injections are administered in the same area, it 
should be at least 2 cm apart and should not be close to a vein.
Rationale for 
change
To remove text related to pregnancy kits and to remove instructions 
related to s.c injection of IMP to avoid duplication. Detailed 
instructions are provided in a separate instruction document in the ISF.
Section to be 
changed
Section 4.2.1.1 Other treatments 
Description of 
change
In restricted medications and treatments for NS section, the text was 
updated as follows:
If the patient experiences an intolerable worsening of NS during the 
course of the trial, the patient will be discontinued from trial treatment 
to receive alternative medication and/or receive treatment for NS 
(including restricted medications with the exception of biologs, 
immunoglobulins and investigational products, in which case the 
patient needs to be discontinued from trial treatment) as deemed 
appropriate by the investigator.
These patients In case of early discontinuation from trial 
treatment, the patient will complete early EOT visit and continue be 
followed up as described in the Flow Chart 1 (Footnote 2) for 
early EoT. to be followed for all regular scheduled follow-up visits 
for safety and efficacy assessments.
Rationale for 
change
To clarify wording.
Section to be 
changed
Section 5.1 Assessment of efficacy
Description of 
change
In section "DLQI/CDLQI," the following text was added:
For adolescents, an adapted version of this tool is used, called the 
Children’s Dermatology Life Quality Index (CDLQI).  The 
CDLQI is a questionnaire designed to measure the impact of skin 
disease on the lives of children and young people. The CDLQI has 
been developed to resemble the DLQI, with responses ranging 
from not at all to very much.  Data from the two cannot be 

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combined, because the items and score meaning bands are 
different. CDLQI total score is calculated by summing the scores 
of each question resulting in a range of 0 to 30. Interpretation can 
be done by cut points: 0 (scores of 0–1), no effect;1 (scores of 2–6), 
small effect; 2 (scores of 7–12), moderate effect;3 (scores 13–18), 
very large effect;4 (scores 19–30), extremely large effect 
[R24-3537].
Rationale for 
change
To add description of CDLQI score
Section to be 
changed
Section 5.1 Assessment of efficacy
Description of 
change
In section "Itchy-Qol," the text was updated as follows: 
Itchy-Qol
Itchy QoL is a pruritus-specific quality-of-life (QOL) instrument that 
consists of 22 pruritus-specific items (each score from 1 to 5; the sum 
ranges from 22 to 110) regarding symptoms, functions, and emotions 
and self-perception. [R24-3478].
Rationale for 
change
To correct description of Itchy-QOL
Section to be 
changed
Section 5.2.1 Physical examination
Description of 
change
The following text was added:
During remote visits, an abbreviated body system assessment will 
be conducted by the trained HCP instead of a physical exam. This 
abbreviated body system assessment will include evaluation of 
organ systems associated with AE(s) symptoms and is only 
observational and conversational with patient.
Rationale for 
change
To clarify that an abbreviated body system assessment will be 
conducted by the trained HCP instead of a physical exam during 
remote visits.
Section to be 
changed
Section 5.2.3 Safety laboratory parameters
Description of 
change
Footnote 1 of Table 5.2.3:1 was updated as follows:
1A HBV-DNA should be conducted at screening if Hepatitis B core Antibody is positive and 
Hepatitis B Surface Antigen is negative. These evaluations should be condacted at screening 
and If at screening, Hepatitis B core Antibody is positive and Hepatitis B Surface 
Antigen is negative, HBV-DNA should be repeated at the EOS visit. 
Rationale for 
change
To clarify wording related to HBV infection testing at EoS
Section to be 
changed
Section 5.7 Appropriateness of measurements

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Description of 
change
Text was added as follows:
This is because the prevalence and characteristics of NS may 
differ between patients of different racial origin. It will thus be 
worthwhile to assess if patients of different race will respond 
differently to the study treatment.
Rationale of 
change
To add rationale why race is collected in this trial.
Section to be 
changed
Section 6.2 Details of trial procedures at selected visits
Description of 
change
Text was updated as follows:
All efforts should be made to perform the most critical visits e.g.
randomisation at Visit 2, primary endpoint at Week 16 and end of 
treatment at Week 52/
. These and other visits requiring i.v. 
administration should always be performed at the investigator site 
facility whenever possible. The visits with reduced number of 
assessments and no reoutine lab sampling, e.g. Weeks 28, 36, 40 and 
48 and every second visit during the extended treatment period could 
be performed remotely or using hybrid approach (assessments 
performed at home or at the remote facility closer to the patient’s 
home by the specialized vendor/HCP, if applicable) or performed in 
the investigator site facility, if this is preferable for the patient and the 
investigational site.
Rationale for 
change
To update wording related to home care services.
Section to be 
changed
Section 6.2 Details of trial procedures at selected visits
Description of 
change
Text was updated as follows:
For adolescent patients or if the patient is too sick to complete the 
questionnaires by him/herself or is illiterate, but is able to reply 
verbally, a parent/legal guardian or a member of the trial team should 
read the instructions, questions, and response options aloud to the 
patient and collect the patient’s verbal response in as neutral and 
unbiased a manner as possible. 
Rationale for 
change
To add illiteracy. 
Section to be 
changed
Section 6.2.3 Follow-up period and trial completion
Description of 
change
Text related to regular EoT was updated as follows:
For patients completing the full treatment period up to Week
, the 
EoT vsit is to be scheduled at Visit 15 (Weel 
) or after the extended 

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treatment period (Week
), a follow- up visit should be performed 
weeks after the last administration of trial medication (EoS).
Text related to early treatment discontinuation was updated as follows:
Patients who discontinue the trial treatment early (prior to Week
). 
These patients should be registered as withdrawn from randomized 
treatment in IRT and the eCRF accordingly.
Timepoint of early EoT will be considered the visit when the last 
dose of IMP was administered. In case of early discontinuation 
from trial treatment, every effort should be made to keep the 
patient in the trial and complete all of the remaining visits up to 
Week
 (without IMP administration in that case). At a 
minimum, patients should come to an End-of-study Visit (EoS),
weeks after the last dose to cover full REP. 
Rationale for 
change
To clarify wording related to regular and early EoT. 
Section to be 
changed
Section 7.1
Description of 
change
Text in Null and alternative hypotheses section was updated as 
follows:
H01: There is no difference regarding the proportion odds of the 
primary endpoint (IASI response, defined as a decrease of at least 50%
absolute change in IASI score from baseline at Week 16) between 
spesolimab versus placebo (i.e. odds ratio of spesolimab versus 
placebo is equal to 1) against H11: There is a difference regarding the 
odds proportion of the primary endpoint (IASI response, defined as a 
decrease of at least 50% absolute change in IASI score from baseline 
at Week 16) between spesolimab versus placebo (i.e. odds ratio of 
spesolimab versus placebo is not equal to 1). The trial is considered 
positive, if the null hypothesis of the primary endpoint can be rejected 
and the result is more favorable for spesolimab versus placebo (odds 
proportion in spesolimab group ≥proportion odds in placebo 
group).
…
H02: There is no difference regarding the odds proportion of the key 
secondary endpoint (IGA response, defined as a decrease of at least 
1-grade absolute change in IGA score from baseline at 
Week 16)IGA score of 0 or 1 at Week 16) between spesolimab versus 
placebo against H12: There is a difference regarding the odds
proportion of the key secondary endpoint (IGA response, defined as 
a decrease of at least 1-grade absolute change in IGA score from 

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baseline at Week 16IGA score of 0 or 1 at Week 16) between 
spesolimab versus placebo.
Rationale for 
change
To align with new primary analysis method and key secondary 
endpoint. 
Section to be 
changed
Section 7.2.1 General considerations
Description of 
change
In section "per-protocol set (PPS)," text was updated as follows: 
Per-Protocol Set (PPS)
This patient set includes all patients in FAS who adhered to the CTP 
without any important protocol deviations (iPDs) which lead to 
exclusion from the PPS. This set will be used for sensitivity analysis 
on the primary endpoint and key secondary endpoint. 
Rationale for 
change
To clarify that PPS will also be used for sensitivity analysis on key 
secondary endpoint.
Section to be 
changed
Section 7.2.3 Primary objective analyses
Description of 
change
Text was updated from:
Comparisons between treatment groups regarding the binary endpoint 
variable, response rate at Week 16 in IASI response will be performed 
using a logistic regression model adjusting for the categorical 
covariate age group (adult vs. adolescent) and the categorical covariate 
baseline IASI score (classified into 2 equally sized groups by median). 
The likelihood-ratio test will be used to test for difference between 
treatments. Adjusted odds ratio and risk differences together with 
95% confidence intervals will be used to quantify the effect of 
treatment, comparing spesolimab to placebo as the reference. 
Procedures to follow if the analysis fails to converge will be described 
in the TSAP.  
To:
Comparisons between treatment groups regarding the binary 
endpoint variable, the proportions of IASI response at Week 16 
will be performed using the exact unconditional Suissa-Shuster Z-
pooled test. The risk difference together with 95% confidence 
intervals will be used to quantify the treatment, comparing 
spesolimab to placebo. 
Rationale for 
change
Due to the small number of patients in this trial for an ultra rare 
disease and due to the number of patients within each strata and the 
number of responses observed in the blinded data so far, the original 
primary analysis logistic regression model has a very high risk of non-
convergence, i.e. it is very likely that it cannot be fitted to the data. 
The primary analysis model is therefore changed to an exact 
unconditional Suissa-Shuster Z-pooled test which is an appropriate 
method for small sample size. The original primary analysis model 
will be run as a sensitivity analysis if it converges. 

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Section to be 
changed
Section 7.2.3.1 Sensitivity Analyses
Description of 
change
The following text was added:

A sensitivity analysis to adjust for covariates of age group 
(adult vs. adolescent) and baseline IASI group (classified into 2 
equally sized groups by median) using logistic regression 
model.

Further sensitivity analyses, if any, will be defined in the 
TSAP.
Rationale for 
change
To align with new primary analysis method, the original primary 
analysis model will be run as a sensitivity analysis if it converges. 
Section to be 
changed
Section 7.2.4 Secondary objective analyses
Description of 
change
Text was updated as follows:
For key secondary endpoint, the analyses will be performed on the 
FAS in the same manner as described for the analysis of the primary 
endpoint in Section 7.2.3 but excluding baseline IASI score and 
including baseline IGA as covariate.
For binary secondary endpoints, the analyses will be performed on the 
FAS in the same manner as described for the analysis of the primary 
endpoint in Section 7.2.3 but replacing the baseline IASI score with 
each respective baseline endpoint as covariate.
Rationale for 
change
To align with new primary analysis method. 
Section to be 
changed
Section 7.2.8 Interim analyses
Descrition of 
change
Text was updated as follows:
No interim analysis is planned but aA Data Monitoring Committee 
(DMC) will be in place with tasks as described in Section 8.7.
The primary analysis of this trial is planned to be performed once all 
randomized patients have completed the 16 weeks or early 
discontinued from the trial, to support an early submission; a database 
lock for the primary analysis will then be performed. Further interim
analyses may be conducted during the open label treatment period to 
support, for example, regulatory interactions and/or regulatory filing. 
Final analysis is planned to be performed at the end of the trial once 
all patients have completed the trial (including any follow-up period if 
applicable). 
Rationale for 
change
To clarify that interim analyses are planned in this trial.

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Section to be 
changed
Section  8.1 Trial approval, patient information, informed consent
Description of 
change
One sentence was added:
The patient will continue with the assessments for which he/she 
consented at the beginning of the trial (as an adolescent).  
Rationale for 
change
To clarify that adolescents who achieve age of legal consent will 
continue with the assessments for which they consented at the 
beginning of the trial.
Section to be 
changed
Section 9.1 published references
Description of 
change
The following changes were made to the reference section:
R22-2031 was updated:
Krause K, Kessler B, Weller K, et al. German version of 
ItchyQoL: validation and initial clinical findings. Acta Derm 
Venereol. 2013;93(5):562-568.Desai NS, Poindexter GB, 
Monthrope YM, Bendeck SE, Swerlick RA, Chen SC. A pilot 
quality-of-life instrument for pruritus. J Am Acad Dermatol. 
2008;59(2):234–44.
R24-3478 was added:
R24-3478
Desai NS, Poindexter GB, Monthrope YM, Bendeck 
SE, Swerlick RA, Chen SC. A pilot quality-of-life instrument for 
pruritus. J Am Acad Dermatol; 2008; 59(2); 234-244.
R24-3537 was added:
R24-3537
Lewis-Jones MS, Finlay AY. The children's 
dermatology life quality index (CDLQI): initial validation and 
practical use. Br J Dermatol; 1995; 132(6); 942-949.
Rationale for 
change
To update list of references.
Section to be 
changed
Section 10.1.10 ISS – Combination of IASI & VISS
Description of 
change
Description of ISS was updated.
Rationale for 
change
To correct inconsistency.
Section to be 
changed
Section 10.2 Trial participant feedback
Description of 
change
The text was updated as follows:
This trial will include an option for adult participants to complete 
anonymized questionnaires,‘Trial Participant Feedback 
Questionnaire’, to provide feedback on their clinical trial experience. 
Individual participant level responses will not be reviewed by 
investigators.

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Rationale for 
change
To clarify that the questionnaire is only available for adult 
participants.
Section to be 
changed
Section 10.2 Trial participant feedback
Description of 
change
The following text was removed:
Optional Caregiver Feedback Questionnaires:
If applicable, this trial will include an option for caregivers to 
complete anonymized questionnaires, ‘Caregiver Feedback 
Questionnaire’, to provide feedback on the clinical trial experience. 
Individual caregiver level responses will not be reviewed by 
investigators. 
Responses will be used by the sponsor to understand where 
improvements can be made in the clinical trial process. These 
questionnaires will not collect data about the participant’s disease, 
symptoms, treatment effect, or AEs and therefore will not be part of 
the trial data or clinical trial report. The questionnaires will be 
implemented after local regulatory approval and after consent of the 
caregiver. Providing feedback is optional and not required for 
participation in the trial.
Rationale for 
change
A questionnaire for caregivers is not available. Therefore the related 
text to caregivers was removed.
Section to be 
changed
Several sections
Description of 
change
Corrected typos and spelling errors
Rationale for 
change
Administrative change

 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c38465777
3.0
clinical-trial-protocol-version-03
EvasayilTM:A placebo-controlled trial to evaluate the efficacy and safety of
spesolimab in the treatment of patients with Netherton syndrome
Author-Clinical Trial Leader
25 Sep 2024 17:43 CEST
Approval
26 Sep 2024 14:03 CEST
Author-Trial Statistician
27 Sep 2024 15:15 CEST
Verification-Paper Signature
Completion
09 Oct 2024 03:57 CEST
Boehringer 
~11111~ lngelhein1 

Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c38465777
3.0