Clinical trial NCT04399837
Conditions: Generalized Pustular Psoriasis
Sponsor: Boehringer Ingelheim
Start date: 2020-06-04; Completion date: 2022-11-23
Enrollment: 123 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a study in adolescents and adults with Generalized Pustular Psoriasis (GPP). People between 12 and 75 years old can take part in the study. The study is open to people who had GPP flare-ups in the past but whose skin is clear or almost clear when they join the study. The purpose of the study is to test 3 different doses of a medicine called spesolimab and to see whether it helps to prevent GPP flare-ups.

Participants are put into 4 groups by chance. Three groups get different doses of spesolimab. The fourth group gets a placebo. Placebo looks like spesolimab but does not contain any medicine.

Spesolimab and placebo are given as an injection under the skin. Participants are in the study for about 1 year and 4 months. During this time, they visit the study site about 15 times. For the first 11 months, participants get spesolimab or placebo injections every month. At the study visits, the doctors check participants' skin for signs of a new GPP flare-up. The doctors also check the general health of the participants.

If a participant has a GPP flare-up during the study, more visits may be necessary. In case of a flare-up, participants get a dose of spesolimab as an infusion into a vein.

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None arm 4: None
Interventions: intervention 1: Spesolimab intervention 2: Placebo
Intervention descriptions: intervention 1: Solution for injection intervention 2: Solution for injection

Protocol documents:
Prot_000.pdf: 
001-MCS-40-106_RD-03 (17.0) / Saved on: 18 Mar 2019
Clinical Trial Protocol
TITLE PAGE
TITLE PAGE
Document Number:
c28020464-04
EudraCT No.
EU Trial No.
2018-003081-14
BI Trial No.
1368-0027
BI Investigational
Medicinal Product(s)
BI 655130 (Spesolimab)
Title
Effisayil™2: Multi-center, randomized, parallel group, double 
blind, placebo controlled, Phase IIb dose-finding study to evaluate 
efficacy and safety of BI 655130 (Spesolimab) compared to 
placebo in preventing generalized pustular psoriasis (GPP) flares 
in patients with history of GPP
Lay Title
A study to test whether BI 655130 (Spesolimab) prevents flare-ups 
in patients with Generalized Pustular Psoriasis
Clinical Phase
Phase IIb
Clinical Trial Leader
Phone: 
Coordinating 
Investigator
Phone: 
Fax: 
Current Version and 
Date
Version 4.0, 28 July 2022
Original Protocol 
Date
Version 1.0, 23 October 2019
Page 1 of 194
Proprietary confidential information.
2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-04
Clinical Trial Protocol
Page 2 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim 
Original Protocol date
23 October 2019
Revision date
28 July 2022
BI trial number
1368-0027
Title of trial
Effisayil™2: Multi-center, randomized, parallel group, double blind, 
placebo controlled, Phase IIb dose-finding study to evaluate efficacy
and safety of BI 655130 (Spesolimab) compared to placebo in 
preventing generalized pustular psoriasis (GPP) flares in patients with 
history of GPP
Coordinating
Investigator 
Trial site(s)
Multi-center trial conducted globally
Clinical phase
Phase IIb
Trial rationale
Current treatment options for controlling acute flare of GPP, complete 
resolution of symptoms and prevention of reoccurrence of flares are 
limited and often do not provide sustained efficacy. Moreover, current 
therapeutic options are not suitable for life-long treatment due to their 
side effect profile and existing contraindications. The motivation of 
this study is to provide dose-ranging data for 3 dose regimens of BI 
655130 compared to placebo and to evaluate efficacy, safety, and 
tolerability of BI 655130 at preventing GPP flares compared to 
placebo in patients with a history of GPP and currently (at screening 
and at randomization) presenting with a Generalized Pustular 
Psoriasis Physician Global Assessment (GPPGA) score of 0 or 1 
(clear or almost clear).
Trial objective(s)
The primary objective of the trial is to demonstrate a non-flat dose 
response curve and evaluate the dose-response relationship for 3
subcutaneous dosing regimens of BI 655130 (with each regimen 
consisting of a single loading dose and a separate maintenance 
subcutaneous dosing regimen) versus placebo, on the primary 
endpoint, the time to the first GPP flare onset up to week 48.
The secondary objective is to demonstrate superiority versus placebo 
for each of BI 655130 high dose (300 mg q4w) and BI 655130 
medium dose (300 mg q12w) on the primary endpoint, the time to the 
first GPP flare onset up to week 48, as well as the key secondary 
endpoint, the occurrence of at least one GPP flare up to week 48.
Another objective is to evaluate safety and tolerability of multiple s.c. 


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-04
Clinical Trial Protocol
Page 3 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
doses of BI 655130 in patients with history of GPP.
The use of i.v. dose of BI 655130 for treating patients with onset of 
acute GPP flare will be evaluated for safety and efficacy as an 
additional objective.
Trial endpoints
Primary endpoint: 

Time to first GPP flare (defined by increase in GPPGA score 
by ≥ 2 from baseline and the pustular component of GPPGA ≥ 
2) up to week 48.
Key Secondary Endpoint (For the secondary objective only):
The key secondary endpoint of the study which is included in the 
statistical testing strategy (see Section 7 for details) in a hierarchical 
manner subsequent to performance of the test on the primary endpoint
in the formal analysis is:

The occurrence of at least one GPP flare (defined by increase 
in GPPGA score by ≥ 2 from baseline and the pustular 
component of GPPGA ≥ 2) up to week 48.
Secondary Endpoints:
The below-defined secondary endpoints, for the secondary objective 
only, are included into the statistical testing strategy in a hierarchical 
manner subsequent to performance of the test on the key secondary 
endpoint in the formal analysis. The study is not powered for the 
performance of these additional statistical comparisons.

Time to first worsening of Psoriasis Symptom Scale (PSS) up 
to week 48 defined as a 4-point increase in total score from 
baseline.

Time to first worsening of Dermatology Quality of Life Index
(DLQI) up to week 48 defined as a 4-point increase in total 
score from baseline.
The below-defined secondary endpoints, for the secondary objective 
only, are not included in the statistical testing strategy of the formal
analysis of the trial.

Sustained remission, defined as a patient with a GPPGA score 
of 0 or 1 (clear or almost clear) at all visits up to week 48,
without intake of rescue medication, or investigator-prescribed 
SoC.

The occurrence of treatment emergent adverse events (TEAEs)


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-04
Clinical Trial Protocol
Page 4 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
Trial design
This is a multicenter, randomized, parallel group, double-blind, 
placebo-controlled Phase IIb dose finding study to evaluate efficacy 
and safety compared to placebo with multiple subcutaneous (s.c.) 
doses of BI 655130/placebo in adolescents from 12 years to less than 
18 years of age and adult patients with history of GPP and currently 
presenting (at screening and at randomization) with a GPPGA score 
of 0 or 1 (clear or almost clear). Patients will continue to receive 
randomized maintenance treatment until their last dose at Week 44 if 
no flare occurs. In the event of a flare, the patient will receive rescue 
treatment with i.v. open label dose of BI 655130. Upon response of 
the flare, the patient will continue receiving open label s.c. dose of BI 
655130. These patients will receive open-label treatment until 44 
weeks after randomization, when the patient will receive the last dose.
The maintenance treatment period ends at week 48.
The primary statistical analysis of the trial will be performed once all 
randomized patients have either completed or early discontinued from
the 48 week maintenance treatment period.
Total number of patients
randomized
120 including at least 8 adolescent patients aged 12 years to less than 
18 years of age evaluable for the primary endpoint  (at least 2 
adolescents per treatment group)
Number of patients on 
each treatment
30 patients on BI 655130 300 mg s.c. q4 weeks (Arm 1)
30 patients on BI 655130 300 mg s.c. q12weeks (Arm 2)
30 patients on BI 655130 150 mg s.c. q12 weeks (Arm 3)
30 patients on placebo (Arm 4)
Diagnosis
Patients with history of Generalized Pustular Psoriasis (GPP) and 
currently with GPPGA score of 0 or 1 (clear/almost clear)
Main in- and exclusion 
criteria
Inclusion Criteria: 
Each patient must meet all of the following inclusion criteria to be 
included into the trial:

Patients with a known and documented history of GPP per 
ERASPEN criteria (see Section 3.3.1) regardless of IL36RN 
mutation status, with at least 2 presentations of moderate to severe 
GPP flares with fresh pustulation (new appearance or worsening) 
in the past.

Patients with a GPPGA score of 0 or 1 at screening and 
randomization.

Patients who are not on concomitant GPP treatment at time of 
randomization (V2) must have had at least two presentations of 
moderate to severe GPP flare in the past year, at least one of 
which had evidence of either fever and/or elevated CRP and/or 
elevated WBC and/or asthenia and/or myalgia.  


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-04
Clinical Trial Protocol
Page 5 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019

Patients who are not on concomitant GPP treatment at time of 
randomization (V2) but who were on concomitant GPP treatment 
until shortly before randomization (V2) (≤ 12 weeks before 
randomization), these patients must have a history of flaring while 
on concomitant treatment for GPP or in case of dose reduction or 
discontinuation of their concomitant medication.

Patients who are on concomitant treatment regimen with retinoids 
and/or methotrexate and/or cyclosporine must stop at the day of 
randomization (V2). These patients must have a history of flaring 
while on concomitant treatment for GPP or in case of dose 
reduction or discontinuation of these concomitant medications.  

Male or female patients, aged 12 to 75 years at screening. For all 
patients, a minimum weight of 40 kg is required.

Signed and dated written informed consent and assent in 
accordance with ICH-GCP and local legislation prior to admission 
in the trial.

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. 
Exclusion Criteria:

Patients with SAPHO (Synovitis–acne–pustulosis–hyperostosis–
osteitis) syndrome.

Patients with primary erythrodermic psoriasis vulgaris.

Severe, progressive, or uncontrolled hepatic disease, defined as 
>3-fold Upper Limit of Normal (ULN) elevation in AST or ALT 
or alkaline phosphatase, or >2-fold ULN elevation in total
bilirubin.

Relevant chronic or acute infections including active tuberculosis, 
human immunodeficiency virus (HIV) infection or viral hepatitis 
at the time of randomization.
Test product(s)
Solution for injection (s.c. dose): BI 655130 150 mg/PFS (150 
mg/mL), 1 mL fill volume
Solution for infusion (i.v. dose): BI 655130 450 mg/vial (60 mg/mL), 
7.5 mL fill volume
dose
Arm 1: 600 mg total loading dose at Week 1/Day1 followed by 
maintenance treatment 300 mg s.c. q4 weeks


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-04
Clinical Trial Protocol
Page 6 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
Arm 2: 600 mg total loading dose at Week 1/Day1 followed by 
maintenance treatment  300 mg s.c. q12 weeks
Arm 3: 300 mg total loading dose at Week 1/Day1 followed by 
maintenance treatment 150 mg s.c. q12 weeks
Rescue Treatment: 900 mg i.v. dose in the event of the first GPP flare
mode of 
administration
s.c. for maintenance treatment and i.v. for rescue treatment
Comparator product(s)
Placebo comparator
dose
Arm 4: Loading dose Placebo at Week 1/Day 1 followed by 
maintenance treatment placebo
mode of
administration
s.c.
Duration of treatment
Patients will continue to receive randomized treatment until their last 
dose at Week 44 if no flare occurs. The maintenance treatment period 
ends at week 48.
Statistical methods
For the primary objective, proof of concept and evaluation of the 
dose-response relationship for the activity of BI 655130 on the 
primary endpoint will be determined using a multiple comparison 
procedure with modelling techniques (MCPMod) with respect to 
achieving a non-flat dose response curve at the 1-sided alpha level of 
0.05. As a basis for the MCPMod analysis a Cox regression model 
on the time to first GPP flare up to week 48 is used.
If the primary objective is successfully achieved, the secondary 
objective is then to perform formal testing on the superiority of BI 
300mg q4w and/or BI 300 mg q12w versus placebo.
A formal statistical hypothesis test will be performed, at an overall 1-
sided alpha level of 0.025, on the primary endpoint of time to first 
GPP flare up to week 48. A stratified log-rank test will be 
implemented for each dose of BI 300 mg q4w and BI 300 mg q12w
versus placebo, with stratification by the factor, concomitant use of 
systemic GPP medication at randomization (yes or no) with
multiplicity being controlled by the truncated Hocherg procedure. 
Formal testing of all other endpoints included in the testing hierarchy 
(i.e. the key secondary, and secondary endpoints), will then be 
performed, if the analysis on the primary endpoint is successful. The 
remaining alpha to be used for the key secondary endpoint analysis
will be 0.025 (1-sided) if both high and medium doses of BI 655130 
are statistically significantly superior to placebo on the primary 
endpoint. The key secondary endpoint will be analyzed using a 
Cochran-Mantel Haenszel test, in a similar manner to the analysis 
performed on the primary endpoint, for each dose of BI 655130 300
mg q4w and BI 655130 300 mg q12w versus placebo and a truncated 
Hochberg procedure will be used to control for multiplicity. If only 
one (high or medium) dose of BI 655130 was statistically significant
on the test of the primary endpoint, then the same dose will be tested 


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-04
Clinical Trial Protocol
Page 7 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
on the key secondary endpoint with a 1-sided alpha of 0.00625. If 
neither dose is declared to be statistically significantly superior to 
placebo for the primary endpoint, then no further formal testing in the 
hierarchical sequence will be conducted.
Descriptive comparison of adult versus paediatric data will be 
performed.


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03                                                                              Clinical Trial Protocol                                                                  Page 8 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
FLOW CHARTS
FLOW CHART 1 
Screening
Randomized Treatment Period
Follow-up 
Loading
Maintenance 
Visit
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12
V13
V14/
EoS114
V15/
EoS215
Week
-12 to 0
1
4
8
12
16
20
24
28
32
36
40
44
48
16 wks 
after last 
dose
Day
-84 to -1
1
29
57
85
113
141
169
197
225
253
281
309
337
Visit Window (days)
N.A.
0
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
+7
Informed consent
X
Infection testing
X1a,1b
X1a
X1a,18
Demographics
X
Medical history
X
Smoking history
X
Physical examination3
XC
XC,T
XT
XT
XT
XT
XT
XT
X,T
XT
XT
XT
XT
XT
XT
Vital signs4
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy test5
XS
XU,(S)
XU,(S)
XU,(S)
XU,(S)
XU,(S)
XU,(S)
XU,(S)
XU,(S)
XU,(S)
XU,(S)
XU,(S)
XU,(S)
XU,(S)
XU,(S)
12 lead-ECG6
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Safety laboratory tests8
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Review of in-/exclusion 
criteria
X
X
Photographs of skin/skin 
lesions9
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Skin biopsies (optional)16
prior to dose
X
X


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03                                                                              Clinical Trial Protocol                                                                  Page 9 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
  FLOW CHART 1 (cont.)
Screening
Randomized Treatment Period
Follow-
up 
Loading
Maintenance 
Visit
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12
V13
V14/ 
EoS114
V15/
EoS215
Week
-12 to 0
1
4
8
12
16
20
24
28
32
36
40
44
48
16 wks 
after last 
dose
Day
-84 to -1
1
29
57
85
113
141
169
197
225
253
281
309
337
Visit Window (days)
N.A.
0
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
+7
GPPGA
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
GPPASI
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PSS; 
 
X
X
X
X
X
X
X
X
X
X
X
X
X
DLQI
 
X
X
X
X
X
X
X


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03                                                                              Clinical Trial Protocol                                                                  Page 10 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
FLOW CHART 1 (cont.)
Screening
Randomized Treatment Period
Follow-up 
Loading
Maintenance 
Visit
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12
V13
V14/ EoS114
V15/
EoS215
Week
-12 to 0
1
4
8
12
16
20
24
28
32
36
40
44
48
16 wks after last 
dose
Day
-84 to -1
1
29
57
85
113
141
169
197
225
253
281
309
337
Visit Window (days)
N.A.
0
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
+7
 
IRT call
X
X
X
X
X
X
X
X
X
X
X
X
X
X21
Dispense/Administer
study drug
X
X
X
X
X
X
X
X
X
X
X
X
Local tolerability13
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events 
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
Study Completion
X
X
Vital Status
X19
X20
Open Label Extension 
Trial
X
 C, complete physical examination; CGI-I, Clinical Global Impression – Improvement; d, Day; DLQI, Dermatology Quality of Life Index; ECG, 
Electrocardiogram; EoS, end of study; EQ-5D-5L, EuroQoL 5 Dimension 5 Level GPPASI, Generalized Pustular Psoriasis Area and Severity Index: GPPGA, Generalized Pustular 
Psoriasis Physician Global Assessment;
; IHC, Immunohistocompatibility Complex; IRT, Interactive Response Technology; 
 
 Nab, neutralizing Antibodies; 
; OLE, 
Open Label Extension, PRO, Patient Reported Outcome; PSS, Psoriatic Symptom Scale; 
; S, serum; T, Targeted physical examination; 
 
U, urine; V, Visit; 
; 
1 a) Infection testing includes tuberculosis, hepatitis B, hepatitis C, and HIV assessments. See Table 5.2.3: 1.; b) For patients who sign the informed consent ≥4 weeks prior to V2, 
infection testing must be repeated 2 to 4 weeks prior to V2.
.
3Physical examination: C=complete, T=targeted. Refer to Section 5.2.1


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03                                                                              Clinical Trial Protocol                                                                  Page 11 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
4Vital signs: a) On non-study–drug administration days, vital sign assessments are to be done prior to blood sampling; b) On study drug administration days, vital signs will be assessed at 
predose (prior to blood sampling), 10 mins after the end of drug administration and at Visit 2 and Visit 3 additional measurements will be performed approximately 60 minutes after the 
end of  drug administration (i.e. 60 minutes after last injection). Refer to Section 5.2.2.
5Only applicable for women of childbearing potential. S – serum pregnancy test (performed at screening). U – urine pregnancy tests will be performed at all other visits indicated. Urine
pregnancy testing should be done prior to study drug administration. Study drug should only be administered in case of a negative test result. In case of a positive urine pregnancy test, a 
serum pregnancy (S) test will be done (via central lab) and study drug administration will be postponed until negative result of serum pregnancy test is available.
6ECG measurements should always precede blood sampling and drug administration.
7
 
8Safety laboratory tests include clinical chemistry, haematology, coagulation, and urinalysis, and will be performed centrally. See Section 5.2.3 and Table 5.2.3: 1.
9Photographs of skin/skin lesions are to precede skin biopsies and study drug administration.
10Collection of serum biobanking sample is optional. Participating patients are required to give informed consent specifically for biobanking. Samples will be stored at a Biobanking 
facility for future research.
11 a) These measurements are to be completed by the patient on his/her own, without any help from or interpretation by other people. If the patient is too sick to complete the questionnaires 
him/herself but is able to reply verbally, a member of the study 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 manner as possible. If this is not possible either, the questionnaires are not to be completed. The order of completion for PROs is recommended to be as 
following: PSS; DLQI: PainVAS; EQ-5D-5L; WPAI-GPP; SF-36; PGI-S and PGI-C. 
11 b) DLQI, EQ-5D-5L, PGI-S and PGI-C are to be completed at V2, V3, V4, V5, V8, V11 and V14/EoS1 visit only.
11d) For PRO completion by the adolescent patients, please refer to Section 6.2 for further guidance and details.  
 
.
13Local tolerability at the administration site of BI 655130/placebo (s.c.) will be assessed during the study drug administration and at the time of AE assessment by questioning 
retrospectively since the last visit. Any observed local tolerability reaction (s), e.g. swelling, induration, heat, redness, pain, and other findings should be reported as an adverse event. 
14V14 will be recorded as the End of Study visit (i.e., EoS1) for patients who qualify and agree to enter the OLE trial (1368-0025). V14 will also be recorded as End of Study Visit (EoS 1)
for patients who prematurely discontinue with the last dose of treatment up to and including Day 232 and who agree to complete all remaining study visits up to Wk 48 from 
randomization. Since these patients prematurely discontinued, they would not qualify to enter OLE trial. See section 3.3.4.1.
15EoS2 visit is applicable for patients who do not qualify or who do not agree to enter OLE trial (1368-0025) at Week 48. EoS2 is also applicable for patients who prematurely discontinue 
with the last dose of treatment after Day 232. Since these patients prematurely discontinued, they would not qualify to enter OLE trial. 
16Skin biopsy is optional and is only to be done for patients who have consented for this procedure. V2 and V14 skin biopsies (optional): 1 lesional or non lesional (if no lesions are 
present) skin biopsy of 5 mm punch (split into half for IHC and RNASeq) should be collected prior to study drug administration. 
18 Only applicable if infection testing was not done at V14/EoS1 visit.
19 Vital Status will be collected at V14 for patients who prematurely discontinue with the last dose of treatment up to and including Day 232 and who agree to be contacted further but do 
not agree for physical visits. See Section 5.2.6.1 for further details. 
20 Vital Status will be collected at V15 for patients who prematurely discontinue with the last dose of  treatment after Day 232 and who agree to be contacted further but do not agree for 
physical visits. See Section 5.2.6.1 for further details. 
21IRT registration is expected once at End of Study visit (as applicable) for a patient.


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03                                                                              Clinical Trial Protocol                                                                  Page 12 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
FLOW CHART 2
(GPP FLARE IV RESCUE)
Flare 
confirmation
Rescue Treatment Period 
(i.v.)
Open Label Maintenance Treatment Period (s.c.)
Follow-up
Visit
F0
R1
R2
R3
R4
R5
R6
R7
VX13
V>X13
V14/EoS114
EoS215
Week*
0
1
1
1
2
3
4
8
12
Every 4 weeks prior to 
Week 48 of 
randomization per
original maintenance 
treatment schedule in 
Flowchart 1
Week 48 of 
randomization
per original 
maintenance 
treatment 
schedule in 
Flowchart 1
16 wks after 
last dose
Day relative to R1
1**
4
8
15
22
29
57
85
Visit Window (days)
±3
±3
±3
±7
±3
Criteria to receive rescue treatment
X
Infection Testing
X
X18
Physical examination1
XC,T
XT
XT
XT
XT
XT
XT
XT
XT
XT
XC,T
Vital signs2
X
X
X
X
X
X
X
X
X
X
X
Fever Assessment3
X
X
Pregnancy test4
XU,(S)
XU,(S)21
XU,(S)
XU,(S)
XU,(S)
XU,(S)
12 lead-ECG5
X
X21
X
X
X
X
Safety laboratory tests6
X
X
X
X
X
X
X
X
X
X
X
Photographs of skin/skin lesions7
X
X
X
X
X
X
X
X
X
X
X
X
Skin biopsies (optional)8 – prior to 
dose
X
X
X


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03                                                                              Clinical Trial Protocol                                                                  Page 13 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
FLOW CHART 2
(GPP Flare IV Rescue) (cont.)
Flare 
confirmation
Rescue Treatment Period
(i.v.)
Open Label Maintenance Treatment
Period (s.c.)
Follow-up
Visit
F0
R1
R2
R3
R4
R5
R6
R7
VX13
V>X13
V14/EoS114
EoS215
Week*
0
1
1
1
2
3
4
8
12
Every 4 
weeks prior to 
Week 48 of 
randomization
per original 
maintenance 
treatment 
schedule in 
Flowchart 1
Week 48 of 
randomization
per original 
maintenance 
treatment 
schedule in 
Flowchart 1
16 wks after 
last dose
Day relative to R1 
1**
4
8
15
22
29
57
85
Visit Window (days)
±3
±3
±3
±7
±3
 
GPPGA
X
X
X
X
X
X
X
X
X
X
X
X
PSS; 
X
X
X
X
X
X
X
X
X
X
IRT call
X
X21
X
X22
X23
Dispense/administration study drug
X
X21
X
X17
Local tolerability12\
X
X21
X
X
Adverse events 
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
Study Completion
X
X
Vital Status
X19
X20
Open Label Extension Trial
X
*Week in the flow chart represents the end of each week (e.g. End of Week1=D8, End of Week2 =D15, End of Week3 = D22, End of Week4 =D29, etc.).
**The day of administration of rescue treatment = Day 1. All subsequent study days are counted from this Day 1 in Flow Chart 2 if there is no additional specification.


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03                                                                              Clinical Trial Protocol                                                                  Page 14 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
1Physical examination: C=complete, T=targeted. Refer to Section 5.2.1
2Vital signs: a) On non-study–drug administration days, vital sign assessments are to be done prior to blood sampling; b) On (i.v.) study drug administration days, vital signs will be 
assessed at predose (prior to blood sampling), at approximately 5 mins after the end of infusion, and 1 hour after the end of infusion; c) On (s.c.) study drug administration days, vital signs 
will be assessed at pre-dose (prior to blood sampling ) and 10 mins after the end of drug administration. Refer to Section 5.2.2.
3Fever will be assessed at the day the patient presents to the clinic/hospital with GPP flare and prior to IMP administration.  If the patient will receive medication for fever treatment, the 
fever assessment will be performed prior to taking the anti-fever treatment. This fever assessment must be taken whether or not the patient has an elevated temperature and whether or not 
the patient will require anti-fever treatment.
4Only applicable for women of childbearing potential. S – serum pregnancy test. U – urine pregnancy tests will be performed at all other visits indicated. Urine
pregnancy testing should be done prior to study drug administration. Study drug should only be administered in case of a negative test result. In case of a positive urine pregnancy test, a 
serum pregnancy (S) test will be done (via central lab with the exception of R1 and R3 (if patient qualifies to receive i.v. dosing) visits where serum pregnancy test can be performed 
locally)) and study drug administration will be postponed until negative result of serum pregnancy test is available.
5ECG measurements should always precede blood sampling and drug administration
6Safety laboratory tests include clinical chemistry, haematology, coagulation, and urinalysis, and will be performed centrally. Local Labs are to be used for dosing decisions prior to i.v. 
administration. For all other visits, central labs are to be used. . See Section 5.2.3 and Table 5.2.3: 1.
7Photographs of skin/skin lesions are to precede skin biopsies and study drug administration.
8Skin biopsy is optional and is only to be done for patients who have consented for this procedure. Skin biopsies (optional) will be collected for each of the three visits (R1, R6 and EoS1 
visit): 1 lesional or non-lesional (if no lesions are present) skin biopsy of 5 mm punch (split into half for IHC and RNASeq) should be collected prior to study drug administration. 
 
.
10These measurements are to be completed by the patient on his/her own, without any help from or interpretation by other people. If the patient is too sick to complete the questionnaires
him/herself but is able to reply verbally, a member of the study 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 manner as possible. If this is not possible either, the questionnaires are not to be completed. The order of completion for PROs is recommended to be as 
following: PSS; 
For PRO completion by the adolescent patients, please refer to Section 6.2 for further guidance and details.  
11 HCRU (healthcare resource utilization) data include the number of hospitalizations and length of stay in days, as well as the number of outpatient visits and emergency room visits (If 
applicable). Data should be collected for the time period since the last visit.
12 Local tolerability at the administration site of BI 655130 will be assessed during the study drug administration (i.v. or s.c.) and at the 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.
13 If the first dose of OL s.c. maintenance treatment is outside of any scheduled visit window by ±7 days per Flow Chart 1, it needs to be assigned to one of the scheduled visits by 
extending each visit time window to -13/+14 days of the original planned visit date. See Table 3.1:1 for the detailed rules of visit assignment. Then the following OL s.c. maintenance 
doses (if applicable) will be administered within original visit window by ±7 days per Flow Chart 1. Note: Once the OL s.c. visit assignment is calculated by referring to Flow Chart 1, all 
study procedures scheduled for this first dose of OL s.c. maintenance treatment visit and subsequent OL maintenance treatment visits should be completed as per  Flow Chart 2.
14Visit at Week 48 of randomization will be planned for all patients who receive rescue treatment with BI 655130. It will be recorded as the End of Study visit (i.e., EoS1) for patients who 
qualify and agree to enter the OLE trial (1368-0025). V14 will also be recorded as End of Study Visit (EoS1) for patients who prematurely discontinue with the last dose of  treatment up 
to and including Day 232  and who agree to complete all remaining study visits up to Wk 48 from randomization. Since these patients prematurely discontinued, they would not qualify to 
enter OLE trial. See section 3.3.4.1.
15EoS2 is applicable for patients who do not qualify or who do not agree to enter OLE trial (1368-0025) at Week 48. EoS2 is also applicable for patients who prematurely discontinue with 
the last dose of treatment after Day 232. Since these patients prematurely discontinued, they would not qualify to enter OLE trial. . 
 


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03                                                                              Clinical Trial Protocol                                                                  Page 15 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
17Actual dose is administered either every 4 weeks or every 12 weeks dependent upon the current maintenance dosing scheme the patient is following.
18 Only applicable if infection testing was not done at V14/EoS1 visit.
19 Vital Status will be collected at V14 for patients with the last dose of treatment up to and including Day 232 and who agree to be contacted further but do not agree for physical visits. 
See Section 5.2.6.1 for further details. 
20 Vital Status will be collected at V15 for patients with the last dose of  treatment after Day 232 and who agree to be contacted further but do not agree for physical visits. See Section 
5.2.6.1 for further details. 
21 Only applicable for patients meeting protocol specified criteria for receiving D8 dosing. See Table 3.1:3 for criteria for receiving D8 dosing. 
22 IRT call is applicable for dosing visits only (i.e. q12 weeks or q4 weeks in case a patient has been switched to intensified maintenance treatment schedule).
23 IRT registration is expected once at End of Study visit (as applicable) for a patient.


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 16 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
TABLE OF CONTENTS
TITLE PAGE .........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ...................................................................2
FLOW CHARTS....................................................................................................................8
FLOW CHART 1...................................................................................................................8
FLOW CHART 2
(GPP FLARE IV RESCUE) .............................................................12
TABLE OF CONTENTS ....................................................................................................16
ABBREVIATIONS..............................................................................................................20
1.
INTRODUCTION.............................................................................................23
1.1
MEDICAL BACKGROUND...........................................................................23
1.2
DRUG PROFILE..............................................................................................26
1.3
RATIONALE FOR PERFORMING THE TRIAL.......................................32
1.4
BENEFIT - RISK ASSESSMENT...................................................................33
1.4.1
Benefits...............................................................................................................33
1.4.2
Risks ...................................................................................................................33
1.4.3
Discussion...........................................................................................................39
2.
TRIAL OBJECTIVES AND ENDPOINTS....................................................40
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS......40
2.1.1
Main objectives..................................................................................................40
2.1.2
Primary endpoint(s)..........................................................................................40
2.1.3
Secondary endpoint(s) ......................................................................................41
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.......................44
3.1
OVERALL TRIAL DESIGN...........................................................................44
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)....................................................................................54
3.3
SELECTION OF TRIAL POPULATION .....................................................55
3.3.1
Main diagnosis for trial entry ..........................................................................56
3.3.2
Inclusion criteria ...............................................................................................56
3.3.3
Exclusion criteria ..............................................................................................57
3.3.4
Withdrawal of patients from treatment or assessments................................59
3.3.4.1
Discontinuation of trial treatment .......................................................................59
3.3.4.2
Withdrawal of consent to trial participation .......................................................60
3.3.4.3
Discontinuation of the trial by the sponsor.........................................................60
4.
TREATMENTS.................................................................................................61
4.1
INVESTIGATIONAL TREATMENTS .........................................................61
4.1.1
Identity of the investigational medicinal products.........................................61


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 17 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
4.1.2
Selection of doses in the trial and dose modifications....................................62
4.1.3
Method of assigning patients to treatment groups.........................................64
4.1.4
Drug assignment and administration of doses for each patient....................65
4.1.5
Blinding and procedures for unblinding.........................................................67
4.1.5.1
Blinding...............................................................................................................67
4.1.5.2
Unblinding and breaking the code ......................................................................68
4.1.6
Packaging, labelling, and re-supply.................................................................69
4.1.7
Storage conditions.............................................................................................69
4.1.8
Drug accountability...........................................................................................69
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ..............................................................................................70
4.2.1
Other treatments and emergency procedures................................................70
4.2.1.1
Emergency procedures........................................................................................70
4.2.1.2
Additional treatments..........................................................................................71
4.2.2
Restrictions ........................................................................................................72
4.2.2.1
Restrictions regarding concomitant treatment before randomization.................72
4.2.2.2
Restrictions regarding concomitant treatment during the trial (Post V2)...........74
4.2.2.3
Restrictions on diet and life style........................................................................76
4.2.2.4
Contraception requirements................................................................................76
4.3
TREATMENT COMPLIANCE......................................................................76
5.
ASSESSMENTS................................................................................................77
5.1
ASSESSMENT OF EFFICACY......................................................................77
5.2
ASSESSMENT OF SAFETY...........................................................................81
5.2.1
Physical examination ........................................................................................81
5.2.2
Vital signs...........................................................................................................81
5.2.3
Safety laboratory parameters ..........................................................................82
5.2.4
Electrocardiogram ............................................................................................86
5.2.5
Other safety parameters...................................................................................86
5.2.6
Assessment of adverse events...........................................................................87
5.2.6.1
Definitions of AEs ..............................................................................................87
5.2.6.2
Adverse event collection and reporting ..............................................................90
5.6
OTHER ASSESSMENTS.................................................................................96


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 18 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
5.7
APPROPRIATENESS OF MEASUREMENTS............................................96
6.
INVESTIGATIONAL PLAN...........................................................................97
6.1
VISIT SCHEDULE...........................................................................................97
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ...............97
6.2.1
Screening and run-in period(s)........................................................................99
6.2.2
Treatment period(s)........................................................................................100
6.2.3
Follow-up period and trial completion..........................................................102
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE 
SIZE..................................................................................................................103
7.1
NULL AND ALTERNATIVE HYPOTHESES ...........................................104
7.2
PLANNED ANALYSES.................................................................................115
7.2.1
General considerations ...................................................................................115
7.2.2
Primary endpoint analyses.............................................................................115
7.2.3
Secondary endpoint analyses .........................................................................119
7.2.5
Safety analyses.................................................................................................120
7.2.7
Interim analyses ..............................................................................................122
7.3
HANDLING OF MISSING DATA ...............................................................122
7.4
RANDOMISATION .......................................................................................125
7.5
DETERMINATION OF SAMPLE SIZE .....................................................126
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY, AND ADMINISTRATIVE STRUCTURE ....132
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT .......................................................................................................132
8.2
DATA QUALITY ASSURANCE ..................................................................133
8.3
RECORDS.......................................................................................................133
8.3.1
Source documents ...........................................................................................134
8.3.2
Direct access to source data and documents.................................................134
8.3.3
Storage period of records ...............................................................................135
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS ..............................135
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY....135
8.5.1
Collection, storage and future use of biological samples and 
corresponding data .........................................................................................135
8.6
TRIAL MILESTONES...................................................................................136
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ...............................136
9.
REFERENCES................................................................................................138
9.1
PUBLISHED REFERENCES........................................................................138
9.2
UNPUBLISHED REFERENCES..................................................................141
10.
APPENDICES.................................................................................................143
10.1
INSTRUCTIONS FOR USE..........................................................................143
10.1.1
Physician’s Global Assessment for Generalized Pustular Psoriasis 
(GPPGA)..........................................................................................................143


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 19 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
10.1.5
Psoriasis Symptom Scale ................................................................................154
10.1.6
Diagnosis of Anaphylaxis................................................................................155
10.1.10
Dermatology Life Quality Index (DLQI)......................................................159
11
DESCRIPTION OF GLOBAL AMENDMENT(S) .....................................166
11.1
GLOBAL AMENDMENT 1 ..........................................................................166
11.2
GLOBAL AMENDMENT 2 ..........................................................................182


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 20 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
ABBREVIATIONS
ADA
Anti-Drug Antibodies
AE
Adverse Event
AESI
Adverse Event of Special Interest
AD
Atopic Dermatitis
ALT
Alanine Aminotransferase
AP
Alkaline Phosphatase
AST
Aspartate Aminotransferase
AUC
Area under the Curve
BI
Boehringer Ingelheim
CA
Competent Authority
CI
Confidence Interval
Cmax
Maximum Concentration
Cmin
Minimum Plasma Concentration
CGI-I
Clinical Global Impression – Improvement
CRA
Clinical Research Associate
CRF
Case Report Form, paper or electronic (sometimes referred to as “eCRF”)
CRO
Contract Research Organisation
CRP
C-reactive protein
CT Leader
Clinical Trial Leader
CT Manager
Clinical Trial Manager
CTP
Clinical Trial Protocol
DILI
Drug Induced Liver Injury
DLQI
Dermatology Quality of Life Index
DMC
Data Monitoring Committee
EC
Ethics Committee
ECG
Electrocardiogram
(e)COA
(electronic) Clinical Outcome Assessment
eDC
Electronic Data Capture
EoS
End of Study
ERASPEN
European Rare And Severe Psoriasis Expert Network
EudraCT
European Clinical Trials Database


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 21 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
FC
Flow Chart
FUP
Follow-up
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
GPP
Generalized Pustular Psoriasis
GPPGA
Generalized Pustular Psoriasis Physician Global Assessment
HA
Health Authority
i.v.
intravenous
IB
Investigator’s Brochure
ICH
International Council on Harmonisation
IEC
Independent Ethics Committee
IMP
Investigational Medicinal Product
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 Antibodies
OPU
Operative Unit
PD
Pharmacodynamics
PK
Pharmacokinetics
PoC
Proof of Concept
PPP
Palmoplantar Psoriasis
PPS
Per-Protocol set
PRO(s)
Patient Reports Outcome(s)
PSS
Psoriasis Symptom Scale
q.d.
quaque die (once a day)


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 22 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
RA
Regulatory Authority
REP
Residual Effect Period
s.c.
subcutaneous
SAE
Serious Adverse Event
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
TB
Tuberculosis
TEAE
Treatment-emergent adverse event
Tmax                    Timepoint of maximum plasma concentration
  
TSAP
Trial statistical analysis plan
TST
Tuberculin Skin Test
ULN
Upper Level of Normal
WOCBP
Woman of childbearing potential


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 23 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Clinical Presentation of Generalized Pustular Psoriasis (GPP):
The severe skin and systemic auto inflammatory disease GPP is a rare, serious condition that 
presents as recurring episodes of severe flares affecting the skin and internal organs (R15-
1421, R16-0933), representing a true medical emergency with potentially life threatening 
consequences.  The seriousness of the condition is reflected in the many systemic 
complications of GPP and the associated mortality.  
In order to adequately treat GPP, flares need to be treated, but maintenance therapy also 
needs to be given to prevent future flares.
Treatment of acute GPP flares aims at the rapid control of the serious condition via 
controlling the systemic signs (CRP, fever, neutrophilia) and pustulation (e.g. visible sign of 
the inflammation) to prevent infection and onset of other complications making the event life 
threatening. In addition, the rapid response to associated dermatologic lesions (response to at 
least almost clear) and symptoms is key and the sustained control of the signs and symptoms 
of the GPP flare. 
As descriptions for GPP are discordant among standard dermatology textbooks (R17-3403), 
the European Rare And Severe Psoriasis Expert Network (ERASPEN) has defined consensus 
criteria that include as key diagnosis criteria for acute GPP the presence of primary, sterile, 
macroscopically visible pustules on non-acral skin (excluding cases where pustulation is 
restricted to psoriatic plaques), with or without systemic inflammation, with or without 
plaque-type psoriasis, either relapsing (>1 episode) or persistent (>3 months).
Chronic GPP describes the state in between disease flares that may be characterized by the 
persistence of residual skin symptoms such as erythema and scaling and minor pustulation.
Co-morbidities:
The classic presentation of acute GPP was first described as a recurrent pustular form of 
psoriasis by von Zumbusch in 1909 (R16-0932). While GPP and plaque psoriasis can occur 
at the same time in an individual patient (R17-3403), GPP is distinct from plaque psoriasis in 
clinical presentation, pathophysiology, histopathology, response to therapies, epidemiology 
and genetics.
The clinical presentation of GPP is quite different from psoriasis vulgaris (PV) in its’ 
episodic nature, often with normal appearing skin between very acute and severe disease 
flares. GPP is clinically characterized by the preponderance of pustules as the primary lesion 
on an erythematous base rather than red plaques covered with silvery scales representing the 
primary lesion of typical plaque psoriasis. In addition, the histopathological hallmarks of GPP 
are distinct spongiform pustules of Kogoj located in the subcorneal portion of the epidermis. 
GPP may be associated with systemic symptoms (fever, increased CRP and neutrophilia) and 


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 24 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
severe extra-cutaneous organ manifestations (liver, kidney failure, CV shock). While patients 
with GPP may have pre-existing or co-existing PV, it is possible to clinically distinguish 
patients with primary plaque disease (PV) who have a secondary pustular component from 
patients who have primary pustular disease (GPP) with a concomitant plaque component, 
based on the sequence of manifestations (primary lesion pustule rather than plaque) and the 
localization of a GPP pustule on an erythematous base rather than a PsO plaque.  
Treatment options
Current treatment options for controlling acute flare of GPP and maintenance of response and 
prevention of future flares are limited and do not provide sustained efficacy (R16-0933). No 
treatments are currently approved for GPP in the US and no centrally approved treatments are 
available in the EU, though retinoids, oral steroids, cyclosporine or methotrexate are being 
recommended (R17-3600). Although these treatments are described to be effective in 70 –
84% of patients (R17-3600) these data observations are based on a retrospective cohort study 
from Japan without clearly defined endpoints (R17-3626). Furthermore, these treatments 
cannot be used long-term due to side effects and contraindications (retinoids: teratogenicity, 
hair loss; cyclosporine: excessive hair growth, renal toxicity; MTX: liver toxicity).
Secukinumab (Cosentyx®), infliximab (Remicade®), ixekizumab (Taltz®), brodalumab
(Lumicef®), adalimumab (Humira®), guselkumab (Tremfya®), Risankizumab (Skyrizi™), 
and certolizumab (Cimzia®) are only registered in Japan for the treatment of GPP and plaque 
psoriasis. For secukinumab, authorization was granted on the basis of long-term treatment 
data (52 weeks) derived from a single open label clinical trial conducted in 12 patients with 
chronic GPP and an endpoint at 16 weeks (R16-1462). Treatment trials supporting licensing 
in Japan have treated residual disease for an extended period of time, providing no evidence 
of how to appropriately treat acute GPP flares.  
Biologics (mostly TNF inhibitors, occasionally IL-1 or IL-17 inhibitors) are increasingly used 
to treat more severe, extensive or treatment resistant patients with GPP, based on small 
published case series (R17-3603). However, these drugs are also associated with limitations 
in efficacy (incomplete and delayed responses are frequent) and safety as well as 
contraindications (infusion reactions, tuberculosis, cardiovascular disease). 
Unmet Medical Need 
Acute GPP flares of varying severity occur in most patients and are commonly triggered by 
external stimuli, such as infection, corticosteroid use or withdrawal, non adherence and dose 
reduction of current standard of care treatment, stress or pregnancy (R16-0933). Moderate or 
severe GPP flares cause significant morbidity and mortality (R16-0933) due to tender, painful 
skin lesions, extreme fatigue, high fever, peripheral blood neutrophilia and acute phase 
response and sepsis. GPP flares are a true medical emergency requiring urgent intervention to 
stop the inflammation. If the inflammation is not controlled quickly, there is sloughing of the 
skin leaving the body unprotected from external pathogens resulting in bacteremia, most 
commonly staph sepsis and unable to prevent the leakage of essential proteins and 
electrolytes. The consequence is hypoalbuminemia, peripheral edema, hypovolemic and/or 


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 25 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
septic shock, with shut down of hepatic and renal function. The morbidity and mortality 
without supportive care is substantial.
The acute phase is associated with a mean duration of hospitalization of 10 days (range 3-44 
days) (R16-0933). Patients with GPP are known to be at an increased risk of death (R16-
3932); (R16-0581). Six case series have published on deaths among patients with GPP (R16-
2698);(R16-1463); (R16-0933); (R17-3898);(R17-3456); (R17-3605). Mortality estimates 
range from 2% in France (R16-2698) to 7% in Malaysia (R16-0933) and 7.7% in Thailand 
(R17-3456). In the US, Zelickson et al (R17-3605) conducted a case series on hospitalized 
patients with GPP at the Mayo clinic from 1961 to 1989 and reported a mortality rate of 
3.2%. The most commonly reported causes of death in GPP patients were related to sepsis.
Mortality rates are also likely underestimated due to lack of identifying the cause of death as 
GPP and are largely driven by infectious complications and extra-cutaneous organ 
manifestations such as renal, hepatic, respiratory and cardiac failure (R16-0933). After 
responding to treatment or spontaneous flare cessation, it is estimated that up to 50% of
patients may suffer from chronic GPP characterized by persistent erythema and scaling that 
may also include joint symptoms. 
Moreover, in countries with lower incidence of GPP, the differential diagnosis can be 
delayed.  This is partly due to the absence of a treatment protocol for GPP once it is 
diagnosed.
Based on the limitations described above, current therapeutic options are not suitable for life-
long treatment and do not provide sustained responses in most patients. Therefore, there is a 
high need to develop (i) a highly effective treatment with rapid onset of action for patients 
presenting with an acute GPP flare; and (ii) to develop an effective treatment for prevention 
of the occurrence of flares that is safe and tolerable for lifelong treatment.
Role of IL-36R Signaling in GPP
The classic presentation of GPP flares as described by von Zumbusch is strongly correlated 
with polymorphisms in the IL36-R signaling pathway (R15-1421, R14-5158). Individuals 
with loss-of-function mutations of the IL36RN gene which encodes an endogenous IL36R 
antagonist (IL-36RN) have dramatically higher incidence of GPP, indicating that 
uncontrolled upregulation of IL36 signaling due to defective IL36RN antagonism leads to the 
inflammatory episodes observed in GPP. Genetic human studies have demonstrated the 
occurrence of GPP clusters in families with a loss of function mutation in IL36RN, which 
results in uncontrolled IL36R signaling (R14-5158).  Mutations in other genes linked to the 
IL36 pathway such as CARD14 (R16-0929) also lead to GPP. A recently published gene 
expression study indicates sustained activation of IL-1 and IL-36 in GPP, inducing neutrophil 
chemokine expression, infiltration, and pustule formation, concluding that the IL-1/ IL-36 
inflammatory axis is a potent driver of disease pathology in GPP (R17-3602). Moreover, a 
recent meta-analysis investigated 233 published GPP cases. They found that 49 (21.0%) of 
233 cases carried recessive IL36RN alleles. Those 49 recessive IL36RN alleles defined a 
GPP phenotype characterized by early onset and high risk of systemic inflammation (R16-
0930).


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 26 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
IL36R is a cell surface receptor involved in inflammatory responses in skin and gut. It is a 
novel member of the IL1R family that forms a heterodimeric complex with the IL1R 
accessory protein. The heterodimeric IL36R system with stimulating (IL36α, IL36β, IL36γ) 
and inhibitory ligands (IL36Ra) shares a number of structural and functional similarities to 
other members of the IL1/IL1R family, such as IL1, IL18 and IL33 (R17-3602). All IL1 
family members (IL1α, IL1β, IL18, IL36α, IL36β, IL36γ, and IL38) signal through a unique, 
cognate receptor protein which, upon ligand binding, recruits the common IL1RacP subunit 
and activates NFkB and MAP kinase pathways in receptor-positive cell types. In human skin 
tissues, IL36R is expressed in keratinocytes, dermal fibroblasts and infiltrating myeloid cells.  
IL36R activation in skin tissue drives the production of inflammatory mediators (e.g. CCL20, 
MIP-1β, TNF-α, IL12, IL17, IL23, TGF-β) and modulates the expression of tissue 
remodeling genes (e.g. MMPs, TGF-β). Therefore, the link between GPP and mutations in 
the IL36RN is somewhat analogous to the well-established neonatal onset of sterile 
multifocal osteomyelitis, periostitis, and pustulosis caused by absence of interleukin-1–
receptor antagonist. In this case, absence of the receptor antagonist allows unopposed action 
of interleukin-1, resulting in life-threatening systemic inflammation with skin and bone 
involvement (R17-3602). These clinical features responded to empirical treatment with the 
recombinant interleukin-1–receptor antagonist anakinra (P09-07583).
1.2
DRUG PROFILE
Mode of action
BI 655130 is a humanized antagonistic monoclonal IgG1 antibody that blocks human IL36R 
signaling. Binding of BI 655130 to IL36R is anticipated to prevent the subsequent activation 
of IL36R by cognate ligands (IL36 α, β and γ) and downstream activation of pro-
inflammatory and pro-fibrotic pathways with the aim to reduce epithelial cell/ fibroblast/ 
immune cell-mediated inflammation and interrupt the inflammatory response that drives 
pathogenic cytokine production in inflammatory diseases including generalized pustular 
psoriasis (GPP), palmoplantar pustulosis (PPP), Atopic Dermatitis (AD), Hidradenitis 
Suppurativa (HS) and inflammatory bowel disease (IBD).
Key pharmacokinetic characteristics
BI 655130 has been characterized by typical IgG1 monoclonal antibody pharmacokinetics. 
PK data showed that exposure increased with increasing dose in a dose proportional manner 
from 0.3 mg/kg to 20 mg/kg following IV administration of BI 655130 to healthy volunteers. 
The half-life of BI 655130 was approximately 4 weeks in the linear dose range in healthy 
volunteers and approximately 3 weeks in GPP patients. PK data suggests target-mediated 
drug disposition (TMDD) kinetics for BI 655130 at doses lower than 0.3 mg/kg. Comparing 
the exposures between the 300 mg SC dose and 300 mg IV dose, a SC bioavailability of 
~70% was determined. No differences in PK were observed between Caucasians and 
Japanese subjects.


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 27 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
Residual Effect Period
The Residual Effect Period (REP) of BI 655130 is 16 weeks. This is the period after the last 
dose with measurable drug levels and/or pharmacodynamic effects still likely to be present.
Data from clinical studies
For a more detailed description of the BI 655130 profile, please refer to the current Investigator’s 
Brochure (IB; 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 


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 28 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
to 10 mg/kg body weight and 20 subjects assigned to placebo. Safety and tolerability of all 
tested i.v. doses was good. There were no SAEs. AEs 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 dose-
dependency was observed.
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 20mg/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 (IB; c03320877).
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 to 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). 


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 29 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
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.
Safety
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%).


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 30 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
Safety laboratory tests and the evaluation of vital signs, oral body temperature, local 
tolerability, and electrocardiogram recordings revealed no clinically relevant findings.
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 trial (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 hours 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 


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 31 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
the current IB (c03320877) 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
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).


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 32 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
1.3
RATIONALE FOR PERFORMING THE TRIAL
The strong genetic link between the IL36 signaling pathway and GPP and experimental data 
identifying IL-36 as the dominant cytokine driving GPP (R17-3602) suggest that inhibition of 
IL36R signaling with the humanized anti-IL36R antibody BI 655130 (Spesolimab) would be 
beneficial in treatment of GPP flares as well as in prevention of flares.  In addition, a recent 
characterization of individuals with homozygous IL36R KO mutations revealed that normal 
immune function was broadly preserved suggesting that IL36 signaling pathway inhibition 
does not compromise host defenses (R17-3632).
Current treatment options for controlling acute flare of GPP, complete resolution of 
symptoms and prevention of reoccurrence of flares are limited and do not provide sustained 
efficacy (R16-0933). No treatments are currently approved for controlling acute flare of GPP 
in the US or centrally approved for GPP in the EU, though a combination of retinoids, 
cyclosporine or methotrexate has been recommended as primary option for controlling 
worsening of chronic GPP (R17-3600). The use of these for treatment or prevention of GPP 
flare is based on anecdotal retrospective case reports, making this trial prospectively testing a 
treatment that has shown efficacy for acute flare more important to conduct. Preventing GPP 
flares with a safe and effective treatment will meet a high unmet need to have a proven 
treatment available for patients with frequent recurrence of this disruptive condition with high 
morbidity and associated mortality.
An open-label, single arm study trial (1368.11) has been conducted and demonstrates the 
proof-of-concept of a single dose of BI 655130 in patients with a moderate to severe flare of 
GPP. In total, seven patients have been treated with a single IV administration of 10mg/kg of
BI 655130. A single dose of BI 655130 resulted in the rapid and sustained remission of 
clinical symptoms, with a good safety and tolerability profile. For further details and most 
recent results refer to the current IB (c03320877) and published letter in the New England 
Journal of Medicine (P19-01888). A follow-up randomized, double-blinded and placebo 
controlled Phase II study has been designed and is ongoing to confirm the efficacy and safety 
in this population (1368-0013). Also, an open-label, long term extension study (1368-0025) is 
ongoing to assess the safety and efficacy of BI 655130 treatment in patients with Generalized 
Pustular Psoriasis (GPP), who have completed the previous BI 655130 GPP trials.
The primary objective of this Phase IIb GPP trial is to provide dose-ranging data for 3 dose 
regimens of BI 655130 (with each regimen consisting of a loading dose and a separate 
maintenance subcutaneous dose) compared to placebo and to evaluate efficacy, safety, and 
tolerability of BI 655130 at preventing GPP flares compared to placebo in patients with a 
history of recurrent GPP and currently (at screening and at randomization) presenting with a 
GPPGA score of 0 or 1 (clear or almost clear). Three subcutaneous (s.c.) doses will be used 
in order to establish benefit/risk of prevention across a wide range of exposure, and i.v.
treatment will be used to treat patients having onset of acute GPP flare, thereby gathering 
further data regarding the treatment of flares.
GPP is being extremely rare in general and especially in the paediatric population. It is 
anticipated that only a subset of available paediatric GPP patients would meet the criteria for 
GPP trial inclusion, thus limiting the feasibility of clinical development in this patient 


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 33 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
population. Thus, a separate clinical program in the paediatric population to sufficiently 
demonstrate efficacy and safety of BI 655130 is considered unfeasible. Therefore, 
adolescents from the age of 12 years and above will be included in the adult clinical program.
Based on the similarity of disease pathophysiology and mechanism of action of BI 655130 
between adolescents and adults and available data on extrapolation of safety and efficacy 
from adults to adolescents it is anticipated that adolescent patients aged 12 and < 18 years are 
expected to have a therapeutic benefit with an acceptable safety profile (see Section 4.1.2 for 
further details).
In order to be able to address future scientific questions, patients will be asked to voluntarily 
donate biospecimens for banking (please see Section 5.4). If the patient agrees, banked 
samples may be used for future biomarker research and drug development projects, e.g. to 
identify patients that are more likely to benefit from a treatment or experience an adverse 
event (AE), or to gain a mechanistic or genetic understanding of drug effects and thereby 
better match patients with therapies.
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 GPP patients. Data
from the completed PoC trial 1368.11 demonstrate that BI 655130 treatment rapidly reduces 
the flare severity and clears pustules, the primary lesion in GPP, a disease closely linked to 
loss of function mutations in the natural IL36R antagonist. Please refer to IB for additional 
details (c03320877).
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).
A total of an estimated 378 subjects have been exposed to single or multiple i.v. doses of BI 
655130 as of September 2019. For additional details please refer to IB (c03320877). BI 
655130 was safe and well tolerated in four healthy volunteers trials evaluating the i.v. and s.c. 
formulation.
1.4.2
Risks
There are no identified or potential risks for BI 655130, based on the toxicology program or 
any clinical trials conducted for this product to date (see also Section 1.2). No other IL-36 
receptor antagonist is currently approved, providing information on identified risks in 
molecules of this class.
The risks shown in the table below are hypothetical in nature; these are derived from general 
safety considerations of immunomodulatory drugs.


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 34 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
In order to protect the patient’s safety during conduct of this trial, an independent Data 
Monitoring Committee has been established for the periodic review of clinical trial safety 
data.
Table 1.4.2: 1
Risks
Hypothetical risks 
of clinical relevance 
for this trial
Summary of data, rationale for 
the risk
Mitigation strategy
Investigational Medicinal Product
Drug-induced liver 
injury (DILI)
Rare but severe event, thus under 
constant surveillance by sponsors 
and regulators.
Timely detection, evaluation, and 
follow-up of laboratory alterations 
in selected liver laboratory 
parameters to ensure patients´ 
safety. See also Section 5.2.6,
adverse events of special interest”
Systemic 
hypersensitivity 
reaction
After administration of any biologic 
agent or protein, there is a possibility 
of occurrence of adverse immune 
reactions which can be systemic (e.g. 
anaphylactic reactions) or local (e.g. 
redness, pruritus, and or swelling at 
the injection site).
Patients with a history of 
allergy/hypersensitivity to the 
systemically administered trial 
medication agent or its excipients are 
excluded from the trial.
In case of systemic 
hypersensitivity reactions 
including anaphylactic reaction 
emerging during or after 
administration of trial medication, 
the investigator should consider in 
accordance with severity of the 
reaction and local standard of care 
to interrupt and treat the condition. 
Systemic hypersensitivity reaction 
is defined as AESI. It is subject to 
close monitoring and investigators 
are requested to assess these 
conditions using the criteria 
discussed in the statement paper 
from Sampson HA [R11-4890].


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 35 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
Table 1.4.2: 1
Risks (cont.)
Hypothetical risks 
of clinical 
relevance for this 
trial
Summary of data, rationale 
for the risk
Mitigation strategy
Infections
Inhibition of the immune 
response with an immune-
modulating biologic may 
increase the risk of infections.
A recent characterisation of 
individuals with homozygous 
IL36R KO mutations revealed 
that normal immune function 
was broadly preserved 
suggesting that IL36 signalling 
pathway inhibition does not 
compromise host defenses [R17-
3632].
Screening procedures for 
infections will be established for 
this trial. Patients with any 
relevant chronic or acute 
infections including human 
immunodeficiency virus (HIV), 
viral hepatitis or tuberculosis are 
excluded from the trial. 
Treatment of infections should 
be initiated promptly according 
to standards of care.
Severe infections and 
opportunistic infections are 
considered AESI for this trial.
These conditions and serious 
infections are subject to close 
monitoring.
Malignancies
Inhibition of the immune 
response with an immune-
modulating biologic may 
increase the risk of a decreased 
immune defence against 
malignancies.
A recent characterisation of 
individuals with homozygous 
IL36R KO mutations revealed 
that normal immune function 
was broadly preserved 
suggesting that IL36 signalling 
pathway inhibition does not 
compromise host defences [R17-
3632].
Patients with a recent 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 BI 655130.
Diagnostics and treatment have 
to be initiated according to local 
standard of care.
Malignancies represent always 
serious adverse events and are 
subject to close monitoring.
Peripheral 
Neuropathy
Three cases reported by the 
investigator as Guillain-Barré 
Timely detection, evaluation, and 
follow-up of suspected 


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 36 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
Hypothetical risks 
of clinical 
relevance for this 
trial
Summary of data, rationale 
for the risk
Mitigation strategy
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.
peripheral neuropathies to ensure 
patients´ safety. 
Targeted Follow up questions to 
gather detailed information in 
case of any event during trial to 
ensure proper decision making. 
Trial treatment discontinuation 
criteria as well as criteria for trial 
treatment restart are 
implemented for relevant cases.
Table 1.4.2: 1
Risks (cont.)
Hypothetical risks 
of clinical 
relevance for this 
trial
Summary of data, rationale 
for the risk
Mitigation strategy
Trial procedures
Blood Sampling 
As with all blood sampling, 
there is a risk of mild pain, local 
irritation, or bruising (a black or 
blue mark) at the puncture site. 
Furthermore, there is a small 
These risks will be addressed by 
careful safety monitoring and 
risk mitigation measures such as
(a) close clinical monitoring for 


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 37 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
Hypothetical risks 
of clinical 
relevance for this 
trial
Summary of data, rationale 
for the risk
Mitigation strategy
risk of light-headedness and/or 
fainting. In rare cases, the 
puncture site can also become 
infected or nerves may be 
damaged, inducing long-lasting 
abnormal sensations 
(paresthesia), impaired 
sensation of touch and 
persistent pain.
AEs;
(b) selection of experienced sites 
and site staff;
(c) training.
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 
(a) close clinical monitoring for 
AEs;
(b) selection of sites with 
experienced site staff;
(c) training.
Other risks
Withdrawal of 
Standard of Care 
and Administration 
of Placebo/ BI 
655130
If the standard therapy is 
withdrawn and the patient is 
randomized to receive a 
placebo/BI 655130, the 
patient´s condition could get 
worse during the course of the 
trial.
In the event of a GPP flare, the 
option of rescue treatment with 
open label BI 655130 is available 
for patients on placebo. Also, in 
an event of disease worsening, 
treatment with standard of care is 
always an option per physician 
discretion for all randomized 
patients
Based on the findings in the nonclinical studies conducted to date and in accordance with 
international regulatory guidelines, the inclusion of Women of Child Bearing Potential 
(WOCBP) in this study is justified. To minimize the risk of unintentional exposure of an 
embryo or foetus to the investigational drug, WOCBP must agree to the requirements for the 
pregnancy testing and contraceptive methods described in the protocol.
Benefit-Risk Assessment in context of COVID-19 pandemic for patients participating in 
clinical trials investigating Spesolimab:
A thorough assessment based on the data available as of 18 May 2020 has been conducted to 
evaluate whether spesolimab may pose a higher risk associated with COVID-19 infection. 
Additionally, the general risk of COVID-19 infection in context of the trial population’s 


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 38 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
underlying disease and common co-morbidities was assessed. The key aspects of the 
assessment are summarized below. 
Spesolimab is an immune-modulating humanized monoclonal antibody that blocks the human 
IL-36 receptor and thereby the pro-inflammatory IL-36 pathway. Available non-clinical and 
clinical data in 378 subjects (see Investigators Brochure Version 7) 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 pandemic. Patients participating in trials with spesolimab are expected to benefit from trial 
treatment and interruption of treatment may worsen their disease. Published guidance for the 
use of biologics during the COVID-19 pandemic recommends to continue treatment with 
biologics (e.g. NICE COVID-19 rapid guideline: severe asthma [R20-2257], American 
College of Allergy, Asthma&Immunology [R20-2258], and National Psoriasis Foundation
[R20-2256]). In line with this guidance no systematic testing for SARS-CoV-2 is required to 
be performed on the trial. However, the investigator may choose to perform the testing as per 
his/her discretion if useful based on individual medical consideration and in the case of 
suspected COVID-19 infection. 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.
Every subject or patient will be assessed thoroughly, and individual benefit-risk assessments 
are made prior to study entrance and during the study by the investigator in respect of SARS-
CoV-2 infection. As any other acute infection a suspected or diagnosed COVID-19 infection 


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 39 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
should be treated according to the standard of care and interruption of study medication 
should be considered. In case of a confirmed infection, trial treatment will be discontinued 
immediately and appropriate measures for monitoring, treatment and quarantine will be 
implemented. The investigators will take the totality of information related to each single 
patient and the local COVID-19 situation into consideration when performing the individual 
benefit-risk assessment on a case-by-case basis. The patient may resume trial treatment 
following recovery from a SARS-CoV-2 infection if the patient is expected to derive clinical 
benefit, as agreed between the investigator and sponsor.
1.4.3
Discussion
Considering the medical need of the development of an effective and well tolerated drug for 
preventing GPP flares and the demonstrated effectiveness of BI 655130 (Spesolimab) for 
treatment of incident flares, the benefit of this trial is considered to outweigh the potential 
risks for and justifies the administration of BI 655130 (Spesolimab) to patients with
Generalized Pustular Psoriasis (GPP). Due to the lack of mechanism- or compound-related 
safety signals and the antagonistic mode of action of BI 655130 it is considered likely that 
GPP patients will not be exposed to undue risks.


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 40 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
The present trial will be performed to characterize the dose-response curve for BI 655130 in 
patients with a history of GPP (per European Rare and Severe Psoriasis Expert Network 
(ERASPEN) criteria) who are now (at screening and at randomization) presenting with a 
GPPGA score of 0 or 1 (clear, or almost clear). 
The primary objective of the trial is to demonstrate a non-flat curve and evaluate the dose-
response relationship for 3 subcutaneous dosing regimens of BI 655130 (with each regimen 
consisting of a single loading dose and a separate maintenance subcutaneous dosing regimen) 
versus placebo, on the primary endpoint, the time to the first GPP flare onset up to week 48.
The secondary objective is to demonstrate superiority versus placebo for each of BI 655130 
300 mg q4 weeks and BI 655130 300 mg q12 weeks on the primary endpoint, the time to the 
first GPP flare onset up to week 48, as well as the key secondary endpoint, the occurrence of 
at least one GPP flare up to 48 weeks.
Treatment comparisons will be made for randomized patients regardless of treatment 
adherence or discontinuation, and any use of rescue medication or investigator-prescribed 
SoC prior to week 48 (see Section 3.1 for definition), will be considered to represent the 
onset of a GPP flare.
Another objective is to evaluate safety and tolerability of multiple s.c. doses of BI 655130 in 
patients with history of GPP.
The use of i.v. dose of BI 655130 for treating patients with onset of acute GPP flare will be 
evaluated for safety and efficacy as an additional objective.
2.1.2
Primary endpoint(s)
The primary endpoint of the study is: 

Time to first Generalized Pustular Psoriasis (GPP) flare (defined by increase in 
Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) score by ≥ 2
from baseline and the pustular component of GPPGA ≥ 2) up to week 48.
For the estimand concept on the above-defined primary endpoint definition, any use of rescue 
medication, or investigator-prescribed Standard of Care (SoC), will be considered to 
represent a GPP flare onset.


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 41 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
2.1.3
Secondary endpoint(s)
Key Secondary Endpoint:
For the secondary objective of the trial only, the key secondary endpoint which is included in 
the statistical testing strategy (see Section 7 for details) in a hierarchical manner subsequent 
to performance of the test on the primary endpoint is:

The occurrence of at least one GPP flare (defined by increase in GPPGA score by ≥ 2 
from baseline and the pustular component of GPPGA ≥ 2) up to week 48.
For the estimand concept on the above-defined key secondary endpoint definition, any use of 
rescue medication, or investigator-prescribed SoC, prior to week 48 will be considered to 
represent the onset of a GPP flare.
For the primary objective (i.e., dose-finding analysis) of the trial, this endpoint will be 
considered as secondary in nature only instead of key secondary.
Secondary Endpoints:
The below-defined secondary endpoints, for the secondary objective of the trial only, are 
included into the statistical testing strategy in a hierarchical manner subsequent to 
performance of the test on the key secondary endpoint. The study is not powered for the 
performance of these additional statistical comparisons.

Time to first worsening of Psoriasis Symptom Scale (PSS) up to week 48 defined as a 
4-point increase in total score from baseline. Intake of rescue medication, or 
investigator-prescribed SoC, will be considered as onset of a worsening.

Time to first worsening of Dermatology Quality of Life Index (DLQI) up to week 48 
defined as a 4-point increase in total score from baseline. Intake of rescue medication, 
or investigator-prescribed SoC, will be considered as onset of a worsening.
The below-defined secondary endpoints, for the secondary objective of the trial only, are not 
included into the statistical testing strategy.

Sustained remission, defined as a patient with a GPPGA score of 0 or 1 (clear or 
almost clear) at all visits up to week 48, without intake of rescue medication, or 
investigator-prescribed SoC.
Safety endpoint:

The occurrence of treatment emergent adverse events (TEAEs)


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 42 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 43 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 44 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN 
This is a multicenter, randomized, parallel group, double-blind, placebo-controlled Phase IIb 
study comprising of 3 active doses compared to placebo in adolescents from 12 years to less 
than 18 years of age and adult patients with history of GPP and currently presenting (at 
screening and at randomization) with a GPPGA score of 0 or 1 (clear or almost clear). Active 
treatment arms consist of active loading dose and active maintenance treatment. Please see 
Section 2.1.1 for details regarding the main objectives of the trial.  
Approximately 120 eligible patients with generalized pustular psoriasis (GPP) will be 
randomized in a 1:1:1:1 ratio to one of the following treatment arms (See Figure 3.1: 1):
Arm 1: BI 655130
600 mg total loading dose at Week 1/Day1 followed by 
maintenance treatment 300 mg s.c. q4 weeks
Arm 2: BI 655130
600 mg total loading dose at Week 1/Day1 followed by 
maintenance treatment 300 mg s.c. q12 weeks
Arm 3: BI 655130
300 mg total loading dose at Week 1/Day1 followed by 
maintenance treatment 150 mg s.c. q12 weeks
Arm 4: Placebo
Loading dose Placebo at Week 1/Day 1 followed by maintenance 
treatment placebo
The randomization will be stratified accounting for the stratification factor, use of systemic 
GPP medications at randomization (yes versus no) (see Section 7.4), and the blocking factors, 
region (Japan versus Non-Japan) and population (Adults versus Adolescents) (see Section 
7.4). A sufficient number of patients will be screened to meet the treatment goal of 120 
patients including at least 8 adolescent patients. Patients are considered enrolled (screened) in 
the study once they have signed the informed consent. All patients will receive the first dose 
of study medication on Day 1. 
Each randomized patient will receive 4 injections (loading dose) at Week 1/Day 1 followed 
by 2 injections (maintenance treatment) at subsequent visits until Week 44 if no flare occurs. 
This is required to keep the blinding. Please refer to Section 4.1.4 and Table 4.1.4: 1 for 
further details. The maintenance treatment period ends at Week 48.  
The primary statistical analysis of the trial will be performed once all randomized patients 
have either completed or early discontinued from the 48 week maintenance treatment period.
Patients will be offered to enter into an open label extension (OLE) trial (1368-0025), if they 
have completed the treatment period in this study up to EoS1(i.e. without premature 
discontinuation of trial treatment), agree to participate in the OLE trial and meet the 
eligibility criteria for the OLE trial.


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 45 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
Patients who do not qualify to enter into the open label extension (OLE) trial or who may 
have qualified, but do not agree to participate in the OLE trial, will be followed as described 
in section 3.3.4.1 handling of patients with premature treatment discontinuation.
The primary analysis of this trial is planned to be performed once all randomized patients
have completed or early discontinued from the 48 week treatment period; 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 randomized patients have completed the trial (including any follow-
up period) if applicable.
The primary analysis and final analysis may be performed as a single analysis (at the time of
trial completion), if, prior to the time of the primary analysis, the trial team agrees that the 
expected time interval between the planned analyses is insufficient to justify the performance 
of separate analyses.
Handling of GPP Flares: 
If a patient experiences the first GPP flare (increase in GPPGA score by ≥ 2 from baseline 
and the pustular component of GPPGA ≥ 2) during the randomized maintenance treatment 
period, a rescue treatment with i.v. open label dose of 900 mg BI 655130 should be
administered (R1/D1). The investigators should encourage the patient to inform them at the 
first signs of onset of a GPP flare. If a patient suspects that they have a GPP flare in between 
the protocol specified scheduled visits, they should contact the investigator to determine 
whether to make an unscheduled visit and return to the clinic/site for assessment. After 
confirming the onset of a GPP flare requiring treatment and subsequently receiving the i.v. 
dose of BI 655130, the patients will be seen at R2/D4 and R3/D8 of week1 (daily if 
hospitalized), week 2, week 3, week 4, and week 8 of the rescue treatment period (see Flow 
Chart 2). A patient may qualify to receive another rescue treatment with open label i.v. dose 
of 900 mg of BI 655130 at R3/D8, if either of the following criteria are met.

For patients with GPPGA score of  ≥3 and a pustular component of GPPGA of 
≥2 at R1: the total GPPGA is ≥2 and the pustular component of GPPGA is  ≥2 at 
R3/D8.

For patients with GPPGA score of 2 and a pustular component of GPPGA of ≥2 
at R1: the pustular component of GPPGA is  ≥2 at R3/D8.
For patients who receive the administration of the first rescue treatment with open label i.v. 
(OL) BI 655130 for the first GPP flare up to Week 34 (Day 239) of randomization, after 12 
weeks following the day of rescue i.v. treatment administration (R1 in Flow Chart 2) and 
response of the GPP flare, they will start the OL s.c. maintenance treatment period to receive 
the OL s.c. dose of 300 mg BI 655130 q12w. The visits of BI 655130 q12w during the OL 
s.c. maintenance treatment period should follow Flow Chart 1. Therefore, the visit of the first 
s.c. OL maintenance treatment should be assigned to a planned visit per Flow Chart 1 by 
comparing to the day of the first randomized treatment (V2/D1 in Flow Chart 1). If the first 
dose of OL s.c. maintenance treatment is outside of any scheduled visit window by ±7 days 
per Flow Chart 1, it needs to be assigned to one of the scheduled visits by extending each 
visit time window to -13/+14 days of the original CTP planned visit date, defined relative to 


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 46 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
the day of first randomized treatment, Day 1. See Table 3.1: 1 for the detailed rules of visit 
assignment for the first dose of OL s.c. maintenance treatment. Then the following OL s.c. 
maintenance doses (if applicable) will be administered within original visit window by ±7 
days per Flow Chart 1.  Note that once the first dose of OL s.c. visit assignment referring to 
Flow Chart 1 is calculated (see Table 3.1:1), all study procedures scheduled for this visit and 
subsequent OL maintenance treatment visits should be completed as per  open label 
maintenance treatment period in Flow Chart 2.
During the maintenance treatment with OL s.c. dose of 300 mg BI 655130 q12 weeks, if the 
patient’s GPPGA total score increases by ≥ 1 (with or without the presence or new 
appearance of pustules), or if there is an increase in the pustular component of GPPGA ≥ 1
from any of the previous OL maintenance visit(s), then the investigator may treat the patient 
with intensified maintenance therapy with open label s.c. dose of 300 mg BI 655130 q4
weeks. 
During the OL maintenance treatment period, the patients are to come q4 weeks irrespective 
of whether the patient is on q12 week dosing schedule or q4 week intensified maintenance 
dosing schedule.


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 47 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
Table 3.1: 1
Time windows for the visit assignment of the first OL s.c. maintenance 
treatment based on planned visit day in Flow Chart 1
Applicable for patients who receive the administration of the first rescue treatment with open 
label i.v. (OL) BI 655130 for the first GPP flare up to Week 34 (Day 239) of randomization
1 The first dose of s.c. OL maintenance treatment is scheduled at 12 weeks after the 1st rescue i.v. treatment of BI 655130.
This visit should be organized within the allowed time window relative to the day of the rescue treatment (per Flow Chart 2), 
and subsequently, by comparing to the day of the first randomized treatment (Day 1) and by applying the rules presented in 
this table, assigned to a scheduled OL maintenance dosing visit (per Flow Chart 1)
2 The latest possible day to give the first dose of OL s.c. BI 655130 is Day 323 (i.e. the last day of Week 46), it will be 
assigned to Week 44 visit.
3 The extended time window is only for the first dose of OL s.c. maintenance treatment, the time window for subsequent 
visits will be based on Flow Chart 1.
For patients who receive the administration of the first rescue treatment with open label 
i.v. (OL) BI 655130 for the first GPP flare after Week 34 (Day 239) of randomization,
they will not receive any further open label s.c. maintenance treatment of BI 655130 after 
the rescue treatment period. Depending on when the rescue i.v. treatment was 
administered these patients may not need to attend all scheduled visits in the rescue 
treatment period as described in Flow Chart 2 prior to Week 48 of randomization. Please 
refer to Table 3.1:2 for the follow up visits required based on the time of their 
administrations of rescue treatment with BI 655130. These patients will be rolled over
into the open label extension (OLE) trial at week 48 (after randomization) if they agree to 
Time window for the day of the1st s.c. 
OL maintenance treatment with BI 
655130 relative to the randomization 
day, Day 11
Assigned Visit Number/Planned Week for the 1st s.c. OL maintenance 
treatment with BI 655130
From
To
Visit Number
Planned Week
Planned Visit 
day
Based on the extended 
time window (only for 
the first dose3)
Day 82
Day 99
5
Week 12
85
-3/+14 days
Day 100
Day 127
6
Week 16
113
-13/+14 days
Day 128
Day 155
7
Week 20
141
-13/+14 days
Day 156
Day 183
8
Week 24
169
-13/+14 days
Day 184
Day 211
9
Week 28
197
-13/+14 days
Day 212
Day 239
10
Week 32
225
-13/+14 days
Day 240
Day 267
11
Week 36
253
-13/+14 days
Day 268
Day 295
12
Week 40
281
-13/+14 days
Day 296
Day3232
13
Week 44
309
-13/+14 days


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 48 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
and there is a clinical improvement (as per investigator judgement), otherwise, they will 
be followed for 16 weeks through EoS2.
Table 3.1: 2
Scheduled follow up visits (per Flow Chart 2) for patients who
receive the first rescue treatment with BI 655130 for the first GPP 
flare after Week 34 of randomization and will not receive any open 
label maintenance treatment. 
1EoS1should be performed at least 7 days after the last rescue treatment with i.v. OL BI 655130 is 
given. 
2If it was determined that a patient does not qualify or not agree to roll over to OLE, the patient still 
needs to attend the visits planned in the table if possible.
Handling of Investigator Prescribed Standard of Care (SoC) for GPP disease during 
Randomized Maintenance Treatment Period:
It is strongly recommended to avoid prescription of SoC to patients for GPP disease 
especially during the randomized maintenance treatment period. 
If a patient on randomized (blinded) treatments experiences disease worsening but does not 
meet the GPP flare definition (See Table 3.1: 3), it is highly recommended that the 
investigator does not prescribe Standard of Care (SoC) but to wait until the patient meets the 
definition of a GPP flare in order that an OL i.v. dose of BI 655130 may be administered 
instead at this time. During the randomized maintenance treatment period, if a patient is given 
any investigator prescribed SoC for GPP disease worsening, the patient needs to discontinue 
from any further study drug. Please refer to section 3.3.4.1 for further details on handling of 
patients with premature treatment discontinuation. 
Time window for the first rescue i.v. 
treatment with BI 655130 for the 1st GPP 
Flare relative to the randomization day, Day 1
Required follow up visits2
Start
End
Visit Number
Day 240
Day 260
R1, R2, R3, R4, R5, R6, R7, V14/EoS1
Day 261
Day 295
R1, R2, R3, R4, R5, R6, V14/EoS1
Day 296
Day 302
R1, R2, R3, R4, R5, V14/EoS1
Day 303
Day 309
R1, R2, R3, R4, V14/EoS1
Day 310
Day 316
R1, R2, R3, V14/EoS1
Day 317
Day 337
R1, R2, R3,V14/EoS11


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 49 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
Handling of Investigator Prescribed Standard of Care (SoC) for GPP disease during 
Rescue Treatment Period of the 1st GPP Flare:
Use of investigator prescribed SoC for GPP during the first 4 weeks of receiving i.v. rescue 
treatment with open label BI 655130 at R1/D1 is not allowed. The patient may be treated
with SoC as per PI’s discretion, but the patient needs to discontinue from any further study 
drug if SoC was given. In this case, the patient remains in the trial and, given his/her 
agreement, ideally should complete all the scheduled visits in rescue treatment period within 
Flow Chart 2 and as per Table 3.1:1 and then the remaining study visits in Flow Chart 1 as 
applicable up to Wk 48 from randomization. Please also refer to section 3.3.4.1 for further 
details on handling of patients with premature treatment discontinuation. 
If a patient achieves at least a partial response (See Table 3.1: 1) to i.v. rescue treatment with 
open label BI 655130, then topical treatments/topical corticosteroids, methotrexate, 
cyclosporine and retinoids may be used after four weeks following i.v. rescue treatment with 
open label BI 655130 at R1/D1. These patients may continue on receiving open label s.c. BI 
655130.
See section 4.2.2.2 for further details on the restricted medications list post visit 2 and 
exceptions. 
Handling of Investigator Prescribed Standard of Care (SoC) for GPP disease during 
Open Label Maintenance Treatment Period:
If the patient experiences any further disease worsening during the maintenance treatment 
with OL s.c. dose of 300 mg BI 655130 q12 weeks, investigator should treat the patient with 
intensified maintenance therapy with open label s.c. dose of 300 mg BI 655130 q4 weeks 
before prescribing any SoC. During the OL  maintenance treatment period, if a patient is 
given any investigator prescribed SoC (with the exception of topical treatments/topical 
corticosteroids, methotrexate, cyclosporine and retinoids) for GPP disease worsening, the 
patient needs to discontinue from any further study drug. Please refer to section 3.3.4.1 for 
further details on handling of patients with premature treatment discontinuation.


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 50 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
Table 3.1: 3
Study definitions
GPP Disease Worsening 
Disease worsening is defined as worsening of clinical 
status or GPP skin and systemic symptoms requiring 
treatment intervention in the investigator’s opinion. In the 
case that rescue medication with BI 655130 has not been 
given before, it is recommended, however, to wait until a 
patient meets the definition of a GPP flare in order that 
rescue medication could be administered instead of SoC.
GPP Flare 
Increase in GPPGA score by ≥ 2 from baseline* and the 
pustular component of GPPGA ≥ 2.
*Baseline value for efficacy measurements is the last 
value measured before 1st IMP dose at V2. 
Rescue Medication (OL i.v. 
dose of BI 655130)
Rescue with open label (OL) i.v. dose of BI 655130 to 
treat the first GPP flare during randomized treatment 
period. Rescue medication with OL i.v. dose of BI 655130 
is only allowed for the first flare during the 48 week 
randomized treatment period. 
Criteria to receive rescue 
treatment with  Open Label 
(OL) i.v. dose of 900 mg BI 
655130 at R3/D8 of rescue 
treatment period

For patients with  GPPGA score of  ≥3 and a 
pustular component of GPPGA of ≥2 at R1: the 
total GPPGA is ≥2 and the pustular component of 
GPPGA is  ≥2 at R3/D8.

For patients with GPPGA score of 2 and a 
pustular component of GPPGA of ≥2 at R1: the 
pustular component of GPPGA is  ≥2 at R3/D8 
Response to GPP Flare 
Treatment 
After rescue treatment with OL i.v. dose of BI 655130 (at 
R1/D1 or at R1/D1 and R3/D8), responders are patients 
who show no flare symptoms of moderate/severe intensity 
with a GPPGA score of <3 and a pustular component 
score of <2. In addition, the patient must have a decrease 
in GPPGA score by ≥ 1 from R1/D1.
Partial Response to GPP 
flare treatment
A GPPGA score 0 or 1 was not achieved, but a reduction 
in GPPGA score (to <3) or GPPGA pustule sub-score (to 
<2) was observed after receiving the rescue treatment with 
OL i.v. dose of BI 655130.
Criteria to switch the patient 
from OL s.c. dose of 300 mg 
BI 655130 q12 weeks to 
intensified maintenance 
therapy with open label s.c. 
dose of 300 mg BI 655130 
q4 weeks
If patient’s GPPGA total score increases by ≥1 (with or 
without the presence or new appearance of pustules), or if 
there is an increase in the pustular component of GPPGA 
≥1 from any of the previous OL maintenance visit(s).


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 51 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
Table 3.1: 3
Study definitions (Contd.)
Investigator prescribed 
Standard of Care (SOC) 
for GPP Disease

Medications used for treating worsening of GPP 
symptoms or clinical status (i.e. disease worsening) 
without GPP flare. It is recommended, however, to wait 
until a patient meets the definition of a GPP flare in 
order that rescue medication with BI 655130 could be 
administered instead in the case that rescue medication 
was never given before.
Or

Medications used for treating patients without a 
response of a GPP flare after two weeks following i.v. 
dose rescue treatment with open label BI 655130 at 
R1/D1 (see also Response of a GPP Flare above).
  Or

Medications used for treating any new GPP flare (i.e. 
subsequent flares) after receiving rescue medication for 
the first GPP flare experienced by the patient on the 
trial.
Note: Any use of Investigator Prescribed SoC for GPP 
disease during the trial will lead to the discontinuation of 
the trial treatment with the following exceptions.
Use of topical treatment/topical corticosteroid,
methotrexate, cyclosporine and retinoids is permitted after 
four weeks following i.v. dose rescue treatment with open 
label BI 655130 at R1/D1 and also during the OL 
maintenance treatment period. Refer to section 4.2.2.2 for 
further details.


Boehringer Ingelheim
    08 April 2021
BI Trial No.: 1368-0027
c28020464-03                                                                                Clinical Trial Protocol                                                                Page 52 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
Figure 3.1: 1
Overall study design
** In an event a patient experiences 1st GPP flare, please refer to Figure 3.1:2 and Section 3.1 for further details.
1 If the patient’s GPPGA total score increases by ≥ 1 (with or without the presence or new appearance of pustules), or if there is an increase in the pustular 
component of GPPGA ≥ 1, the investigator may treat the patient with intensified maintenance therapy of OL BI 655130 s.c. 300 mg q4weeks. Please refer to 
Section 3.1.
LD = Loading Dose; EoS = End of Study
2EoS 1: V14 will be recorded as the End of Study visit (i.e., EoS1) for patients who qualify and agree to enter the OLE trial (1368-0025). V14 will also be recorded as End of Study visit 
for patients who prematurely discontinue with the last dose of treatment up to and including Day 232 and who agree to complete all remaining study visits up to Wk 48 from 
randomization. Since these patients prematurely discontinued, they would not qualify to enter OLE trial. 
3EoS 2: It is applicable to patients who do not qualify or who do not agree to enter into the OLE Trial (1368-0025) at Wk 48. EoS2 is also applicable for 
patients who prematurely discontinue with the last dose of treatment after Day 232.  Since these patients prematurely discontinued, they would not qualify to
enter OLE trial. EoS2 will be their End of Study visit for the trial. 


Boehringer Ingelheim
    08 April 2021
BI Trial No.: 1368-0027
c28020464-03                                                                                Clinical Trial Protocol                                                                Page 53 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
1increase in GPPGA score by ≥ 2 from baseline and the pustular component of GPPGA ≥ 2
2Week represents the end of each week (e.g. End of Week1=D8, End of Week2 =D15, End of Week3 = D22, End of Week4 =D29, etc.). w* represents * weeks after the rescue treatment . 
3 Investigator may treat the patient with intensified maintenance therapy of OL BI 655130 s.c. 300 mg q4 weeks if the patient meets protocol specified criteria. Please refer to Section 3.1.
4 Patients who receive rescue treatment with BI 655130 up to Week 34 (Day 239) of randomization will start the OL s.c. maintenance treatment 12 weeks later following the response of the 
GPP flare. If the first dose of OL s.c. maintenance treatment is outside of any scheduled visit window by ±7 days per Flow Chart 1, it needs to be assigned to one of the scheduled visits 
following the rules in Table 3.1:1; Patients who receive rescue treatment with BI 655130 after Week 34 (Day 239) of randomization are to attend visits as described in Table 3.1:2.  
@The day of administration of rescue treatment = Day 1. All subsequent study Days are counted from this Day 1 except for ‘Last dose’ for the maintenance treatment, EoS1 and EoS2.
*Dosing days. Please refer to Section 3.1 for further details.  
5EoS1, V14 will be recorded as the End of Study visit (i.e., EoS1) for patients who qualify and agree to enter the OLE trial (1368-0025). V14 will also be recorded as End of Study visit for 
patients who prematurely discontinue with the last dose of treatment up to and including Day 232 and who agree to complete all remaining study visits up to Wk 48 from randomization. 
Since these patients prematurely discontinued, they would not qualify to enter OLE trial.
6EoS2 is applicable for patients who do not qualify or who do not agree to enter OLE trial (1368-0025) at Week 48. EoS2 is also applicable for patients who prematurely discontinue with 
the last dose of treatment after Day 232. Since these patients prematurely discontinued, they would not qualify to enter OLE trial. 
Figure 3.1: 2 Study design in the event a patient experiences 1st GPP flare


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 54 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
The rationale of this phase IIb trial is to provide dose-ranging data for 3 dose regimens of BI 
655130 compared to placebo and demonstrate a non-flat dose response curve, as well as to 
provide statistical evidence regarding the superiority for BI dose vs. placebo on the primary 
and key secondary endpoint. This trial with BI 655130 and placebo is to be conducted in 
patients with a known history of frequent GPP flares and currently (at screening and at 
randomization) with GPPGA score of 0 or 1 (clear/almost clear). Patients with frequent flares 
(with at least 2 presentations/year, at least one of which had evidence of either fever and/or 
elevated CRP and / or elevated WBC.) of GPP without background medication or patients 
under treatment with background medications which is not adequately controlling the disease 
or not well tolerated are the primary group with an unmet need for a proven, safe treatment to 
prevent flares.  Thus, these patients are proper study population to participate in this trial. In 
trial 1368.11 (PoCP trial in GPP), the patients had a treatment free period (no other 
concomitant GPP treatments) during which all flares were successfully treated with BI 
655130. As all patients experiencing flares in that trial were successfully treated, treating 
with placebo in this trial (1368-0027) is a reasonable control to provide an estimate of the 
number of flares prevented by subcutaneous BI 655130.  Treatment of the incident flares with 
intravenous BI 655130 will provide further evidence of the effectiveness in treating incident 
flares.  For treatment of incident flares, a second randomization between BI 655130 and 
placebo is not justified due to the high IV exposure and long maintained effect seen in 
1368.11, in addition, the placebo effect will have already been evaluated in trial 1368-0013.  
Based on data from 1368.11 which demonstrated rapid treatment onset of control of flare 
symptoms and resolution including sustained response up to 20 weeks, a parallel group, 
randomized, double-blind and placebo controlled trial where GPP patients with GPPGA score 
of 0 or 1 (clear/almost clear) was considered most appropriate to evaluate the efficacy, safety
and tolerability of BI 655130 at preventing GPP flares in patients with history of GPP.  In the 
1368-0027 trial, any randomized patient, who experiences a disease flare during the trial 
duration of sufficient severity to have a medical need to treat, will be offered rescue treatment 
with open label i.v. dose of BI 655130.
The incidence of flares in an untreated population is unknown, so a placebo regimen is 
essential for this trial.  Demonstrating a high incidence is essential to demonstrating that 
patients benefit from preventive treatment.  No active control group is included in this trial as 
there is currently no drug approved for the prevention of GPP flare. Secukinumab 
(Cosentyx®), infliximab (Remicade®), ixekizumab (Taltz®), brodalumab (Lumicef®), 
adalimumab (Humira®), guselkumab (Tremfya®), Risankizumab and certolizumab 
(Cimzia®) are only registered in Japan for the treatment of GPP. For secukinumab, 
authorization was granted because of long-term treatment data (52 weeks) derived from a 
single open label clinical trial conducted in 12 patients with chronic GPP symptoms and an 
endpoint at 16 weeks (R16-1462). In the absence of a treatment studied in controlled trials for 
prevention, the results of any active control would not be interpretable in comparison to 
Spesolimab. Moreover, due to the absence of approved drugs and a commonly accepted 
treatment algorithm, patients in this trial would have a very heterogenous pre-treatment 


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 55 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
history as different SoC are preferentially used in different countries, which prevents the 
selection of suitable active comparator which is relevant for all patients. 
Thus, study 1368-0027 will be a multicenter, randomized, double-blind, placebo-controlled 
Phase IIb dose finding study with multiple doses of BI 655130/placebo in patients with 
history of GPP flares and currently (at the time of screening and at randomization) with 
GPPGA score of 0 or 1 (clear/almost clear). The primary objectives of this trial are described 
in Section 2.1.1. It is planned that patients will continue to receive randomized treatments
until the end of the treatment period. 
For this trial, it is planned to include patients with history of GPP regardless of the mutation 
status (the status will be investigated during the trial) for the following reason:

Efficacy has been seen in GPP patients both with and without the IL36RN mutation (early 
response to flare treatment with BI 655130 in 1368.11).

In addition to the described IL36RN mutation, other mutations in the same gene and other 
genes linked to the IL36 pathway have been described (please see Section 1.1 “Medical 
Background”).  This points to a general role of the IL36 pathway as disease trigger/driver.

Mutation status is only available for a subset of GPP patients.
Patients who show no flare symptoms of moderate/severe intensity at EoS1 and who satisfy 
the inclusion/exclusion criteria of subsequent open-label extension trial (1368-0025) will 
receive an option to continue receiving treatment for GPP with s.c. dosing once the patient 
completes EoS1 on this trial. See Section 3.1 for additional details on the trial design.
3.3
SELECTION OF TRIAL POPULATION
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 have 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 and assessed as eligible will be allowed to 
continue to randomisation and treatment.
A suitable number of countries/sites will participate globally in order to minimize the risk of 
under recruiting and to meet the goal of 120 patients (including 8 adolescent patients) 
randomized. Due to the rareness of the disease, a high number of sites will participate relative 
to the number of patients required. 
A log of all patients enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the Investigator Site File (ISF) irrespective of whether they have been treated 
with investigational drug or not.
If a patient is randomized in error (does not meet all inclusion criteria or meets one or more 
exclusion criteria), the sponsor should be contacted immediately.


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 56 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
3.3.1
Main diagnosis for trial entry
This study will assess the treatment of patients with history of GPP flares with stable disease 
at the time of randomization.
At screening, the confirmation of history (diagnosis) of GPP is based on the consensus 
diagnostic criteria defined by the ERASPEN (R18-1705) and the patients must have had 
previous evidence (for past GPP flares) of either fever, and/or asthenia, and/or myalgia, 
and/or elevated C-reactive protein, and/or leukocytosis with peripheral blood neutrophilia 
(above ULN). 
The ERASPEN diagnosis criteria are:
Primary, sterile, macroscopically visible pustules on non-acral skin (excluding cases where 
pustulation is restricted to psoriatic plaques)

With or without systemic inflammation

With or without plaque-type psoriasis

Either relapsing (>1 episode) or persistent (>3 months)
Please refer to Section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the in- and exclusion criteria.
3.3.2
Inclusion criteria
Each patient must meet all of the following inclusion criteria to be included into the trial:
1. Patients with a known and documented history of GPP per ERASPEN criteria (see 
Section 3.3.1) regardless of IL36RN mutation status, with at least 2 presentations of 
moderate to severe GPP flares with fresh pustulation (new appearance or worsening) in 
the past.
2. Patients with a GPPGA score of 0 or 1 at screening and randomization.
3. Patients who are not on concomitant GPP treatment at time of randomization (V2) must 
have had at least two presentations of moderate to severe GPP flare in the past year, at 
least one of which had evidence of either fever and/or elevated CRP and/or elevated 
WBC, and/or asthenia and/or myalgia.
4. Patients who are not on concomitant GPP treatment at time of randomization (V2) but 
who were on concomitant GPP treatment until shortly before randomization (V2) (≤ 12 
weeks before randomization), these patients must have a history of flaring while on 
concomitant treatment for GPP or in case of dose reduction or discontinuation of their 
concomitant medication.
5. Patients who are on concomitant treatment regimen with retinoids and/or methotrexate 
and/or cyclosporine must stop at the day of randomization (V2). These patients must have 


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 57 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
a history of flaring while on concomitant treatment for GPP or in case of dose reduction 
or discontinuation of these concomitant medications.  
6. Male or female patients, aged 12 to 75 years at screening. For all patients, a minimum 
weight of 40 kg is required.
7. Signed and dated written informed consent and assent in accordance with ICH-GCP and 
local legislation prior to admission in the trial.
8. 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 sterilisation methods include hysterectomy, bilateral
salpingectomy and bilateral oophorectomy. Tubal ligation is not a method of permanent sterilization. A postmenopausal 
state is defined as no menses for 12 months without an alternative medical cause.
3.3.3
Exclusion criteria
Patients meeting any of these exclusion criteria must not be enrolled into the trial:
1. Patients with SAPHO (Synovitis–acne–pustulosis–hyperostosis–osteitis) syndrome.
2. Patients with primary erythrodermic psoriasis vulgaris.
3. Severe, progressive, or uncontrolled hepatic disease, defined as >3-fold Upper Limit of 
Normal (ULN) elevation in AST or ALT or alkaline phosphatase, or >2-fold ULN 
elevation in total bilirubin.
4. Treatment with:
a.
Any restricted medication as specified in the CTP, or any drug considered likely 
to interfere with the safe conduct of the study, as assessed by the investigator.
b. Any prior exposure to BI 655130 or another IL36R inhibitor biologic.
5. 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. 
6. Relevant chronic or acute infections including active tuberculosis, human 
immunodeficiency virus (HIV) infection or viral hepatitis at the time of randomization. 
A patient can be re-screened if the patient was treated and is cured from the acute 
infection.
7. Active or Latent TB: 

Patients with active tuberculosis should be excluded

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 


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 58 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
investigator within the last 3 years and at the latest at the time of screening (i.e. 2 
to 4 weeks before study drug administration); patients may be re-screened once to 
meet this criterion)

Patients with suspected false positive or indeterminate QuantiFERON® (or if 
applicable, T-Spot®) TB result may be re-tested once 

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 ≥10mm (≥5mm if receiving ≥15mg/d prednisone or 
its equivalent) is considered positive.
8. History of allergy/hypersensitivity to the systemically administered trial medication 
agent or its excipients. 
9. Exclusion criteria removed in global amendment 1. Numbering of subsequent criteria 
was not changed.
10. Any documented active or suspected malignancy or history of malignancy within 5 
years prior to screening, except appropriately treated basal or squamous cell 
carcinoma of the skin or in situ carcinoma of uterine cervix. 
11. 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). Exception: Patients on the 1368-0013 study who are in 
the screening period and who did not get a chance to get randomized on the 1368-
0013 trial due to the study meeting target number of randomized patients or who did 
not qualify to get randomized into the 1368-0013 study can be enrolled on the 1368-
0027 study if they meet all inclusion/exclusion criteria.
12. Women who are pregnant, nursing, or who plan to become pregnant while in the trial. 
Women who stop nursing before the study drug administration do not need to be 
excluded from participating; they should refrain from breastfeeding for 16 weeks after 
the last study drug administration.
13. Major surgery (major according to the investigator’s assessment) performed within 12 
weeks prior to receiving first dose of study drug or planned during the study, e.g. hip 
replacement, aneurysm removal, stomach ligation, as assessed by the investigator.
14. Evidence of a current or previous disease, medical condition (including chronic 
alcohol or drug abuse or congestive heart disease or any condition) other than GPP, 
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 study participant unreliable to adhere to the 
protocol, comply with all study visits/procedures or to complete the trial, compromise 
the safety of the patient or compromise the quality of the data.


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 59 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
3.3.4
Withdrawal 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.
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 sections 5.2.6.2.1 and 
5.2.6.2.2).
3.3.4.1
Discontinuation of trial treatment
An individual patient will discontinue trial treatment if:

The patient wants to discontinue trial treatment, without the need to justify the decision.

The patient has repeatedly shown to be non-compliant with important trial procedures 
and, in the opinion of both, the investigator and sponsor representative, is not willing or 
able to adhere to the trial requirements in the future. 

The patient needs to take concomitant medication that interferes with 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 (as defined in Section 5.2.6.1.4) is detected without identification 
of an alternative cause in the work-up according to the “DILI checklist”, the patient 
should not receive subsequent doses of 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 GPP symptoms requiring treatment with restricted 
medication (Section 4.2.2.1) in the investigator’s opinion.

The patient experiences an infection with SARS-CoV-2 (as confirmed by PCR test). The 
patient may resume trial treatment following recovery from SARS-CoV-2 infection if the 
patient is expected to derive clinical benefit, as agreed between the investigator and 
sponsor.

If peripheral neuropathy is suspected, treatment with spesolimab should be temporarily 
discontinued until a full neurological investigation has been conducted.  After completion 
of the neurological investigation, treatment can be restarted based on medical judgement 
of the investigator. 
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. 


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 60 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
Even if the trial treatment is discontinued, the patient remains in the trial and, given his/her 
agreement considering the GCP-guidelines, ideally should follow all of the remaining 
scheduled study visits and procedures as outlined in the Flow Chart 1 or Flow Chart 2 (as 
applicable) and Section 6.2.3 up to Wk 48 from randomization; If a patient is not willing to 
follow the whole visit schedule, the patient should at a minimum be followed for 16 weeks 
after last study drug administration (REP) and at least the scheduled visit at Week 48 (i.e. at 
the end of treatment period) should be conducted. Patients refusing to return to the study site 
should at least provide safety information by phone at the respective visits.
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. This 
discussion, as well as the patient’s decision, should be well documented in the source. 
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. Emergence of any efficacy/safety information invalidating the earlier positive benefit-
risk-assessment that could significantly affect the continuation of the trial.
Deviations from GCP, the trial protocol, or the contract impairing the appropriate conduct of 
the trial.
Further 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).


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 61 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
The investigational product has been manufactured by BI Pharma GmbH & Co. KG, 
Biberach, Germany. The BI 655130 molecule is an anti-human IL-36 receptor monocloncal 
antibody heterodimer with a molecular weight of approximately 146 kDa.
BI 655130 solution for injection (s.c. administration) is formulated at 150mg/mL presented in 
a 1mL pre-filled syringe (150mg/syringe).
BI 655130 solution for infusion (i.v. administration) is formulated at 60 mg/mL presented in 
a 10 mL vial with a nominal fill volume of 7.5 mL (450 mg).
4.1.1
Identity of the investigational medicinal products
Table 4.1.1: 1
Test Product: BI 655130 (Spesolimab)
BI 655130 for Maintenance Treatment (including loading dose):
Substance:
BI 655130
Pharmaceutical formulation:
Solution for injection
Source:
BI Pharma GmbH & Co. KG, Biberach, Germany
Unit strength:
BI 655130 150 mg/PFS (150 mg/mL), 1 mL fill volume
Posology:
Arm 1: 600 mg total loading dose at Week 1/Day1 
followed by maintenance treatment 300 mg s.c. q4 weeks
Arm 2: 600 mg total loading dose at Week 1/Day1 
followed by maintenance treatment 300 mg s.c. q12 
weeks
Arm 3: 300 mg total loading dose at Week 1/Day1 
followed by maintenance treatment 150 mg s.c. q12 
weeks
Mode of administration:
s.c. injection


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 62 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
Table 4.1.1: 1 (cont’d)
Test Product: BI 655130 (Spesolimab)
BI 655130 for Rescue Treatment (at R1/D1 Or at R1/D1 & R3/D8): 
Substance:
BI 655130
Pharmaceutical formulation:
Solution for infusion
Source:
BI Pharma GmbH & Co. KG, Biberach,  
Germany
Unit strength:
BI 655130 450 mg/vial (60 mg/mL), 7.5 mL 
fill volume
Posology:
900 mg i.v. dose 
Mode of administration:
i.v. infusion 
Table 4.1.1: 2
Placebo comparator
Substance:
Placebo to match Solution for Injection(BI 655130)
Pharmaceutical formulation:
Solution for injection
Source:
BI Pharma GmbH & Co. KG, Biberach, Germany
Unit strength:
Placebo to match Solution for Injection (BI 655130), 
1mL PFS
Posology:
Arm 4: Loading dose Placebo at Week 1/Day 1 
followed by maintenance treatment placebo
Mode of administration:
s.c. injection
4.1.2
Selection of doses in the trial and dose modifications
In the proof-of-concept trial 1368.11 in GPP patients, a single intravenous dose of 10 mg/kg 
of BI 655130 was tested. The proof-of-concept (PoC) for IL36R inhibition in GPP was 
achieved in these patients who showed rapid clinical responses (for further detail, refer to 
Section 1.2). GPPASI score was measured at weeks 1, 4, 12 and 20 and the positive response 
was maintained up to week 20 following this single i.v. dose of BI 655130. Additionally, a 
300 mg s.c dose of BI 655130 has been tested in healthy volunteers to obtain PK information 
following sub-cutaneous administration of BI 655130.
The aim of the current trial (1368-0027) is to provide dose-ranging data for 3 subcutaneous 
dosing regimens of BI 655130 with the proposed doses of 300 mg s.c. q4w and 300 mg s.c. 
q12w after a loading dose of 600 mg each and 150 mg q12w after a loading dose of 300 mg. 
These three doses/regimen were selected to test a wide range in exposure to thoroughly 
evaluate the exposure-response relationship of BI 655130 in GPP patients.


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 63 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
If a patient experiences a GPP flare (increase in GPPGA score by ≥ 2 from baseline and the 
pustular component of GPPGA ≥ 2) during the randomized maintenance treatment period, a 
rescue treatment with i.v. open label dose of 900 mg BI 655130 is to be administered at 
R1/D1. A patient may qualify to receive another dose of i.v. open label 900 mg BI 655130 at 
R3/D8 if protocol specified criteria are met (please refer to Table 3.1:1).  The 900 mg BI 
655130 i.v dose was selected based on positive data from 1368.11 and thus considered 
reasonable to continue with the dose of 10 mg/kg to maintain the PK exposures observed in 
the trial 1368.11. A fixed dose of 900 mg was selected to give the flexibility to recruit 
patients greater than 70 kg body weight. BI 655130 has been tested in healthy volunteers up 
to 20 mg/kg (given weekly in the MRD trial 1368.2) and was shown to be safe and tolerable. 
Evaluation of the PK data in GPP patients suggest that BI 655130 exposure in patients was 
lower when compared to PK in healthy volunteers (HVs). Thus, the selected fixed dose (900 
mg single i.v. dose) is anticipated to be within safety limits for patients with a lower weight 
as well.
Including adolescent patients with a minimum weight of 40 kg is not expected to pose any 
safety concern as the predicted exposures in adolescents with the doses planned are expected 
to be below the maximum exposures tested in healthy volunteer trials. Using the population 
PK model built from healthy volunteers and PK data from PPP patients, one thousand
simulations were performed for a typical 40 kg subject taking into account inter-individual 
variability in model parameters. 
Forty kilograms was chosen for the simulations as this represents the weight of the lightest 
subject that could be enrolled in this trial.  Assuming the subjects receive the highest 
maintenance dose of 300 mg q4w until week 32 and then receives a 900 mg IV rescue dose at 
week 33 (worst case scenario for exposure, where the IV dose is administered 1 week after 
the last s.c. dose representing administration at tmax), the predicted median Cmax following 
rescue dosing is 487,000 µg/L (314,000 – 756,000 µg/L (90% prediction interval)). This is 
well below the maximum observed concentration of 992,000 µg/L following the maximum 
tested dose of 20 mg/kg qw (x4 doses) in trial 1368.2. 
Similarly, the model predicted median AUC over 12 weeks following rescue dosing is 
9,620,000 µg/L *day (6,320,000 – 14,100,000 µg/L*day (90% prediction interval)) which is 
well below the model predicted AUC over 12 weeks of 31,900,000 µg/L*day (26,300,000 –
38,700,000 µg/L*day (90% prediction interval)) following the maximum tested dose of 20 
mg/kg qw (x4 doses) in trial 1368.2.
The weight cutoff was chosen as 40 kg (median weight of a 12 year old subject) and not 30 
kg (3rd percentile for a 12 year old subject) because the probability of exceeding the 
maximum observed concentration was calculated as 0.5% for subjects weighing 40 kg while 
the probability of exceeding the maximum observed concentration was 4.4% for subjects 
weighing 30 kg.
The expected exposure profile is shown in Figure 4.1.2:1. The blue line and shaded area 
represents the median and 90% prediction interval following 300 mg q4w maintenance 
dosing and then administration of a rescue dose at week 33 for a typical 40 kg adolescent, 
taking into account inter-individual variability in model parameters. The black line and 
shaded area represents the median and 90% prediction interval for the same scenario in 


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 64 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
adults. The dashed blue line represents the maximum observed concentration of 992,000 ug/L 
following 20 mg/kg qw IV (4 doses) given in adults in trial 1368.2 which is the highest 
regimen tested to date in healthy volunteers.
The figure shows similar overlapping concentration time profiles for adults subjects (shown 
in grey) compared to an adolescent who meets the minimum weight requirement of 40 kg 
(shown in blue) although slightly higher exposure is expected in adolescents. Additionally, 
although the figure below demonstrates similarity in exposure between adults and adolescents 
for the highest dose to be tested, this similarity in exposure holds for all lower dose groups. 
Overall, the dosing regimens to be tested in adolescents is expected to be similar to adults and 
within the safe exposure range established for Spesolimab in adult patients.
Figure 4.1.2:1
Expected exposure profile
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.
During Visit 2 and after the patient’s eligibility is confirmed, patients will be randomized to 
blinded treatment arms according to a randomization plan in a 1:1:1:1 ratio. Randomization 
will be stratified by the stratification factor, concomitant use of systemic GPP medications at
randomization (yes versus no) (see Section 7.4) and the blocking factors, region (Japan 
versus Non-Japan) and population (Adults versus Adolescents) (see Section 7.4). The 
assignment will occur in a blinded fashion via Interactive Response Technology (IRT).


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 65 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
At randomization as well as subsequent medication administration visits (including rescue 
treatment administration visit (s) with OL BI 655130 in the event that a patient experiences a 
GPP flare), IRT will assign medication numbers. Note that the medication number is different 
from the patient 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 study drug, a urine pregnancy test will be performed on site. If 
this test has a positive result, the administration of study drug should not proceed and this 
urine test should be confirmed by a serum pregnancy test.
To maintain the treatment blind during the trial, all patients will receive 4 injections at Week 
1/Day 1 for the loading dose followed by 2 injections at subsequent dosing visits in the every 
4 weeks schedule.
Table 4.1.4: 1
Treatments used in this trial
Randomized Maintenance Treatment Period
Arm
Loading Dose
(Blinded)
Week 1/Day 1
Maintenance Treatment
(Blinded)
Week 4 through Week 44
Arm 1: 
300 mg BI 
655130 q 4 
weeks
4 x BI 655130 150 mg/PFS 2 x BI 655130 150 mg/PFS s.c. q4 weeks
Maintenance Treatment Period
Arm
Loading Dose
(Blinded)
Week 1/Day 1
Maintenance Treatment
(Blinded)
Week 4 through Week 44 
Arm 2: 
300 mg BI 
655130 q 12 
weeks
4 x BI 655130 150 mg/PFS 2 x BI 655130 150 mg/PFS s.c. q12 weeks
(i.e. at Week 12, Week 24, Week 36)
2 x Placebo to match Solution for Injection 
(BI 655130),  1mL PFS, at the intervening 
visits (i.e. at Week 4, Week 8, Week 16, 
Week 20, Week 28, Week 32, Week 40 and 
Week 44)


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 66 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
Table 4.1.4:1 (cont’d) Treatments used in this trial
Maintenance Treatment Period
Arm
Loading Dose
(Blinded)
Week 1/Day 1
Maintenance Treatment
(Blinded)
Week 4 through Week 44 
Arm 3: 
150 mg BI 
655130 q 12 
weeks
2 x BI 655130 150 mg/PFS 
2 x Placebo BI 655130 
150mg/ml, 1mL PFS, 
0mg/syringe
1 x BI 655130 150 mg/PFS 150 mg s.c. + 1 x 
Placebo to match Solution for Injection (BI 
655130),  1mL PFS s.c. q12 weeks (i.e. at 
Week 12, Week 24, Week 36)
2 x Placebo to match Solution for Injection 
(BI 655130),  1mL PFS at the intervening 
visits (i.e. at Week 4, Week 8, Week 16, 
Week 20, Week 28, Week 32, Week 40 and 
Week 44)
Arm 4: 
Placebo
4 x Placebo BI 655130 
150mg/ml, 1mL PFS, 
0mg/syringe
2 x Placebo to match Solution for Injection 
(BI 655130),  1mL PFS s.c. q4 weeks
In case of a GPP Flare
Rescue Treatment
(Open Label)
at R1/Day 1 Or at R1/Day1 
& R3/Day8
Maintenance Treatment
(Open Label)
2 x BI 655130 450 mg/vial 
(60 mg/mL)
2 x BI 655130 150 mg/PFS s.c. q12weeks
Or
2 x BI 655130 150 mg/PFS s.c. q4weeks           
(intensified maintenance therapy)
During the randomized maintenance treatment period (Blinded) and maintenance treatment 
period (Open Label), the treatment will be administered subcutaneously. Injections during 
randomized maintenance treatment period will be given in a double blind fashion. Injections 
being given in the same area should be at least 2 cm apart and should not be close to a vein. 
The injection site should avoid sites where the skin is tender, bruised, erythematous, or 
indurated, and should be alternated to other areas for subsequent doses. Detailed instructions 
for administration of the s.c. injections are provided in the ISF.
OL 900 mg BI 655130 i.v. dose(s) will be used as GPP flare treatment, followed by a 
maintenance dosing schedule with OL 300 mg BI 655130 s.c. q12 weeks (and subsequently
OL 300 mg BI 655130 s.c. q4 weeks, if needed). The infusion solution is intended to be 


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 67 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
intravenously administered over a period of 90 minutes. 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 minutes (3 hours).  Patients should be closely monitored for signs and symptoms of 
hypersensitivity reactions for 1 hour following the end of i.v. study drug administration. 
Hypersensitivity reactions should be treated according to medical standards.  Further based 
on his/her medical judgment the investigator will provide medications as needed. Detailed 
instructions for the preparation of the i.v. infusion solution, the volume to be administered 
and the infusion rate are provided in the ISF.
Subcutaneous administration of biologic agents may involve the risk of local (injection site) 
or systemic hypersensitivity reactions. Therefore, patients should be closely monitored for 
signs and symptoms of injection site or systemic hypersensitivity reactions following study 
drug administration. Study personnel should observe the injection site for signs of redness, 
swelling or hardness. They should also ask subjects 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 
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 and will be agreed on between investigator and BI 
clinical monitor (see also Section 6.2.2).
The administration of the study medication will be done under supervision of the 
investigating physician or a designee at the site. 
Dose modifications or adjustments are not permitted. 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 Day 1. In case of missed visits (during the randomized treatment trial 
period), the patients should be given the assigned medication for both visits (i.e. up to 1
missed visit and the current visit) at the next scheduled visit.
During the COVID-19 pandemic, physical visits to the sites may need to be restricted to 
ensure patient’s safety. Based on a thorough assessment of the benefits and risks, the 
investigator may still decide to continue the trial treatment and the administration of the study 
medication may be performed at patient’s home under the supervision of the investigating 
physician or a designee. The trial medication may be shipped to the patient’s home if 
acceptable according to local law and regulations. This must be approved by the sponsor’s 
trial team.
4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
To maintain the treatment blind during the trial, all patients will receive the blinded 
treatments every 4 weeks. Please refer to Section 4.1.4 and Table 4.1.4: 1 for further details.


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 68 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
The sponsor will remain blinded with regard to the randomized treatment assignments until 
the last randomized patient has completed or early discontinued from the 48 week treatment
period of the trial and the database is considered ready for unblinding to perform the primary 
analysis of the trial. Note that for the planned interim analysis of this trial (see details in 
Section 7.2.7), only clinical efficacy and safety data for the OL i.v. rescue treatment and OL 
s.c. maintenance treatment periods are intended to be reported; no unblinding of the initial 
randomized s.c. treatments is required.. 
With database lock for the primary trial analysis, the sponsor (including all trial personnel)
will be officially unblinded to the randomization details; investigators and patients will 
remain blinded until the official end of the trial (final trial analysis) when the last patient has 
completed through 16 weeks of trial safety follow-up (if applicable).
If the trial team agrees to perform the primary analysis and final analysis as one single 
analysis (at the time of trial completion), then patients, investigators, and sponsor personnel 
involved in the trial conduct will be unblinded to the randomized treatment assignments after
the database lock has been performed.
The randomization codes will be provided to bioanalytics prior to last patient out of the trial 
to allow for the exclusion from the analyses of PK samples taken from placebo patients. 
Bioanalytics will not disclose the randomization code or the results of individual 
measurements until the trial has been officially un-blinded to the sponsor. Sample drug levels 
and demographic data together with treatment assignments and dosing information may be 
made available to named individuals from the bioanalytics department for the purpose of PK 
dataset generation and analysis in accordance with the sponsor’s standard procedures.
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.
Section 4.1.5.2 provides the rules surrounding breaking of the randomization code.
4.1.5.2
Unblinding and breaking the code
Emergency unblinding will be available to the investigator / designee via IRT (for Japan: 
only to the investigator).  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 the safety of trial participants. The reason for unblinding must 
be documented in the source documents and/or appropriate eCRF page along with the date 
and the initials of the person who broke the code.
In case the automated unblinding option via the IRT system is malfunctioning, the IRT 
service provider can be contacted (24 hours a day coverage) and the treatment allocation can 
be obtained.  IRT support has direct access to the database and the treatment information can 
be manually obtained in case the automated process is not working properly.  Details about 
this process will be included in the ISF.


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 69 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
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 
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 Boehringer Ingelheim Pharma 
GmbH & Co. KG, Biberach, Germany. They will be packaged and labelled in accordance 
with the principles of Good Manufacturing Practice (GMP). Re-supply to the sites will be 
managed via an IRT system, which will also monitor expiry dates of supplies available at the 
sites.
For details of packaging and the description of the label, refer to the ISF.
4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area according to the recommended storage conditions on the medication label. A
temperature log must be maintained for documentation.
If the storage conditions are found to be outside the specified range, the CT Manager, as 
provided in the list of contacts, must be contacted immediately.
The trial medication must be administered in the manner specified in the CTP and 
instructions for IMP preparation handling and administration of BI 655130 or Placebo.
4.1.8
Drug accountability
The investigator or designee will receive the investigational drugs delivered by the sponsor
when the following requirements are fulfilled:

Approval of the clinical trial protocol by the IRB / ethics committee,

Availability of a signed and dated clinical trial contract between the sponsor and the 
investigational site,

Approval/notification of the regulatory authority, e.g. competent authority,

Availability of the curriculum vitae of the Principal Investigator,

Availability of a signed and dated clinical trial protocol,

Availability of the proof of a medical license for the Principal Investigator,

Availability of FDA Form 1572 (if applicable).
Investigational drugs are not allowed to be used outside the context of this protocol. They 
must not be forwarded to other investigators or clinics. 
The investigator or designee must maintain records of the product’s delivery to the trial site, 
the inventory at the site, the use by each patient, and the return to the sponsor or warehouse / 


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 70 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
drug distribution centre or alternative disposal of unused products. If applicable, the sponsor 
or warehouse / drug distribution centre will maintain records of the disposal. 
These records will include dates, quantities, batch / serial numbers, expiry (‘use- by’) dates, 
and the unique code numbers assigned to the investigational medicinal product and trial
patients. The investigator or designee will maintain records that document adequately that 
the patients were provided the doses specified by the Clinical Trial Protocol (CTP) and 
reconcile all investigational medicinal products received from the sponsor. At the time of 
return to the sponsor, the investigator or designee must verify that all unused drug supplies 
have been returned by the clinical trial staff and all used or partially used supplies have been 
destroyed by the trial site, and that no remaining supplies are in the investigator’s possession.
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
All concomitant medications should be carefully evaluated by the investigator and the 
Clinical Trial Manager (CTM) should be contacted when there are questions regarding 
concomitant medications.
The use of Investigator Prescribed SoC will lead to the discontinuation of the trial treatment
except for the use of topical treatment/topical corticosteroids, methotrexate, cyclosporine and 
retinoids during OL rescue treatment period (4 weeks following i.v. dose rescue treatment 
with OL BI 655130 at R1/D1) and OL maintenance treatment period. Please refer to section 
4.2.2.2 and section 3.1 for further details.  Also, please refer to section 3.3.4.1 for further 
details on handling of patients with premature treatment discontinuation. 
The sponsor will not provide/supply SoC treatment (s) to the sites.
4.2.1.1
Emergency procedures
Systemic hypersensitivity including infusion reactions and anaphylactic reaction
In case of systemic hypersensitivity including infusion reactions and anaphylactic reaction, 
emerging during or after infusion/injection of study medication, the investigator should 
consider in accordance with severity of the reaction and local standard of care to
-
Immediately interrupt the infusion/injection
-
Treat with systemic anti-histamines, i.v. steroids, and in case of a severe allergic 
reaction (e.g., anaphylactic reaction) epinephrine
Also draw a plasma sample for IgE and ADA and a serum sample for neutralizing antibody 
(Nab) as detailed in the Lab Manual (Central Laboratory). Consider also the evaluation of 
histamine, serum tryptase, and complement components.


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 71 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
In case of systemic hypersensitivity including infusion reactions, based on patient’s clinical 
course and medical judgment, the infusion may be re-initiated in case of mild or moderate 
systemic hypersensitivity including infusion reactions (according to RCTC grading [R13-
3515] in ISF) at lower speed with gradual increase to complete the infusion as detailed in the 
Instructions for Preparation and Handling of BI 655130 in the ISF. Regardless, the total 
duration of infusion should not exceed 180 minutes (3 hours).
In case of anaphylactic reactions based on published criteria (Appendix 10.1.6; R11-4890) 
that are suspected to be caused by the study medication, the investigator should discontinue 
treatment with BI 655130.
When a non-acute hypersensitivity reaction related to immune complexes (i.e., serum 
sickness) is suspected, draw a sample for the laboratory assessment for circulating immune 
complexes.
In case of potential systemic allergic reaction, blood samples for determination of serum 
tryptase will be collected 0.5 h, 2 h, 6 h, 24 h after onset of the event.
Severe infections (according to RCTC grading: refer to the ISF), serious infections, 
opportunistic or mycobacterium tuberculosis infections
Treatment of the infection should be initiated promptly according to local standard of care. 
No further study medication should be administered until the active infection has resolved. 
Treatment with BI 655130 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,
treatment discontinuation is to be a consideration if deemed clinically appropriate by the 
investigator. In addition, diagnostics and treatment are to be initiated according to local 
standard of care.
4.2.1.2
Additional treatments
No additional treatment is planned. 
However, in case of AEs in need of treatment, the investigator can authorize symptomatic 
therapy. In those cases, patients will be treated as necessary and, if required, kept under 
supervision at the trial site or transferred to a hospital until all medical evaluation results have 
returned to an acceptable level.
All concomitant and/or rescue therapies will be recorded on the appropriate pages of the 
electronic CRF (eCRF).


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 72 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment before randomization
The medications (or classes of medications) listed in Table 4.2.2.1: 1 must not be taken for
the time periods as specified for washout.


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 73 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
Table 4.2.2.1: 1
Restricted medications
Any investigational device or 
product (excludes psoriasis products) 
Other systemic immunomodulating 
treatments (e.g. corticosteroids1, 
cyclophosphamide), tofacitinib 
(Xeljanz®), apremilast (Otezla®)
Other systemic psoriasis treatments 
(e.g. fumarates, any other drug 
known to possibly benefit psoriasis) 
photochemotherapy (e.g., PUVA).
4 weeks prior to Visit 2
GMA (Granulocytes and monocytes 
adsorptive apheresis)2
4 weeks prior to Visit 2
                                                           (Contd. See next Page)
Medication or class of medications
Restriction duration 
Biologic Treatments, e.g.:
secukinumab (Cosentyx®),  
tildrakizumab (Ilumya™) , 
rituximab, ustekinumab (Stelara®), 
risankizumab (Skyrizi™)
natalizumab, alemtuzumab, 
guselkumab (Tremfya®), ixekizumab 
(Taltz®), adalimumab (Humira®),
brodalumab, efalizumab, 
visilizumab, briakinumab. 
infliximab (Remicade®), 
certolizumab (Cimzia®)
12 weeks or 5 half-lives, whichever is shorter, prior to Visit 2 
(randomization)
Investigational products for psoriasis 
12 weeks or 5 half-lives, whichever is shorter, prior to Visit 2 
(randomization)
IL36R inhibitors
Not allowed 
Etanercept (Enbrel®) 
live virus vaccinations2
6 weeks prior to Visit 2


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 74 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
Table 4.2.2.1: 1
Restricted medications (cont’d)
Topical corticosteroids 
Must be stopped at the day of randomization. 
Anakinra (Kineret®)
7 days prior to Visit 2
methotrexate, cyclosporine, retinoids
Must be stopped at the day of randomization. 
Patients can be on these background medications at screening 
visit (V1), however they can only be randomized (V2) into 
this trial on the day of their next scheduled dose for the 
background treatment (where the patient should not take the 
dose) but instead be randomized on the trial.
1No restriction on inhaled corticosteroids to treat asthma or corticosteroid drops administered in the eye or ear.
2 Live virus vaccination and use of GMA should be restricted until the end of the trial.
In the event a patient with prior use of biologic treatment, systemic steroids or 
immunomodulating treatments is enrolled, past medical records are required to document
when these treatments were stopped. All concomitant therapies will be recorded (including 
time of intake and dose on study days) on the appropriate pages of the CRF.
4.2.2.2
Restrictions regarding concomitant treatment during the trial (Post V2)
The following listed medications are not permitted throughout the study participation unless 
they are prescribed by investigators to treat disease worsening of GPP. However it is strongly 
recommended not to prescribe SoC even for GPP disease especially when patients are on the 
randomized treatment (See details about investigator-prescribed SoC for GPP disease in 
Section 3.1 and Section 4.2.1). The use of Investigator Prescribed SoC for GPP will lead to 
the discontinuation of the trial treatment with some exceptions as described below.
Biologic Treatments:
Treatment with biologics are not allowed throughout the study. 
Topical Treatments:
Topical treatment and any other therapies (e.g. Phototherapy) for GPP are not allowed 
throughout the study with the following exceptions:

Topical treatment for other conditions (e.g. fungal infections, plaque psoriasis etc.) is 
allowed.

Topical treatment is permitted for treatment of GPP after 4 weeks following i.v. dose 
rescue treatment with OL BI 655130 at R1/D1.

Topical treatment is permitted for treatment of GPP during the OL maintenance treatment 
period.
Medication or class of medications
Restriction duration 


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 75 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
Topical corticosteroids:
Topical corticosteroids for the treatment of GPP are not allowed throughout the study with 
the following exceptions:

Topical corticosteroid for other conditions (e.g. fungal infections, plaque psoriasis etc.) 
may be initiated post visit 2 if needed. 

Topical corticosteroid is permitted for treatment of GPP after 4 weeks following i.v. dose 
rescue treatment with OL BI 655130 at R1/D1.

Topical corticosteroid is permitted for treatment of GPP during the OL maintenance 
treatment period.
Systemic Immunomodulating Treatments:
Systemic immunomodulating treatments (e.g. corticosteroids, cyclophosphamide), tofacitinib 
(Xeljanz®), apremilast (Otezla®) and other systemic psoriasis treatments (e.g. fumarates, any 
other drug known to possibly benefit psoriasis) photochemotherapy (e.g., PUVA) for the 
treatment of GPP are not allowed.
Methotrexate, Cyclosporine, Retinoids:

Randomized Treatment Period: Treatment with Methotrexate, Cyclosporine, Retinoids
are not allowed. 

Rescue Treatment Period and Open Label Maintenance Treatment Period: 
Methotrexate, Cyclosporine, or Retinoids may be allowed for the treatment of GPP only 
for those who have received a flare rescue treatment with i.v. dose of BI 655130 and 
have a partial response to the rescue treatment as following. 
After at least 4 weeks from the rescue treatment at R1/D1, it is recommended to first initiate 
treatment with topical corticosteroids to manage skin symptoms, and then if further 
adjunctive treatment is required, then methotrexate, cyclosporine and/or retinoids may be 
initiated and continued with stable dosing until the patient achieves GPPGA score 0 or 1 or 
as per the investigator’s judgement.
Other Medications/Products: 
Treatment with the following medications/products are not allowed throughout the study.

Investigational products for psoriasis

IL36R inhibitors

Etanercept

Live virus vaccinations

Any investigational device or product (excludes psoriasis products) 

Anakinra (Kineret®)

GMA (Granulocytes and monocytes adsorptive apheresis)


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 76 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
4.2.2.3
Restrictions on diet and life style
No specific restrictions on diet or life style of the patients are required.
4.2.2.4
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 during the trial, and for a period of at least 16 weeks after the last study drug 
administration. 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).

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 16 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
Administration of the study medication will be done in the study center (or at home in 
exceptional cases such as COVID-19 pandemic where physical visits to the clinic may not be 
possible. See section 4.1.4 and section 6.1 for additional details) under the supervision of the 
investigator or a designee. The measured plasma concentrations will provide additional 
confirmation of compliance.


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 77 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
The primary, key secondary, secondary and further endpoints of the study are specified in 
Sections 2.1.2 and 2.1.3, and 2.2.2, respectively.
Skin condition will be assessed by using the Generalized Pustular Psoriasis Physician Global 
Assessment (GPPGA) 
 
 
 
 
 
In addition to the above assessments, patient reported outcomes such as PSS, 
 
DLQI, 
 will also be collected/assessed.
Additional details for efficacy assessments evaluated in this study are provided below.  
Methodological details for the evaluation of the scores/index are described in the ISF.
Generalized Pustular Psoriasis Physician Global Assessment (GPPGA)
GPPGA relies on clinical assessment of the GPP patient’s skin presentation. It is a modified 
PGA, a physician’s assessment of psoriatic lesions, which has been adapted to the evaluation 
of GPP patients (R15-5200). The investigator (or qualified site personnel) scores the 
erythema, pustules, and scaling of all GPP lesions from 0 to 4. Each component is graded 
separately, the average is calculated, and the final GPPGA is determined from this composite 
score. A lower score indicates a lesser severity, with 0 being clear and 1 being almost clear. 
GPPGA is provided in Appendix 10.1.1; this score will be measured at the time points noted 
in the study Flow Chart 1 or Flow Chart 2 (as applicable).


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 78 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
PSS (Psoriasis Symptom Scale)
The PSS is a 4-item patient-reported outcome (PRO) instrument that was developed to assess 
the severity of psoriasis symptoms in patients with moderate to severe psoriasis (R18-1990). 
When completing this questionnaire, patients should report on symptoms experienced from 
their Generalized Pustular Psoriasis. The symptoms included are:  pain, redness, itching, and 
burning. Current symptom severity is assessed using a 5-point scale ranging from 0 (none) to 
4 (very severe). The symptom scores are added to an unweighted total score (range:  0 to 16).
The PSS instrument is provided in Appendix 10.1.5; this will be measured at the timepoints 
noted in Flow Chart 1 or Flow Chart 2 (as applicable).


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 79 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
DLQI (Dermatology Life Quality Index)
The DLQI is a patient-administered, ten-question, quality of life questionnaire that covers six 
domains including symptoms and feelings, daily activities, leisure, work and school, personal 
relationships and treatment (R05-2548). The DLQI has a one-week recall period. 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 where 0-1 = no effect on patient’s life, 2-5 = small effect, 6-10 
= moderate effect, 11-20 = very large effect, and 21-30 = extremely large effect on patient’s 
life. The higher the score, the more the quality of life is impaired. A 4-point change from 
baseline is considered a clinically important difference (R18-1988).
The DLQI Instrument is provided in Appendix 10.1.10; this will be measured at the 
timepoints noted in Flow Chart 1.


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 80 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 81 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
5.2
ASSESSMENT OF SAFETY
Safety will be assessed descriptively based on:

Treatment Emergent Adverse events

Adverse events of special interest (AESI)

Serious adverse events (SAEs)

Clinical laboratory values (haematology, clinical chemistry, coagulation and urinalysis)

Intensity of adverse events will be assessed by Rheumatology Common Toxicity Criteria 
(RCTC) version 2.0 (refer to ISF for details)

Physical examination

Vital signs (blood pressure, pulse rate, body temperature)

12-lead ECG

Immunogenicity (ADA)
5.2.1
Physical examination
Complete and targeted physical examinations will be performed at visits as described Flow 
Chart 1 or Flow Chart 2 (as applicable). Height and weight of the patient will be recorded at 
the Screening Visit.
Complete physical examination will include vital sign assessment and general appearance as 
well as evaluation of all organ systems. Targeted physical examination will include vital sign 
assessment and evaluation of organ systems associated with AE(s) symptoms or laboratory 
abnormalities.
Clinically relevant abnormal findings will be reported as baseline conditions or AEs.
5.2.2
Vital signs
Vital signs evaluations will be performed at visits as shown in the Flow Chart 1or Flow Chart
2 (as applicable), prior to blood sampling. This includes measuring temperature, pulse rate, 
systolic/diastolic blood pressure and respiratory rate. Respiratory rate, pulse rate, and blood 
pressure will be measured after patients have been sitting comfortably for at least 5 minutes. 
All recordings should be made using the same type of blood pressure recording instrument on 
the same arm if possible. Measurement of vital signs should precede blood sampling to avoid 
the impact of blood sampling on the vital measurements. 
At visits with s.c. administration, vital signs will be assessed pre-dose and 10 minutes after 
the end of drug administration and at Visit 2 and Visit 3 additional measurements will be 
performed approximately 60 minutes post-dose (i.e. 60 min. after last injection).


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 82 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
At the visit with i.v. administration, vital signs will be assessed pre-dose, at approximately 5 
minutes after the end of infusion and 1 hour after the end of infusion. 
In addition to the temperature being measured along with the vital signs at time points shown 
in the Flow Chart 2, fever (temperature) will also be assessed at the day the patient presents 
to the clinic/hospital with GPP flare and prior to IMP administration. If the patient will 
receive medication for fever treatment, the fever assessment will be performed prior to taking 
the anti-fever treatment. This fever assessment must be taken whether or not the patient has 
an elevated temperature and whether or not the patient takes anti-fever treatment.
At the visit with i.v. study drug administration, patients should be closely monitored for signs 
and symptoms of hypersensitivity reactions for approximately 1 hour after the end of study 
drug administration. Hypersensitivity reactions should be treated according to medical
standards. 
5.2.3
Safety laboratory parameters
For the assessment of laboratory parameters, blood and urine samples will be collected by the 
trial site at the time points indicated in the Flow Chart 1 or Flow Chart 2 (as applicable).  
Patients do not have to be fasted for the blood sampling for the safety laboratory. 
The parameters that will be determined are listed in Table 5.2.3: 1. The laboratory tests will 
be performed at a central laboratory. Instructions regarding sample collection, sample 
handling/processing and sample shipping are included in the laboratory manual in ISF.
However, local labs are to be used at visit(s) involving i.v. administration of open label BI 
655130 in the event a patient has a GPP flare. The labs listed in Table 5.2.3: 2 are to be 
collected and assessed by the investigator prior to study drug infusion to allow for immediate 
subject management; however, split or concurrent samples will be drawn and sent to the 
central laboratory for analysis. It is highly encouraged to collect and assess the labs the day of 
i.v. administration; however in exceptional cases, labs may be collected one day prior to 
ensure lab results are available prior to dosing.
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 (e.g. 
anemia, hypoproteinemia, hypoalbuminemia, hypocalcemia etc.) 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 eDC system). 
The amount of blood taken from the patient concerned will be increased due to this additional 
sampling.
Clinically relevant abnormal findings (e.g. anemia, hypoproteinemia, hypoalbuminemia, 
hypocalcemia etc.) will be reported as baseline conditions or AEs. A clinically relevant value 
may be either in- or outside the reference range. Clinically relevant abnormal laboratory test 


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 83 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
results must be confirmed using an unscheduled visit laboratory kit and should be repeated 
until normalization or stabilization or until an alternative explanation has been found. 
Abnormal laboratory values will be also graded for intensity by using RCTC Version 2.0 
criteria (R13-3515).
Instructions regarding sample collection, sample handling/processing and sample shipping 
are included in the laboratory manual in ISF.
The central laboratory will transfer the results of the analysis to the sponsor.


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 84 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
Table 5.2.3: 1 
Safety laboratory tests
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 tryptase
Amylase1
Lipase1
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 for adults and Bedside Schwartz 
Equation for adolescents ) (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 (Stix)
Urine nitrite
Urine protein
Urine glucose 
Urine ketone 
Urobilinogen 
Urine bilirubin
Urine blood
Urine leukocyte esterase
Urine pH


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 85 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
Table 5.2.3: 1
Safety laboratory tests (cont’d.)
Category
Test name
Infection testing
Hepatitis B Surface Antigen (qualitative)1
Hepatitis B core Antibody1
HBV-DNA (quantitative) at baseline1 and EoS Visit2
QuantiFERON® (or if applicable, T-Spot®) TB1,3,4,5
Hepatitis C Antibodies (qualitative) 1
HIV-1, and HIV-2 Antibody (qualitative) 1
Urine-Sediment (only
if urine analysis abnormal)
microscopic examination
Specific gamma-globulin 
quantification IgE
IgE6
Urine Pregnancy test7. At the 
drug administration
visits, the test will be performed 
prior to the
administration of study drug
Human Chorionic Gonadotropin in urine
Serum Pregnancy test7 (only for 
female
patients of childbearing 
potential)
Human Serum Chorionic Gonadotropin
1To be done at screening. For patients who sign the informed consent ≥ 4 weeks prior to V2, infection testing must be 
repeated 2 to 4 weeks prior to V2.
2An HBV-DNA test should be conducted if Hepatitis B core Antibody is positive and Hepatitis B Surface Antigen is 
negative. These evaluations should be conducted at screening and EoS.
3There 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).
4If the 1st 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.   
5In subjects 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 at EoS.
<For Japan> T-Spot® TB test may be performed at local labs instead of QuantiFERON®-TB test.   
6IgE will be taken in case of systemic hypersensitivity including infusion reaction together with ADA (anti-drug antibodies) 
sample.
7Urine and serum pregnancy testing will be performed as indicated in the Flow Chart 1 or Flow Chart 2 (as applicable).


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 86 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
Table 5.2.3: 2
Laboratory tests to be assessed prior to i.v. rescue treatment with open 
label BI 655130 in an event of a GPP flare (Local Labs)
Category
Test Name
Haematology
Haematocrit, Haemoglobin, Red blood cell count (RBC), White blood 
cell count (WBC), Platelet count
Coagulation
Activated partial thromboplastin time (aPTT),Prothrombin time 
(Quick’s test and INR),Fibrinogen
Enzymes
Aspartate transaminase (AST/GOT), Alanine transaminase 
(ALT/GPT), Alkaline phosphatase (AP)
Substrates
C-Reactive Protein (CRP) , Serum albumin, Creatinine, Total 
bilirubin, Direct bilirubin, eGFR (preferably estimated by CKD-EPI 
formula for adults and Bedside Schwartz Equation for adolescents)
Electrolytes
Sodium, Potassium
Urine Pregnancy test 1. 
Test will be performed prior to the administration 
of study drug
Human Chorionic Gonadotropin in urine
Serum Pregnancy test1 (only for female patients 
of childbearing potential)
Human Serum Chorionic Gonadotropin
1Urine and serum pregnancy testing will be performed as indicated in the Flow Chart 2.
5.2.4
Electrocardiogram
ECG measurements will always precede blood sampling to avoid impact of sampling on the 
ECG results.  The 12-lead ECGs will be recorded and reviewed prior to dosing as scheduled 
in Flow Chart 1 or Flow Chart 2 (as applicable). The investigator or a designee will evaluate 
whether the ECG is normal or abnormal and whether it is clinically relevant, if abnormal. 
ECGs may be repeated for quality reasons and the repeated recording used for analysis. No 
central laboratory will be used for ECG recording.
Additional ECGs may be recorded for safety reasons. The electronic version, if applicable, or 
dated and signed printouts of the ECG, will be regarded as source data and will be stored in 
the patient’s medical file.
Clinically relevant abnormal findings will be reported either as baseline condition (if 
identified at the screening visit) or otherwise as adverse events and will be followed up 
and/or treated as medically appropriate.
5.2.5
Other safety parameters
Local tolerability at the administration site of BI 655130 /placebo will be assessed by the 
investigator during the study drug administration visit (i.v. or s.c.) and at the 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 adverse event.
Grade the intensity of the local tolerability according to RCTC grading (cf. ISF).


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 87 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
In case of an infusion reaction, monitor the patient per standard of care, grade the intensity of
the reaction according to RCTC grading (cf. ISF) and proceed as described in Section 4.2.1.1.
All cases of malignancies, sepsis or other serious infections and disseminated intravascular 
coagulation that are detected during the trial will be reported as SAEs. Please refer to the
current list of “Always Serious AEs” provided in eDC.
5.2.6
Assessment of adverse events
5.2.6.1
Definitions of AEs 
5.2.6.1.1
Adverse event
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a medicinal product and which does not necessarily have to have a 
causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
The following should also be recorded as an AE in the CRF and BI SAE form (if applicable):
Worsening of the underlying disease or of other pre-existing conditions.
Changes in vital signs, ECG, physical examination and laboratory test results, if they 
are judged clinically relevant by the investigator.
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. 


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 88 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
For Japan only: the following events will be handled as “deemed serious for any other 
reason”. AEs which possibly lead to disability will be reported as SAEs.
5.2.6.1.3
AEs considered “Always Serious”
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of AEs, which by their nature, can always be 
considered to be “serious” even though they may not have met the criteria of an SAE as 
defined above.
The latest list of “Always Serious AEs” can be found in the eDC system. A copy of the latest 
list of “Always Serious AEs” will be provided upon request. These events should always be 
reported as SAEs as described in Section 5.2.6.2.
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the time since discontinuation of the drug and must be reported as 
described in 5.2.6.2, subsections “AE Collection” and “AE reporting to sponsor and 
timelines”.
5.2.6.1.4
Adverse events of special interest
The term adverse events of special interest (AESI) relates to any specific AE that has been 
identified at the project level as being of particular concern for prospective safety monitoring 
and safety assessment within this trial, e.g. the potential for AEs based on knowledge from 
other compounds in the same class. AESIs need to be reported to the sponsor’s 
Pharmacovigilance Department within the same timeframe that applies to SAEs, please see 
Section 5.2.6.2.2.
The following are considered as AESIs:
Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory parameters:

An elevation of AST and/or ALT and/or AP ≥3-fold ULN plus 2 times the baseline,
combined with an elevation of total bilirubin ≥2-fold ULN plus 1.5 times the baseline, 
measured in the same blood draw sample, or

aminotransferase (ALT, and/or AST) elevations ≥ 10 fold ULN
These lab findings constitute a hepatic injury alert and the patients showing these lab 
abnormalities need to be followed up according to the “DILI checklist” provided in the ISF.
In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without lab results 
(ALT, AST, total bilirubin) available, the investigator should make sure these parameters are 
analysed, if necessary in an unscheduled blood test. Should the results meet the criteria of 
hepatic injury alert, the procedures described in the DILI checklist should be followed.


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 89 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
Systemic hypersensitivity reactions including Infusion reactions and anaphylactic reaction
Any suspicion of severe systemic hypersensitivity including infusion reactions and any 
anaphylactic reaction should be defined and assessed using the criteria discussed in the 
statement paper from Sampson HA (Section 4.2.1.1 and Appendix 10.1.6; (R11-4890).
Severe infections (according to RCTC grading in the ISF)
Opportunistic and mycobacterium tuberculosis infections
These include pneumocystis jirovecii, BK virus disease including PVAN, CMV, post-
transplant lymphoproliferative disorder (EBV), progressive multifocal leucoencephalopathy, 
bartonellosis (disseminated only), blastomycosis, toxoplasmosis, coccidioidomycosis, 
histoplasmosis, aspergillosis (invasive only), candidiasis (invasive or pharyngeal), 
cryptococcosis, other invasive fungi (mucormycosis (zygomycosis, rhizopus, mucor, 
lichtheimia), scedosporium/pseudallescheria boydii, fusarium), legionellosis, listeria 
monocytogenes (invasive only), tuberculosis, nocardiosis, non-tuberculous mycobacterium, 
salmonellosis (invasive only), HBV reactivation, herpes simplex (invasive only), herpes 
zoster, strongyloides (hyperinfection syndrome and disseminated forms only), 
paracoccidioides, penicillium marneffei, sporothrix schenckii, cryptosporidium species 
(chronic only), microsporidiosis, leishmaniasis (visceral only), trypanosoma cruzi infection 
(Chagas’ disease) (disseminated only), campylobacteriosis (invasive only),  shigellosis 
(invasive only), vibriosis (invasive due to vibrio vulnificus), HCV progression (R17-2617).
Peripheral Neuropathy
Any event suspected or diagnosed as Peripheral Neuropathy would be considered as an AESI.
For the treatment interruption rules, please see Section 3.3.4.1.
Protocol-specified AESI can be classified as serious or non-serious but all AESI must be 
reported in an expedited manner similar to serious adverse events on a SAE form (i.e. non 
serious AESI must be reported on the SAE form and follow the same reporting timelines as 
for serious AEs).
5.2.6.1.5
Intensity (severity) of AEs
The intensity grading of AEs will be performed according to RCTC Version 2.0 developed 
by the Outcome Measures in Rheumatology (OMERACT) organization (R13-3515). Refer to 
the ISF for intensity/severity classification. 
Intensity options are:
Grade 1 
mild
Grade 2 
moderate
Grade 3 
severe
Grade 4 
life-threatening


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 90 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
5.2.6.1.6
Causal relationship of AEs
Medical judgement should be used to determine whether there is a reasonable possibility of a 
causal relationship between the adverse event and the given study treatment, considering all 
relevant factors, including pattern of reaction, temporal relationship, de-challenge or re-
challenge, confounding factors such as concomitant medication, concomitant diseases and 
relevant history. 
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:

The event is consistent with the known pharmacology of the drug.

The event is known to be caused by or attributed to the drug class.

A plausible time to onset of the event relative to the time of drug exposure.

Evidence that the event is reproducible when the drug is re-introduced.

No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications).

The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome).

An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is reduced).
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:

No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks 
of drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned).

Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives).
Of note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger.

Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned).

Disappearance of the event even though the trial drug treatment continues or remains 
unchanged.
5.2.6.2
Adverse event collection and reporting
5.2.6.2.1
AE Collection
The investigator shall maintain and keep detailed records of all AEs in the patient files.
The following must be collected and documented on the appropriate CRF(s) by the 
investigator:


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 91 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
For patients rolling over into open label extension trial (1368-0025):

From signing the informed consent of the parent trial onwards until the first dose of trial 
medication in the extension trial:

all AEs (non-serious and serious) and all AESIs.
For patients not rolling over into subsequent OLE trial (1368-0025):

From signing the informed consent onwards until the individual patient’s end of study:

all AEs (serious and non-serious) and all AESIs.

After the individual patient’s end of study:

the investigator does not need to actively monitor the patient for AEs but should 
only report any occurrence of cancer and related SAEs and related AESIs of 
which the investigator may become aware of by any means of communication, 
e.g. phone call. Those AEs should be reported on the BI SAE form, but not on the 
CRF.
Vital Status Data Collection
Patients who discontinue trial medication prematurely and who agree to be contacted further
but do not agree to physical visits, should be followed up as described in Section 3.3.4.1, 
withdrawal from trial treatment. From then on until the individual patient’s end of the trial the 
investigator must report all deaths/fatal AEs regardless of relationship, and trial treatment 
related SAEs and trial treatment related AESIs the investigator becomes aware of. 
Please refer to Flow Chart 1 or Flow Chart 2 (as applicable) for additional details on vital 
status collection time points.
5.2.6.2.2
AE reporting to the sponsor and timelines
The investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form immediately (within 24 hours) to the sponsor’s 
unique entry point (country specific reporting process will be provided in the ISF). The same 
timeline applies if follow-up information becomes available. In specific occasions, the 
investigator could inform the sponsor upfront via telephone. This does not replace the
requirement to complete and send the BI SAE form.
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information the same rules and timeline apply as for initial 
information. All (S)AEs, including those persisting after individual patient’s end of trial must 
be followed up until they have resolved, have been assessed as “chronic” or “stable” , or no 
further information can be obtained.
5.2.6.2.3
Pregnancy
Urine pregnancy testing should be done prior to study drug administration. Study 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 


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 92 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
considered of childbearing potential and pregnancy testing is necessary as well. The testing 
schedule is specified in the Flow Chart 1 or Flow Chart 2 (as applicable).
In rare cases, pregnancy might occur in a clinical trial. Once a patient has been enrolled in the 
clinical trial and has taken trial medication, the investigator must report any drug exposure 
during pregnancy in a trial participant immediately (within 24 hours) by means of Part A of 
the Pregnancy Monitoring Form to the sponsor’s unique entry point.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Studies (Part B).
The ISF will contain the Preg nancy 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.


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 93 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 94 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 95 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 96 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
5.6
OTHER ASSESSMENTS
Photography of skin/skin lesions (irrespective of presence of lesions or not) will be 
performed in all patients for additional documentation. Front and back trunk, legs and arms, 
as well as target lesions photographs will be taken preferably at the time points specified in 
the Flow Chart 1 and Flow Chart 2 per instructions 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 all study participants as allowed by local 
regulations. This is because the prevalence and characteristics of psoriasis may differ 
between patients of different racial origin. It will thus be worthwhile to assess if patients of 
different race will respond differently to the study treatment.


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 97 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
6.
INVESTIGATIONAL PLAN
For investigational sites where patients below 18 years of age will be enrolled, trial visits
should take place at a location within the clinical site that has a child-friendly infrastructure
(e.g. an environment that is familiar to the patients, the setting is physically appropriate, if
desired by the patient, parent(s)/legal guardian are allowed to stay with them during the trial
procedures). Furthermore, site-personnel should be knowledgeable and skilled in dealing with 
the pediatric population and its age-appropriate needs.
6.1
VISIT SCHEDULE
All patients are to adhere to the visit schedule specified in the Flow Chart 1 or Flow Chart 2
(as applicable). 
All deviations from the planned visit schedule are to be documented. If any visit has to be 
rescheduled, subsequent visits should follow the original visit date schedule !"#$"%$#&'( 
)*+, 
*#-(+,./#&.+- 0.1.& 23. Additional visits for the purpose of retesting of laboratory parameters 
or AE monitoring may be included as deemed necessary by the investigator.
For detailed description of the trial procedures, please refer to the Flow Chart 1 or Flow Chart 
2 (as applicable).
Details relating to study drug administration are provided in Section 4.1.4.
In exceptional cases, if standard visits at the trial sites are impossible because of COVID-19 
related safety risks or restrictions, the study visit may be performed at the patient’s home or 
remotely (via telephone and/or internet based means of communication). The visit may also 
be performed as a combination of home and remote visit (via telephone and/or internet based 
means of communication). The study drug administration may be performed at patient’s 
home under the supervision of the investigating physician or a designee. The trial medication 
may be shipped to the patient’s home if acceptable according to local law and regulations.
All home/remote visits need to be discussed with and approved by the sponsor’s trial team. 
Local regulatory and legal requirements of the participating country still apply.
All COVID-19 related deviations from the original schedule of visits and procedures will be 
documented and the implications considered for the analysis of the trial data.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
Study procedures to be performed at each visit are listed in the Flow Chart 1 or Flow Chart 2
and respective sections of this protocol. Refer to Section 5 for explanations of the specified 
assessments and procedural details.
The patients’ questionnaires (PSS, DLQI, 
 
) are to be completed on his/her own in a pre-specified order in a quiet area/room 


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 98 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
before any other visit assessments or treatments, and, if possible, before any interaction with 
the investigator or other members of the study team, and, without any help from or
interpretation by other people. If the patient is too sick (to complete the questionnaires 
him/herself but is able to reply verbally, a member of the study 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 manner as possible. If this is not possible either, 
the questionnaires are not to be completed. 
At each applicable visit (see Flow Chart 1 or Flow Chart 2 as applicable), the order of 
completion for PROs is recommended to be as follows:
PRO collection and completion for Adolescent Patients:
. 
Adolescent patients below age 16 (i.e. 12 -15 years) do not have to complete DLQI and SF-
36. All other PROs (PSS, 
 are to be completed by 
all adolescent patients. If adolescent patients do not feel comfortable answering any 
questionnaires, they may not be completed. For adolescent patients, PSS 
 are 
the most important questionnaires which may be prioritized over the others.
Separate from the PROs above, the evaluation of efficacy assessments (GPPGA, 
 
 
for a patient 
are to be conducted by the same physician throughout the study.
 
 
Safety laboratory tests
If blood sampling for central lab safety analyses at the trial site is not possible in exceptional 
cases (e.g., due to COVID-19 pandemic), these analyses can be performed at a local lab until 
central lab testing becomes available. The results of the local lab tests must be transferred to 
the investigator to ensure medical review and proper documentation of the lab results with 
clinical relevance for safety in the eCRF. For the minimum required safety lab parameters, 
follow Table 5.2.3: 2.


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 99 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
6.2.1
Screening and run-in period(s)
Screening Period
After patients have been informed about the trial, written informed consent in accordance 
with GCP and the local legislation must be obtained prior to performing any study related 
procedures.
Once consent is obtained, the patient is considered to have started the screening process, and 
is assigned a unique patient number by the IRT system. The patient is to be recorded on the 
enrolment log and be registered in the IRT system as a screened patient. Study requirements, 
including the procedure for the follow-up of prematurely withdrawn patients, must be fully 
explained to the patient. The importance of staying in the study until completion of all 
requirements is to be emphasized.
Screening (Visit 1) should normally take place no more than 84 days before Visit 2. Visit 1 
procedures may be completed over multiple physical visits, if needed. For the comprehensive 
list of the trial procedures required at the Screening Visit (Visit 1) please refer to Flow Chart 
1.
Demographics:
Informed consent date, gender, ethnicity and race (if allowed by local law) will be collected 
and reported in the eCRF.
Baseline Conditions
Chronic diseases, current observable conditions, any new clinically relevant findings 
discovered from the physical examination, ECG, safety labs, and any condition requiring 
therapy (excluding GPP) will be reported on the Baseline Condition eCRF page.
Infection Screening:
Infection testing will include tuberculosis, hepatitis B, hepatitis C, and HIV assessments (see
Table 5.2.3: 1). 
Medical History:
Regarding the GPP, a detailed history of the previous flares (frequency, intensity etc.) in the 
past will be collected and reported in eCRF. Also, previous and concomitant treatment for 
GPP will be reported.
Information on clinically significant previous and concomitant illnesses, other than GPP, or 
any clinically significant signs or symptoms that are present before informed consent, or pre-
existing conditions identified through findings from assessments and examinations done 
during the screening visits will be recorded as medical and surgical history at screening. 
 


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 100 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
Review of inclusion/exclusion criteria:
Selection criteria will be reviewed carefully.
IRT:
All patients who are screened must be registered with IRT.
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 a previously screen failed patient will be permitted once. 
Rescreening transaction must be registered in the IRT system.  A new patient number will be 
provided 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 Investigator Site File (ISF).
For the comprehensive list of the trial procedures required at the Screening Visit (Visit 1)
please refer to the Flow Chart 1.
6.2.2
Treatment period(s)
The treatment period is lasting from V2 until V14/End of Study 1 (EoS1) visit. Study related 
procedures during treatment period will be performed as specified in the Flow Chart 1 or 
Flow Chart 2 (as applicable).
Upon completion of screening and confirmation of patient eligibility, patients will be 
randomized to receive one of four treatments. Please refer to Section 4.1.4 and Table 4.1.4:1
for further details.
Administration of the study drug should be the last activity at visits with study drug 
administration, with the exception of post dose vital signs assessments. Details relating to 
study drug administration are provided in Section 4.1.4.
Please refer to Section 3.1 for additional details on Handling of GPP flares and Handling of 
Investigator Prescribed Standard of Care (SoC) for GPP disease. For details of trial 
procedures please follow Flow Chart 1 or Flow Chart 2 (as applicable).
For information pertaining to laboratory tests, ECG, vital signs, local tolerability, and 
physical examination, see Section 5.2.
Skin/Skin lesion photographs will be taken on site at visits specified in Flow Chart 1 or 
Flow Chart 2 (as applicable) and are to be taken prior to study drug administration (for details 
see Section 5.6).
Pregnancy Testing
Urine pregnancy testing for all women of child-bearing potential will be conducted on-site at 
visits with study drug administration and must be negative to continue treatment. More 
frequent testing should be done if required by the local regulation and / or authority or per 
investigator judgment.


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 101 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
The pregnancy testing should be done prior to study drug administration. A positive urine 
test must be confirmed with a serum pregnancy test.
Blood Sampling
Blood sampling (e.g., for safety lab) should be done prior to study drug administration, if 
applicable. Fasting is not required for blood sampling. 
For information pertaining to 
, ADA/Nab, 
, see Sections 5.3 and 5.4. Blood 
sampling for PK assessments should be done within 2 hours prior to study drug 
administration.
Clinical monitoring after study drug administration:
At visits with s.c. study drug administration, vital signs will be assessed pre-dose and at 
approx. 10 minutes after the end of study drug administration(s) and at Visit 2 and Visit 3 
additional measurements will be performed approximately 60 minutes post-dose (i.e. 60 min 
after last injection). Local tolerability at the administration site of BI 655130 /placebo will be 
assessed by the investigator during the study drug administration (i.v. or s.c.) visits [as noted 
in the Flow Chart 1 or Flow Chart 2 (as applicable)]. and at the 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 adverse event.
They should also ask subjects 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 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.
During i.v. drug administration, vital signs will be assessed pre-dose, at approximately 5 
minutes after the end of infusion, and 1 hour after the end of infusion. Patients should be 
closely monitored for signs and symptoms of hypersensitivity reactions for approximately 1 
hour after the end of infusion. Hypersensitivity reactions should be treated according to 
medical standards.
Unscheduled visits
The investigator should encourage patients to return to the clinic/site at the first sign of onset 
of a GPP flare. If a patient suspects that they have a GPP flare in between the protocol 
specified scheduled visits, they should make an unscheduled visit and return to the clinic/site 
for assessment.
The patient may be called in for additional unscheduled visits due to safety reason at the 
discretion of the investigator or the sponsor, unless the patient has withdrawn his/her consent. 
The patient may also contact the site due to safety reason for an unscheduled visit. 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 


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 102 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
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.
Concomitant medication review
Data concerning concomitant medications and procedures will be collected throughout the 
trial, as specified in the Flow Chart 1 or Flow Chart 2 (as applicable). These data will be 
obtained at scheduled or unscheduled trial visits based on information provided in the patient 
diaries, provided spontaneously by the patient or as a result of questioning the patient.
6.2.3
Follow-up period and trial completion
For all treated patients termination of study medication and trial completion must be recorded 
on the corresponding eCRF.  
V14 will be recorded as the End of Study visit (i.e., EoS1) for patients who qualify and agree 
to enter the OLE trial (1368-0025). V14 will also be recorded as End of Study Visit for 
patients who prematurely discontinue with the last dose of treatment up to and including Day 
232 and who agree to complete all remaining study visits up to Wk 48 from randomization. 
Since these patients prematurely discontinued, they would not qualify to enter OLE trial. 
The EoS2 visit is applicable for patients who do not qualify or who do not agree to enter into 
the OLE trial (1368-0025) at Week 48. EoS2 is also applicable for patients who prematurely 
discontinue with the last dose of treatment after Day 232. Since these patients prematurely 
discontinued, they would not qualify to enter OLE trial. 
End of Study visit must be registered in IRT system for all randomized patients. 
Please refer to Section 3.3.4.1 for further details on handling of patients with premature 
treatment discontinuation. 
Early Randomized Treatment Discontinuation:
Patient who discontinue randomized study treatment early prior to week 44. These patients 
should be registered as withdrawn from randomized treatment in IRT. 
Early Trial Discontinuation: 
Patient who will not enter OLE trial and has not reached the end of study visit, EoS1 or EoS2 
visit within the specified window per protocol (e.g. due to withdrawal of consent, lost to 
follow-up, death etc.).
Trial Completion
Trial completion for an individual patient is defined as a patient who has completed end of 
study visit per protocol. It could be EoS1 visit or EoS2 visit as defined above.


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 103 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
The trial is designed as a randomized, parallel group, double blind, placebo controlled, dose 
finding study to show superiority in the prevention of re-occurrence of flares for 
administration of BI 655130 300 mg q4w (high dose), 300 mg q12w (medium dose), and 150 
mg q12w (low dose) respectively versus placebo in patients with a history of GPP (per 
ERASPEN criteria) and with a GPPGA score of 0 or 1 (clear, or almost clear) at screening 
and at randomization. 
Primary Objective
The primary objective is to provide dose-ranging data for 3 dose regimens of BI 655130 
compared to placebo on the primary endpoint of the time to the first GPP flare onset up to 
week 48. Proof of concept for the activity of BI 655130 will be determined using a multiple 
comparison procedure with modelling techniques (MCPMod) with respect to achieving a 
non-flat dose response curve, while keeping full control of the type I error at 0.05, one-sided. 
To achieve this, the log hazard ratio of each active dose vs. placebo is first obtained via a Cox 
regression model on the time to first GPP flare. These estimates are the basis then for the 
non-flat dose response MCPMod assessment.
Secondary Objective
If the primary objective regarding achievement of a non-flat dose response curve is 
successful, the secondary objective will then be performed, which is to perform formal 
testing on the superiority of BI 300 mg q4w and/or BI 300 mg q12w versus placebo, on the 
primary endpoint, the time to the first GPP flare onset up to week 48, and on the key 
secondary endpoint, the occurrence of at least one GPP flare during the 48 week maintenance 
treatment period. The target number of patients with GPP flare events in this trial is 27 but 
note that the actual number of events observed until primary analysis is driven by the time-
point of the analysis.
A formal statistical hypothesis test will first be performed, at an overall 1-sided alpha level of 
0.025, on the primary endpoint of time to first GPP flare up to week 48. A stratified log-rank 
test will be implemented for each dose of BI 300 mg q4w (high dose) and BI 300 mg q12w
(medium dose) versus placebo, with stratification by the factor, concomitant use of systemic
GPP medication at randomization (yes or no), and multiplicity will be controlled by the 
truncated Hochberg procedure (using a truncation fraction of 0.5). Subsequently, formal 
testing of all other endpoints included in the testing hierarchy (i.e. the key secondary, and 
then the secondary endpoints)  will be performed, if the test on the primary endpoint is 
successful for at least one of the two doses (high or medium dose) of BI 655130.
The analysis of the key secondary endpoint for the proportion of patients with the occurrence 
of at least one GPP flare up to week 48 will be conducted subsequent to the test on the 
primary endpoint using a Cochran-Mantel Haenszel test, stratified by the factor concomitant 
use of systemic GPP medication at randomization (yes or no), for each of BI 655130 high and
medium doses versus placebo. A truncated Hochberg procedure will be used to control for 
multiplicity on the tests of the key secondary endpoint, at an overall 1-sided alpha level of 


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 104 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
0.025, if both doses were statistically significant on the test of the primary endpoint. If only 
one (high or medium) dose of BI 655130 was statistically significant on the test of the 
primary endpoint, then the same dose will be tested on the key secondary endpoint with a 1-
sided alpha of 0.00625 (see Section 7.1 for further details). If neither dose is declared to be 
statistically significantly superior to placebo for the primary endpoint, then no further testing 
in the hierarchical sequence will be conducted. Subsequent tests on the secondary endpoints 
included in the testing strategy (i.e. the time to first worsening of PSS up to week 48, and 
then on the time to first worsening of DLQI up to week 48), as well as tests on the primary 
and key secondary endpoints for the lowest dose of BI 655130 150 mg q12w versus placebo,
are described in detail in Section 7.1.
The primary analysis of the trial will be done once all patients randomized have either 
completed or discontinued from 48 weeks of treatment. The primary endpoint analysis may 
include more than the target number of patients with a GPP flare event. In this situation, it is 
not planned to perform an additional analysis of the primary endpoint whereby the exact 
number of target patients with a GPP event only are included.
To support a potential BI 655130 acute GPP flare treatment submission, an interim analysis 
of the clinical efficacy and safety data collected during the BI 655130 OL i.v rescue and s.c. 
maintenance treatment periods may be performed. For further details refer to Section 7.2.7.
The stratification factor, concomitant use of systemic GPP medications at randomization (yes 
or no) and the blocking factors, region (Japan or Non-Japan) and population (Adults versus 
Adolescents) will be included into the randomization of this trial. The blocking factors of 
region is implemented to ensure that sufficient patients per treatment group are recruited 
specifically to support individual country submission in Japan and the blocking factors of
population is implemented to ensure there will be paediatric patients randomized to each 
treatment group to support paediatric investigational plan. The two blocking factors are not 
intended to be used as an adjustment factor in the primary and key secondary analyses of 
efficacy (See Section 7.2).
7.1
NULL AND ALTERNATIVE HYPOTHESES
The null and alternative hypotheses are described below. Statistical testing will be performed 
based on one-sided hypotheses with corresponding one-sided p-values. Note that for 
publication purposes also two sided p-values may be derived if needed. Details of this will be 
specified in the TSAP.
Primary objective: Dose Finding
The null hypothesis is that there is a flat dose response curve comparing the placebo and the 
BI 655130 dose groups. The alternative hypothesis is that there is a non-flat dose response 
curve indicating a benefit of BI 655130 over Placebo. 
The MCPMod procedure allows for simultaneous evaluation of different potential dose 
response shapes, whilst protecting the false positive rate using a one-sided level α of 0.05.
The pre-specified models and their parameters used for this test are outlined in Section 7.2.2.


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 105 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
Secondary objective: Formal Statistical Testing
If the primary objective regarding the achievement of a non-flat dose response curve is 
successful, the secondary objective will then be performed, which is to perform formal
pairwise testing on the superiority of the high and medium doses of BI 655130 versus 
placebo, on each of the endpoints included in the statistical testing hierarchy as described 
below.
Formal testing of all trial endpoints in the testing hierarchy (primary, key secondary, and 
secondary endpoints) will be performed at a one-sided alpha level of 0.025. The overall 
testing strategy used to control the type I error for each of the endpoints and for each of the 
treatments is described below. Overall the testing strategy will follow a closed testing 
principle defining five families of endpoints/comparisons. The first family and the second 
family consist of the primary and key secondary endpoint comparisons for the high and 
medium doses of BI 655130 vs placebo respectively. The third family consists of the
secondary endpoint comparisons on the time to first worsening of PSS for the high and 
medium dose of BI 655130 vs placebo. The fourth family consist of the secondary endpoint
comparisons on the time to first worsening of DLQI for these same two doses of BI 655130 
vs placebo. The fifth family includes the test of the BI 655130 low dose (BI 655130 300mg 
q12w) vs placebo on the primary and key secondary endpoints only. 
First family: Test of the Primary Endpoint 
The null and alternative hypothesis for each of the BI high and medium doses versus placebo 
on the primary endpoint, the time to first GPP flare up to week 48 (defined by an increase in 
GPPGA score by ≥2 from baseline and the pustular component of GPPGA ≥2), are:
(1) BI 655130 300 mg q4w vs. Placebo
H0,11: Effect of BI 655130 300 mg q4w on prolonging the time to the first GPP flare 
up to week 48 ≤ Placebo;
versus the alternative hypothesis
HA,11: Effect of BI 655130 300 mg q4w on prolonging the time to the first GPP flare
up to week 48 > Placebo.
(2) BI 655130 300 mg q12w vs. Placebo
H0,12: Effect of BI 655130 300 mg q12w on prolonging the time to the first GPP 
flare up to week 48 ≤ Placebo;
versus the alternative hypothesis
HA,12: Effect of BI 655130 300 mg q12w on prolonging the time to the first GPP 
flare up to week 48 > Placebo.


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 106 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
Regarding the first family, to control the overall type I error rate at a one-sided alpha = 0.025 
for the comparison of both high and medium doses of BI 655130 vs. Placebo on the primary 
endpoint, the truncated Hochberg method will be applied. The weight of the truncated 
Hochberg method is chosen as 0.5. If both primary endpoint p-values are ≤ 0.01875 (one-
sided), then both comparisons involving the two BI 655130 dose regimens will be declared to 
be statistically significant. If the maximum of the p-values for the two dose comparisons is 
>0.01875 (one-sided), then the remaining p-value will be tested at the 0.0125 (one-sided 
level) and declared to be statistically significant only if that p-value is ≤ 0.0125 (one-sided). 
The remaining alpha to be used in the second family will be 0.025 (one-sided) if both high 
and medium doses of BI 655130 are statistically significantly superior to Placebo on the 
primary endpoint. If only one comparison is successful then alpha will be 0.025/4=0.00625 
according to the truncated Hochberg procedure with a weight of 0.5. If neither dose is 
declared to be statistically significantly superior to Placebo for the primary endpoint, then no 
further formal testing in the hierarchical sequence will be conducted.
Second family: Test of the Key Secondary Endpoint 
Further hypotheses will be tested on the key secondary endpoint in a hierarchical manner if 
the test for at least one dose of BI 655130 on the first family is successful.
The null and alternative hypotheses for the key secondary endpoint, the occurrence of 
patients having developed a GPP flare up to week 48, are:
(3) BI 655130 300 mg q4w vs. Placebo
H0,21: The proportion of patients who do not experience a GPP flare up to week 48
on BI 655130 300 mg q4w ≤ Placebo;
versus the alternative hypothesis
HA,21: The proportion of patients who do not experience a GPP flare up to week 48 
on BI 655130 300 mg q4w > Placebo
(4) BI 655130 300 mg q12w vs. Placebo
H0,22: The proportion of patients who do not experience a GPP flare up to week 48
on BI 655130 300 mg q12w ≤ Placebo;
versus the alternative hypothesis
HA,22: The proportion of patients who do not experience a GPP flare up to week 48
on BI 655130 300 mg q12w > Placebo
If both high and medium doses of BI 655130 on the primary endpoint are successful, then the 
truncated Hochberg procedure will be used to control for multiplicity on the key secondary 
endpoint in the second family. The weight of the truncated Hochberg method is chosen as 


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 107 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
0.5. If both key secondary endpoint p-values are ≤ 0.01875 (one-sided), then both
comparisons involving the two BI 655130 dose regimens will be declared to be statistically 
significant. If the maximum of the p-values for the two dose comparisons is >0.01875 (one-
sided), then the remaining p-value will be tested at the 0.0125 (one-sided level) and declared 
to be statistically significant only if that p-value is ≤ 0.0125 (one-sided). The remaining 
alpha, ’, to be used in the tests on the following secondary endpoints will be 0.025 (one-
sided) if both doses of BI 655130 are statistically significantly superior to placebo on the key 
secondary endpoint. If only one comparison is successful then ’ will be 0.025/4=0.00625 
according to the truncated Hochberg procedure with a weight of 0.5. If neither dose is 
declared to be statistically significantly superior to placebo for the key secondary endpoint, 
then no further formal testing in the hierarchical sequence will be conducted.
If only one (high or medium) dose of BI 655130 on the primary endpoint is successful then 
the same dose will be tested on the key secondary endpoint with a one-sided alpha= 0.00625. 
If this comparison is successful, then further tests on this dose for the next secondary 
endpoint in the hierarchy will be performed with a one-sided alpha= 0.00625.
Third and fourth families: Test of the Secondary Endpoints
Further hypotheses will be tested on the two secondary endpoints, the time to first worsening 
of PSS up to week 48 and the time to first worsening of DLQI up to week 48 in a hierarchical 
manner if the test for at least one dose of BI 655130 on the second family is successful.
The null and alternative hypotheses for the secondary endpoint, the time to first worsening of 
PSS up to week 48, are:
(5) BI 655130 300 mg q4w vs. Placebo 
H0,31: Effect of BI 655130 300 mg q4w on prolonging the time to first worsening of 
PSS up to week 48 ≤ Placebo;
versus the alternative hypothesis
HA,31: Effect of BI 655130 300 mg q4w on prolonging the time to first worsening of 
PSS up to week 48 > Placebo.
(6) BI 655130 300 mg q12w vs. Placebo
H0,32: Effect of BI 655130 300 mg q12w on prolonging the time to first worsening of 
PSS up to week 48 ≤ Placebo;
versus the alternative hypothesis
HA,32: Effect of BI 655130 300 mg q12w on prolonging the time to first worsening of 
PSS up to week 48 > Placebo


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 108 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
The null and alternative hypotheses for the secondary endpoint, time to first worsening of 
DLQI up to week 48, are:
(7) BI 655130 300 mg q4w vs. Placebo
H0,41: Effect of BI 655130 300 mg q4w on prolonging the time to the first worsening 
of DLQI up to week 48 ≤ Placebo;
versus the alternative hypothesis
HA,41: Effect of BI 655130 300 mg q4w on prolonging the time to the first worsening 
of DLQI up to week 48 > Placebo
(8) BI 655130 300 mg q12w vs. Placebo
H0,42: Effect of BI 655130 300 mg q12w on prolonging the time to the first 
worsening of DLQI up to week 48 ≤ Placebo;
versus the alternative hypothesis
HA,42: Effect of BI 655130 300 mg q12w on prolonging the time to the first 
worsening of DLQI up to week 48 > Placebo
If both doses of BI 655130 on the key secondary endpoints are declared to be statistically 
significant, then a graphical procedure as shown in the end of the section will be used to 
attribute the remaining ´ to the testing of each of the (hierarchically-ordered) secondary 
endpoints.
If only one (high or medium) dose of BI 655130 on the key secondary endpoint is successful, 
then the same dose will be tested on the third family endpoint and then, if the dose is declared 
to be statistically significant in the third family, on the fourth family endpoint with a one-
sided alpha= 0.00625 in a hierarchical order.
Fifth family: Test of the Low Dose BI 655130 vs Placebo
Further hypotheses for the low dose of BI 655130 (150 mg q12w) will be tested on the 
primary endpoint, and subsequently on the key secondary endpoint, in a hierarchical manner, 
if the test for at least one dose of BI 655130 (High or Medium) on the third and fourth family 
is successful.
The null and alternative hypotheses to be tested are:
(9) Primary endpoint for BI 655130 150 mg q12w vs. Placebo
H0,13: Effect of BI 655130 150 mg q12w on prolonging the time to the first GPP 
flare up to week 48 ≤ Placebo;
versus the alternative hypothesis


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 109 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
HA,13: Effect of BI 655130 150 mg q12w on prolonging the time to the first GPP 
flare up to week 48 > Placebo.
(10)
Key Secondary endpoint for BI 655130 150 mg q12w vs. Placebo
H0,23: The proportion of patients who do not experience a GPP flare up to week 48
on BI 655130 150 mg q12w ≤ Placebo;
versus the alternative hypothesis
HA,23: The proportion of patients who do not experience a GPP flare up to week 48
on BI 655130 150 mg q12w > Placebo
Tests on the fifth family for the BI low dose will be performed as shown below with alpha 
transferred only if successful testing has occurred previously on both of the two secondary 
endpoints of at least one dose (High or Medium) in the hierarchical chain.
The flowchart in the case that both high and medium doses of BI 655130 on the primary 
endpoint and key secondary endpoints are declared to be statistically significant, is as 
presented below:


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 110 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
Truncated Hochberg with truncation factor= 0.5 and one-sided alpha= 0.025
*The fraction of alpha transferred from one endpoint to the next endpoint.  
BI 300 mg q4w vs.
Placebo
BI 300 mg q12w vs.
Placebo
First family: 
Time to first 
GPP flare up to 
Week 48
Second family:
Occurrence of at least 
one GPP flare up 
to Week 48  
Under H0,11: 
P value is P0,11
Truncated Hochberg with truncation factor= 0.5
and one-sided alpha= 0.025
Both H0,11 and H0,12 are rejected
Under H0,12: 
P value is P0,12
Under H0,21: 
P value is P0,21
Under H0,22: 
P value is P0,22
                                                      α/2
α/2
Third family:
Time to first 
worsening of PSS
up to Week 48
Fourth family: 
Time to first 
worsening of DLQI 
up to Week 48 
Graphical procedure; One-sided alpha α=0.025
Both H0,21 and H0,22 are rejected  
Under H0,31: 
P value is P0,31
Under H0,32: 
P value is P0,32
Under H0,41: 
P value is P0,41
Under H0,42: 
P value is P0,42
Under H0,13: 
P value is P0,13
Under H0,23: 
P value is P0,23
Fifth family:
Time to first GPP flare up to 
Week 48
Occurrence of at least one GPP
flare up to week 48
BI 150 mg 
q12w vs.
Placebo
0.75*
0.75*
0.25*
0.25*
1*
1*
1*


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 111 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
If both high and medium doses of BI 655130 on the primary endpoint are statistically 
significant and only one of high and medium doses of BI 65510 on the key secondary 
endpoint is statistically significant, then the remaining α’=0.00625 will be used to test the 
following endpoints of the corresponding dose of BI 655130 and the low dose in a 
hierarchical order. The flowchart is as presented below:


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 112 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
Truncated Hochberg with truncation factor= 0.5 and one-sided alpha= 0.025
Note: BI= the single dose that was successful on the key secondary endpoint (BI 300 mg q4w
or BI 300 mg q12w)
*The fraction of alpha transferred from one endpoint to the next endpoint.
BI 300 mg q4w vs.
Placebo
BI 300 mg q12w vs.
Placebo
First family: 
Time to first 
GPP flare up to 
Week 48
Second family:
Occurrence of at least 
one GPP
flare up to week 48  
Under H0,11: 
P value is P0,11
Truncated Hochberg with truncation 
factor= 0.5 and one-sided alpha= 0.025
both H0,11 and H0,12 are rejected
Under H0,12: 
P value is P0,12
Under H0,21: 
P value is P0,21
Under H0,22: 
P value is P0,22
Third family:                             
Time to first 
worsening of PSS up to
Week 48 
Fourth family: 
Time to first 
worsening of DLQI  up
to Week 48
Only one BI dose is rejected  
Under H0,3BI: 
P value is P0,3 BI
Under H0,4 BI: 
P value is P0,4 BI
Under H0,13: 
P value is P0,13
Under H0,23: 
P value is P0,23
Fifth family:
Time to first GPP flare up to 
Week 48
Occurrence of at least a GPP
flare up to week 48
BI 150 mg 
q12w vs.
Placebo
One-sided alpha α=0.00625
1*
1*
1*


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 113 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
If only one of high and medium doses of BI 655130 on the primary endpoint is statistically 
significant, then the remaining alpha=0.00625 will be used to test the following endpoints of 
the corresponding dose of BI 655130 and then the low dose in a hierarchical order. The
flowchart is as presented below:


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 114 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
Truncated Hochberg with truncation factor= 0.5 and one-sided alpha= 0.025
Note: BI= the single dose that was successful on the primary endpoint (BI 300 mg q4w or BI 
300 mg q12w)
*The fraction of alpha transferred from one endpoint to the next endpoint.
BI 300 mg q4w vs.
Placebo
BI 300 mg q12w vs.
Placebo
First family: 
Time to first 
GPP flare up to 
Week 48
Second family:
Occurrence of at least one GPP
flare up to week 48  
Under H0,11: 
P value is P0,11
One-sided alpha= 0.00625
Only one BI dose is rejected
Under H0,12: 
P value is P0,12
Under H0,2BI: 
P value is P0,2 BI
Third family:                             
Time to first 
worsening of PSS up to 
Week 48
Fourth family: 
Time to first 
worsening of DLQI  up to 
Week 48
One-sided alpha α=0.00625
Under H0,3 BI: 
P value is P0,3 BI
Under H0,4 BI: 
P value is P0,4 BI
Under H0,13: 
P value is P0,13
Under H0,23: 
P value is P0,23
Fifth family:
Time to first GPP flare up to 
Week 48
Occurrence of at least one GPP
flare up to week 48
BI 150 mg 
q12w vs.
Placebo
1*
1*
1*


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 115 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
7.2
PLANNED ANALYSES
7.2.1
General considerations
There will be 3 main patient populations in this trial for analyses: the randomized set (RS), 
the safety set (SAF), and the per-protocol set (PPS).
Randomized Set 
This patient set includes all randomized patients. Treatment assignment will be as 
randomized. This is the main analysis set for presentation of efficacy. 
Safety Set 
This patient set includes all patients who were randomized and received at least one dose of 
study drug. It will be the main analysis set for presentation of safety. Patients will be 
analyzed according to the actual treatment.
Per-Protocol Set  
This patient set includes all patients in the RS who adhered to the CTP without any IPVs 
(potentially affecting the study outcome) which lead to exclusion from the PPS. This set will 
be used for sensitivity analysis on the primary and key secondary efficacy endpoints which 
are included in the testing hierarchy.
 
Important violations of the protocol will include violations of the key inclusion and exclusion 
criteria, incorrect medications taken, concomitant use of restricted medications, and any other 
violations of the protocol deemed important by the study team. All decisions concerning 
important protocol violations will be made prior to un-blinding of the database for the 
primary 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.
A Clinical Trial Report will be prepared for the primary analysis.
7.2.2
Primary endpoint analyses
The time to first GPP flare up to week 48, defined by an increase in GPPGA score from 
baseline by ≥2 and a GPPGA pustulation subscore ≥2, is the primary endpoint of this trial.
Any use of rescue medication (see Section 3.1) or investigator-prescribed SoC prior to the 
first onset of a GPP flare is considered to indicate the onset of such a flare. 
Primary Objective: Dose Finding
The primary analysis for the primary objective consists of a MCPMod-based testing (with 
respect to a non-flat dose response curve). MCPMod (multiple comparison and modelling 


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 116 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
techniques) [R10-1424] is used to evaluate several possible dose response models (patterns), 
and to identify the best-fitting model or subset of models (while keeping full control of the 
type I error at 0.05, one-sided). 
The generalized MCPMod procedure for time to event endpoints (Pinheiro et al. 2014 [R15-
4293]) is based on the log hazard ratio of the active doses vs. placebo obtained via a Cox 
regression model on the time to first GPP flare. In detail the hazard function for patient i in 
stratum m (systemic concomitant use of GPP medications at randomization (yes or no)) is 
assumed to have the form 
Λ(t) = λ(t)exp(βX + βX + βX)
where
-
Λ(t)is the hazard for patient i at time t
-
λ(t) is the unspecified, non-negative, baseline hazard function that is assumed to 
be the same for all subjects in stratum m
-
X, X, X are  indicator variables representing the treatment group with X = 1 if 
patient belongs to the active treatment group i and 0 otherwise 
-
exp(β) with k=1,2,3 is the respective hazard ratio for the 3 active treatment groups
The MCPMod test is based on the estimated log hazard rates β (k=1, 2, 3) as well as the 
estimated variance-covariance matrix obtained from the Cox regression model fit. In 
particular the placebo adjusted version of MCPMod will be applied.
For the PoC testing and for the sample size calculation, the contrasts of each of the models to 
be tested must be pre-defined. The following cases has been selected to cover the plausible 
and a diverse range of potential dose response patterns. 


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 117 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
Table 7.2.2: 1
Candidate case scenarios
HR for each group vs Placebo in candidate cases*
The response 
patterns
300 mg day1 
150 mg q12w
600 mg day1 
300 mg q12w
600 mg day1 
300 mg q4w
Linear
0.64
0.41
0.10
Emax1
0.17
0.13
0.10
Emax2
0.11
0.10
0.10
Exponential
0.70
0.47
0.10
*The HRs are derived based on following models using planned total doses (i.e. the sum of all doses 
before Week 48): Linear; Emax1: assumes 70% of the maximum effect is achieved at low dose; Emax2: 
assumes 95% of the maximum effect is achieved at low dose; Exponential: assumes 35% of the 
maximum effect is achieved at medium dose. The scenarios in the table cover both the plausible and a 
diverse range of potential dose response patterns. For other HR combinations that is different but similar 
to the trend of the ones in the table, the primary analysis is robust and provide sufficient power. Hazard 
rates are rounded to two decimals.
The optimal contrasts corresponding to the candidate models are calculated and shown in 
Table 7.2.2: 2 (please note that no contrast for placebo is presented since placebo adjusted 
MCPMod test is applied). In the trial analysis stage, these optimal contrasts will be updated 
using the estimated variance-covariance matrix from the collected data (as suggested e.g. in 
[R15-4293]). The updated contrast coefficients will be described in the CTR. 
Table 7.2.2: 2
Contrast coefficients
Contrast coefficients for dose
Model
300 mg day1 
150 mg q12w
600 mg day1 
300 mg q12w
600 mg day1 
300 mg q4w
Linear
-0.177
-0.353
-0.919
Emax1
-0.492
-0.579
-0.650
Emax2
-0.565
-0.579
-0.588
Exponential
-0.146
-0.307
-0.940
A non-flat dose response is established if at least one contrast test (after adjusting for 
multiplicity using MCP step in MCPMod approach) is statistically significant, thereby 
rejecting the null hypothesis of a flat dose-response curve and indicating a benefit of BI 
655130 over placebo. If a non-flat dose response is established, the statistically significant 
model(s) from the above candidate set are refitted to the data to generate new estimates for all 
model parameters.


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 118 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
If considered necessary and for the purpose of further model refinement, MCPMod might be 
repeated on the primary endpoint but with an extended set of shapes including the original 
candidates. Furthermore, covariates may be taken into account in further sensitivity analyses. 
Details of these analyses will be described in the TSAP.
Other analyses of the primary endpoint will include:

Alternative PK metrics including model predicted metrics (e.g. cumulative AUC) for 
the dose regimens will be evaluated.
Secondary Objective: Formal Statistical Testing
Formal Statistical analysis
The primary analysis for the secondary objective on the time to first GPP flare up to week 48
for each dose of BI 655130 versus placebo will be tested using the stratified log-rank test
stratified by the systemic concomitant use of GPP medications at randomization (yes or no) 
and based on the RS.
Kaplan-Meier (KM) estimates of the survival/failure probabilities at 1-monthly intervals, as 
well as the median time-to-event, will be provided by treatment. Confidence intervals will be 
based on two-sided α= 0.05. A Kaplan-Meier graph will also be produced.
If a patient discontinues the treatment early, the follow-up of the patient will be still 
continued and the primary analysis will include patients’ on- and off-treatment data up to 
Week 48. If a patient has no GPP flare event through 48 weeks of study, or is lost to follow-
up or withdrawn from the trial prior to achieving such an event, then the primary endpoint 
will be censored at the day of the last visit upon which it was confirmed that no GPP flare
had yet been observed.  
  
The primary method for handling of missing data on the time to first flare is described in 
Section 7.3.
Secondary analysis of the primary endpoint will include:

A sensitivity analysis utilizing the PPS to evaluate the impact on treatment outcomes of 
patients who may have relevant deviations from the conduct described in the CTP;

Analysis of an additional estimand whereby for patients who used rescue medication or 
investigator-prescribed SoC prior to the first onset of a GPP flare is considered to indicate 
the onset of such a flare. For patients who use restricted medication for other disease and 
not for the onset of a GPP flare, data will be censored for further analysis following the 
use and imputed using the methods described in Section 7.3.

Sensitivity analyses which utilize alternative methods for the handling of missing data as 
described in Section 7.3.

Descriptive comparisons between the levels of each stratification (concomitant use of 
systemic GPP medications at randomization (yes or no)) and blocking factors (region 
(Japan or Rest of world) and population (adults versus adolescents)) will be performed.


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 119 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
7.2.3
Secondary endpoint analyses
Key Secondary Endpoint Analysis
Primary Objective: Dose Finding
For the dose finding analysis of the study, there are no key secondary endpoints defined.
Secondary Objective: Formal Statistical Testing
For the formal analysis of the study, the treatment effect on the key secondary endpoint, the 
occurrence of at least one GPP flare up to week 48, will be tested in a hierarchical manner as 
a part of the pre-specified testing strategy, subsequent to the test of the primary endpoint, 
which is defined in Section 7.1
The stratified Cochran-Mantel-Haenszel (CMH) test will be performed for each dose of BI 
655130 versus placebo stratified by the concomitant use of systemic GPP medications at
randomization (yes or no), and based on the RS. The difference in the proportion of patients 
who do not experience a GPP flare, and the associated confidence intervals will be presented 
for each active group versus the placebo group using the Mantel-Haenszel type weighted 
average of differences using weights as proposed by Greenland & Robins [R09-1299].
Any use of rescue medication or investigator-prescribed SoC prior to the onset of the first 
GPP flare is considered to represent a failure, i.e. the onset of a GPP flare event. Furthermore, 
as described for the primary endpoint analysis, the key secondary endpoint analysis will also 
include both on- and off-treatment data of all patients up to Week 48. 
The primary method for handling of missing data on the occurrence of at least one GPP flare
is described in Section 7.3.
Secondary analyses of the key secondary endpoint will be the same as those defined for the 
primary endpoint. In addition, a sensitivity analysis using a landmark test will be performed 
to evaluate treatment effects. This test will compare Kaplan Meier estimates at Week 48 
between each dose of BI 655130 and placebo whereby the variance of each KM estimate is 
calculated by the Greenwood’s formula. Further details for the landmark test will be 
described in the TSAP. 
Secondary Endpoint Analysis:
For the formal analysis of the study, the treatment effect on the following secondary 
endpoints, 1) Time to first worsening of PSS up to week 48 (defined as a 4-point increase in 
total score from baseline), and, 2) Time to first worsening of DLQI up to week 48 (defined as 
a 4-point increase in total score from baseline), will be tested in a hierarchical manner as a 
part of the pre-specified testing strategy, subsequent to the test of the primary and key 
secondary endpoints, which is defined in Section 7.1. 
The time to first worsening of PSS up to week 48, where any use of rescue medication or 
investigator-prescribed SoC prior to observing the endpoint is considered to represent a 
worsening of the PSS, will be tested for each dose of BI 655130 vs. placebo using the


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 120 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
stratified log rank test stratified by the factor, concomitant use of systemic GPP medications 
at randomization (yes or no) and based on the RS.
The time to first worsening of DLQI up to week 48, where any use of rescue medication or 
investigator-prescribed SoC will be considered to represent a worsening of the DLQI, will be 
analysed in the same manner as described for the time to first worsening of PSS.
Imputation rules of missing data for the above two secondary endpoints will be described in 
Section 7.3.
All secondary endpoints will be descriptively displayed. Descriptive comparison for adults 
versus adolescents will be performed for secondary endpoints in the hierarchical testing.
Statistical tests on the remaining secondary binary endpoints will be performed as described 
for the key secondary endpoint.
7.2.5
Safety analyses
Adverse events will be coded using the current version of Medical Dictionary for Regulatory 
Activities (MedDRA) coding dictionary. Standard BI summary tables and listings will be 
produced.
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. To this end, all adverse events occurring between start of treatment and end 
of the residual effect period will be considered ‘treatment-emergent’; the residual effect 
period (REP) is defined as 16 weeks after the last dose of trial medication. Note that for 
patients who continue into the extension trial (1368-0025), all TEAE up to the time-point of 
first dose of the trial medication in the extension trial will be available for display in the 
current study. Adverse events that start before first drug intake and deteriorate under 
treatment will also be considered as ‘treatment-emergent’. For all subjects who received 
rescue medication with BI 655130, safety assessments including adverse events, laboratories, 
vital signs etc. which occurred subsequent to such intake will be excluded from presentations 
according to the planned treatments; these data will, however, be included in summaries 
where all data after any use of BI 655130 are displayed.
Frequency, severity, and causal relationship of adverse events will be tabulated by system 
organ class (SOC) and preferred term after coding according to the current version of the 
MedDRA at database lock.
The exposure adjusted incidence rate (per 100 subject years) of a selected treatment emergent 
adverse event is defined as the number of subjects experiencing the adverse event per 


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 121 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
treatment group during time at risk divided by the total time of subjects at risk in that 
treatment group to contribute the event to the analysis multiplied by 100 (per 100 subject 
years), where:
      Time at risk [subject years] = (date of onset of TEAE – study drug start date + 1) / 365.25
If, for a subject, the selected treatment emergent adverse event didn’t occur then the time at 
risk will be censored at min (date of death, [for patients who didn’t roll over to the extension 
trial] last contact date per EoS page, [for patients who roll over into the extension trial] date 
of first dose in extension trial – 1 day, drug stop date + 112 days, date of rescue medication of 
BI 655130). For each selected treatment emergent AE, the exposure adjusted incidence rate 
will be calculated as: 
      Incidence rate [1/100 Subject years (pt-yrs)] = 100 * number of subjects with AE / 
Total AE- specific time at risk [subject years].
Laboratory data will be analysed both quantitatively as well as qualitatively. The latter will 
be done via comparison of laboratory data to their reference ranges. Values outside the 
reference range as well as values defined as clinically relevant will be highlighted in the 
listings. 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 to findings before start of treatment.
Immunogenicity data will be analysed in a descriptive way.


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 122 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
 
 
7.2.7
Interim analyses
To support a potential BI655130 acute flare treatment submission, an interim analysis of the 
clinical efficacy and safety data collected during the BI 655130 OL i.v rescue treatment and 
s.c. maintenance treatment periods for GPP flare may be performed. The interim data 
snapshot will include the data from the i.v. rescue treatment period and OL maintenance 
treatment period. The initial randomized s.c. treatments will remain blinded and these data 
will not be analysed as part of this interim analysis.  The timing of the interim analysis is 
driven by the timing of the submission of the acute flare treatment. Further details on the 
specifications for this interim analysis will be presented in the trial statistical analysis plan.
In order to ensure the patient’s safety during the trial, a fully external DMC, independent of 
the trial and project teams, will review all available un-blinded safety data as well as selected 
efficacy data at regular intervals following first-patient-in. A DMC SAP which describes the 
analyses required for assessment by the DMC will be produced. Further details will be 
provided in a DMC charter.
7.3
HANDLING OF MISSING DATA
Every effort will be made to collect complete data at all visits. However, missing data will 
still occur and approaches to handle this are proposed below.
It is generally assumed that given the severity of a GPP flare, patients will always report to 
the investigator in a timely manner in order to ensure that proper treatment is received so that 
the developing flare can be rapidly treated. For the primary endpoint, only observed GPP 
flare events will be included in the primary analysis. No further imputation will be 
implemented on the missing values of GPPGA score and/or missing GPPGA pustule 
subscore. This will be the primary imputation method for the primary analysis. The same 
imputation strategy will be used for the two secondary endpoints, time to first worsening of 
PSS and time to first worsening of DLQI in the hierarchical testing procedure. The detailed 
censoring rules as outlined in Table 7.3: 1 will be used.


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 123 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
Table 7.3: 1
Primary Method: Description of censoring rules for primary endpoint, 
and two secondary endpoints in hierarchical testing procedure
Situation
Outcome 
(event or 
censored)
Date of outcome
Without post randomization assessment
No use of rescue medication or 
investigator-prescribed SoC
Censored
Date of randomization
The first use of rescue medication or 
investigator-prescribed SoC 
Event
Date of the first use of 
rescue medication or 
investigator-prescribed SoC 
whichever comes earlier
With post randomization assessment
No event, and, no use of rescue 
medication or investigator-prescribed 
SoC
Censored
Date of last assessment with 
no event confirmed
The first event, or the first use of rescue 
medication or investigator-prescribed 
SoC
Event
Date of first event, or the 
date of first use of rescue 
medication or investigator-
prescribed SoC whichever 
comes earlier
The sensitivity analysis (Sensitivity Method) will utilize different rules to deal with missing 
values in the above-defined endpoints. The alternative censoring rules for sensitivity analysis 
are defined in Table 7.3: 2.


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 124 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
For the primary analysis of the key secondary endpoint:
Missing GPPGA or GPPGA pustule subscores will not be imputed and only observed values 
will be utilized. If a patient is followed up to Week 48 and there is no flare, use of rescue 
medication or investigator-prescribed SoC reported, then this patient will be considered as a 
responder (i.e., no flare event) for the key secondary endpoint. 
If for any reason, one or more patients are lost to follow-up or early discontinuation from the 
study before reaching the time-point of Week 48, then a sequential regression multiple 
imputation method will be implemented to impute the assessment of whether a flare event has 


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 125 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
occurred by each visit at a binary level (Yes vs. No). This is a monotone increasing variable, 
so once a flare has occurred by a particular visit, all subsequent visits will also by definition 
have had a preceding flare. The imputation will include covariates, GPPGA subscore 
(pustules, scaling, erythema), as ordinal variables with values 0, 1, 2, 3 and 4. First, any non-
monotone missing values will be imputed as the next observed value. Then the achieved 
monotone missing data will be imputed per the following steps:
1.
Multiple Imputation of Missing data: A sequential logistic regression method is used 
to impute missing values of binary key secondary endpoint (Flare: Yes vs. No) at 
each visit. 
For Visit 2, the GPPGA subscores (pustules, scaling, erythema) at Visit 2 as well as 
treatment, may be included as variables in the imputation model. If the assessment 
of a patient at Visit 2 is observed or imputed as a flare event, then the assessments 
of all subsequent visits of this patient will be imputed as flare events. 
Visit 3 will be imputed in the same way but now including the GPPGA subscores 
(pustules, scaling, erythema) up to Visit 3, treatment and the response of patient at 
Visit 2 (Flare: Yes vs. No). All visits after an observed or imputed flare event with 
a flare event are again imputed as an event. Using the same approach, all visits will 
be imputed in order up to Visit 14 (Week 48). 
2.
Analysis of Completed Datasets: The imputed complete dataset will be used to 
perform the corresponding statistical analysis per permutation as specified in Section 
7.2.3.
3.
Combine Results: PROC MIANALYZE combines the analysis results from step 2 
and generates valid statistical inferences by accounting for the variability introduced 
by the MI process using Rubin’s rules (R12-2378).
Further imputation rules for secondary endpoints and further endpoints will be described in TSAP if 
necessary. With respect to safety evaluations, it is not planned to impute missing values.
7.4
RANDOMISATION
If applicable, BI will arrange for the randomization and the packaging and labeling of trial 
medication. The randomization 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. Access to the codes will be controlled and documented.
Stratification for the concomitant use of systemic GPP medications at randomization (yes or 
no) will be done. If a patient received any GPP medication within 4 weeks prior to or at 
randomization, then this patient will be categorized as “yes” and otherwise, “no”. Primary 
and key secondary efficacy analyses will be performed including an adjustment for this 
stratum.
Blocking for region (Japan versus Rest of World) will be done in order to ensure that 
sufficient patients per treatment group are recruited specifically to support individual country 


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 126 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
submission in Japan; this factor will be treated as operational factor and will not be included 
into the analyses of efficacy endpoints. 
Blocking for population (Adults versus Adolescents) will be done in order to ensure that there 
will be adolescent patients randomized in each treatment group for paediatric investigational 
plan; this factor will be treated as operational factor and will not be included into the analyses 
of efficacy endpoints. 
The first twelve adolescent patients will be randomized in a 1:1:1:1 ratio to the four arms 
regardless of concomitant use of systemic GPP medications at randomization (yes vs. no) and 
blocking factor region (Japan vs. Rest of world). This is to ensure that within each 
randomized arm, there are at least 2 randomized adolescent patient. Any additional 
adolescent patients within each stratum (concomitant use of systemic GPP medications at 
randomization (yes vs. no) and each blocking factor region (Japan vs. Rest of world), will be 
randomized in a 1:1:1:1 ratio to the four arms.
The adult patients within each stratum (concomitant use of systemic GPP medications at 
randomization (yes vs. no) and each blocking factor region (Japan vs. Rest of world), will be 
randomized in a 1:1:1:1 ratio to the four arms. 
The block size of the randomization will be documented in the CTR.
The process of randomization is done via an IRT. Practical aspects of the treatment allocation 
process are detailed in Section 4.1.3.
7.5
DETERMINATION OF SAMPLE SIZE
Based on an application of the defined testing strategy, a power calculation has been 
performed for sample size assessment on the dose finding analysis (primary objective) and on 
the formal analysis (secondary objective) of the trial.
The effect of each dose of BI 655130 on preventing a GPP flare in patients with a history of 
GPP will be compared relative to placebo where the high and medium doses of BI 655130 
(300 mg q4w and 300 mg q12w) are assumed to be closely effective, while the lowest dose 
(150 mg q12w) is assumed to be a sub-therapeutic dose. Most patients will withdraw from 
their prior GPP medication when they enter the trial, therefore the overall GPP flare rate is 
expected to be higher for these patients within the first three months of the maintenance 
treatment period (due to withdrawal of previous medication being a potential trigger for onset 
of a GPP flare event).
Under the base scenario, the overall hazard ratio between BI 300 mg q4w and placebo is 
assumed to be 0.1, between BI 300 mg q12w and placebo is assumed to be 0.15 and between 
BI 150 mg q12w and placebo is assumed to be 0.3. It assumes a piecewise exponential
distribution (i.e., first 3 month vs post 3 months) for the time to first GPP flare of each arm in 
this trial. It is anticipated that within the first 3 months of treatment, with dose of BI 300 mg 
q4w, BI 300 mg q12w and BI 150 mg q12w, that approximately 1.7%, 2.6% and 5.1% of 
patients will experience a first GPP flare per month respectively under the base scenario. In 


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 127 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
contrast, the first flare rate on placebo within the first 3 months is expected to be much higher, 
i.e. approx. 17.1% per month under the base scenario. After 3 months, the overall first flare 
rate is expected to decline and, thereafter, to be stable for the remainder of the trial.  The 
expected first flare rate after 3 months is 0.3%/month for patients on BI 300 mg q4w, 
0.4%/month for patients on BI 300 mg q12w, 0.9%/month for patients on BI 150 mg q12w
and 3%/month for patients on the placebo arm under the base scenario.
It is expected to take about 13 months to recruit 120 randomized patients in this trial. The 
primary analysis will be performed when last patient completes or early discontinue the 48-
week treatment. At that time, the target number of events will be 27. The powers of this trial 
are not driven by the target number of events but based on the number of events truly 
observed at the time of primary analysis. 
Table 7.5: 1 shows the success probability estimates for the dose finding analysis based on 
the primary endpoint when the primary analysis is performed at the time that the last patient 
has completed or early discontinued 48-week treatment. All calculations are performed using 
R version 3.5.1, for a sample size of 120 patients (1:1:1:1 ratio), and a 1-sided type I error of 
0.05. 
The probability of success of this trial is defined as the probability to obtain a significant test 
for non-flat dose-response curve.
Based on these assumptions, the success probability is approximately 99.5% for the base 
scenario described above.
In the case that there is no treatment benefit, the false positive probability is limited by the α-
level for the significance testing of the non-flat dose-response curve of 5% (one-sided). 


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 128 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
Table 7.5: 1
Dose-Finding analysis - Multiplicity-adjusted success probability 
given a total sample size of 120 patients based on MCPMod alpha-
level of 5% (one-sided).
Scenario
First flare rates assumption:
BI 655130 300 mg q4w vs.
BI 655130 300 mg q12w vs.
BI 655130 150 mg q12w vs. 
Placebo**
Hazard Ratio: 
BI 655130 300 
mg q4w vs. 
placebo;
BI 655130 300 
mg q12w vs. 
placebo;  
BI 655130 150 
mg q12w vs. 
placebo
*Success 
probability 
to 
demonstrate 
non-flat 
dose-
response
curve
First flare rates 
per month 
within first 3
months
First flare rates per 
month (post 3 
month) 
Base
1.7% vs.
2.6% vs.
5.1% vs.
17.1%
0.3% vs.
0.4% vs.
0.9% vs.;
3.0%
0.1
0.15
0.3
99.5%
BaseMinus
1.7% vs.
2.6% vs.
5.1% vs.
11.4%
0.3% vs.
0.4% vs.
0.9% vs.;
2.0%
0.15
0.225
0.45
90.7%
Low 
effect 
10.3% vs.
10.3% vs.
10.3% vs.
15.5 % vs.
1.6% vs.
1.6% vs.
1.6% vs.
      2.4%
0.67;
0.67;
0.67
28.8%
No effect
13.5 % vs.
13.5 % vs.
13.5 % vs.
13.5 %
2.5% vs.
2.5% vs.
2.5% vs.
2.5%
1;
1;
1
5.0%
* Success probabilities have been calculated using R Version 3.5.1 based on simulations (10000 simulations per scenario), 
using DoseFinding R-package 0.9-16 [R15-2001].
** The primary trial analysis will be performed once the last randomized patient has completed 48 weeks on treatment. Each 
patient will participate in the trial for a maximum of 48 week
Table 7.5: 2 shows the power estimates for the formal analysis based on the primary 
endpoint and key secondary endpoint when the primary analysis is performed at the time that 
the last patient has completed or early discontinued 48-weeek treatment and non-flat dose-
response curve in the dose finding analysis has been demonstrated. All calculations are 
performed using R version 3.5.1, for a sample size of 120 patients (1:1:1:1 ratio) and a 1-
sided type I error of 0.025.  


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 129 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
The 120 patients are planned to be recruited in order that a power of at least 90% for at least 
one successful dose of BI 655130 (High or Medium doses) versus placebo on the primary and 
key secondary endpoints can be achieved under the base scenario as defined above. 


Boehringer Ingelheim
     28 July 2022
BI Trial No.: 1368-0027
c28020464-03                                                                          Clinical Trial Protocol                                                                   Page 130 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
Table 7.5: 2
Power to achieve statistical significance with BI 655130 High and Medium doses versus Placebo on primary endpoint 
and key secondary endpoint conditional on the successful dose-finding analysis
Scenario
First flare rates assumption:
BI 655130 300 mg q4w vs.
BI 655130 300 mg q12w vs.
(BI 655130 150 mg q12w) **  
Placebo
Hazard Ratio:
BI 655130 300 mg 
q4w vs. placebo;
BI 655130 300 mg 
q12w vs.
(BI 655130 150 mg 
q12w
vs.)**
placebo
Median event (first 
flare) free time by 
month
Approximately
total number of
events (first 
flare) observed 
during 48-week 
treatment
Formal testing part:
Power at least one BI dose is stat. 
sig. vs Placebo*
First flare 
rates per 
month within 
first 3 months 
First flare 
rates per 
month post-
first 3 months 
Success on 
primary 
endpoint
Success on 
primary and key 
secondary 
endpoints
BasePlus 
1.7% vs.
2.6% vs.
(5.1% vs.)
24.4%
0.3% vs.
0.4% vs.
(0.9% vs.);
4.2%
0.07
0.105
(0.21)
225.4;
146.3;
(65.6);
4.2
2;
3;
6;
20
99.9%
99.9%


Boehringer Ingelheim
     28 July 2022
BI Trial No.: 1368-0027
c28020464-03                                                                           Clinical Trial Protocol                                                                   Page 131 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
Table 7.5: 2
Power to achieve statistical significance with BI 655130 High and Medium doses versus Placebo on primary endpoint 
and key secondary endpoint conditional on the successful dose-finding analysis (cont.).
Scenario
First flare rates assumption:
BI 655130 300 mg q4w vs.
BI 655130 300 mg q12w vs.
(BI 655130 150 mg q12w) **  
Placebo
Hazard Ratio:
BI 655130 300 mg 
q4w vs. placebo;
BI 655130 300 mg 
q12w vs. (BI 
655130 150 mg 
q12w
vs.)**
placebo
Median event (first 
flare) free time by 
month
Approximately 
total number of
events (first 
flare) observed 
during 48-week 
treatment
Formal testing part:
Power at least one BI dose is stat. 
sig. vs Placebo*
First flare 
rates per 
month within 
first 3 
months 
First flare 
rates per 
month post-
first 3 
months 
Success on 
primary 
endpoint
Success on 
primary and key 
secondary 
endpoints
Base
1.7% vs.
2.6% vs.
(5.1% vs.)
17.1%
0.3% vs.
0.4% vs.
(0.9% vs.);
3.0%
0.1
0.15
(0.3)
225.4;
146.3;
(65.6);
9.9
2;
3;
6;
16;
98.6%
96.0%
BaseMinus
1.7% vs.
2.6% vs.
(5.1% vs.)
11.4%
0.3% vs.
0.4% vs.
(0.9% vs.);
2.0%
0.15
0.225
(0.45)
225.4;
146.3;
(65.6);
21.6
2;
3;
6;
12
83.4%
69.5%
* Success probabilities have been calculated using R Version 3.5.1 based on simulations (10000 simulations per scenario). 
** Low dose (in brackets) is only used for dose finding analysis but not included in the power calculation for the formal analysis


Boehringer Ingelheim
22 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 132 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND
ADMINISTRATIVE STRUCTURE
The trial will be carried out in accordance with the Medical Devices Directive (93/42/EEC) and the 
harmonised standards for Medical Devices (ISO 14155, current version).
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, the Japanese GCP regulations (Ministry of Health and Welfare Ordinance No. 
28, March 27, 1997) and other relevant regulations. Investigators and site staff must adhere to 
these principles. Deviation from the protocol, the principles of ICH GCP or applicable 
regulations as will be treated as “protocol deviation”.
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains the 
responsibility of the treating physician of the patient.
The investigator will inform the sponsor immediately of any urgent safety measures taken to 
protect the trial patients against any immediate hazard, as well as of any serious breaches of 
the protocol or of ICH GCP.
The Boehringer Ingelheim transparency and publication policy can be found on the following 
web page: trials.boehringer-ingelheim.com. The rights of the investigator and of the sponsor
with regard to publication of the results of this trial are described in the investigator contract. 
As a rule, no trial results should be published prior to finalisation of the Clinical Trial Report.
The certificate of insurance cover is made available to the investigator and the patients, and is
stored in the ISF.
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB / Independent Ethics Committee 
(IEC and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to patient participation in the trial, written informed 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/assent and any additional patient-information 
form retained by the investigator as part of the trial records. A signed copy of the informed 
consent/assent form (as applicable) 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 where
his/her assent will be collected according to the regulatory and legal requirements of the


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 133 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
participating country. The refusal of an adolescent to participate must be accepted
independently 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 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 parent(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/assent 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/assent 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/assent and re-consenting/re-assenting process should be properly documented in 
the source documentation.
8.2
DATA QUALITY ASSURANCE
A risk-based approach is used for trial quality management. It is initiated by the assessment 
of critical data and processes for trial subject protection and reliability of the results as well as 
identification and assessment of associated risks. An Integrated Quality and Risk 
Management Plan documents the rationale and strategies for risk management during trial 
conduct including monitoring approaches, vendor management and other processes focusing 
on areas of greatest risk.
Continuous risk review and assessment may lead to adjustments in trial conduct, trial design 
or monitoring approaches. 
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
8.3
RECORDS
CRFs for individual patients will be provided by the sponsor. See Section 4.1.5.2 for rules 
about emergency code breaks. For drug accountability, refer to Section 4.1.8.


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 134 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
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)

Originals or copies of laboratory results and other imaging or testing results, with proper 
documented medical evaluation (in validated electronic format, if available)

Completion of patient’s participation in the trial” (end date; in case of premature 
discontinuation document the reason for it).

Prior to allocation of a patient to a treatment into a clinical trial, there must be 
documented evidence in the source data (e.g. medical records) that the trial participant 
meets all inclusion criteria and does not meet any exclusion criteria. The absence of 
records (either medical records, verbal documented feedback of the patient or testing 
conducted specific for a protocol) to support inclusion/exclusion criteria does not make
the patient eligible for the clinical trial.
8.3.2
Direct access to source data and documents
The investigator /institution will allow site trial-related monitoring, audits, IRB / IEC review 
and regulatory inspections. Direct access must be provided to the CRF and all source 
documents/data, including progress notes, copies of laboratory and medical test results, which 
must be available at all times for review by the CRA, auditor and regulatory inspector 


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 135 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
(e.g. FDA). They may review all CRFs and informed consents. The accuracy of the data will 
be verified by direct comparison with the source documents described in Section 8.3.1. The 
sponsor will also monitor compliance with the protocol and GCP.
Remote source data verification is acceptable in exceptional cases where onsite monitoring 
visits cannot take place due to circumstances like the COVID-19 pandemic or other relevant 
reasons. This must first be approved by the sponsor’s trial team.
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. 
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY
Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principles 7 and 12 of the WHO GCP 
handbook.
Individual patient data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the following exceptions:
Personalised treatment data may be given to the patient’s personal physician or to other 
appropriate medical personnel responsible for the patient’s welfare. Data generated at the site
as a result of the trial need to be available for inspection on request by the participating 
physicians, the sponsor’s representatives, by the IRB / IEC and the regulatory authorities.
8.5.1
Collection, storage and future use of biological samples and corresponding 
data 
Measures are in place to comply with the applicable rules for the collection, biobanking and 
future use of biological samples and clinical data, in particular

Sample and data usage has 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


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 136 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019

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.
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 project-independent external Data Monitoring Committee (DMC) will be established to 
assess the safety and efficacy of BI 655130 in this clinical trial at specified intervals through 
the final time-point (End of Study Visit). Measures will be put in place to ensure blinding of 


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 137 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
the sponsor and all other trial participants. The tasks and responsibilities of the DMC will be 
specified in a charter. The DMC will maintain written records of all its meetings.
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 clinical trial portal 
(Clinergize) to facilitate document exchange and maintain electronic ISF. 
BI has appointed a Clinical Trial Leader (CT Leader), responsible for coordinating all 
required activities, in order to 
-
manage the trial in accordance with applicable regulations and internal SOPs,
-
direct the clinical trial team in the preparation, conduct, and reporting of the trial,
-
ensure appropriate training and information of Clinical Trial Managers (CT 
Managers), Clinical Research Associates (CRAs), and investigators of participating 
countries.
The organisation of the trial in the participating countries will be performed by the respective 
local or regional BI-organisation (Operating Unit, OPU) in accordance with applicable 
regulations and BI SOPs, or by a Contract Research Organisation (CRO) with which the 
responsibilities and tasks will have been agreed and a written contract filed before initiation 
of the clinical trial.
Data Management and Statistical Evaluation will be done by BI according to BI SOPs.
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, Central Laboratory Manual, and 
other vendor specific manuals (as applicable) available in the ISF.


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 138 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
9.
REFERENCES
9.1
PUBLISHED REFERENCES
P09-07583
Aksentijevich I, Masters SL, Ferguson PJ, Dancey P, Frenkel J, van Royen-
Kerkhoff A, et al. An autoinflammatory disease with deficiency of the 
interleukin-1-receptor antagonist. N Engl J Med. 2009;360(23):2426-37.
P19-01888
Bachelez H, Choon SE, Marrakchi S, Burden AD, Tsai TF, Morita A, et.al. 
Inhibition of the Interleukin-36 Pathway for the Treatment of Generalized 
Pustular Psoriasis. N Engl J Med. 2019. 380(10).
R05-2548
Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI)--a simple 
practical measure for routine clinical use. Clin Exp Dermatol. 
1994;19(3):210-6.
R07-4311
Yellen SB, Cella DF, Webster K, Blendowski C, Kaplan E. Measuring 
fatigue and other anemia-related symptoms with the Functional Assessment 
of Cancer Therapy (FACT) measurement system. J Pain Symptom Manage. 
1997;13(2):63-74.
R09-1299
Greenland S, Robins JM. Estimation of a common effect parameter from 
sparse follow-up data. Biometrics 41, 55 - 68 (1985)
R10-0936
Walters SJ, Brazier JE. Comparison of the minimally important difference 
for two health state utility measures: EQ-5D and SF-6D. Qual Life Res. 
2005;14(6):1523-32.
R10-1424
Pinheiro J, Bornkamp B, Bretz F. Design and analysis of dose-finding 
studies combining multiple comparisons and modeling procedures. J 
Biopharm Stat 16 (5), 639 - 656 (2006)
R10-6267
Wang DD, Zhang S, Zhao H, Men AY, Parivar K. Fixed dosing versus 
body size-based dosing of monoclonal antibodies in adult clinical trials. J 
Clin Pharmacol. 2009;49(9):1012-24.
R11-4890
Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson NF, Jr., Bock 
SA, Branum A, et al. Second symposium on the definition and management 
of anaphylaxis: summary report--Second National Institute of Allergy and 
Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J 
Allergy Clin Immunol. 2006;117(2):391-7.
R12-1920
Herdman M, Gudex C, Lloyd A, Janssen M, Kind P, Parkin D, et al. 
Development and preliminary testing of the new five-level version of EQ-
5D (EQ-5D-5L). Qual Life Res. 2011;20(10):1727-36.
R12-2378
Rubin DB. Multiple imputation for nonresponse in surveys. New York: 
John Wiley & Sons (1987)
R13-3515
Woodworth T, Furst DE, Alten R, Bingham CO, 3rd, Yocum D, Sloan V, et 
al. Standardizing assessment and reporting of adverse effects in 
rheumatology clinical trials II: the Rheumatology Common Toxicity 
Criteria v.2.0. J Rheumatol. 2007;34(6):1401-14.


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 139 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
R14-5158
Marrakchi S, Guigue P, Renshaw BR, Puel A, Pei XY, Fraitag S, et al. 
Interleukin-36-receptor antagonist deficiency and generalized pustular 
psoriasis. N Engl J Med. 2011;365(7):620-8.
R15-1421
Onoufriadis A, Simpson MA, Pink AE, Di Meglio P, Smith CH, Pullabhatla 
V, et al. Mutations in IL36RN/IL1F5 are associated with the severe 
episodic inflammatory skin disease known as generalized pustular psoriasis. 
Am J Hum Genet. 2011;89(3):432-7.
R15-2001
Bornkamp B, Pinheiro J, Bretz F. Package 'DoseFinding' (February 19, 
2015). http: // cran. rproject. org/ web/ packages/ Dose Finding/
DoseFinding.pdf (access date: 28 April 2015); Comprehensive R Archive 
Network (2015)
R15-4293
Model-based dose finding under modeluncertainty using eneralparametric 
models”. Pinheiro et al. 2014
R15-5200
Langley RG, Feldman SR, Nyirady J, van de Kerkhof P, Papavassilis C. 
The 5-point Investigator's Global Assessment (IGA) Scale: A modified tool 
for evaluating plaque psoriasis severity in clinical trials. J Dermatolog 
Treat. 2015;26(1):23-31.
R16-0030
Pickard AS, Neary MP, Cella D. Estimation of minimally important 
differences in EQ-5D utility and VAS scores in cancer. Health Qual Life 
Outcomes. 2007;5:70.
R16-0032
Ware JE. SF-36 health survey update. Spine 2000;25(24):3130-3139.
R16-0033
Frendl DM, Ware JE. Patient-reported functional health and well-          
being outcomes with drug therapy: a systematic review of randomized trials 
using the SF-36 health survey. Med Care 2014;52(5):439-445.
R16-0581 
Mehta NN, Azfar RS, Shin DB, Neimann AL, Troxel AB, Gelfand JM
Patients with severe psoriasis are at increased risk of cardiovascular 
mortality: cohort study using the General Practice Research Database.
Eur Heart J 31 (8), 1000 - 1006 (2010)
R16-0929
Berki DM, Liu L, Choon SE, David Burden A, Griffiths CEM, Navarini 
AA, et al. Activating CARD14 Mutations Are Associated with Generalized 
Pustular Psoriasis but Rarely Account for Familial Recurrence in Psoriasis 
Vulgaris. J Invest Dermatol. 2015;135(12):2964-70.
R16-0930
Hussain S, Berki DM, Choon SE, Burden AD, Allen MH, Arostegui JI, et 
al. IL36RN mutations define a severe autoinflammatory phenotype of 
generalized pustular psoriasis. J Allergy Clin Immunol. 2015;135(4):1067-
70 e9.
R16-0932
von Zumbusch L. Psoriasis und pustuloses Exanthem. Archives of 
Dermatology and Syphilology. 1910;99:335-46.
R16-0933
Choon SE, Lai NM, Mohammad NA, Nanu NM, Tey KE, Chew SF. 
Clinical profile, morbidity, and outcome of adult-onset generalized pustular 
psoriasis: analysis of 102 cases seen in a tertiary hospital in Johor, 
Malaysia. Int J Dermatol. 2014;53(6):676-84.


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 140 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
R16-1462
Imafuku S, Honma M, Okubo Y, Komine M, Ohtsuki M, Morita A, et al. 
Efficacy and safety of secukinumab in patients with generalized pustular 
psoriasis: A 52-week analysis from phase III open-label multicenter 
Japanese study. J Dermatol. 2016;43(9):1011-7.
R16-1463
Borges-Costa J, Silva R, Goncalves L, Filipe P, Soares de Almeida L, 
Marques Gomes M Clinical and laboratory features in acute generalized 
pustular psoriasis: a retrospective study of 34 patients. Am J Clin Dermatol 
12 (4), 271 - 276 (2011)
R16-2698
Augey F, Renaudier P, Nicolas JF Generalized pustular psoriasis 
(Zumbusch): a French epidemiological survey. Eur J Dermatol 16 (6), 669 -
673 (2006)
R16-3360
Brunasso AM, Salvini C, Massone C. Efalizumab for severe palmo-plantar 
psoriasis: an open-label pilot trial in five patients. J Eur Acad Dermatol 
Venereol. 2009;23(4):415-9.
R16-3932
Horreau C, Pouplard C, Brenaut E, Barnetche T, Misery L, Cribier B, et al
Cardiovascular morbidity and mortality in psoriasis and psoriatic arthritis: a 
systematic literature review. J Eur Acad Dermatol Venereol 27 (Suppl 3), 
12 - 29 (2013)
R17-2617
Winthrop KL, Novosad SA, Baddley JW, Calabrese L, Chiller T, Polgreen 
P, et al. Opportunistic infections and biologic therapies in immune-
mediated inflammatory diseases: consensus recommendations for infection 
reporting during clinical trials and postmarketing surveillance. Ann Rheum 
Dis. 2015;74(12):2107-16.
R17-3403
Navarini AA, Burden AD, Capon F, Mrowietz U, Puig L, Koks S, et al. 
European consensus statement on phenotypes of pustular psoriasis. J Eur 
Acad Dermatol Venereol. 2017;31(11):1792-9.
R17-3456
Tay YK, Tham SN. The profile and outcome of pustular psoriasis in 
Singapore: a report of 28 cases. Int J Dermatol 36 (4), 266 - 271 (1997)
R17-3600
Robinson A, Van Voorhees AS, Hsu S, Korman NJ, Lebwohl MG, Bebo 
BF, Jr., et al. Treatment of pustular psoriasis: from the Medical Board of the 
National Psoriasis Foundation. J Am Acad Dermatol. 2012;67(2):279-88.
R17-3602
Johnston A, Xing X, Wolterink L, Barnes DH, Yin Z, Reingold L, et al. IL-
1 and IL-36 are dominant cytokines in generalized pustular psoriasis. J 
Allergy Clin Immunol. 2017;140(1):109-20.
R17-3603
Levin EC, Debbaneh M, Koo J, Liao W. Biologic therapy in erythrodermic 
and pustular psoriasis. J Drugs Dermatol. 2014;13(3):342-54.
R17-3605
Zelickson BD, Muller SA Generalized pustular psoriasis: a review of 63 
cases. Arch Dermatol 127 (9), 1339 - 1345 (1991)
R17-3626
Japanese Journal of Dermatology. 2010;120(4):815-39.
R17-3632
Mahil SK, Catapano M, Di Meglio P, Dand N, Ahlfors H, Carr IM, et al. 
An analysis of IL-36 signature genes and individuals with IL1RL2 
knockout mutations validates IL-36 as a psoriasis therapeutic target. Sci 
Transl Med. 2017;9(411).


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 141 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
R17-3898
Jin H, Cho HH, Kim WJ, Mun JH, Song M, Kim HS, et al
Clinical features and course of generalized pustular psoriasis in Korea.
J Dermatol 42, 674 - 678 (2015)
R18-1702
Review Report - Cosentyx. Pharmaceutical and Medical Devices Agency 
(PMDA) Nov. 12, 2015.
R18-1705
Diagnostic Criteria: European Rare and Severe Psoriasis Expert Network 
(ERASPEN); 2018
R18-1988
Finlay AY. Cardiff University, Department of Dermatology;  [Available 
from: http: // sites. cardiff.ac. uk/ dermatology/ quality-of-life/
dermatology-quality-of-life-index-dlqi/ dlqi-instructions-for-use-and-
scoring/.
R18-1989
Hawker GA, Mian S, Kendzerska T, French M. Measures of adult pain: 
Visual Analog Scale for Pain (VAS Pain), Numeric Rating Scale for Pain 
(NRS Pain), McGill Pain Questionnaire (MPQ), Short-Form McGill Pain 
Questionnaire (SF-MPQ), Chronic Pain Grade Scale (CPGS), Short Form-
36 Bodily Pain Scale (SF-36 BPS), and Measure of Intermittent and 
Constant Osteoarthritis Pain (ICOAP). Arthritis Care Res (Hoboken). 
2011;63 Suppl 11:S240-52.
R18-1990
Rentz AM, Skalicky AM, Burslem K, Becker K, Kaschinski D, Esser D, et 
al. The content validity of the PSS in patients with plaque psoriasis. J 
Patient Rep Outcomes. 2017;1(1):4.
R20-2256
National Psoriasis Foundation (NPF) Task Force. Updated: COVID-19 
Recommendations
R20-2257
National Institute for Health and Care Excellence (NICE). COVID-19 rapid 
guideline: severe asthma NICE guideline 
R20-2258
American Academy of Allergy Asthma & Immunology. An Update on 
COVID-19 for the Practicing Allergist/immunologist
R96-0739
Ware JE, Sherbourne CD. The MOS 36-item short-form health survey (SF-
36). Med Care 30, 473 - 383 (1992)
R96-2382
EuroQol G. EuroQol--a new facility for the measurement of health-related 
quality of life. Health Policy. 1990;16(3):199-208.
R96-3541
Fredriksson T, Pettersson U. Severe psoriasis--oral therapy with a new 
retinoid. Dermatologica. 1978;157(4):238-44.
R97-1093
Ware JE, editor. SF-36 Health Survey: Manual and Interpretation 
Guide.Boston: The Health Institute, New England Medical Center; 1993.
R97-1149
Guy W, 048 HAMA Hamilton anxiety scale. In: ECDEU Assessment 
Manual for Psychopharmacol ogy.Rockville: U.S. Department of Health, 
Education, and Welfare, Public Health Service, Alcohol, Drug Abuse, and 
Mental Health Administration , 194 - 198 (1976)
9.2
UNPUBLISHED REFERENCES
c03320877
Investigator's Brochure.  Current Version.


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 142 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
c09985235-01
 Single-blind, partially 
randomised, placebo-controlled Phase I study to investigate safety, 
tolerability, pharmacokinetics and pharmacodynamics of single rising 
intravenous doses of BI 655130 in healthy male volunteers, April 7, 2017.


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 143 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
10.
APPENDICES
10.1
INSTRUCTIONS FOR USE
10.1.1
Physician’s Global Assessment for Generalized Pustular Psoriasis (GPPGA)
PGA Score for GPP
0 = If mean=0 for all three components 
1 = If 0 < mean <1.5
2 = If (1.5 <= mean <2.5)
3 = If 2.5 <= mean <3.5
4 = If mean >=3.5
Source:  (R15-5200)
Erythema
0 = Clear:  
Normal or postinflammatory hyperpigmentation 
1 = Almost Clear:  
Faint, diffuse pink or slight red
2 = Mild:  
Light red
3 = Moderate:
Bright red 
4 = Severe:
Deep fiery red
Pustules
0 = Clear:
No visible pustules
1 = Almost Clear:
Low density occasional small discrete (non coalescent) pustules 
2 = Mild:
Moderate density grouped discrete small pustules (non coalescent) 
3 = Moderate:
High density pustules with some coalescence
4 = Severe:
Very high density pustules with pustular lakes
Scaling/crusting
0 = Clear:
No scaling and no crusting
1 = Almost Clear:
Superficial focal scaling or crusting restricted to periphery of lesions 
2 = Mild:
Predominantly fine scaling or crusting
3 = Moderate:
Moderate scaling or crusting covering most or all of lesions 
4 = Severe:
Severe scaling or crusting covering most or all lesions


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 144 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 145 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 146 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 147 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 148 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 149 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 150 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 151 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 152 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 153 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 154 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
10.1.5
Psoriasis Symptom Scale 
Listed below are a set of problems that people with psoriasis have said are important. For 
each question, click on the circle that best describes the severity of your symptoms during the 
past 24 hours. Please answer every question.
1. How severe was your pain from your psoriasis during the past 24 hours?
o
None
o
Mild
o
Moderate
o
Severe
o
Very severe
2. How severe was the redness from your psoriasis during the past 24 hours?
o
None
o
Mild
o
Moderate
o
Severe
o
Very severe
3. How severe was your itching from your psoriasis during the past 24 hours?
o
None
o
Mild
o
Moderate
o
Severe
o
Very severe
4. How severe was your burning from your psoriasis during the past 24 hours?
o
None
o
Mild
o
Moderate
o
Severe
o
Very severe
Source:  (R18-1990)
©2015, Boehringer Ingelheim International GmbH


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 155 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
10.1.6
Diagnosis of Anaphylaxis
Clinical criteria for diagnosing anaphylaxis (R11-4890).
Anaphylaxis is highly likely when any one of the following 3 criteria are fulfilled
1. Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue, or both (eg, generalized hives, pruritus or flushing, swollen lips-tongue-
uvula)
AND AT LEAST ONE OF THE FOLLOWING
a. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced PEF, 
hypoxemia)
b. Reduced BP or associated symptoms of end-organ dysfunction (eg, hypotonia [collapse], 
syncope, incontinence)
2. Two or more of the following that occur rapidly after exposure to a likely allergen for 
that patient (minutes to several hours):
a. Involvement of the skin-mucosal tissue (eg, generalized hives, itch-flush, swollen lips-
tongue-uvula)
b. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced PEF, 
hypoxemia)
c. Reduced BP or associated symptoms (eg, hypotonia [collapse], syncope, incontinence)
d. Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting)
3. Reduced BP after exposure to known allergen for that patient (minutes to several hours):
a. Infants and children: low systolic BP (age specific) or greater than 30% decrease in 
systolic BP*
b. Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from that 
person’s baseline 
PEF, Peak expiratory flow; BP, blood pressure.
*Low systolic blood pressure for children is defined as less than 70 mm Hg from 1 month to 1 year, less than (70 mm Hg
+[2 x age] from 1 to 10 years, and less than 90 mm Hg from 11 to 17 years.


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 156 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 157 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 158 of 194
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 159 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
10.1.10
Dermatology Life Quality Index (DLQI)
DERMATOLOGY LIFE QUALITY INDEX     
DLQI
Hospital No:
Date:
  Score:
Name:
Diagnosis:
Address:
The aim of this questionnaire is to measure how much your skin problem has affected 
your life OVER THE LAST WEEK.  Please check one box for each question.
1.
Over the last week, how itchy, sore, painful or 
stinging has your skin been?
Very much
A lot
A little
Not at all




2.
Over the last week, how embarrassed or self 
conscious have you been because of your skin?
Very much
A lot
A little
Not at all




3.
Over the last week, how much has your skin 
interfered with you going shopping or looking after 
your home or yard?
Very much
A lot
A little
Not at all




Not relevant 
4.
Over the last week, how much has your skin 
influenced the clothes you wear?
Very much
A lot
A little
Not at all




Not relevant 
5.
Over the last week, how much has your skin affected 
any social or leisure activities?
Very much
A lot
A little
Not at all




Not relevant 
6.
Over the last week, how much has your skin made it 
difficult for you to do any sport?
Very much
A lot
A little
Not at all




Not relevant 
7.
Over the last week, has your skin prevented you from 
working or studying?
yes
no


Not relevant 
If "No", over the last week how much has your skin 
been a problem at work or studying?
A lot
A little
Not at all 



8.
Over the last week, how much has your 
skin 
created problems with your partner or any of your 
close friends or relatives? 
Very much
A lot
A little
Not at all




Not relevant 


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 160 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
Dermatology Life Quality Index (DLQI) (cont’d.)
9.
Over the last week, how much has your 
skin 
caused any sexual difficulties?
Very much
A lot
A little
Not at all




Not relevant 
10. Over the last week, how much of a problem has the 
treatment for your skin been, for example by making 
your home messy, or by taking up time?
Very much
A lot
A little
Not at all




Not relevant 
Please check you have answered EVERY question. Thank you
Source:  (R05-2548)
©AY Finlay, GK Khan, April 1992


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 161 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 162 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 163 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 164 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 165 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 166 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
11
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Date of amendment
29 July 2020
EudraCT number
EU number
2018-003081-14
BI Trial number
1368-0027
BI Investigational Medicinal
Product(s)
BI 655130 (Spesolimab)
Title of protocol
Effisayil™ 2: Multi-center, randomized, parallel 
group, double blind, placebo controlled, Phase IIb 
dose-finding study to evaluate efficacy and safety 
of BI 655130 (Spesolimab) compared to placebo in 
preventing generalized pustular psoriasis (GPP) 
flares in patients with history of GPP
Global Amendment due to urgent safety reasons
Global Amendment
X
Section to be changed
Clinical Trial Protocol Synopsis Table:  Trial 
Objective(s), Trial Design and Rescue Medication
Description of change
The use of a single i.v. dose of BI 655130 for 
treating patients with onset of acute GPP flares will 
be evaluated for safety and efficacy as an 
additional objective.
Rationale for change
Added the option for a 2nd i.v. rescue dose for 
patients who meet criteria, therefore removed the 
word “single” to avoid confusion as the patient 
could receive 2 rescue doses with i.v. BI 655130 
(at R1/D1 and R3/D8) if protocol specified criteria 
is met. 
Section to be changed
Clinical Trial Protocol Synopsis Table:  Trial 
Design and Section 3.1 Overall Trial Design
Description of change
Updated the text as following in synopsis (See text 
in bold):
This is a multicenter, randomized, parallel group, 
double-blind, placebo-controlled Phase IIb dose 
finding study to evaluate efficacy and safety 
compared to placebo with multiple subcutaneous 
(s.c.) doses of BI 655130/placebo in adolescents 
from 12 years to less than 18 years of age and 
adult patients with history of GPP and currently 
presenting (at screening and at randomization) with 
a GPPGA score of 0 or 1 (clear or almost clear).


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 167 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
Updated the text as following in Section 3.1 (See 
text in bold):
This is a multicenter, randomized, parallel group, 
double-blind, placebo-controlled Phase IIb study 
comprising of 3 active doses compared to placebo 
in adolescents from 12 years to less than 18 
years of age and adult patients (adult and 
adolescent) with history of GPP and currently 
presenting (at screening and at randomization) with 
a GPPGA score of 0 or 1 (clear or almost clear).
Rationale for change
Adapted the trial design text to match the wording 
from the PIP Decision.
Section to be changed
Clinical Trial Protocol Synopsis Table:  Total 
Number of patients randomized
Description of change
Changed from “12-17 years”  to “12 years to less 
than 18 years of age”. For the adolescent patients, 
it was also clarified that 2 adolescents per treatment 
group will be included.  
Rationale for change
Adapted to match the wording from the PIP 
Decision.
Section to be changed
Clinical Trial Protocol Synopsis Table: Main In-
and exclusion criteria & Section 3.3.2 Inclusion 
Criteria.
Description of change
Inclusion Criteria #3, 4 and 5 were updated as 
following (see text in bold):
Inc#3 Patients who are not on concomitant GPP 
treatment at time of randomization (V2) must have 
had at least two presentations of moderate to severe 
GPP flare in the past year, at least one of which had 
evidence of either fever and/or elevated CRP 
and/or elevated WBC and/or asthenia and/or 
myalgia.  
Inc#4 Patients who are not on concomitant GPP 
treatment at time of randomization (V2) but who 
were on concomitant GPP treatment until shortly 
before randomization (V2) (≤ 12 weeks before 
randomization), these patients must have a history 
of flaring while on concomitant treatment for 
GPP or in case of dose reduction or 
discontinuation of their concomitant medication.
Inc#5 Patients who are on concomitant treatment 
regimen with retinoids and/or methotrexate and/or 
cyclosporine must stop at the day of randomization 


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 168 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
(V2). These patients must have a history of flaring 
while on concomitant treatment for GPP or in 
case of dose reduction or discontinuation of these 
concomitant medications.
Rationale for change
Clarification/Update
Section to be changed
Clinical Trial Protocol Synopsis Table: Main In-
and exclusion criteria & Sections 3.3.3 Exclusion 
Criteria.
Description of change
Removed Exclusion Criteria #9.
Adolescent patients (12-17 years) with hereditary 
fructose intolerance (HFI).
Rationale for change
It is the Sponsor’s position that patients with HFI 
do not need to be excluded from the trial as the BI 
655130 formulations do not include fructose. 
Regarding the sucrose content of the formulation, 
in humans, sucrose is catabolized to 
monosaccharides, glucose and fructose by sucrase 
or isomaltase glycoside hydrolases in the intestines 
after oral ingestion. However, as these enzymes are 
limited to the microvilli of the duodenum, sucrose 
is eliminated unchanged through urinary excretion 
after intravenous administration. Therefore, 
patients with HFI should not have adverse effects 
related to the exposure to sucrose.
Section to be changed
Flow Chart 1 and 2, Footnote 9 in Flow Chart 1 
and Footnote 7 in Flowchart 2, Section 5.6 Other 
Assessments and Section 6.2.2 Treatment Periods
Description of change
Revised from Photographs of skin lesions" to 
"Photographs of skin/skin lesions"
Rationale for change
Clarification. Since the patients are coming in with 
clear/almost clear skin condition, there may not be 
any lesions on the body. However, the expectation 
is that photographs are taken in all  regions 
specified in Section 5.6 irrespective of presence of 
lesions or not.
Section to be changed
Flow Chart 1&2, Footnotes 19& 20 of Flow chart 
1&2 and Section 5.2.6.2.1 AE collection
Description of change
Vital status collection time points included and 
clarified.
Rationale for change
Clarification
Section to be changed
Flowchart 1 – screening visit window, Flow Chart 
1- Footnote 1, Section 6.2.1 Screening and Run-In 


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 169 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
Periods and Figure 3.1:1.
Description of change
Updated screening visit window (day) in Flow 
chart 1 from “-28 days to -1 day” to  “-84 days to -
1 day”. 
Updated screening visit window (week) in Flow 
chart 1 from “-4 wks to 0” to  “-12 wks to 0” day”.
Also updated screening period as following is 
section 6.2.1
Screening (Visit 1) should normally take place no 
more than 28 84 days before Visit 2. Visit 1 
procedures may be completed over multiple 
physical visits, if needed. 
Updated Flow chart 1- Footnote 1 as footnote 1a) 
&1b) as following:
1a) Infection testing includes tuberculosis, 
hepatitis, hepatitis C, and HIV assessments. 
b) For patients who sign the informed consent ≥ 
4 weeks prior to V2, infection testing must be 
repeated 2 to 4 weeks prior to V2.
Updated the screening window to -84 to -1 day in 
figure 3.1:1.
Rationale for change
Updated the screening visit window to -84 days to 
– 1 day to account for washout period for biologics. 
Also clarified that for patients who sign the 
informed consent ≥ 4 weeks prior to V2, infection 
testing must be repeated 2 to 4 weeks prior to V2 to 
rule out active infection prior to study drug 
administration.
Section to be changed
Flow Chart 1- Footnote  4, Section 5.2.2 Vital 
Signs and Section 6.2.2 Treatment Periods
Description of change
It was clarified that on s.c. study drug 
administration days, vital signs will be assessed at 
predose (prior to blood sampling) and 10 mins after 
the end of drug administration and at Visit 2 and 
Visit 3 additional measurements will be 
performed approximately 60 minutes after the 
end of  drug administration (i.e. 60 minutes 
after last injection).
Rationale for change
Update. Visits 2 and 3 represent the first visits, 
where trial medication will be administered –
which is why the time window for the monitoring 
of vital signs has been extended during these visits. 


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 170 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
Section to be changed
Flow Chart 1- Footnote 5 and Flow Chart 2-
Footnote 4
Description of change
Added clarification that if urine pregnancy test is 
positive, study drug administration will be 
postponed until negative result of serum pregnancy 
test is available. 
Rationale for change
Clarification
Section to be changed
Flow Chart 1- Footnote 16, Flow Chart 2- Footnote 
8 and Section 5.5.1 Methods and timing of sample 
collection
Description of change
Clarified that optional lesional or non-lesional (if
no lesions are present) skin biopsies are to be 
collected. 
In Section 5.5.1, it was further clarified that
in an event of a GPP flare, a lesional biopsy will 
be collected at the site of most inflammatory 
(deepest red erythema) lesion. For consistency, all
future biopsies should be taken from this lesion 
or closest proximity (absolutely same anatomical
area).
Rationale for change
Clarification
Section to be changed
Flow Chart 1- Footnote 13, Flow Chart 2- Footnote 
12, Section 5.2.5 and Section 6.2.2
Description of change
Updated 
From:  
At the visit with i.v. administration, the local 
tolerability will be assessed approximately 1 hour 
after the end of infusion and at visits with s.c. 
administration, local tolerability will be assessed 
approximately 10 mins after the end of s.c. 
injection(s).
To:
Local tolerability at the administration site of BI 
655130/placebo will be assessed during the study 
drug administration (i.v. or s.c.) and at the 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.
Rationale for change
Clarified that the local tolerability reactions should 
be captured as AEs reporting and added the 
retrospective questioning for local tolerability 


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 171 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
reactions to the next visit in order to capture any 
potential adverse event consistent with a local 
tolerability reaction.
Section to be changed
Flow Chart 1 and 2 -Footnotes 14 &15, Section 3.1
Overall Trial Design, Footnotes 2& 3 of  Figure 
3.1:1, Footnotes 5&6 of  Figure 3.1:1 overall trial 
design, Section 3.3.4.1 Discontinuation of trial 
treatment and Section 6.2.3 follow-up period and 
trial completion
Description of change
Clarified that V14 will be recorded as the End of 
Study visit (i.e., EoS1) for patients who qualify and 
agree to enter the OLE trial (1368-0025). V14 will 
also be recorded as End of Study Visit for patients 
who prematurely discontinue with the last dose of 
treatment up to and including Day 232 and who 
agree to complete all remaining study visits up to 
Wk 48 from randomization. Since these patients 
prematurely discontinued, they would not qualify 
to enter OLE trial. It was also clarified that EoS2 
visit is applicable for patients who do not qualify or 
who do not agree to enter into the OLE trial at 
Week 48. EoS2 is also applicable for patients who 
prematurely discontinue with the last dose of 
treatment after Day 232. Since these patients 
prematurely discontinued, they would not qualify 
to enter OLE trial. 
In Section 3.3.4.1, it was further clarified that even 
if the trial treatment is discontinued, the patient 
remains in the trial and, given his/her agreement 
considering the GCP-guidelines, ideally should 
follow all of the remaining scheduled study visits 
and procedures as outlined in the Flow Chart 1 or 
Flow Chart 2 (as applicable) and Section 6.2.3 up 
to Wk 48 from randomization; If a patient is not 
willing to follow the whole visit schedule, the 
patient should at a minimum be followed for 16
weeks after last study drug administration (REP) 
and at least the scheduled visit at Week 48 (i.e. at 
the end of treatment period) should be conducted. 
Patients refusing to return to the study site should 
at least provide safety information by phone at the 
respective visits.
Definition of Trial Completion was also updated as 
following:
Trial completion for an individual patient who 


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 172 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
qualifies and agrees to enter OLE trial has 
completed end of study visit per protocol. It 
could be EoS1 visit or EoS2 visit as defined 
above. at week 48 or a patient who doesn’t qualify 
to enter OLE trial or who may have qualified, but 
do not agree to participate on the OLE trial and has 
completed EoS2 visit per protocol. 
Rationale for change
Provided clarification on the expectation of visits 
to be completed  including end of study visit for all 
patients irrespective of premature discontinuation 
or not. 
Section to be changed
Flow Chart 2 - Footnote 21
Description of change
“For Visit R3, added an “X” with a new 
coordinating footnote #21 for  “pregnancy test”, 
‘12 Lead ECG”, “IRT call”, 
“dispense/administration study drug” and “local 
tolerability” 
Rationale for change
Update. If a patient meets a protocol specified 
criteria for receiving R3/D8 dosing, then these 
procedures are to be completed.
Section to be changed
Abbreviations
Description of change
Included abbreviations for Alkaline Phosphatase 
and Tuberculin Skin Test
Rationale for change
Update
Section to be changed
Section 1.1 Medical Background and  Section 3.2
Discussion of trial design, including choice of 
control groups
Description of change
Added certolizumab (Cimzia®)  to the list of 
medications that have been approved in Japan for 
treatment of GPP. 
Rationale for change
Certolizumab has been approved in Japan for 
treatment of GPP.
Section to be changed
Section 1.2 Drug Profile (Data from clinical 
studies)
Description of change
Added Hidradenitis Suppurativa (HS)
Rationale for change
Included Hidradenitis Suppurativa (HS) as this is 
also considered to be an inflammatory disease 
similar to GPP, PPP, AD and IBD. 
Section to be changed
Section 1.2 Drug Profile (Data from clinical 
studies)
Description of change
Included additional details on the 1368.3 trial 


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 173 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
results.
Rationale for change
Updated information as this 1368.3 is completed 
with CTR archived in 2018.
Section to be changed
Section 1.2 Drug Profile
Description of change
Included additional results/data  for 1368.15 trial 
Rationale for change
Update based on IB version 7
Section to be changed
Section 1.4 Benefit-Risk Assessment
Description of change
A total of more than 212 an estimated 378
subjects have been exposed to single or multiple 
i.v. doses of BI 655130 as of September 20182019.
Also included the summary of  Benefit-Risk 
Assessment in context of COVID-19 pandemic for 
patients participating in clinical trials investigating 
Spesolimab.
Rationale for change
Exposure data has been updated based on SEP 
2019 DSUR which was included in IB version 7.
Summary of Spesolimab Benefit-Risk Assessment 
in context of COVID-19 infection has been 
included.
Section to be changed
Description of change
Rationale for change
Section to be changed
Section 3.1 Overall Trial Design and Table 3.1:3 
Study Definitions
Description of change
Included the following criteria for receiving i.v. 
infusion with 900 mg of BI 655130 on R3/D8. 

For patients with GPPGA score of  ≥3 
and a pustular component of GPPGA of 
≥2 at R1: the pustular component of 
GPPGA is  ≥2 and total GPPGA is ≥2 at 
R3/D8.

For patients with GPPGA score of 2 and 
a pustular component of GPPGA of ≥2 at 
R1: the pustular component of GPPGA is  
≥2 at R3/D8.


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 174 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
Rationale for change
Update. In an event of a GPP flare, in addition to 
receiving i.v. rescue treatment with OL BI 655130 
on R1/D1, another dose of i.v. BI 655130 is being 
allowed on R3/D8 if the patient meets protocol 
specified criteria.  
Section to be changed
Section 3.1 Overall Trial Design and Flow Chart 2 
– footnote 13
Description of change
It was clarified that once the OL s.c. visit 
assignment is calculated by referring to Flow Chart 
1, all study procedures scheduled for this first dose 
of OL s.c. maintenance treatment visit and 
subsequent OL maintenance treatment visits should 
be completed per Flow Chart 2.
Rationale for change
Clarification
Section to be changed
Section 3.1 Overall Trial Design and Table 3.1:3 
Study Definitions
Description of change
Included the following threshold for switching 
from OL s.c. dose of 300 mg BI 655130 q12 weeks
to intensified maintenance therapy with open label 
s.c. dose of 300 mg BI 655130 q4 weeks.
If the patient’s GPPGA total score increases by 
≥ 1 (with or without the presence or new 
appearance of pustules), or if there is an 
increase in the pustular component of GPPGA ≥ 
1 from any of the previous OL maintenance 
visit(s), then the investigator should may treat the 
patient with intensified maintenance therapy with 
open label s.c. dose of 300 mg BI 655130 q4 
weeks. 
Rationale for change
Updated Information. Included criteria to switch 
the patient from OL s.c. dose of 300 mg BI 655130 
q12 weeks to intensified maintenance therapy with 
open label s.c. dose of 300 mg BI 655130 q4 
weeks.
Section to be changed
Section 3.1 Overall Trial Design, Table 3.1:3 Study 
Definitions and  Section 4.2.2 Restrictions
Description of change
Included allowance of use of topical treatments and 
topical corticosteroids after four weeks following 
i.v. dose rescue treatment with open label BI 
655130 at R1/D1and during OL maintenance 
treatment period. Use of these treatments does not 
lead to IMP discontinuation.


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 175 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
Rationale for change
Clarification/Update.
Section to be changed
Section 3.1 Overall Trial Design
Description of change
Added the following text:
The primary analysis of this trial is planned to 
be performed once all randomized patients have 
completed or early discontinued from the 48 
week treatment period; 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 randomized patients have 
completed the trial (including any follow-up 
period) if applicable.
The primary analysis and final analysis may be 
performed as a single analysis (at the time of 
trial completion), if, prior to the time of the 
primary analysis, the trial team agrees that the 
expected time interval between the planned 
analyses is insufficient to justify the 
performance of separate analyses.
Rationale for change
Updated and provided brief summary on timing of 
primary and final analysis. Further details are also 
described in Section 7 of the CTP. 
Section to be changed
Figure 3.1:1 Overall Study Design
Description of change
Updated figure and footnotes as following: 
** Please refer to Figure 3.1:2 for study design in 
the event experiences 1st GPP flare and Section 3.1 
for further details.
1 Investigator should treat the patient with intensified 
maintenance therapy of OL BI 655130 s.c. 300 mg 
q4weeks if the patient experiences any further disease 
worsening. If the patient’s GPPGA total score 
increases by ≥ 1 (with or without the presence or 
new appearance of pustules), or if there is an 
increase in the pustular component of GPPGA ≥ 1, 
the Investigator may treat the patient with 
intensified maintenance therapy of OL BI 655130 
s.c. 300 mg q4weeks. 
2 V14 will be recorded as the End of Study visit 
(i.e., EoS1) for patients who qualify and agree to 
enter the OLE trial (1368-0025). V14 will also be 
recorded as End of Study Visit (EoS 1) for 
patients who prematurely discontinue with the 
last dose of treatment up to and including Day 
232 and who agree to complete all remaining 


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 176 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
study visits up to Wk 48 from randomization. 
Since these patients prematurely discontinued, 
they would not qualify to enter OLE trial.
EOS1: Visit will be conducted at week 48 from 
randomization visit. This is the last visit for 
patients who qualify and agree to enter into the 
OLE trial. This visit will be their End of Study visit 
for this trial.
3EoS 2 visit is applicable to patients who do not qualify 
or who do not agree to enter into the OLE Trial (1368-
0025) at Wk 48. EoS2 visit is also applicable for
patients who prematurely discontinue with the last dose 
of treatment after D232. Since these patients 
prematurely discontinued, they would not qualify to 
enter OLE trial. These patients need to be followed for 
16 weeks after the last dose of the study drug 
administration.  EoS2 will be their End of Study visit 
for the trial. 
Rationale for change
Update/Clarification
Section to be changed
Table 3.1:2
Description of change
Footnotes updated as following
1EoS1should be performed at least 7 days after R1the 
last rescue treatment with i.v. OL BI 655130 is given. 
2If patients on randomized treatment and flare at the 
visit of V14 (Week 48), the investigator could still treat 
the patient with the rescue treatment with BI 655130 
and determine whether to roll over the patient by 
planning another visit 7 days after R1.  
32If it was determined that a patient does not qualify or 
not agree to roll over to OLE, the then at the time of the 
decision, no furtherpatient still needs to attend the 
visits listed in this table beyond will be required, patient 
will go directly to EoS2planned in the table if 
possible.
Rationale for change
Update/Clarification
Section to be changed
Figure 3.1:2 Study Design in the event a patient 
experiences 1st GPP Flare
Description of change
Updated figure and footnotes as following:
3Investigator may treat the patient with intensified 
maintenance therapy of OL BI 655130 s.c. 300 mg 
q4 weeks if the patient experiences any further 
disease worsening meets protocol specified criteria. 
Please refer to Section 3.1.
*Dosing days. Please refer to Section 3.1 for 
further details.  
5 V14 will be recorded as the End of Study visit 


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 177 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
(i.e., EoS1) for patients who qualify and agree to 
enter the OLE trial (1368-0025). V14 will also be 
recorded as End of Study Visit (EoS 1) for 
patients who prematurely discontinue with the 
last dose of treatment up to and including Day 
232 and who agree to complete all remaining 
study visits up to Wk 48 from randomization.
Since these patients prematurely discontinued, 
they would not qualify to enter OLE trial. EoS1, 
Visit will be conducted at week 48 from 
randomization visit. This is the last visit for 
patients who qualify and agree to entre into the 
OLE trial.
6EoS2 is applicable for patients who do not qualify 
or who do not agree to enter OLE trial (1368-
0025) at Week 48. EoS2 is also applicable for
patients who prematurely discontinue with the 
last dose of treatment after D232. Since these 
patients prematurely discontinued, they would 
not qualify to enter OLE trial. 
Rationale for change
Update/Clarification
Section to be changed
Section 3.3.4 Withdrawal of patients from 
treatment or assessments
Description of change
Removed the following statement:
Every effort should be made to keep the patients in 
the trial: if possible on treatment, or at least to 
collect necessary data until 16 weeks following the 
last study drug administration.
Rationale for change
Removed duplicate information as sections 3.3.4.1 
& 3.3.4.2 includes details on handling of patients 
with premature treatment or trial discontinuation. 
Section to be changed
Table 4.1.1:1 BI 655130 for Rescue Treatment, 
Section 4.1.2 Selection of doses in the trial and 
dose modifications , and Table 4.1.4:1Treatments 
used in the trial
Description of change
BI 655130 for Rescue Treatment (at RI/D1 Or at 
R1/D1& R3/D8)
Rationale for change
Updated and Clarified the visits where rescue dose 
with i.v. OL BI 655130 could be given to the 
patient. 


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 178 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
Section to be changed
Section 4.1.5.1 Blinding
Description of change
Added a statement in section 4.1.5.1 that if interim 
analysis is performed, only data with rescue 
treatment periods will be used and therefore no 
unblinding of randomized treatments will be 
required. 
Rationale for change
Clarification/Update. The interim analysis may be
performed to support potential submission for acute 
flare treatment with i.v. regimen. Keeping blinding 
of the randomized s.c. treatment ensures the 
integrity of the trial.
Section to be changed
Section 5.2 Assessment of Safety
Description of change
Removed “Injection site reactions” and added with 
“Immunogenicity (ADA)”
Rationale for change
Injection site reactions was removed as Local 
tolerability assessments will be performed 
throughout the trial. The assessment of local 
tolerability will be based on reported adverse 
events. 
Immunogenicity (ADA) was added for consistency 
with Section 7.2.5 of the CTP.
Section to be changed
Section 5.2.3 Safety Lab Parameters
Description of change
Updated text to clarify that local labs are to be used 
at visits involving i.v. administration of OL BI 
655130. The following statement has been included 
as well. 
It is highly encouraged to collect and assess the 
labs the day of i.v. administration; however in 
exceptional cases, labs may be collected one day 
prior to ensure lab results are available prior to 
dosing.
Rationale for change
Clarification
Section to be changed
Table 5.2.3:1 Safety Lab Tests & Section 3.3.3 


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 179 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
Exclusion criteria
Description of change
Footnote 1 in table 5.2.3:1 updated to clarify that 
for patients who sign the informed consent ≥ 4 
weeks prior to V2, infection testing must be 
repeated 2 to 4 weeks prior to V2.
Footnote 1 added to the infection tests which are to 
be collected only at screening.
Footnote 3 was clarified that TST can be done at 
site if retest QuantiFERON test result is 
indeterminate.
Exclusion 7 and footnotes 3, 4 and 5 in table 
5.2.3:1 were also updated to include option for 
using alternative test/procedure (as per local 
standards) to rule out TB if tuberculin skin test is 
not used within some countries. 
Rationale for change
Clarification/Updated Information
Section to be changed
Section 6.2.1 Rescreening
Description of change
Added the following clarification. 
Rescreening transaction must be registered in the 
IRT system.  A new patient number will be 
provided which will be linked to the previous 
patient number in the IRT system.
Rationale for change
Clarification
Section to be changed
Section 6.2.3 Follow-up period and trial 
completion
Description of change
Added clarification that End of Study visit must be 
registered in IRT system for all randomized 
patients.
Rationale for change
Clarification
Section to be changed
Section 7 Stats Methods and Determination of 
Sample Size
Description of change
Removed “During the conduct of the trial, the 
event rate will be closely monitored in a blinded 
way. If the event rate is lower than expected, the 
sample size may be expanded to ensure that at the 
time when the last randomized patient has 
completed (or discontinued from) 48 weeks of 
treatment, that at least the target number of events 
has been observed.”
Rationale for change
It is expected that sufficient events could be 
observed in current target population. So the 
monitoring is not needed. 


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 180 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
Section to be changed
Section 7 Stats Methods and Determination of 
Sample Size Section 7.2.7 Interim Analysis
Description of change
Added the following statement is Section 7:
To support a potential BI 655130 acute GPP flare 
treatment submission, an interim analysis of the 
clinical efficacy and safety data collected during 
the BI 655130 OL i.v rescue and s.c. maintenance 
treatment periods may be performed. For further 
details refer to Section 7.2.7.
Added further description is section 7.2.7 on the 
interim analysis for i.v. rescue treatment period and 
OL maintenance treatment period.
Rationale for change
This interim analysis is needed to support potential 
submission for acute flare treatment.
Section to be changed
Section 7.4 Randomization
Description of change
The first twelve adolescent patients will be 
randomized in a 1:1:1:1 ratio to the four arms 
regardless of concomitant use of systemic GPP 
medications at randomization (yes vs. no) and 
blocking factor region (Japan vs. Rest of world).
Rationale for change
To ensure at least 2 adolescent patients in each 
randomized treatment arm
Section to be changed
Section 7 Stats Methods and Determination of 
Sample Size, Section 7.5 Determination of Sample 
Size and Table 7.5:1
Description of change
Changed “final  analysis” to “primary analysis”
Rationale for change
Correction
Section to be changed
Section 8.3.1 Source Documents
Description of change
Removed the following text as this is not 
applicable.
Before sending or uploading those copies, the 
investigator must ensure that all patient identifiers 
(e.g. patient’s name, initials, address, phone 
number, social security number) have properly 
been removed or redacted from any copy of the 
patients’ source documents
Rationale for change
The text was removed as it is not applicable for the 
trial. There is no source documents that are being 
sent to external committees such as adjudication 
committee etc. 


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 181 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 182 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
11.2
GLOBAL AMENDMENT 2
Date of amendment
19 April 2021
EudraCT number
EU number
2018-003081-14
BI Trial number
1368-0027
BI Investigational Medicinal
Product(s)
BI 655130 (Spesolimab)
Title of protocol
Effisayil™ 2: Multi-center, randomized, parallel 
group, double blind, placebo controlled, Phase IIb 
dose-finding study to evaluate efficacy and safety 
of BI 655130 (Spesolimab) compared to placebo in 
preventing generalized pustular psoriasis (GPP) 
flares in patients with history of GPP
Global Amendment due to urgent safety reasons
Global Amendment
X
Section to be changed
Clinical Trial Synopsis Table: Statistical Methods
Description of change
Included the following text in synopsis:
Descriptive comparison of adult versus 
paediatric data will be performed.
Rationale for change
Added the clarification to align with the Pediatric 
Investigational Plan. 
Section to be changed
Flow chart 1
Description of change
Added a footnote 21 to clarify that IRT registration 
is expected once at End of Study visit (as 
applicable) for a patient.
Rationale for change
Clarification
Section to be changed
Flow Chart 2
Description of change

Add a footnote 22 that "IRT call" is applicable 
for dosing visits only (q 12wks or q 4 wks in 
case the patient has been switched to intensified 
maintenance treatment schedule)

Added a footnote 23 to clarify that IRT 
registration is expected once at End of Study 
visit (as applicable) for a patient.


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 183 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019

Clarified foot note 4 as following: 
Only applicable for women of childbearing 
potential. S – serum pregnancy test. U – urine 
pregnancy tests will be performed at all other 
visits indicated. Urine
pregnancy testing should be done prior to study 
drug administration. Study drug should only be 
administered in case of a negative test result. In 
case of a positive urine pregnancy test, a serum 
pregnancy (S) test will be done (via central lab 
with the exception of R1 and R3 [if patient 
qualifies to receive i.v. dosing] visits where 
serum pregnancy test can be performed locally) 
and study drug administration will be 
postponed until negative result of serum 
pregnancy test is available.
Rationale for change
Clarification
Section to be changed
Section 1.4.2 Risks
Description of change
Added the following guidance related to COVID-
19 vaccination:
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.
Rationale for change
Update
Section to be changed
Section 3.1: Handling of Investigator Prescribed 
Standard of Care (SoC) for GPP disease during Rescue 
Treatment Period of the 1st GPP Flare
Description of change
Clarified that use of Investigator prescribed SoC 
during the first 4 weeks of receiving i.v. rescue 
treatment with open label BI 655130 at R1/D1 is 
not allowed and if used, it will lead to patient 
discontinuation from trial treatment. Allowed 
treatment with topical treatments/topical 
corticosteroids, methotrexate, cyclosporine and 
retinoids after 4 weeks following i.v. rescue 
treatment with open label BI 655130 at R1/D1. 
These patients may continue on receiving open 
label s.c. BI 655130.
Rationale for change
Experience from other completed and ongoing GPP 
trials as well as feedback from investigators 
indicate that a most patients are benefitting from 
i.v. rescue treatment with Spesolimab, especially 
with regards to the cardinal symptom of pustulosis. 


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 184 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
However, a subset of these patients still suffer from 
residual symptoms and may require adjunctive 
treatment.  Therefore the use of methotrexate, 
cyclosporine and retinoids is being allowed after 4 
weeks following i.v. rescue treatment in order to 
bridge the period before open label s.c. treatment is 
started. As this will be allowed only 4 weeks after 
the first dose of i.v. rescue treatment no primary or 
secondary endpoints will be affected.
Section to be changed
Section 3.1: Handling of Investigator Prescribed 
Standard of Care (SoC) for GPP disease during Open 
Label Maintenance Treatment Period
Description of change
Allowed treatment with methotrexate, cyclosporine 
and retinoids during OL maintenance treatment 
period.
Rationale for change
Clarified/updated the time point after
Completing the rescue treatment period when 
additional non-restricted GPP treatment may be 
initiated.
Section to be changed
Table 3.1:3 Study Definitions
Description of change

Clarified what should be considered as baseline 
value for efficacy measurements.
Baseline value for efficacy measurements is 
the last value measured before 1st IMP dose 
at V2.

Updated the below text for “Investigator 
Prescribed Standard of Care” as following: 
Note: Any use of Investigator Prescribed SoC 
for GPP disease during the trial will lead to the 
discontinuation of the trial treatment with the 
following exceptions. 
Use of topical treatment/topical corticosteroid, 
methotrexate, cyclosporine and retinoids is 
permitted after four weeks following i.v. dose 
rescue treatment with open label BI 655130 at 
R1/D1 and also during the OL maintenance 
treatment period. Refer to section 4.2.2.2 for 
further details.
Rationale for change
Clarification/Update
Section to be changed
Table 3.1:3 Study Definitions
Description of change
Added Definition for Partial Response to GPP flare 
treatment:


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 185 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
a GPPGA score 0 or 1 was not achieved, but a 
reduction in GPPGA score (to <3) or GPPGA 
pustule sub-score (to <2) was observed after 
receiving the rescue treatment with OL i.v. dose of 
BI 655130.
Rationale for change
Update
Section to be changed
Figure 3.1:1 Study Design in the event a patient 
experiences 1st GPP Flare
Description of change
Removed “o” from footnote#3 as it was a 
typographical error.
3EoS 2: It is applicable to patients who do not 
qualify or who do not agree to enter into the OLE 
Trial (1368-0025) at Wk 48. EoS2 is also 
applicable for o patients who prematurely
discontinue with the last dose of treatment after 
Day 232. Since these patients prematurely 
discontinued, they would not qualify to enter OLE 
trial. EoS2 will be their End of Study visit
for the trial.
Rationale for change
Corrected typographical error
Section to be changed
Figure 3.1:2 Study Design in the event a patient 
experiences 1st GPP Flare
Description of change
Updated figure to clarify that any use of 
Investigator Prescribed SoC for GPP disease during 
the trial will lead to the discontinuation of the trial 
treatment with the following exceptions. Use of 
topical treatment/topical corticosteroid,
methotrexate, cyclosporine and retinoids is 
permitted after four weeks following i.v. dose 
rescue treatment with open label BI 655130 at 
R1/D1 and also during the OL maintenance 
treatment period.
Rationale for change
Clarification/Update
Section to be changed
Section 3.3 Selection of Trial Population
Description of change
A suitable number of countries/sites will participate 
globally in order to minimize the risk of under 
recruiting and to meet the goal of 120 patients 
(including 8 adolescent patients) randomized.
Due to the rareness of the disease, a high number 
of sites will participate relative to the number of 
patients required. 
Rationale for change
Clarification to align what is noted under synopsis, 
section 3.1 and section 7.5.


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 186 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
Section to be changed
Section 3.3.4.1: Discontinuation of Trial Treatment
Description of change
Included the following as one of the 
discontinuation of trial treatment reasons:
• Worsening of clinical status or GPP symptoms 
requiring treatment with restricted medication 
(Section 4.2.2.1) in the investigator’s opinion.
• The patient experiences an infection with 
SARS-CoV-2 (as confirmed by PCR test). The 
patient may resume trial treatment following 
recovery from SARS-CoV-2 infection if the 
patient is expected to derive clinical benefit, as 
agreed between the investigator and sponsor.
Rationale for change
Update
Section to be changed
Section 4.1.4 Drug Assignment and Administration 
of doses for each patient
Description of change
Added the following statement: During the 
COVID-19 pandemic, physical visits to the sites 
may need to be restricted to ensure patient’s 
safety. Based on a thorough assessment of the 
benefits and risks, the investigator may still 
decide to continue the trial treatment and the 
administration of the study medication may be 
performed at patient’s home under the 
supervision of the investigating physician or a 
designee. The trial medication may be shipped 
to the patient’s home if acceptable according to 
local law and regulations. This must be 
approved by the sponsor’s trial team.
Rationale for change
Added pre-emptive mitigations to ensure patient
safety and trial continuity during the COVID-19
pandemic.
Section to be changed
Section 4.2.1: Other treatments and emergency 
procedures
Description of change
The following update was made.
The use of Investigator Prescribed SoC will lead to 
the discontinuation of the trial treatment
except for the use of topical treatment/topical 
corticosteroids, methotrexate, cyclosporine and
retinoids during OL rescue treatment period (4 
weeks following i.v. dose rescue treatment
with OL BI 655130 at R1/D1) and OL maintenance
treatment period.


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 187 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
Rationale for change
Update
Section to be changed
Table 4.2.2.1:1: Restricted Medication Table
Description of change
Wash out requirement of the phototherapy and 
topical treatments was removed. Also, for topical 
corticosteroids, there is no wash out requirement 
prior to randomization, however these must be 
stopped at the day of randomization. 
Rationale for change
Topical treatments/phototherapy:  are not expected 
to have any substantial impact on the core 
symptoms of the GPP disease (erythema, scaling, 
pustulosis) and therefore wash out requirement was 
removed.
Topical corticticosteroids: As there is no washout 
for systemic treatment such as cyclosporine, 
methotrexate and retinoids, no washout is 
considered to be needed for topical steroids which 
are not as effective. However, as their impact on 
“soft” disease symptoms like erythema and itching 
cannot be ruled out, and therefore they should be 
stopped at the time of randomization.
Section to be changed
Section 4.2.2.2 Restrictions regarding concomitant 
treatment during the trial (Post V2)
Description of change
Topical Treatments:
Topical treatment and any other therapies (e.g. 
Phototherapy) for GPP are not allowed throughout 
the study with the following exceptions: 

Topical treatment for other conditions (e.g. 
fungal infections, plaque psoriasis etc.) is 
allowed. 

Topical treatment is permitted for treatment of 
GPP after 4 weeks following i.v. dose rescue 
treatment with OL BI 655130 at R1/D1.

Topical treatment is permitted for treatment of 
GPP during the OL maintenance treatment 
period.
Topical corticosteroids:
Topical corticosteroids for the treatment of GPP 
are not allowed throughout the study with the 
following exceptions:

Topical corticosteroid for other conditions 
(e.g. fungal infections, plaque psoriasis etc.) 
may be initiated post visit 2 if needed. 


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 188 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019

Topical corticosteroid  is permitted for 
treatment of GPP after 4 weeks following i.v. 
dose rescue treatment with OL BI 655130 at 
R1/D1.

Topical corticosteroid is permitted for 
treatment of GPP during the OL maintenance 
treatment period.
Methotrexate, Cyclosporine, Retinoids:  
Randomized Treatment Period: Treatment with 
Methotrexate, Cyclosporine, Retinoids are not 
allowed.
Rescue Treatment Period and Open Label 
Maintenance Treatment Period:  Methotrexate, 
Cyclosporine, or Retinoids may be allowed for 
the treatment of GPP only for those who have 
received a flare rescue treatment with i.v. dose 
of BI 655130 and have a partial response to the 
rescue treatment as following.
After at least 4 weeks from the rescue treatment 
at R1/D1, it is recommended to first initiate 
treatment with topical corticosteroids to manage 
skin symptoms, and then if further adjunctive 
treatment is required, then methotrexate, 
cyclosporine and/or retinoids may be initiated 
and continued with stable dosing until the 
patient achieves GPPGA score of 0 or 1. The 
treatment with methotrexate, cyclosporine 
and/or retinoids should be immediately 
discontinued after the patient achieves GPPGA 
score of 0 or 1.
Rationale for change
Clarification
Section to be changed
Section 4.3 Treatment Compliance
Description of change
Updated the text as following:
Administration of the study medication will be 
done in the study center (or at home in 
exceptional cases such as COVID-19 pandemic 
where physical visits to the clinic may not be 
possible. See section 4.1.4 and section 6.1 for 
additional details) under the supervision of the 
investigator or a designee.
Rationale for change
Update


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 189 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
Section to be changed
Table 5.2.3:1 Safety Laboratory Tests
Description of change

Correction made to typographical error to 
footnote 3 and 4 – replaced “undetermined” to 
“indeterminate”

Clarified that for adolescent patients, Bedside 
Schwartz Equation will be used for eGRF 
calculation. 

Made the following updates to the following  
lab parameters for Urinalysis (Stix):
Urine erythrocytes replaced with Urine blood
Urine Leukocytes replaced with Urine 
leukocyte esterase
Rationale for change
Correction to typographical errors.
Clarification on the equation to be used for 
adolescent patients for eGFR calculation. 
Updated to match with what is being 
analyzed/reported by the central lab.
Section to be changed
Section 6.1: Visit Schedule
Description of change
Added the following statement: 
In exceptional cases, if standard visits at the 
trial sites are impossible because of COVID-19 
related safety risks or restrictions, the study 
visit may be performed at the patient’s home or 
remotely (via telephone and/or internet based 
means of communication). The visit may also be 
performed as a combination of home and 
remote visit (via telephone and/or internet based 
means of communication). The study drug 
administration may be performed at patient’s 


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 190 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
home under the supervision of the investigating 
physician or a designee. The trial medication 
may be shipped to the patient’s home if 
acceptable according to local law and 
regulations.
All home/remote visits need to be discussed with 
and approved by the sponsor’s trial team. Local 
regulatory and legal requirements of the 
participating country still apply.
All COVID-19 related deviations from the 
original schedule of visits and procedures will 
be documented and the implications considered 
for the analysis of the trial data.
Rationale for change
Added pre-emptive mitigations to ensure patient
safety and trial continuity during the COVID-19
pandemic.
Section to be changed
Section 6.2: Details of Trial Procedures at selected 
visits
Description of change
Added the following text:
Safety laboratory tests
If blood sampling for central lab safety analyses 
at the trial site is not possible in exceptional 
cases (e.g., due to COVID-19 pandemic), these 
analyses can be performed at a local lab until 
central lab testing becomes available. The 
results of the local lab tests must be transferred 
to the investigator to ensure medical review and 
proper documentation of the lab results with 
clinical relevance for safety in the eCRF. For the 
minimum required safety lab parameters, follow
Table 5.2.3: 2.
Rationale for change
Added pre-emptive mitigations to ensure patient
safety, trial continuity and validity of the data
during the COVID-19 pandemic.
Section to be changed
Section 6.2.2: Treatment Period(s)
Description of change
Updated as following:
Study drug allocation via the IRT system and
Administration of the study drug should be the last 
activity at visits with study drug administration, 
with the exception of local tolerability and post 
dose vital signs assessments. Details relating to 
study drug administration are provided in Section 
4.1.4.


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 191 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
Rationale for change
Update
Section to be changed
Section 7.2.2: Primary Endpoint Analysis
Description of change
Updated as following:
Descriptive comparisons between the levels of 
each stratification (concomitant use of systemic 
GPP medications at randomization (yes or no)) 
and blocking factors (region (Japan or Rest of 
world) and population (adults versus 
adolescents)) will be performed.
A subgroup assessment according to the levels of 
each stratification and blocking factors will be 
assessed descriptively.
Rationale for change
Added the clarification to align with the Pediatric 
Investigational Plan.
Section to be changed
Section 7.2.3: Secondary Endpoint Analysis
Description of change
All secondary endpoints will be descriptively 
displayed. Descriptive comparison for adults 
versus adolescents will be performed for 
secondary endpoints in the hierarchical testing.
Statistical tests on the remaining secondary binary 
endpoints will be performed as described for the 
key secondary endpoint.
Rationale for change
Added the clarification to align with the Pediatric 
Investigational Plan.
Section to be changed
Section 8: Informed Consent, Trial Records, Data 
Protection, Publication Policy, And Administrative 
Structure
Description of change
Added the below bolded text to the paragraph: 
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,
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”.
Rationale for change
Clarification. Since EU countries are also 
participating on the trial, the EU clinical trial 


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 192 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
directive/EU regulation has been included in this 
section.
Section to be changed
Section 8.3.2: Direct Access to source data and 
documents
Description of change
Included the following text as contingency measure 
due to COVID-19:
Remote source data verification is acceptable in 
exceptional cases where onsite monitoring visits 
cannot take place due to circumstances like the 
COVID-19 pandemic or other relevant reasons. 
This must first be approved by the sponsor’s 
trial team.
Rationale for change
Update
Section to be changed
Section 9.1 Published References
Description of change
The following reference #s were deleted as these 
were not referenced in the body of the protocol.
R13-4749, R13-4750, R12-4753, R13-4754, R16-
0020, R16-2960
Rationale for change
Correction


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 193 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
11.3
GLOBAL AMENDMENT 3
Date of amendment
28 Jul 2022
EudraCT number
EU number
2018-003081-14
BI Trial number
1368-0027
BI Investigational Medicinal
Product(s)
BI 655130 (Spesolimab)
Title of protocol
Effisayil™ 2: Multi-center, randomized, parallel 
group, double blind, placebo controlled, Phase IIb 
dose-finding study to evaluate efficacy and safety 
of BI 655130 (Spesolimab) compared to placebo in 
preventing generalized pustular psoriasis (GPP) 
flares in patients with history of GPP
Global Amendment due to urgent safety reasons
Global Amendment
X
Section to be changed
Synopsis
Description of change
Update to contact information.
Rationale for change
Change in Clinical Trial Leader for the trial.
Section to be changed
Table 1.4.2: 1 Risks 
Description of change
The risk “Peripheral Neuropathy” was added to the 
table including a summary of data and mitigation 
strategy.
Rationale for change
Added to inform about the newly added potential 
risk “peripheral neuropathy” deriving from the 
three cases reported as Guillain-Barré syndrome by 
the investigator in Spesolimab trials (details in the 
CTP). The cases were considered as peripheral 
neuropathy by the external neurologist expert 
panel’s assessment. 
Section to be changed
Section 3.3.4.1
Description of change
Following information was added:
“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.” 


Boehringer Ingelheim
28 July 2022
BI Trial No.: 1368-0027
c28020464-03
Clinical Trial Protocol
Page 194 of 194
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
Rationale for change
Added as mitigation strategy to account for the 
three cases reported as Guillain-Barré syndrome in 
Spesolimab trials. The cases were considered as 
peripheral neuropathy by the external neurologist 
expert panel’s assessment (details in the CTP). 
Section to be changed
4.2.2.2 Restrictions regarding concomitant 
treatment during the trial (Post V2)
Description of change
The following text: “The treatment with 
methotrexate, cyclosporine, and /or retinoids 
should be immediately discontinued after the 
patient achieves GPPGA score or 0 or 1.” was 
replaced with “or as per the investigator’s 
judgement.”
Rationale for change
To place decisions regarding the continuation of 
rescue treatment under the judgement of the 
investigator.
Section to be changed
5.2.6.1.4 Adverse events of special interest
Description of change
Added Peripheral Neuropathy as an Adverse events 
of special interest.
Rationale for change
To update reporting requirements to ensure all 
cases of suspected peripheral neuropathy including 
the non-serious ones are analysed quickly.


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c28020464
4.0
clinical-trial-protocol-version-04
Effisayil 2: Multi-center, randomized, parallel group, double blind, placebo
controlled, Phase IIb dose-finding study to evaluate efficacy and safety of BI 655130
(Spesolimab) compared to placebo in preventing generalized pustular psoriasis (GPP)
flares in  patients with history of GPP
Author-Clinical Trial Leader
08 Aug 2022 16:15 CEST
Approval-Clinical Pharmacokinetics
09 Aug 2022 15:47 CEST
Approval-Therapeutic Area
15 Aug 2022 08:29 CEST
Approval-Biostatistics
15 Aug 2022 14:52 CEST
Approval-Team Member Medicine
15 Aug 2022 18:03 CEST


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c28020464
4.0

SAP_001.pdf: 
 
 001-MCS-50-415_RD-01 (3.0) / Saved on: 18 Jan 2021 
 
TITLE PAGE 
TRIAL STATISTICAL ANALYSIS PLAN 
 
c39181950-02 
BI Trial No.: 
1368-0027 
Title: 
Multi-center, randomized, parallel group, double blind, placebo 
controlled, Phase IIb dose-finding study to evaluate efficacy and 
safety of BI 655130 (spesolimab) compared to placebo in 
preventing generalized pustular psoriasis (GPP) flares in patients 
with history of GPP 
Including Revised Protocol # 4 [c28020464-04] 
Investigational 
Product(s): 
Spesolimab, BI 655130 
Responsible trial 
statistician(s): 
 
Tel.: 
 
Fax: 
 
Date of statistical 
analysis plan: 
2 Dec 2022 
Version: 
2.0 Final 
Page 1 of 84 
Proprietary confidential information 
© 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights 
reserved. 
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission. 
 


Boehringer Ingelheim  
TSAP for BI Trial No: 1368.0027 
c39181950-02 
Page 2 of 84 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
 
001-MCS-50-415_RD-01 (3.0) / Saved on 18 Jan 2021 
1. 
TABLE OF CONTENTS 
TITLE PAGE ........................................................................................................................... 1 
1. 
TABLE OF CONTENTS...................................................................................... 2 
LIST OF TABLES ................................................................................................................... 5 
2. 
LIST OF ABBREVIATIONS .............................................................................. 6 
3. 
INTRODUCTION ................................................................................................. 8 
4. 
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY ...................... 9 
5. 
ENDPOINTS(S) .................................................................................................... 9 
5.1 
PRIMARY ENDPOINT(S) ................................................................................ 10 
5.2 
SECONDARY ENDPOINT(S) .......................................................................... 11 
5.2.1 
Key secondary endpoint(s) ................................................................................. 11 
5.2.2 
Secondary endpoints ........................................................................................... 12 
5.4.2 
Demographic and other baseline characteristics ............................................. 15 
 
 
 
 
 
 
6. 
GENERAL ANALYSIS DEFINITIONS .......................................................... 18 
6.1 
TREATMENTS ................................................................................................... 18 
6.2 
IMPORTANT PROTOCOL DEVIATIONS.................................................... 20 
6.3 
SUBJECT SETS ANALYSED ........................................................................... 20 
 
 
6.5 
POOLING OF CENTRES ................................................................................. 23 
6.6 
HANDLING OF MISSING DATA AND OUTLIERS .................................... 23 
6.6.1 
Withdrawals ........................................................................................................ 23 
6.6.2 
Efficacy data ........................................................................................................ 23 
6.6.2.1 Randomized treatment period ...................................................................................... 24 
6.6.2.2 Flare treatment and OL maintenance treatment periods .............................................. 28 
6.6.3 
Safety data ........................................................................................................... 29 
6.6.8 
Time since first diagnosis ................................................................................... 31 
6.7 
BASELINE, TIME WINDOWS, AND CALCULATED VISITS .................. 31 
7. 
PLANNED ANALYSIS ...................................................................................... 36 
7.1 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ......... 37 
7.2 
CONCOMITANT DISEASES AND MEDICATION ..................................... 38 
 
 
7.4 
PRIMARY ENDPOINT(S) ................................................................................ 40 


Boehringer Ingelheim  
TSAP for BI Trial No: 1368.0027 
c39181950-02 
Page 3 of 84 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
 
001-MCS-50-415_RD-01 (3.0) / Saved on 18 Jan 2021 
7.4.1 
Primary analysis of the primary endpoint(s) ................................................... 40 
 
 
 
7.5 
SECONDARY ENDPOINT(S) .......................................................................... 43 
7.5.1 
Key secondary endpoint(s) ................................................................................. 43 
7.5.1.1 
Primary analysis of the key secondary endpoint(s) .............................................. 43 
 
 
 
7.5.2 
Secondary endpoint(s) ........................................................................................ 44 
 
 
7.8 
SAFETY ANALYSIS .......................................................................................... 52 
7.8.1 
Adverse Events .................................................................................................... 52 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8. 
TIMEPOINT OF RELEASE OF TREATMENT INFORMATION ............. 64 
9.  
REFERENCES .................................................................................................... 65 


Boehringer Ingelheim  
TSAP for BI Trial No: 1368.0027 
c39181950-02 
Page 4 of 84 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
 
001-MCS-50-415_RD-01 (3.0) / Saved on 18 Jan 2021 
11. 
HISTORY TABLE .............................................................................................. 84 


Boehringer Ingelheim  
TSAP for BI Trial No: 1368.0027 
c39181950-02 
Page 5 of 84 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
 
001-MCS-50-415_RD-01 (3.0) / Saved on 18 Jan 2021 
LIST OF TABLES 
Table 5.1: 1 
Summary of intercurrent events handling for time-to-event endpoints during 
the randomized maintenance treatment period ................................................. 10 
Table 5.2: 1 
Summary of handling intercurrent events for binary endpoint during the 
randomized maintenance treatment period ....................................................... 12 
Table 6.1: 1 
Flow chart of analysis phases of the study ....................................................... 18 
Table 6.3: 1 
Subject sets analyzed ........................................................................................ 22 
Table 6.6.2: 1 Primary Method (PM):  Description of censoring rules for primary endpoint, 
and two secondary endpoints ............................................................................ 25 
Table 6.6.2: 2 Sensitivity Method (SM): Description of censoring rules for primary 
endpoint and two secondary endpoints in hierarchical testing procedure ........ 26 
Table 6.6.2: 3 Summary of missing data handling approaches under corresponding 
Estimand ........................................................................................................... 29 
Table 6.7: 1 
Time windows for assignment of efficacy, safety lab, vital signs, and 
biomarker to visits for the randomized maintenance treatment period ............ 32 
Table 6.7: 2 
Time windows for assignment of efficacy, safety lab, vital signs, and 
biomarker to visits for the flare treatment period ............................................. 33 
Table 6.7: 3 
Time windows for assignment of efficacy, safety lab, vital signs, and 
biomarker to visits for the OL maintenance treatment period .......................... 34 
Table 7.1: 1 
Categories for summary of continuous variables ............................................. 38 
Table 7.4:1 
Total dose per treatment arm during randomized maintenance treatment 
period ................................................................................................................ 40 
Table 7.8.1: 1 Project MedDRA search criteria for User Defined Adverse Event Concepts .. 55 
 
Table 11: 1 
History table ..................................................................................................... 84 
 


Boehringer Ingelheim  
TSAP for BI Trial No: 1368.0027 
c39181950-02 
Page 6 of 84 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
 
001-MCS-50-415_RD-01 (3.0) / Saved on 18 Jan 2021 
2. 
LIST OF ABBREVIATIONS 
Term 
Definition / description 
 
 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ALQ 
Above the upper limit of quantification 
AP 
Alkaline phosphatase 
AST 
Aspartate aminotransferase 
ATC3 
Anatomical-Therapeutic-Chemical classification level 3 
AUC0-∞ 
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity 
BLQ 
Below the lower limit of quantification 
BMI 
Body mass index 
BSA 
Body surface area 
CARE 
Clinical data analysis and reporting environment 
CGI 
Clinical Global Impression 
Cmax 
Maximum measured concentration of the analyte in plasma 
CRF 
Case report form 
CRP 
C-reactive protein 
CTP 
Clinical trial protocol 
CTR 
Clinical trial report 
CV 
Arithmetic coefficient of variation 
CTCAE 
Common Terminology Criteria for Adverse Events 
DBLM 
Database lock meeting 
DNA 
Deoxyribonucleic acid 
DLQI 
Dermatology Life Quality Index 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EM 
Estimand for randomized maintenance period 
EMR 
Estimand for randomized maintenance period considering the use of 
restricted medication use for other purpose 
EMA 
European Medicines Agency 
EN 
Estimand for flare treatment period that considers intercurrent as non-
responder 
EN-ID8 
Estimand for flare treatment period that considers intercurrent as non-
responder including data after the use of second flare treatment at R3/D8 
ES 
Enrolled set 
EC 
Estimand that excludes data after the occurrence of intercurrent events 
during randomized maintenance period 
EudraCT 
European union drug regulating authorities clinical trials 
gCV 
Geometric coefficient of variation 
gMean 
Geometric mean 
GPP 
Generalized pustular psoriasis 
GPPASI 
Generalized Pustular Psoriasis Area and Severity Index 
GPPASI 50 
Achievement of a ≥ 50 % reduction in GPPASI total score compared to 
baseline 


Boehringer Ingelheim  
TSAP for BI Trial No: 1368.0027 
c39181950-02 
Page 7 of 84 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
 
001-MCS-50-415_RD-01 (3.0) / Saved on 18 Jan 2021 
Term 
Definition / description 
GPPASI 75 
Achievement of a ≥ 75 % reduction in GPPASI total score compared to 
baseline 
GPPGA 
Generalized Pustular Psoriasis Physician Global Assessment 
IL 
Interleukin 
iPD 
Important protocol deviation 
KM 
Kaplan-Meier 
MedDRA 
Medical Dictionary for Regulatory Activities 
MCP-Mod 
The Multiple Comparison Procedures and Modeling 
NOA 
Not analyzed 
NOP 
No peak detectable 
NOR 
No valid result 
NOS 
No sample available 
NRI 
No response imputation 
OC 
Observed cases excluding data after intercurrent event 
OC-ID8 
Observed cases excluding data after intercurrent event but include data 
after the use of second flare iv treatment at R3/D8 
OR 
Original results 
PD 
Pharmacodynamic(s) 
PGI-C 
Patient Global Impression of Change 
PGI-S 
Patient Global Impression of Severity 
PK 
Pharmacokinetic(s) 
PKS 
PM 
Pharmacokinetic parameter set 
Primary method of censoring rule 
PSS 
Psoriasis symptom scale 
Q1 
1st quartile 
Q3 
3rd quartile 
RAGe 
Report appendix generator 
REP 
Residual effect period 
RNA 
Ribonucleic acid 
RS 
Randomized set 
SAE 
Serious adverse event 
SD 
Standard deviation 
SDL 
Subject data listing 
SI 
SM 
Système international d’unités 
Sensitivity method of censoring rule 
SoC 
Standard of Care 
TPSS 
Target Plaque Severity Score 
ULN 
Upper limit of normal range 
UDAEC 
User-defined Adverse Event Category 
VAS 
Visual analogue scale 
WPAI-GPP 
Work Productivity and Activity Impairment Questionnaire: GPP 
 
 


Boehringer Ingelheim  
TSAP for BI Trial No: 1368.0027 
c39181950-02 
Page 8 of 84 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
 
001-MCS-50-415_RD-01 (3.0) / Saved on 18 Jan 2021 
3. 
INTRODUCTION 
As per ICH E9 (1), the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the CTP and its amendments, 
and to include detailed procedures for executing the statistical analysis of the primary and 
secondary variables and other data. 
This TSAP assumes familiarity with the CTP. In particular, the TSAP is based on the planned 
analysis specification as written in CTP Section 7 “Statistical Methods and Determination of 
Sample Size”. Therefore, TSAP readers may consult the CTP for more background 
information on the study, e.g., on study objectives, study design and population, treatments, 
definition of measurements and variables, and planning of sample size, and randomisation. 
The statistical analyses will be performed within the validated working environment CARE, 
including SASTM (current Version 9.4, by 
), and SASTM-
based tools (e.g., macros for the analyses of AE data or laboratory data; Report Appendix 
Generator system (RAGe) for compilation/formatting of the CTR appendices). R version 
4.1.1 with "DoseFinding" package will be used for analysis based on MCP-Mod.  
Study data will be stored in a trial database within the BRAVE system. 
 
The primary analysis of the double-blinded randomize period this trial is planned to be 
performed once all randomized subjects have completed or early discontinued the 48-week 
study period. The final analysis is planned to be performed once all randomized subjects have 
completed the study (including any residual effect period). Both are described in this TSAP.  
To support a potential spesolimab early acute flare treatment submission, interim analyses of 
the open-label clinical efficacy and safety data following occurrence of a first GPP flare 
treated with open-label spesolimab use will be performed. Data cut-off for the interim 
analyses will be described in a separate document.  


Boehringer Ingelheim  
TSAP for BI Trial No: 1368.0027 
c39181950-02 
Page 9 of 84 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
 
001-MCS-50-415_RD-01 (3.0) / Saved on 18 Jan 2021 
4. 
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY 
For JDA severity index, the categorization for the laboratory findings WBC count, CRP and 
serum albumin will be done based on the results of the central laboratory measurements not 
eCRF pages. If central laboratory values are not available, eCRF results will be used. 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5. 
ENDPOINTS(S) 
The primary and secondary objectives are defined in CTP as:  
 
the primary objective of this trial is to demonstrate a non-flat curve and evaluate the dose 
response relationship for 3 subcutaneous dosing regimens of spesolimab versus placebo, on 
the primary endpoint, the time to the first GPP flare onset up to week 48.  
 
The secondary objective is to demonstrate superiority versus placebo for each of BI 655130 
300 mg q4 weeks and BI 655130 300 mg q12 weeks on the primary endpoint, the time to the 
first GPP flare onset up to week 48, as well as the key secondary endpoint, the occurrence of 
at least one GPP flare up to 48 weeks.  
 
To align with the documentation of flare treatment submission, in this trial statistical analysis 
plan (TSAP) and future clinical trial report (CTR), “flare treatment period” will be used in 
replacement of “rescue treatment period”. The “flare treatment” is equivalent to “rescue 
treatment” or “rescue medication” in the following text. All of them indicate the open label 
(OL) i.v. dose of spesolimab to treat the first GPP flare during the randomized treatment 
period. 


Boehringer Ingelheim  
TSAP for BI Trial No: 1368.0027 
c39181950-02 
Page 10 of 84 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
 
001-MCS-50-415_RD-01 (3.0) / Saved on 18 Jan 2021 
5.1 
PRIMARY ENDPOINT(S) 
The primary endpoint of the study is defined in CTP as:  
 
Time to first Generalized Pustular Psoriasis (GPP) flare (defined by increase in Generalized 
Pustular Psoriasis Physician Global Assessment (GPPGA) score by ≥ 2 from baseline and the 
pustular component of GPPGA ≥ 2) up to week 48.  
 
A composite strategy will be applied as the primary Estimand for randomized maintenance 
treatment period (abbreviated to EM). Under EM Estimand, in addition to the event defined 
by increase in Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) score 
by ≥ 2 from baseline and the pustular component of GPPGA ≥ 2, any intercurrent events, i.e., 
any use of rescue medication with OL i.v. spesolimab, or investigator-prescribed Standard of 
Care (SoC) to treat GPP worsening, will be considered to represent the onset of a GPP flare.  
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
The strategies for handling intercurrent events under Estimands are summarized as follows in 
Table 5.1:1.  
 
Table 5.1: 1 
Summary of intercurrent events handling for time-to-event endpoints during 
the randomized maintenance treatment period 
Intercurrent events 
Composite  
EM 
Use of rescue 
medication with i.v. 
spesolimab  
Composite 
(Event*) 
Investigator-
prescribed Standard 
of care to treat GPP 
worsening 
Composite 
(Event*) 
Use restricted 
medication for other 
indications 
Treatment Policy 
*The subject will be set as an event or censored at the time intercurrent event happens 


Boehringer Ingelheim  
TSAP for BI Trial No: 1368.0027 
c39181950-02 
Page 11 of 84 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
 
001-MCS-50-415_RD-01 (3.0) / Saved on 18 Jan 2021 
 
Per CTP Section 2.1,  
the treatment comparison within the randomized maintenance period will be made for 
randomized subjects regardless of treatment adherence or discontinuation.  
 
Treatment discontinuation is not considered as an intercurrent event in this trial. Any events 
occurred up to week 48 will be considered, regardless of treatment adherence or 
discontinuation.   
 
See Section 10.1.2 for details on the derivation of the GPPGA total score. 
5.2 
SECONDARY ENDPOINT(S) 
5.2.1 
Key secondary endpoint(s) 
The key secondary endpoint of the study is defined in CTP Section 2 as: 
 
The occurrence of at least one GPP flare (defined by increase in GPPGA score by ≥ 2 from 
baseline and the pustular component of GPPGA ≥ 2) up to week 48. 
 
This endpoint is considered as key secondary endpoint for secondary objective (i.e., 
demonstrate the superiority of spesolimab versus placebo), while for the primary objective 
(i.e., dose-finding analysis), is considered as secondary in nature only instead of key 
secondary.  
 
Per CTP Section 7, 
This (the key secondary endpoint) is a monotone increasing variable, so once a flare has 
occurred by a particular visit, all subsequent visits will also by definition have had a 
preceding flare. 
 
Once the first GPP flare occurs, all subsequent visits will be regarded as the occurrence of 
GPP flare. The Estimands applied for primary endpoint are also applicable for the key 
secondary endpoint. The detailed handling of intercurrent events under different Estimands 
for the key secondary endpoint is described in Table 5.2: 1, which also applies to the 
secondary and further binary endpoints. The missing data handling for the visits after 
censoring will be described in Section 6.6.2 
 
Under the primary Estimand EM, for the key secondary endpoint, the occurrence of the first 
GPP flare (defined by increase in GPPGA score by ≥ 2 from baseline and the pustular 
component of GPPGA ≥ 2) is a treatment failure while the use of rescue treatment of i.v. 
spesolimab or use of investigator-prescribed SoC will also lead to treatment failure.  
 


Boehringer Ingelheim  
TSAP for BI Trial No: 1368.0027 
c39181950-02 
Page 12 of 84 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
 
001-MCS-50-415_RD-01 (3.0) / Saved on 18 Jan 2021 
Table 5.2: 1 
Summary of handling intercurrent events for binary endpoint during the 
randomized maintenance treatment period 
Intercurrent events 
Composite  
EM 
C
r
E
Intercurrent event 
Use of rescue 
medication with i.v. 
spesolimab  
Composite 
(Treatment failure a) (
Investigator-
prescribed Standard 
of care to treat GPP 
worsening 
Composite 
(Treatment failure a) (
Use restricted 
medication for other 
indications 
Treatment Policy 
(
a Treatment failure indicates the occurrence of GPP flare for key secondary endpoint. For the binary endpoints that indicate 
positive disease outcome, such as sustained remission, no PSS sub score>1 and DLQI of 0 or 1, the treatment failure 
indicates that the prespecified endpoint is not achieved. 
b Data will be censored (set as missing) after the specified intercurrent event. 
5.2.2 
Secondary endpoints 
Three efficacy endpoints and one safety endpoint are defined as secondary endpoints.  
 
Per CTP Section 2, the below-defined secondary endpoints, for the secondary objective of the 
trial, are included in the formal testing along with the primary endpoint and the key secondary 
endpoint:  
 
• Time to first worsening of Psoriasis Symptom Scale (PSS) up to week 48 defined as a 
4-point increase in total score from baseline.  
• Time to first worsening of Dermatology Quality of Life Index (DLQI) up to week 48 
defined as a 4-point increase in total score from baseline.  
 
The Estimands specified for primary endpoint will be applied to the secondary time-to-event 
endpoints per Table 5.1:1. 
 
For further details on the derivation of the PSS score, and the DLQI score, refer to Sections 
10.1.5, and 10.1.6, respectively. 
 
Per CTP Section 2, the below-defined secondary endpoint, for the secondary objective of the 
trial, is not included in the formal testing procedure: 
 
Sustained remission, defined as a subject with a GPPGA score of 0 or 1 (clear or almost 
clear) at all visits up to week 48. 
 
As a binary endpoint, the Estimands applied in key secondary endpoint are also applicable to 
this secondary endpoint per Table 5.2:1.  
 


Boehringer Ingelheim  
TSAP for BI Trial No: 1368.0027 
c39181950-02 
Page 13 of 84 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
 
001-MCS-50-415_RD-01 (3.0) / Saved on 18 Jan 2021 
Note that, similar as the key secondary endpoint, i.e., the occurrence of GPP flare, the 
sustained remission is a monotone increasing variable.  Once the remission (GPPGA total 
score 0 or 1) is not achieved or the intercurrent event (can lead to treatment failure) has 
occurred by a certain visit, the status of sustained remission will be not achieved for all 
subsequent visits up to week 48.  
 
Per CTP Section 2, the secondary safety endpoint is defined as:  
 
The occurrence of Treatment Emergent Adverse Events (TEAEs).  


Boehringer Ingelheim  
TSAP for BI Trial No: 1368.0027 
c39181950-02 
Page 14 of 84 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
 
001-MCS-50-415_RD-01 (3.0) / Saved on 18 Jan 2021 
5.4.1 
Safety Endpoints 
Safety endpoints are defined per CTP Section 5.2 
 
Intensity of AEs was assessed during the trial according to Rheumatology Common Toxicity 
Criteria (RCTC) version 2.0. At the time of the data analysis, selected laboratory parameters 
will be assessed by Common Terminology Criteria for Adverse Events (CTCAE) in addition 
to RCTC grades, where possible. The specific definition of CTCAE grades is described in 
Section 10.3 
 


Boehringer Ingelheim  
TSAP for BI Trial No: 1368.0027 
c39181950-02 
Page 15 of 84 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
 
001-MCS-50-415_RD-01 (3.0) / Saved on 18 Jan 2021 
5.4.2 
Demographic and other baseline characteristics 
The following demographic parameters will be defined: sex, ethnicity, race, sub-race of 
Asian, age, height, weight, BMI, smoking status, and region of sites.  
Age [years] will be determined as the difference between year of birth and year of informed 
consent. BMI will be calculated as weight [kg] / height [m]2 (based on the last available 
weight measurement prior to the first randomized dose on V2/D1).  
Medical History for GPP include mutation status (IL36RN, CARD14 and AP1S3), as well as 
the details, if any, on the presence of concurrent chronic plaque psoriasis or chronic 
erythrodermic psoriasis will be summarized. The method by which diagnosis of GPP was 
confirmed is also collected. 
Disease characteristics will include the details on typical flare, most severe flare, longest flare, 
and most recent flare prior to consent. 
Time since first diagnosis [years] will be calculated as the difference between date of first 
diagnosis and date of informed consent, divided by 365.25. For calculation in the context of 
incomplete information on the date of first diagnosis, according to Section 6.6.8.  
In addition to the mutation status captured via the eCRF, the genes of interest also get re-
sequenced. Hereby the mutation status will be defined based on the absence or presence of 
potential pathogenic IL36RN, CARD14 and AP1S3 variations based on existing functional or 
potential functional impact of the mutation. Based on this analysis the following groupings 
may be presented: 
- 
Subjects with a mutation in any of the 3 genes vs. subjects with no mutation at all 
- 
Subjects with a mutation in IL36RN (irrespective of the mutation status in the other 
genes) vs. subjects without an IL36RN mutation 
- 
Subjects with a mutation in CARD14 (irrespective of the mutation status in the other 
genes) vs. subjects without an CARD14 mutation 
- 
Subjects with a mutation in AP1S3 (irrespective of the mutation status in the other genes) 
vs. subjects without an AP1S3 mutation 
- 
Subjects with a mutation in CARD14 or AP1S3 but no mutation for IL36RN vs. subjects 
not fulfilling this criterion 
 
These re-sequenced results for the mutation status of IL36RN will be the basis for the 
subgroup classification as described in Section 6.4. 


Boehringer Ingelheim  
TSAP for BI Trial No: 1368.0027 
c39181950-02 
Page 16 of 84 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
 
001-MCS-50-415_RD-01 (3.0) / Saved on 18 Jan 2021 


Boehringer Ingelheim  
TSAP for BI Trial No: 1368.0027 
c39181950-02 
Page 17 of 84 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
001-MCS-50-415_RD-01 (3.0) / Saved on 18 Jan 2021 


Boehringer Ingelheim  
TSAP for BI Trial No: 1368.0027 
c39181950-02 
Page 18 of 84 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
 
001-MCS-50-415_RD-01 (3.0) / Saved on 18 Jan 2021 
6. 
GENERAL ANALYSIS DEFINITIONS 
6.1 
TREATMENTS 
For basic study information on the treatment to be administered, assignment to treatment, and 
selection of dose, refer to Section 3 and 4 of the CTP. 
For the analysis of adverse event, the study phases are defined as in Table 6.1:1.  
Table 6.1: 1 
Flow chart of analysis phases of the study  
Study analysis 
phase 
Description 
Start (included) 
End (included) 
Screening phase 
Screening 
Earliest of (Date of 
informed consent, first 
screening procedure) 
Date/time of start of the first randomized 
study treatment minus 1 minute 
Randomized 
maintenance 
treatment phase  
On randomized 
treatment period  
Date/time of start of the 
first randomized study 
treatment (V2/D1) 
Earliest of i) Date/time of start of the 
rescue treatment with i.v. spesolimab 
minus 1 minute.  ii) Date of the end of 
last randomized study treatment + REP 
2(112 days) at 23:59. iii) Date/time of 
the first treatment in OLE trial 1368.25 
if the subject is rolled over, iv) last 
contact date on End of Study page at 
23:59 if subject is not  rolled over.  
Flare treatment 
phase (if 
applicable) 
On flare treatment 
period 
Date/time of start of the 
first rescue treatment 
with spesolimab i.v. 900 
mg  
Earliest of i) Date/time of start of the 
first OL maintenance treatment minus 1 
minute.  ii) Date of the end of last rescue 
treatment + REP 2 (112 days) at 23:59. 
iii) Date/time of the first treatment in 
OLE trial 1368.25 if the subject is rolled 
over, iv) last contact date on End of 
Study page at 23:59 if subject is not  
rolled over  
OL maintenance 
phase (if 
applicable) 
On OL 
maintenance 
treatment period 
Date/time of start of the 
first OL maintenance 
treatment  
Earliest of i) Date of the end of last OL 
maintenance treatment + REP 2 (112 
days) at 23:59. ii) Date/time of the first 
treatment in OLE trial 1368.25 if the 
subject is rolled over, iii) last contact 
date on End of Study page at 23:59 if 
subject is note rolled over.  
Off treatment 
phase1 
Off-treatment 
period 
 
Date of the end of last 
study treatment 
(including randomized 
treatment, flare treatment 
and OL maintenance 
treatment) + REP 2 (112 
days) + 1 day at 0:00 
i) Date/time of the first treatment in OLE 
trial 1368.25 if subject is rolled over, ii) 
last contact date on End of Study page at 
23:59 if subject is not rolled over. 
 
Dates are defined individually per subject. An analysis phase will not extend beyond the start date of the following phase. 
1 The off-treatment period only exists if the last contact date is after the date of end of last study treatment + 112 days. 
2 Per CTP Section 7.2.5, all adverse events occurring between start of treatment and end of the residual effect period will be 
considered ‘treatment-emergent’; the residual effect period (REP) is defined as 16 weeks after the last dose of trial 
medication. Therefore, 112 days is included in the period  
 


Boehringer Ingelheim  
TSAP for BI Trial No: 1368.0027 
c39181950-02 
Page 19 of 84 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
 
001-MCS-50-415_RD-01 (3.0) / Saved on 18 Jan 2021 
Efficacy analyses (Section 7.4, 7.5 and 7.6.1) that are on randomized maintenance treatment 
phase will take the intercurrent events into account under the concept of Estimand (see 
Section 5.1, 5.2, and 5.3) 
Treatment groups for the randomized treatment period according to the randomized/actual 
treatment (see Table 6.1: 1) will be labelled as follows: 
 
• "Placebo" (i.e., randomized to received placebo) 
• "Speso SC Low" (i.e., randomized to spesolimab 150 mg s.c. q12w) 
• "Speso SC Medium" (i.e., randomized to spesolimab 300 mg s.c. q12w) 
• "Speso SC High" (i.e., randomized to spesolimab 300 mg s.c. q4w) 
• "Speso SC Total"(across spesolimab randomized treatments) 
• "Overall Total"(across randomized treatments), where appropriate. 
“Speso SC Total” is applicable in disposition, demographics and baseline characteristics, 
compliance summaries, AE, clinically significant abnormal lab values and others as deemed 
necessary. 
 
“Overall Total” is applicable in disposition, demographics and baseline characteristics, 
compliance summaries and others as deemed necessary.  
• "Overall Speso"(across spesolimab treatments, regardless of i.v. or s.c. treatments), 
where appropriate. 
“Overall Speso” is applicable in AE, clinically significant abnormal lab values and others 
when summarizing the safety outcomes post any spesolimab use. 
 Treatment groups for the loading dose received on Day 1 of the randomized treatment period 
according to the randomized treatment (see Table 6.1: 1) will be labelled as follows:  
• "Speso SC Loading Low " (i.e., randomized to spesolimab 150 mg s.c. q12w) 
• "Speso SC Loading High" (i.e., randomized to spesolimab 300 mg s.c. q4w or 
spesolimab 300 mg s.c. q12w) 
Treatment groups for the flare treatment period will be labelled as follows: 
• "Speso IV Total"(i.e., received at least one flare treatment spesolimab 900mg i.v.) 
• "Speso IV SD"(i.e., received i.v. flare treatment at Day 1 of flare treatment period) 
• "Speso IV DD"(i.e., received i.v. flare treatment at Day 1 and Day 8 of flare 
treatment period) 


Boehringer Ingelheim  
TSAP for BI Trial No: 1368.0027 
c39181950-02 
Page 20 of 84 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
 
001-MCS-50-415_RD-01 (3.0) / Saved on 18 Jan 2021 
Treatment groups for OL maintenance treatment period will be labelled as follows: 
 
• "Speso OL SC"(i.e., received at least one OL maintenance treatment) 
 
When applicable, output columns should be arranged in the order as given above. 
More details on the technical implementation of these analyses are provided in the ADS Plan 
of this TSAP.  
6.2 
IMPORTANT PROTOCOL DEVIATIONS 
Listings of protocol deviations will be provided to be discussed at the MQRM, at the Trial 
Oversight Meeting prior to DBL or at the RPM. At these meetings, it will be determined 
whether a discrepant data value can be used in analyses or whether correction is needed. Each 
protocol deviation must be assessed to determine whether it is an important protocol deviation 
(iPD). Refer to the Integrated Quality and Risk Management Plan (IQRMP) Section 4.1 for 
the detailed specifications of PDs and iPDs (32). For the process of identification of iPDs, 
refer to "Identify and Manage Important Protocol Deviations (iPD) (3). 
 
If any iPDs are identified, they are to be summarized into categories and will be captured in 
the MQRM/RPM minutes or the TOM minutes and additionally via an accompanying Excel 
spreadsheet. The iPDs may lead to exclusion of subjects from analysis sets (e.g., the Per 
Protocol Set), referring to IQRMP. The documentation of the iPD categories and how to 
handle iPDs in the analysis is included in the DV domain specifications and stored within the 
TMF in EDMS. 
 
All COVID-19 related protocol deviations, regardless of important or non-important ones will 
be included in the DV domain as well. See BI-KMED-COPS-HTG-0141 “CTR writing 
guidance for trials impacted by the COVID-19 pandemic” (31)  and BI-KMED-COPS-HTG-
0117 “IQRM and Centralized Monitoring during COVID-19 - Guidance for Trial Teams” 
(33) for details.  
 
A summary of iPD decisions will be documented in the decision log. 
6.3 
SUBJECT SETS ANALYSED 
The following analysis sets will be defined for the randomized maintenance treatment period 
of this trial: 
• Enrolled Set (ES) 
This subject set includes all subjects who signed informed consent. It will be used to 
display the subject disposition. 
• Randomized Set (RS): 
This subject set includes all randomized subjects. Treatment assignment will be used 
as randomized. It will be used for analyses of subject for baseline demographics and 


Boehringer Ingelheim  
TSAP for BI Trial No: 1368.0027 
c39181950-02 
Page 21 of 84 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
 
001-MCS-50-415_RD-01 (3.0) / Saved on 18 Jan 2021 
disease characteristics and is the main set for the analyses of efficacy endpoints during 
the randomized maintenance treatment period. 
• Safety Analysis Set (SAF): 
This subject set includes all subjects who were randomized and received at least one 
dose of study drug. This is the main analysis set for safety. Subjects will be analyzed 
according to the actual treatment received. 
• Per-Protocol Set (PPS): 
This subject set includes all subjects in the randomized set who adhered to the CTP 
without any iPDs which are flagged for exclusion from the PPS. The PPS will be used 
for sensitivity analysis on the primary and key secondary endpoints. 
For the flare treatment period, the following set is defined as below: 
• Safety Analysis set for flare treatment period (SAF-FT): 
This subject set includes all subjects who took at least one flare treatment with OL i.v. 
dose of spesolimab. This is the main analysis set for efficacy and safety during the 
flare treatment period. 
For the OL maintenance treatment period, the following set is defined as below: 
• Safety Analysis set for OL maintenance treatment period (SAF-MT): 
This subject set includes all subjects who received at least one dose of OL s.c. 
maintenance treatment. This is the main analysis set for efficacy and safety during OL 
maintenance treatment period.  
Handling of Treatment Misallocations in the Analysis Sets 
If a subject is randomized but not treated, they will be reported under their randomized 
treatment group for efficacy analysis according to RS and PPS (per the intent-to-treatment 
principle).  Such subjects are excluded from the safety analyses (SAF) since no randomized 
study medication was taken. 
If a subject is treated but not randomized, they will be excluded from the efficacy analysis and 
safety analysis. However, subjects under such circumstances will be described in the final 
CTR. 
If a subject is randomized but took incorrect treatment during the study, 
• For efficacy analyses according to the RS and PPS, subjects who took incorrect 
treatment will be reported under their randomized treatment group.  
o In the case of stratification error at randomisation, the subjects will be analyzed 
according to the stratum to which they actually belong to (regardless of any 
mis-assignment to treatment based on identification of the wrong stratum from 
IRT), as such an error occurs before randomisation and is therefore consistent 
with regulatory guidance.  


Boehringer Ingelheim  
TSAP for BI Trial No: 1368.0027 
c39181950-02 
Page 22 of 84 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
 
001-MCS-50-415_RD-01 (3.0) / Saved on 18 Jan 2021 
• For the safety analysis based on SAF, the actual treatment will be used as below: 
o For subjects randomized to active spesolimab arms and are planned to receive 
multiple dose administrations of spesolimab, in the case of incorrect 
medication taken, the subjects will still be reported under their randomized 
treatment group for safety analysis, as the overall safety profile is expected to 
be driven by the amount of spesolimab received in totality over the entire 
treatment duration. If the subject receives only a few syringes of the incorrect 
medication at only some dosing visits, it is not expected that the safety profile 
will deviate from the planned treatment regimen. 
o For subjects randomized to placebo: if the subject receives ≥1 syringe of 
randomized spesolimab s.c., they will be reported as treated under Speso SC 
Low dose group. 
The discussion of all exceptional cases and the decisions on the allocation of subjects to 
populations will be made at the last the RPM/DBLM. 
Table 6.3: 1 
Subject sets analyzed 
Subject Set 
Class of endpoint 
ES 
RS 
PPS 
SAF 
SAF-FT 
SAF-MT 
Disposition 
X 
iPDs 
X 
Demographic 
X 
 
 
 
Baseline characteristics 
X 
X 
Primary endpoint 
X a  
X b  
Key secondary endpoint 
X a  
X b  
Secondary endpoints 
X 
 
 
 
Adverse event 
X 
X 
X 
Lab/other safety/ tolerability 
X 
X 
X 
a Primary analysis 
b Sensitivity analysis 


Boehringer Ingelheim  
TSAP for BI Trial No: 1368.0027 
c39181950-02 
Page 23 of 84 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
 
001-MCS-50-415_RD-01 (3.0) / Saved on 18 Jan 2021 
6.5 
POOLING OF CENTRES 
This section is not applicable because centre/country is not included in the statistical model. 
6.6 
HANDLING OF MISSING DATA AND OUTLIERS 
Section 7.3 of the CTP describes the handling of missing data. 
The original results (OR) approach implies the presentation of data exactly as observed (not 
using time windows and not setting values to missing). 
OR analysis will be performed on parameters and endpoints, such as adverse event, 
concomitant medications, and the use of investigator-prescribed SoC, those are not collected 
based on visits and assignment to time windows will be not necessary. It is not meaningful to 
apply any imputation rule for the replacement of missing values either. 
6.6.1 
Withdrawals 
The reasons for withdrawal from treatment will be reported as indicated on the eCRF.  
6.6.2 
Efficacy data 
Based on the different reasons for subjects’ data missing for different endpoints, various 
approaches will be used to assess the impact of missing data on the efficacy endpoints of this 
trial, depending upon the type of the endpoint and treatment period (See Table 6.6.2:1). 
Approaches to be applied are described below. 
 


Boehringer Ingelheim  
TSAP for BI Trial No: 1368.0027 
c39181950-02 
Page 24 of 84 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
 
001-MCS-50-415_RD-01 (3.0) / Saved on 18 Jan 2021 
6.6.2.1 Randomized treatment period  
Time-to-event efficacy endpoints 
Per CTP Section 7.3, 
It is generally assumed that given the severity of a GPP flare, patients will always report to 
the investigator in a timely manner in order to ensure that proper treatment is received so 
that the developing flare can be rapidly treated. For the primary endpoint, only observed 
GPP flare events will be included in the primary analysis. No further imputation will be 
implemented on the missing values of GPPGA score and/or missing GPPGA pustule 
sub score. This will be the primary imputation method for the primary analysis. The same 
imputation strategy will be used for the two secondary endpoints, time to first worsening of 
PSS and time to first worsening of DLQI in the hierarchical testing procedure. 
 
The detailed rules as outlined in Table 6.6.2:1 will be used as the primary method for 
handling censoring (Primary Method, abbreviated to PM).  
 
Note here, with no event confirmed, censoring will be made at the earliest of the date of End 
of Study, Day 351 and the occurrent date of intercurrent events which hypothetical approach 
applied (per Table 5.1:1). This will also be done even if a subject had an event afterwards. 
Day 351 is the last day of the analysis time window of week 48 per Table 6.7:1. The details 
about analysis time windows can be found in Section 6.7. Such specifications reflect the 
objective of the trial that the treatment comparison for randomized subjects is made within 
48-week study period per CTP Section 2.1.1.  
 
 
 


Boehringer Ingelheim  
TSAP for BI Trial No: 1368.0027 
c39181950-02 
Page 25 of 84 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
 
001-MCS-50-415_RD-01 (3.0) / Saved on 18 Jan 2021 
Table 6.6.2: 1 
Primary Method (PM):  Description of censoring rules for primary 
endpoint, and two secondary endpoints 
Situation 
Outcome (event 
or censored) 
Date of outcome 
Without post randomisation assessment 
No event led by an intercurrent event 
Censored 
Date of randomisation, or the date 
of first dose, whichever comes 
later. 
The first event led by an intercurrent event  
Event 
Date of the first event led by an 
intercurrent event 
With post randomisation assessment 
No event* 
Censored 
Earliest of last contact date on 
End of Study page, Day 351, 
censor date specified by Estimand 
(if applicable) 
The first event* 
Event 
Date of the first event*  
*The event includes the event defined by endpoint and the event led by an intercurrent event per Estimand definition  


Boehringer Ingelheim  
TSAP for BI Trial No: 1368.0027 
c39181950-02 
Page 26 of 84 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
001-MCS-50-415_RD-01 (3.0) / Saved on 18 Jan 2021 
Binary efficacy endpoints 
The multiple imputation method described below (abbreviated to MI) is applicable for the 
primary analysis of the key secondary endpoint and the secondary binary endpoint. 
 
As stated in CTP, missing GPPGA or GPPGA pustulation sub scores will not be imputed and 
only observed values will be utilized. The imputation of binary endpoint will only be done to 
binary level, i.e., success or failure. 
 
Considering the endpoint emphasizes on either the positive side (sustained remission) or 
negative side (occurrence of GPP flare) of disease outcome. The imputation method described 
here will focus on the imputation on the failure to avoid confusion. See Section 5.2 for the 
illustration of treatment failure and monotone increasing. 
 
Prior to the occurrence of failure, if for any reason, one or more subjects have missing visit, 
e.g., due to loss of follow-up or early discontinuation from the study before reaching the time-
point of Week 48, a sequential logistic regression multiple imputation method will be 
implemented to impute the missing outcome by each visit at a binary level (Yes as failure vs. 
No as success).  
 
Before the imputation procedure, any non-monotone missing outcome (binary level) will be 
imputed by the next observed value. The achieved monotone missing data will be then 
imputed per the following steps: 
1. Multiple Imputation of Missing data: A sequential logistic regression method is used 
to impute missing values of binary event (Yes vs. No) at each visit.  


Boehringer Ingelheim  
TSAP for BI Trial No: 1368.0027 
c39181950-02 
Page 27 of 84 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
 
001-MCS-50-415_RD-01 (3.0) / Saved on 18 Jan 2021 
a) Identify the visit with the earliest missing assessment from all subjects, 
denoted as n 
b) For the imputation of missing data at Visit n, the binary level (Yes vs. No) 
available at visit n-1 as well as the corresponding randomized treatment, will 
be included as covariates in the logistic regression imputation model. The 
subjects with missing binary assessment at Visit n will be imputed by the 
imputation model. If the assessment of a subject at Visit n is observed or 
imputed as a failure, the assessments of all subsequent visits up to week 48 of 
this subject will be imputed as failure.  
c) Using the same approach in step b), all visits will be imputed sequentially up 
to Visit 14 (Week 48).  
Note that, the random seed 136827 will be used at the start of the imputation. If a second 
seed is needed, 136828 will be used, and so on so forth as deemed necessary. The 
imputation will be repeated for 100 times. 
 
2. Analysis of Completed Datasets: The imputed complete dataset will be used to 
perform the corresponding statistical analysis per imputation as specified in Section 
7.5 and Section 7.6.1 
 
3. Combine Results: Approaches below will be applied to pool the estimates of the 
response rate for each arm and the risk difference between active arms and placebo 
from each imputed dataset:  
a) For the response rate of each arm, the distributions are not expected to be 
approximately normal, so Rubin’s rules (18) should not be used. Instead, the 
response rate for each arm will be estimated as the mean of individual 
imputations and the corresponding 95% confidence interval will be calculated 
using the MI Wilson (17) approach.  
b) The distribution of risk difference between two arms is approximately normal, 
therefore, Rubin’s rules are applicable. Accordingly, PROC MIANALYZE is 
used to combine the analysis results from step 2 and generate valid statistical 
inferences by accounting for the variability introduced by the MI process.  
Note here, imputing the treatment failure status above is equivalent to imputing the status of 
not achieving remission status for the secondary endpoint.  


Boehringer Ingelheim  
TSAP for BI Trial No: 1368.0027 
c39181950-02 
Page 28 of 84 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
001-MCS-50-415_RD-01 (3.0) / Saved on 18 Jan 2021 


Boehringer Ingelheim  
TSAP for BI Trial No: 1368.0027 
c39181950-02 
Page 29 of 84 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
 
001-MCS-50-415_RD-01 (3.0) / Saved on 18 Jan 2021 
Table 6.6.2: 3 Summary of missing data handling approaches under corresponding Estimand 
*Indicates the approach used as primary analysis for this type of endpoint in the specific treatment period 
EM=primary Estimand for randomized Maintenance treatment period. The use of rescue medication (iv spesolimab) use of 
investigator-prescribed SoC will be considered as on set of GPP flare /treatment failure 
6.6.3 
Safety data 
It is not planned to impute missing values in safety evaluations. 
For the descriptive reporting of safety data by visit, the data available on each visit will be 
summarized for the randomized maintenance treatment period, flare treatment period, and OL 
maintenance treatment period, respectively. 
For safety data that is not collected by visit such as AE and possibly clinically significant 
laboratory abnormality, the original results (OR) to be used for the descriptive reporting for 
corresponding treatment periods. 
Class of endpoint 
Randomized 
maintenance treatment 
period (RS) 
Primary endpoint 
EM-PM* 
 
 
Key secondary 
endpoint 
EM-MI* 
 
Secondary Endpoint 
Binary: 
EM-MI* 
 
 
Time-to-event:  
 EM-PM*, 
 


Boehringer Ingelheim  
TSAP for BI Trial No: 1368.0027 
c39181950-02 
Page 30 of 84 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
 
001-MCS-50-415_RD-01 (3.0) / Saved on 18 Jan 2021 
The only exceptions where imputation might be necessary for safety evaluation are AE dates 
and, start and stop dates for concomitant medications. Missing or incomplete AE dates are 
imputed according to BI standards (see BI-KMED-BDS-HTG-0035 (4)). 
Partial start and stop dates for concomitant medications, and background, investigator-
prescribed SoC, as well as historical medication for GPP will be imputed to enable 
subsequent calculation (but not for display) by the following "worst case" approach: 
 
• If the day of the end date is missing, the end date is set to last day of the month (or to the 
subject's trial completion date, if it is earlier than the last day of the month). 
• If the day and month of the end date are missing, the end date is set to 31st of December of 
the year (or to the subject's trial completion date, if it is earlier than the 31st of December 
of the year). 
• If the day of the start date is missing, the start date is set to first day of the month (except 
for investigator-prescribed SoC, where the first dosing day will be used if first dosing 
happened in the same month). 
• If the day and month of the start date are missing, the start date is set to 1st January of the 
year (except for investigator-prescribed SoC, where the first dosing day/month will be 
used if first dosing happened in the same year). 
• All other cases need to be assessed by the trial team on an individual basis, using the 
above points as guidance. 
If a concomitant medication was ticked to be ongoing, it is expected that the end date is 
missing and will not be imputed for display purposes. 
Missing/incomplete start dates of flare treatment at R1/D1 for a GPP flare will be set to the 
date of occurrence of the applicable flare, the date being consistent with any specification on 
month and/or year of the flare treatment; other situations need to be assessed by the trial team 
on an individual basis. Missing/incomplete start dates of flare treatment at R3/D8 will be set 
to date of the Day 8 visit (if consistent with any specification on the month and/or year) of 
flare treatment period, otherwise it needs to be assessed by the trial team on an individual 
basis. 


Boehringer Ingelheim  
TSAP for BI Trial No: 1368.0027 
c39181950-02 
Page 31 of 84 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
 
001-MCS-50-415_RD-01 (3.0) / Saved on 18 Jan 2021 
6.6.8 
Time since first diagnosis 
For incomplete information on the date of first diagnosis, time since first diagnosis will be 
calculated as follows: 
• If the year of first diagnosis is unknown, time since first diagnosis will be set to 
missing. 
• If day and month of the first diagnosis are unknown, time since first diagnosis will be 
calculated as if diagnosed on the June 30th of that year. 
• If only the day of the first diagnosis is unknown, time since first diagnosis will be 
calculated as if diagnosed on the 15th of that month. 
6.7 
BASELINE, TIME WINDOWS, AND CALCULATED VISITS 
For efficacy and safety analysis, baseline for randomized maintenance treatment period, flare 
treatment period or OL maintenance treatment period, unless otherwise specified, refers to the 
last measurement collected prior to the first dose administered during each treatment period 
separately.  
For each treatment periods, measurements reported with date and time and taken prior to start 
of the first administration of that treatment period will be considered pre-treatment values of 
that treatment period. Measurements reported with a date only (and no time) and taken on the 
day of the first administration will also be considered pre-treatment values.  
Measurements taken after the first study medication for each of treatment periods will be 
considered either on- or off-treatment values based on the definition in Section 6.1 for that 
period, and will be assigned to visits for statistical analysis, if applicable, as defined below. 
Analysis of AE data, concomitant medications, and the use of investigator-prescribed SoC, 
will not be based on visits therefore, no assignment to time windows will be necessary. 


Boehringer Ingelheim  
TSAP for BI Trial No: 1368.0027 
c39181950-02 
Page 32 of 84 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
 
001-MCS-50-415_RD-01 (3.0) / Saved on 18 Jan 2021 
 
The time windows for randomized maintenance treatment period are defined in Table 6.7: 1. 
Table 6.7: 1 
Time windows for assignment of efficacy, safety lab, vital signs, and 
biomarker to visits for the randomized maintenance treatment period  
Visit 
number 
 
Planned day 
Time window 
Visit label 
Window (per CTP) 
Start (extended) 
End (extended) 
 
2 
Day 1  
Day 1d 
0 
Day 1  
Day 1 
3 
Week 4 
Day 29 
+/- 7 days 
Day 2 
Day 43 
4 
Week 8 
Day 57 
+/- 7 days 
Day 44 
Day 71 
5  
Week 12 
Day 85 
+/- 7 days 
Day 72  
Day 99 
6  
Week 16 
Day 113 
+/- 7 days 
Day 100  
Day 127  
7  
Week 20 
Day 141 
+/- 7 days 
Day 128  
Day 155 
8  
Week 24 
Day 169 
+/- 7 days 
Day 156  
Day 183 
9 
Week 28 
Day 197 
+/- 7 days 
Day 184  
Day 211 
10 
Week 32 
Day 225 
+/- 7 days 
Day 212 
Day 239 
11 
Week 36 
Day 253 
+/- 7 days 
Day 240 
Day 267 
12 
Week 40 
Day 281 
+/- 7 days 
Day 268 
Day 295 
13 
Week 44 
Day 309 
+/- 7 days 
Day 296 
Day 323 
14 
Week 48 
Day 337 
+/- 7 days 
Day 324 
Day 351 
 
 
 
 
 
 
Post week 48a 
 
 
Day 352 
EoT +112 days 
Off treatment b  
EoT +113 days 
 
Post Week 48c 
Day 352 
 
 
 
 
 
 
 
All days are counted relative to the day of the first randomized maintenance treatment, which is defined as V2/D1.  
a only applicable to safety lab and vital signs analysis for subjects without any flare treatment or OL maintenance treatment 
who are not rolled over to OLE trial and whose date of EoT is after Day 239.  
b only applicable to safety lab and vital signs analysis for subjects without any flare treatment or OL maintenance treatment 
who are not rolled over to OLE trial and whose EoT is before Day 239 
c only applicable to efficacy and biomarker analysis for subjects without any flare treatment or OL maintenance treatment. 
d measurements post the first randomized maintenance treatment 
 
All safety and efficacy measurements of the flare treatment period will be assigned to visits 
around the planned visit dates relative to R1/D1, i.e., the administration of the first i.v. flare 
treatment. These time windows are defined in Table 6.7: 2.  


Boehringer Ingelheim  
TSAP for BI Trial No: 1368.0027 
c39181950-02 
Page 33 of 84 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
 
001-MCS-50-415_RD-01 (3.0) / Saved on 18 Jan 2021 
Table 6.7: 2 
Time windows for assignment of efficacy, safety lab, vital signs, and 
biomarker to visits for the flare treatment period 
Visit 
number 
 
Planned 
day 
Time window 
Visit label a 
Window (per CTP 
Flow chart 2) 
Start  
(extended) 
End (extended) 
 
R1 
Week 1, Day 1 
Day 1 
exact day 
Day 1  
Day 1  
R2 
Week 1, Day 4 
Day 4 
exact day 
Day 2 
Day 6 
R3 
Week 1, Day 8 
Day 8 
exact day 
Day 7 
Day 10 
R4 
Week 2 
Day 15 
+/- 3 days 
Day 11 
Day 18 
R5 
Week 3 
Day 22 
+/- 3 days 
Day 19 
Day 25 
R6 
Week 4 
Day 29 
+/- 3 days 
Day 26 
Day 43 
R7 
Week 8 
Day 57 
+/- 7 days 
Day 44 
Day 71 
Week 12 
visit b 
Week 12 
Day 85 
+/- 3 days 
Day 72 
Earlier of Day 99 
from first flare 
treatment at 
R1/D1 or the 
day/time before 
first OL 
maintenance 
treatment 
administration if 
applicable 
Days are counted relative to the day of first flare treatment received, which is defined as R1/D1 if not specified otherwise. 
a For subjects who received the administration of the first flare treatment with i.v. spesolimab for the first GPP flare after 
Week 34 (Day 239) from randomisation, they may not need to attend all visits scheduled per Flow Chart 2 of CTP.  
b Week 12 visit of flare treatment period could also be the first visit of the OL maintenance treatment period. The assessments 
before the first OL maintenance treatment could be used for both Week 12 visit of flare treatment period and the baseline for 
OL maintenance treatment. 
 
 
The day of administration of the first OL s.c. maintenance treatment will be treated as V1 for 
OL maintenance treatment period. After V1, subject needs to attend the following visits per 
Flowchart 1 of CTP. In the table and figures for OL maintenance treatment period, all 
following visits should count even subject didn’t receive the treatments in some of the visits. 
For example, when the first administration of OL s.c. maintenance dose was given on Day 
186, Vx+4 will be treated as V1 (the first day and the planned date of V1 is Day 186), Vx+5 
will be treated as V2, Vx+6 will be treated as V3 and etc. (per Table 6.7: 3).  


Boehringer Ingelheim  
TSAP for BI Trial No: 1368.0027 
c39181950-02 
Page 34 of 84 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
 
001-MCS-50-415_RD-01 (3.0) / Saved on 18 Jan 2021 
Table 6.7: 3 
Time windows for assignment of efficacy, safety lab, vital signs, and 
biomarker to visits for the OL maintenance treatment period 
 
 
Time window 
Visit a, c 
Planned 
day*b 
Window  
(per CTP) 
Start  
(extended)b 
End  
(extended) 
Vx 
85 
+/- 7 days 
72 
99 
Vx+1 
113 
+/- 7 days 
100 
127 
Vx+2 
141 
+/- 7 days 
128 
155 
Vx+3 
169 
+/- 7 days 
156 
183 
Vx+4 
197 
+/- 7 days 
184 
211 
Vx+5 
225 
+/- 7 days 
212 
239 
Vx+6 
253 
+/- 7 days 
240 
267 
Vx+7 
281 
+/- 7 days 
268 
295 
Vx+8 
309 
+/- 7 days 
296 
323 
Vx+9 
337 
+/- 7 days 
324 
351 
 
 
 
 
 
Post last OL visit d 
 
 
352 
EoT+112 days 
Off treatment e 
 
 
EoT + 113 
days 
 
Post last OL visit f 
 
 
352 
 
*Days are counted relative to the day of first randomized treatment, which is defined as V2/D1.  
a The visit of the first OL maintenance treatment will be treated as V1 and the following number of visits will be derived 
accordingly.  
b For V1 of OL maintenance treatment period, the planned date of this visit is the day of the first administration of OL s.c. 
maintenance treatment.  
c The visit label for OL maintenance starts with “OL M-”. 
d only applicable to safety lab and vital signs analysis for subjects with OL maintenance treatment who are not rolled over to 
OLE trial and whose date of EoT is after Day 239.  
e only applicable to safety lab and vital signs analysis for subjects who have OL maintenance treatment and are not rolled 
over to OLE trial and whose EoT is before Day 239  
f only applicable to efficacy and biomarker analysis and to subjects with OL maintenance treatment. 
 
 
Repeated and unscheduled efficacy, safety and other measurements will be handled similarly 
to scheduled measurements and will also be assigned to a time window depending upon the 
date of measurement.  For handling of laboratory measurements see also Section 7.8.2. 


Boehringer Ingelheim  
TSAP for BI Trial No: 1368.0027 
c39181950-02 
Page 35 of 84 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
 
001-MCS-50-415_RD-01 (3.0) / Saved on 18 Jan 2021 
 
 
 
 
 
.  
Tables and figures presenting results of the statistical analysis will only display visits at which 
the respective parameter was planned to be collected according to the CTP.  
 


Boehringer Ingelheim  
TSAP for BI Trial No: 1368.0027 
c39181950-02 
Page 36 of 84 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
 
001-MCS-50-415_RD-01 (3.0) / Saved on 18 Jan 2021 
7. 
PLANNED ANALYSIS 
The primary objective is to provide dose-ranging data for 3 dose regimens of spesolimab 
compared to placebo on the primary endpoint of the time to the first GPP flare onset up to 
week 48. If the primary objective regarding achievement of a non-flat dose response curve is 
successful, the secondary objective will be performed, which is to perform formal testing on 
the superiority of spesolimab s.c. treatment versus placebo, on the efficacy endpoints as 
defined in Section 7.1 of CTP.  
Per CTP Section 7  
The primary analysis is planned to be performed once all randomized subjects have 
completed the 48-week treatment observation period. The final analysis is planned to be 
performed at the end of the study once all randomized subjects have completed the study 
(including any follow-up period), if applicable. The two analyses may be performed as a 
single analysis (at the time of trial completion), if, prior to the time of the primary analysis, 
the trial team agrees that the expected time interval between the planned analyses is 
insufficient to justify the performance of separate analyses. 
To support a potential spesolimab GPP flare treatment submission, interim analysis of the 
open-label rescue treatment and subsequent maintenance treatment periods will be performed 
using all open-label data up to a cut-off date, which will be pre-specified in the data cleaning 
plan for the interim analysis. Randomized maintenance s.c. treatments will remain blinded 
and data from the randomized treatment period will not be analyzed in the interim analysis. 
The timing of the interim analysis is driven by the timing of the submission of the flare 
treatment when deemed necessary 
The detailed information of interim analysis is described in Section 7.9 
The format of the listings and tables will follow the BI guideline "Standards for Reporting of 
Clinical Trials and Project Summaries " (BI-KMED-BDS-HTG-0045) (10). 
 
The individual values of all subjects will be listed. Listings will generally be sorted by 
country, center number, patient number and visit (if visit is applicable in the respective 
listing). AE listings will be sorted by assigned treatment (see section 7.8.1 below for details). 
The listings will be contained in Appendix 16.2 (SDL) of the CTR. 
The following standard descriptive statistical parameters will be displayed in summary tables 
of continuous variables: 
N  
 
number of non-missing observations 
Mean   
arithmetic mean 
SD  
 
standard deviation 
Min  
 
minimum 
Q1 
 
lower quartile 
Median  
median 
Q3 
 
upper quartile 
Max   
maximum 


Boehringer Ingelheim  
TSAP for BI Trial No: 1368.0027 
c39181950-02 
Page 37 of 84 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
 
001-MCS-50-415_RD-01 (3.0) / Saved on 18 Jan 2021 
Statistical parameters will be displayed to a defined number of decimal places as specified in 
the BI guideline "Standards for Reporting of Clinical Trials and Project Summaries " (BI-
KMED-BDS-HTG-0045) (10). 
 
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category as well as the percentage (%) relative to the 
respective treatment. Percentages will be rounded to one decimal place. The category missing 
will be displayed if and only if missing values exist. Percentages will be displayed based on 
all subjects in the respective subject set regardless of the status of missingness.  
Disposition of the patient population participating in the trial will be summarized by the 
frequency of subjects screened, randomized, screened but not randomized, randomized but 
not treated, randomized and treated, who completed randomized medication, who were 
prematurely discontinued from trial medication from randomized maintenance treatment, by 
reason, who received flare treatment at R1/D1 and at R3/D8 respectively, who completed 
flare treatment period, who were prematurely discontinued from flare treatment period, by 
reason, who received OL maintenance treatment, who completed the planned OL maintenance 
treatment and who were prematurely discontinued from OL maintenance treatment, by reason.  
7.1 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Only descriptive statistics are planned for this Section of the CTR.  
Descriptive statistics will be presented by treatment for demographic parameters and baseline 
characteristics, based on the RS. The systemic GPP medication use at randomisation will be 
presented by treatment for baseline characteristics as well.  
The presence of mutations (yes or no) in the following genotypes will be descriptively 
presented by treatment for the RS: IL36RN, CARD14, or AP1S3 based on information 
collected via eCRF and the results for the DNA resequencing respectively. 
Characteristics of the trial disease, including details on the past GPP flares prior to trial onset, 
will be displayed for randomized subjects based on the RS.  
For the continuous variables described below, the following categories will be defined, and 
presented according to the number and percentage of subjects in each category. 


Boehringer Ingelheim  
TSAP for BI Trial No: 1368.0027 
c39181950-02 
Page 38 of 84 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
 
001-MCS-50-415_RD-01 (3.0) / Saved on 18 Jan 2021 
Table 7.1: 1 
Categories for summary of continuous variables 
Variable 
Categories 
Age 
< 50 years 
50 to < 65 years 
≧ 65 years 
 
Adolescent: age ≥12 years and <18 
years 
Adult: age ≥18 years 
 
< 65 years 
≧65 years 
 
Weight 
≤70 kg 
>70 to ≤80 kg 
>80 to ≤ 90 kg 
>90 kg 
 
Weight related BE bound 
< 53.8 kg 
≧53.8 to < 91 kg 
≧ 91 kg 
 
BMI 
< 25 kg/m2 
25 to < 30 kg/m2 
≧ 30 kg/m2 
 
Time since first diagnosis 
≤ 1 year 
> 1 to ≤ 5 years 
> 5 to ≤ 10 years 
> 10 years 
 
7.2 
CONCOMITANT DISEASES AND MEDICATION 
Only descriptive statistics are planned for this section of the report.  
Analyses of concomitant diseases (i.e., baseline conditions) and concomitant medications for 
randomized treatment period will be based on RS. Analyses of concomitant medication for 
flare treatment period and OL maintenance treatment period will be based on the SAF-FT and 
SAF-MT respectively. The grouping should be aligned with the treatment arms specified in 
Section 6.1 of each treatment period, respectively. 
Concomitant diseases and concomitant non-drug therapies will be coded according to the 
most recent version of MedDRA. Concomitant medications will be coded according to the 
most recent version of the World Health Organisation – Drug Dictionary. 
A medication/non-drug therapy will be considered concomitant to each treatment period if it 
• is ongoing at the start of that treatment period or 


Boehringer Ingelheim  
TSAP for BI Trial No: 1368.0027 
c39181950-02 
Page 39 of 84 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
 
001-MCS-50-415_RD-01 (3.0) / Saved on 18 Jan 2021 
• starts within the that treatment period (see Section 6.1 for a definition of study analysis 
phases). 
A medication/non-drug therapy will be considered as prior medication/non-drug therapy, if 
the end date of the medication/therapy is at any time prior to the start of randomized trial 
treatment. 
Concomitant medication use (excluding investigator-prescribed SoC as defined in the CTP) 
will be summarized with frequency and percentage of subjects by ATC3 class and preferred 
name. 
Concomitant use of restricted medication for indications other than GPP will be summarized 
with frequency and percentage of subjects by ATC3 class and preferred name, based on RS. 
The frequency and percentage of subjects with historical medication for GPP will be 
displayed, including presentation by type of historical medication (preferred name), by 
randomized treatment and in total, based on RS. 
The frequency and percentage of subjects with concomitant use of systemic GPP medication 
at randomisation will be displayed, including presentation by type of systemic GPP 
medication (preferred name). In case there are discrepancies between the actual concomitant 
use of systemic GPP medication and the stratum assigned for randomisation from IRT, the 
stratification used for IRT may also be summarized by randomized treatment and in total, 
based on RS.  
All the concomitant medication use from the eCRF will be reviewed by the sponsor medical 
team and the use of investigator-prescribed to treat GPP worsening will be identified and 
documented in the decision log before DBL. The use of investigator-prescribed SoC will be 
summarized separately (see Section 7.6.2).  
Concomitant use of non-drug therapies will be summarized with frequency and percentage. 


Boehringer Ingelheim  
TSAP for BI Trial No: 1368.0027 
c39181950-02 
Page 40 of 84 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
 
001-MCS-50-415_RD-01 (3.0) / Saved on 18 Jan 2021 
 
 
7.4 
PRIMARY ENDPOINT(S) 
7.4.1 
Primary analysis of the primary endpoint(s) 
The primary analysis will be implemented under EM-PM approach (primary Estimand for 
randomized Maintenance period using Primary Method for censoring rules) defined in 
Section 5.1 and Section 6.6.2. 
 
The descriptions below are based on the primary objective and secondary objective, 
respectively.  
 
Primary Objective: Dose Finding 
The Multiple Comparison Procedures and Modeling (MCP-Mod) approach (19, 20) is 
implemented in two main steps: (1) trial design stage; (2) trial analysis stage. The procedures 
for the trial design stage, including the selection of candidate models covering a suitable range 
of dose-response shapes and sample size and power calculations, are provided in the CTP 
Section 7.2.2. The procedures for the trial analysis stage are specified below. 
 
For the primary analysis, the dose-response relationship will be modeled using the total 
planned dose. In this trial, the total is the sum of all planned randomized maintenance doses 
administered to the subject prior to week 48, including both loading and maintenance phase. 
Therefore, it is assumed that the cumulative concentration over time (AUC) and thus the 
cumulative total dose is the key driver of the efficacy response in the modeling part of MCP-
Mod. Table 7.4:1 shows the calculated total doses per treatment arm.  
 
Table 7.4:1 
Total dose per treatment arm during randomized maintenance treatment period 
Treatment arm 
Total dose 
Speso SC Low: 300 mg day 1 
150mg q12w 
300mg at Day 1, 150mg at week 12, week 24 and week 36, 
Total dose:750 mg spesolimab 
Speso SC Medium: 600 mg day 1 
300mg q12w 
600mg at Day 1, 300mg at week 12, week 24 and week 36,  
Total dose:1500 mg spesolimab 
Speso SC High: 600 mg day 1 
300mg q4w 
600mg at Day 1, 300mg at week 4, week 8, week 12, week 36, week 
20, week 24, week 28, w32, w36, week 40, week 44 
Total dose: 3900 mg spesolimab 
Placebo 
Placebo at Day 1, week 4, week 8, week 12, week 16, week 20, week 
24, week 28, w32, w36, week 40, week 44,  
Total dose 0 mg spesolimab 
 
The responses for treatment difference estimate over placebo for each active dose group， 
which is based on the log hazard ratio of the active doses versus placebo, as well as their 
estimated variance-covariance matrix estimate for the primary endpoint are estimated by 
stratified Cox regression model on the time to the first GPP flare. The subsequent MCP-Mod 
analysis are based on the log hazard ratio from the stratified Cox regression model. In the case 


Boehringer Ingelheim  
TSAP for BI Trial No: 1368.0027 
c39181950-02 
Page 41 of 84 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
 
001-MCS-50-415_RD-01 (3.0) / Saved on 18 Jan 2021 
of zero event in one/some of the arms by stratum, the stratified Cox regression model will be 
conducted using Firth’s penalization (21, 22, 23) 
 
Sample code 
PROC PHREG DATA=adtte; 
 CLASS treatment stratification (REF=’placebo’); 
 MODEL aval*cnsr (list)=treatment/ TIES=BRESLOW FIRTH; 
 STRATA stratification; 
 HAZARDRATIO treatment / DIFF=REF CL=WALD ALPHA=0.05; 
 ODS OUTPUT HAZARDRATIOS=hazard; 
RUN; 
 
The multiple comparison procedure will be implemented using optimal contrast tests which 
control the type I error rate at a one-sided 𝛼 = 0.05. The optimal contrasts corresponding to 
each candidate model in the trial design stage are shown in Table 7.2.2:1 of CTP. For the final 
evaluation, these optimal contrasts will be updated using the estimated variance-covariance 
matrix from the collected data. The updated contrast coefficients will be reported in the CTR.  
 
A non-flat dose response curve is established if at least one dose-response model is 
statistically significant, i.e., rejecting the null hypothesis of a flat dose-response curve 
indicates a benefit of spesolimab over placebo. If a non-flat dose response is established, the 
statistically significant models from the above candidate set are refitted to the data without 
any parameter assumptions to generate new estimates for all model parameters.   
 
The final dose-response model is derived as a weighted average over all significant model 
shapes.  The weights for each significant model (Mk) are given by  
 
𝑤(𝑀𝑘) =
𝑒𝑥𝑝(−0.5𝐴𝐼𝐶(𝑀𝑘))
∑
exp (−0.5𝐴𝐼𝐶(𝑀𝑖))
𝐾
𝑖=1
, 
 
where AIC(Mk) is the Akaike Information Criterion (AIC) of model Mk 
 
Estimates for each dose group will be calculated and the final dose-response curve will be 
based on the final model.  
 
The following displays are planned, 
- 
Table of the updated contrast coefficients per dose group and candidate model, together 
with the MCP-Mod test statistics and p-values for each model and the critical values; 
- 
For averaging model, figure of the dose-response curve;  
- 
For all significant model shapes, figures of the dose-response curve plus 95% confidence 
band (of the predicted shape) and 95% CI per dose (estimated from stratified Cox model).  
 
 
Secondary Objective: Formal Statistical Testing 
The primary analysis for the secondary objective on the superiority of spesolimab over 
placebo. Time to first GPP flare up to week 48 for Speso SC High and Speso SC Medium 
versus placebo will be tested using EM-PM approach, i.e., primary Estimand using the 


Boehringer Ingelheim  
TSAP for BI Trial No: 1368.0027 
c39181950-02 
Page 42 of 84 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
 
001-MCS-50-415_RD-01 (3.0) / Saved on 18 Jan 2021 
primary censoring rule, and via the stratified log-rank test stratified by the factor of the 
systemic concomitant use of GPP medications at randomisation (yes or no), based on the RS. 
 
The estimated hazard ratios based on the same stratified Cox regression model as for the 
primary objective will be displayed for active spesolimab treatment arm versus placebo. In the 
case of zero event in one/some of the arms by stratum, the stratified Cox regression model 
will be conducted using Firth’s penalization (21, 22, 23). A hazard ratio of less than one 
favors spesolimab. The treatment comparison will be made regardless of the treatment 
adherence or early discontinuation up to Week 48. 
 
Kaplan-Meier (KM) estimates of the survival/failure probabilities at 4-week intervals, as well 
as the median survival time will be provided by treatment arm. 10th and 25th survival time 
percentile will be provided as deemed necessary. KM estimates of the event probability does 
not take the stratification factor, use of systemic GPP medication at baseline, into account. 
 
As more flare events are expected within the first 3 months after randomisation (per CTP 
Section 7.5), the KM estimates are shown at a 1-week interval for the first 12 weeks of 
observation. Confidence intervals will be based on two-sided α= 0.05 using complementary 
log(-log) transformation (conftype=loglog). A KM curve will also be provided by treatment. 
 
Sample SAS Code 
PROC LIFETEST DATA=adtte; 
 TIME aval*cnsr (list); 
  STRATA stratification / GROUP=treatment TEST=logrank; 
RUN; 
 
The primary method for handling of missing data and censoring rules on the time to the first 
GPP flare is described in Section 6.6.2. 


Boehringer Ingelheim  
TSAP for BI Trial No: 1368.0027 
c39181950-02 
Page 43 of 84 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
001-MCS-50-415_RD-01 (3.0) / Saved on 18 Jan 2021 
7.5 
SECONDARY ENDPOINT(S) 
7.5.1 
Key secondary endpoint(s) 
7.5.1.1 
Primary analysis of the key secondary endpoint(s) 
The key secondary endpoint serves the secondary objective of the trial through formal 
statistical testing procedure.  
 
The primary analysis for the key secondary endpoint will be tested using EM-MI approach, 
i.e., primary Estimand after applying multiple imputation. The stratified Cochran-Mantel-
Haenszel (CMH) test based on the RS will be used. If a subject discontinues the treatment 
early but continues in the study, the primary analysis will include subjects’ on- and off-
treatment data up to Week 48. 
 
The stratified Cochran-Mantel-Haenszel (CMH) test will be performed for each dose level of 
spesolimab versus placebo stratified by the concomitant use of systemic GPP medications at 
randomisation (yes or no) based on the RS. The difference in the proportion of subjects who 
have at least one GPP flare up to week 48, will be presented for each active group versus the 
placebo group using the Mantel-Haenszel type weighted average of risk differences. The 
averaged risk difference will use weights as proposed by Greenland & Robins (24). The 
associated confidence intervals of the averaged risk difference will use Sato’s method (25). 
 
Sample code for CMH test 
 
PROC FREQ DATA=data; 
 TABLES stratification*treatment*response / CMH  commonriskdiff nopercent 
RISKDIFF(COMMON COLUMN=2); 


Boehringer Ingelheim  
TSAP for BI Trial No: 1368.0027 
c39181950-02 
Page 44 of 84 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
 
001-MCS-50-415_RD-01 (3.0) / Saved on 18 Jan 2021 
RUN; 
 
The primary method for handling of missing data on the occurrence of at least one GPP flare 
is described in Section 6.6.2. 
 
In addition to the risk difference up to week 48, as a monotone binary endpoint, the 
proportion of subjects who have at least one GPP flare for each arm up to certain time points 
may also be provided using data handled by EM-MI approach. The certain time points are 
specified as each visit at a 4-week interval up to week 48. 95% confidence interval (CI) of the 
proportion will be calculated using the method of Wilson. 
7.5.2 
Secondary endpoint(s) 
The secondary endpoints defined below, for the secondary objective of the trial only, are 
included into the statistical testing strategy. 
 


Boehringer Ingelheim  
TSAP for BI Trial No: 1368.0027 
c39181950-02 
Page 45 of 84 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
 
001-MCS-50-415_RD-01 (3.0) / Saved on 18 Jan 2021 
Time to first worsening of Psoriasis Symptom Scale (PSS) up to week 48 defined as a 4-point 
increase in total score from baseline. Intake of rescue medication, or investigator-prescribed 
SoC, will be considered as onset of a worsening. 
 
Time to first worsening of Dermatology Quality of Life Index (DLQI) up to week 48 defined as 
a 4-point increase in total score from baseline. Intake of rescue medication, or investigator-
prescribed SoC, will be considered as onset of a worsening. 
 
The primary analyses of the two secondary endpoints are as same as that of the primary 
endpoint using EM-PM approach based on RS. 
 
Subjects with the following situation/s will be censored at Day 1 in all corresponding time-to-
event analyses 
• Without a baseline evaluation in PSS/DLQI 
• Do not eligible for the evaluation of worsening 
o PSS baseline >12; 
o DLQI baseline >26; 
o DLQI questionnaire for subject whose age is under 16.  
 
The below-defined secondary endpoint is not included into the statistical testing strategy of 
the secondary objective. 
 
Sustained remission, defined as a subject with a GPPGA score of 0 or 1 (clear or almost 
clear) at all visits up to week 48, without intake of rescue medication, or investigator-
prescribed SoC.  
 
The primary analysis of the above secondary endpoints is consistent with that of the key 
secondary endpoint using EM-MI approach. 


Boehringer Ingelheim  
TSAP for BI Trial No: 1368.0027 
c39181950-02 
Page 46 of 84 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
 
001-MCS-50-415_RD-01 (3.0) / Saved on 18 Jan 2021 


Boehringer Ingelheim  
TSAP for BI Trial No: 1368.0027 
c39181950-02 
Page 47 of 84 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
 
001-MCS-50-415_RD-01 (3.0) / Saved on 18 Jan 2021 


Boehringer Ingelheim  
TSAP for BI Trial No: 1368.0027 
c39181950-02 
Page 48 of 84 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
 
001-MCS-50-415_RD-01 (3.0) / Saved on 18 Jan 2021 


Boehringer Ingelheim  
TSAP for BI Trial No: 1368.0027 
c39181950-02 
Page 49 of 84 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
 
001-MCS-50-415_RD-01 (3.0) / Saved on 18 Jan 2021 


Boehringer Ingelheim  
TSAP for BI Trial No: 1368.0027 
c39181950-02 
Page 50 of 84 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
001-MCS-50-415_RD-01 (3.0) / Saved on 18 Jan 2021 


Boehringer Ingelheim  
TSAP for BI Trial No: 1368.0027 
c39181950-02 
Page 51 of 84 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
 
001-MCS-50-415_RD-01 (3.0) / Saved on 18 Jan 2021 


Boehringer Ingelheim  
TSAP for BI Trial No: 1368.0027 
c39181950-02 
Page 52 of 84 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
001-MCS-50-415_RD-01 (3.0) / Saved on 18 Jan 2021 
7.8 
SAFETY ANALYSIS 
Safety analyses for randomized maintenance treatment period, flare treatment period and OL 
maintenance treatment period will be performed based on the SAF, SAF-FT and SAF-MT 
respectively following BI standards. Data will be summarized descriptively without any 
imputation based on data available of each corresponding treatment period. In addition, AEs 
post any spesolimab (i.v. or s.c.) will be summarized. No hypothesis testing is planned. 
Since the onset time of an AE will not be collected in the trial, any AE which occurs on the 
same day as the first dose of each treatment period will be assigned to that treatment period.  
7.8.1 
Adverse Events 
AEs will be coded with the most recent version of MedDRA. Subjects will be analyzed 
according to the actual treatment received in each treatment period, i.e., randomized 
maintenance period, flare treatment period and OL maintenance period, respectively. In 
addition, the analysis for overall period post use of any spesolimab (s.c. or i.v.) will be 
performed for all subjects received at least one dose of spesolimab (s.c. or i.v.). 
The exposure adjusted incidence rate (per 100 subject years) of a treatment emergent adverse 
event (TEAE) is defined as the number of subjects experiencing the adverse event per 
treatment group during time at risk divided by the total time of subjects at risk in that 
treatment group to contribute the event to the analysis multiplied by 100 (per 100 subject 
years), where: 


Boehringer Ingelheim  
TSAP for BI Trial No: 1368.0027 
c39181950-02 
Page 53 of 84 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
 
001-MCS-50-415_RD-01 (3.0) / Saved on 18 Jan 2021 
 
Time at risk [subject years] = (date of onset of TEAE – the first dose of treatment in 
the applicable treatment period + 1) / 365.25 for subjects with onset of TEAE 
 
During randomized maintenance treatment period, if the selected treatment emergent adverse 
event did not occur, the time at risk will be censored at the end of the treatment period as 
defined in Section 6.1. 
 
To distinguish the GPP flare symptoms from treatment emergent adverse event, sensitivity 
analysis for the safety during randomized maintenance treatment period will be done by 
censoring the time at risk to 7 days prior to first spesolimab iv treatment for subject who 
received the rescue spesolimab i.v. treatment. For subjects without the flare treatment, the 
time at risk will be censored at the end of the randomized treatment period as specified in 
Section 6.1. 
 
For the randomized maintenance treatment period, analysis of the time to the first specific 
AE, which will be pre-defined in the ISS SAP, may also be provided. Kaplan-Meier (KM) 
estimates of the survival/failure probabilities, as well as the median time-to-event, will be 
displayed by randomized treatment arm. Confidence intervals will be based on two-sided α= 
0.05 using complementary log(-log) transformation (conftype=loglog). A Kaplan-Meier curve 
will also be produced. For subjects who do not experience the defined the event, the time at 
risk will be censored at the end of the treatment period as defined in Section 6.1. 
 
For flare treatment period, if the selected treatment emergent adverse event did not occur, the 
time at risk will be censored at the end of the treatment period as defined in Section 6.1. 
 
For OL maintenance treatment period or overall period post any spesolimab use (i.e., i.v. or 
s.c.), if the selected treatment emergent adverse event did not occur, the time at risk will be 
censored at the end of the treatment period as defined in Section 6.1 for OL maintenance 
phase. 
 
For each selected treatment emergent AE, the exposure adjusted incidence rate will be 
calculated as:  
 
Incidence rate [1/100 Subject years (pt-yrs)] = 100 * number of subjects with AE / 
Total AE-specific time at risk [subject years]. 
The analyses of AEs will be descriptive in nature. All analyses of AEs will be based on the 
exposure adjusted incidence rates (per 100 subject years), as well as the number of subjects 
with AEs and not on the number of AEs. System organ classes (if applicable) will be sorted 
according to the standard sort order specified by the EMA. Preferred terms (if applicable) will 
be sorted by total frequency (within system organ class) across all treatment columns. 
For further details on summarization of AE data, please refer to "Handling and summarization 
of adverse event data for clinical trial reports and integrated summaries" (7) [001-MCG-156] 
and "Handling of missing and incomplete AE dates" (4) [BI-KMED-BDS-HTG-0035].  


Boehringer Ingelheim  
TSAP for BI Trial No: 1368.0027 
c39181950-02 
Page 54 of 84 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
 
001-MCS-50-415_RD-01 (3.0) / Saved on 18 Jan 2021 
The analysis of AEs will be based on the concept of treatment emergent AEs. This means that 
all AEs will be assigned to the screening phase, applicable treatment phase or follow-up phase 
as defined in Section 6.1. 
An overall summary of AEs will be presented. This overall summary will also include 
summary for the class of investigator reported AESIs. 
The following are considered as AESIs (see Sec 5.2.6.1 of CTP): 
 
• Hepatic injury 
 
• Systemic hypersensitivity reactions including infusion reactions and anaphylactic 
reaction 
 
• Severe infections (according to RCTC grading in the ISF, selected laboratory 
parameters will be assessed by CTCAE in addition to RCTC grades, where possible) 
 
• Opportunistic and mycobacterium tuberculosis infections 
 
The investigator identified AESI will be captured from the eCRF and reported as 
“Investigator reported AESI” table.  
In addition, user defined adverse event concepts (UDAEC) identified through specific search 
criteria will be reported separately (Table 7.8.1:1).  
 
 


Boehringer Ingelheim  
TSAP for BI Trial No: 1368.0027 
c39181950-02 
Page 55 of 84 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
 
001-MCS-50-415_RD-01 (3.0) / Saved on 18 Jan 2021 
Table 7.8.1: 1 Project MedDRA search criteria for User Defined Adverse Event Concepts 
User-defined AE category 
Label  
Description 
Infections 
(serious/severe, 
opportunistic) 
Infections ALL 
Combined search strategy based on the individual UDAECs 
described below; the UDAEC “severe infections (investigator-
defined) will be disregarded for this search 
Opportunistic 
infections 
Narrow SMQ “Opportunistic infections” 
Tuberculosis 
infections 
BIcMQ “Infections”:   
Narrow sub-search 8.2 “Tuberculosis related terms”  
Serious infections 
all serious events in SOC “Infections and infestations” 
Severe infections 
all events in SOC “Infections and infestations” of at least 
severe RCTC grade, by HLGT 
Hypersensitivity 
Hypersensitivity ALL Combined search strategy based on the individual UDAECs 
for hypersensitivity described below 
Anaphylactic reaction Narrow SMQ “Anaphylactic reaction” 
Angioedema 
Narrow SMQ “Angioedema” 
Hypersensitivity 
Narrow SMQ “Hypersensitivity” 
DRESS, algorithmic Based on broad SMQ “Drug reaction with eosinophilia and 
systemic symptoms” (SMQ code 20000225), defined using 
algorithm as follows: 
A or (B and C and D) or (B and C and E) or (B and D and E) 
where the categories A, B, C, D and E are defined 
categorisations of the PTs of the SMQ. For PTs of category A 
only narrow scope is used, for all other categories broad 
scope is used. 
For identification of potential DRESS through the 
combination of adverse event occurrences within each of the 
categories B, C, D and E, adverse event start and end dates 
will be used. For the latter, potential DRESS is then identified 
if, within a 7-day period after occurrence of a relevant 
contributing event (assessed on each day between start and 
end date [inclusive] of the initiating event), there is at least 
one adverse event reported (based on start date only) from 
each of the other applicable categories within a specific 
combination of categories as described above (in 
parentheses). 
DRESS, narrow 
Narrow SMQ “Drug reaction with eosinophilia and systemic 
symptoms”, any event within category A only 
Malignancies 
Malignant tumours 
Narrow Sub-SMQ “Malignant tumours” 
Narrow Sub-SMQ “Haematological malignant tumours” 
Narrow Sub-SMQ “Non-Haematological malignant tumours” 
Malignant skin 
tumours 
Broad Sub-SMQ “Skin malignant tumours” 
Skin melanomas 
HLT Skin melanomas (excl. Ocular)  
Non-melanoma skin 
cancer (NMSC)  
Broad Sub-SMQ “Skin malignant tumours” excluding HLT 
Skin melanomas (excl. Ocular)  
Malignancies 
excluding NMSC 
Sub-SMQ “Malignant tumours”  excluding  
NMSC, whereas NMSC is defined above 


Boehringer Ingelheim  
TSAP for BI Trial No: 1368.0027 
c39181950-02 
Page 56 of 84 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
 
001-MCS-50-415_RD-01 (3.0) / Saved on 18 Jan 2021 
User-defined AE category 
Label  
Description 
3-point MACE 
3-point MACE 
BIcMQ “Major Adverse Cardiovascular Events” with   
 Narrow sub-search 1.1 “3-Point MACE (part 1/2)”  
 Narrow sub-search 1.2 “3-Point MACE (part 2/2)” * 
Torsade de Pointes 
Torsade de Pointes 
Broad sub-SMQ “Torsade de pointes/QT prolongation” 
Peripheral neuropathy Peripheral neuropathy SMQ "Demyelination, narrow; 
SMQ "Guillain-Barre syndrome", narrow; 
SMQ "Peripheral neuropathy", narrow 
* this is achieved by retrieving all cases found either by running subsearch 1 in narrow scope (BIcMQ search ID 32019093 ) 
or subsearch 2 (BIcMQ serach ID 32019094) 
 
According to ICH E3 (10), in addition to Deaths and serious adverse events, ‘other 
significant’ AEs need to be listed in the clinical trial report. These will be any non-serious 
adverse event that led to an action taken with study drug (e.g., discontinuation or dose 
reduced or interrupted). An overall summary of adverse events will be presented.  
The exposure-adjusted incidence rate and frequency of subjects with AEs will be summarized 
by treatment, primary system organ class and preferred term. AEs which were considered by 
the investigator to be drug related will be summarized separately. Separate tables will also be 
provided for subjects with SAEs, subjects with AEs leading to study drug discontinuation, 
subjects with AESIs, subjects with other significant AEs (derived based upon ICH E3 (9)), 
User-defined Adverse Event Concepts (UDAEC) (Table 7.8.1:1) and serious UDAEC. AEs 
will also be summarized by maximum intensity. 
For disclosure of AE data on ClinicalTrials.gov, the frequency of subjects with non-serious 
AEs occurring with an incidence of greater than 5 % (in preferred terms) will be summarized 
by treatment, primary system organ class and preferred term. The frequency of subjects with 
SAEs and drug related SAEs will also be summarized respectively. 
 
For disclosure of AE data in the EudraCT register, the frequency of non-serious AEs with an 
incidence of greater than 5 % (in preferred terms) and the frequency of SAEs will be 
summarized. 


Boehringer Ingelheim  
TSAP for BI Trial No: 1368.0027 
c39181950-02 
Page 57 of 84 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
001-MCS-50-415_RD-01 (3.0) / Saved on 18 Jan 2021 


Boehringer Ingelheim  
TSAP for BI Trial No: 1368.0027 
c39181950-02 
Page 58 of 84 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
001-MCS-50-415_RD-01 (3.0) / Saved on 18 Jan 2021 


Boehringer Ingelheim  
TSAP for BI Trial No: 1368.0027 
c39181950-02 
Page 59 of 84 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
001-MCS-50-415_RD-01 (3.0) / Saved on 18 Jan 2021 


Boehringer Ingelheim  
TSAP for BI Trial No: 1368.0027 
c39181950-02 
Page 60 of 84 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
001-MCS-50-415_RD-01 (3.0) / Saved on 18 Jan 2021 


Boehringer Ingelheim  
TSAP for BI Trial No: 1368.0027 
c39181950-02 
Page 61 of 84 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
001-MCS-50-415_RD-01 (3.0) / Saved on 18 Jan 2021 


Boehringer Ingelheim  
TSAP for BI Trial No: 1368.0027 
c39181950-02 
Page 62 of 84 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
001-MCS-50-415_RD-01 (3.0) / Saved on 18 Jan 2021 


Boehringer Ingelheim  
TSAP for BI Trial No: 1368.0027 
c39181950-02 
Page 63 of 84 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
 
001-MCS-50-415_RD-01 (3.0) / Saved on 18 Jan 2021 
To support a potential spesolimab GPP flare treatment submission, interim analyses of the 
open-label rescue treatment and subsequent maintenance treatment periods will be performed 
using all open-label data up to a cut-off date, which will be pre-specified in the data cleaning 
plan for the interim analysis. Randomized maintenance s.c. treatments will remain blinded 
and data from the randomized treatment period will not be analyzed in the interim analysis. 
The timing of the interim analysis is driven by the timing of the submission of the flare 
treatment when deemed necessary 
Further, at the cut-off time point of the interim analysis, if applicable, only data up to its cut-
off date will be included, and some subjects may not have completed all their scheduled visits 
in Flow Chart 2 (see Section 3.1 of CTP). Similarly, for summary tables and figures of the 
interim analysis, these subjects will not be accounted in the planned visits which they haven’t 
yet completed.  
PK analysis, biomarker analysis, and ADA related immunogenicity analysis are not planned 
in the interim analysis 
Missing data imputations will be performed using all available data for each treatment period 
separately up to the respective analysis cut-off date.  


Boehringer Ingelheim  
TSAP for BI Trial No: 1368.0027 
c39181950-02 
Page 64 of 84 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
 
001-MCS-50-415_RD-01 (3.0) / Saved on 18 Jan 2021 
8. 
TIMEPOINT OF RELEASE OF TREATMENT 
INFORMATION 
As discussed in Section 7, if the primary analysis and the final analysis are planned to be 
performed separately, a database lock for the primary analysis will be done and treatment will 
be unblinded to trial and project team members. 
 
The Fast-track approach will be followed:  
Once the last patient has completed their End-of-Treatment (EOT) visit and all corresponding 
data up to week 48 has been entered and cleaned to the level documented in the “Data 
Delivery Request” (DDR) form, the data will be declared ready to be unblinded via the “Data 
Ready to be Unblinded and/or Final Trial Closure Notification” (RUN) form. Then the 
treatment information will be released for analysis. 
The data collection for the off-treatment residual effect period until the End-of-Study (EoS)/ 
Follow-Up visit will continue into the unblinded trial database. Once trial data collection has 
been completed and all data has been entered and cleaned as documented on the RUN form, 
a final data lock will be performed. 
After the release of treatment information, it is expected that only trial data related to the off-
treatment residual effect period will be entered and changed. Therefore, after the timepoint of 
release of treatment information, all changes affecting trial data up to the End-of-Treatment 
(EoT) visit will be documented and summarized in the CTR. 
 
If, prior to the time of the primary analysis, the trial team are in alignment to perform a single 
analysis due to insufficient time to justify the performance of separate analyses, we will 
follow Standard approach:  
The treatment information will be released to unblind the trial database after the last patient 
has completed their End-of-Study/Follow-up visit and all data has been entered and cleaned 
as defined in the “Data Ready to be Unblinded and/or Final Trial Closure Notification” 
(RUN) form. 


Boehringer Ingelheim  
TSAP for BI Trial No: 1368.0027 
c39181950-02 
Page 65 of 84 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
 
001-MCS-50-415_RD-01 (3.0) / Saved on 18 Jan 2021 
9.  
REFERENCES 
1 
CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline Topic 
E9; Note For Guidance on Statistical Principles for Clinical Trials, current version 
2 
001-MCS-40-413: “Identify and Manage Important Protocol Deviations (iPD)”, 
current version; IDEA for CON 
3 
BI-KMED-COPS-TMP-0001: "Important Protocol Deviation (iPD) log", current 
version; IDEA for CON 
4 
BI-KMED-BDS-HTG-0035: "Handling of missing and incomplete AE dates", current 
version; IDEA for CON 
5 
001-MCS-36-472: “Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics”, current version, Group “Biostatistics & Data 
Sciences”, IDEA for CON 
6 
Chan I S F, Zhang Z. Test‐based exact confidence intervals for the difference of two 
binomial proportions[J]. Biometrics, 1999, 55(4): 1202-1209. 
7 
001-MCG-156: "Handling and summarisation of adverse event data for clinical trial 
reports and integrated summaries", current version; IDEA for CON 
8 
BI-KMED-BDS-HTG-0042: "Handling, Display and Analysis of Laboratory Data", 
current version; IDEA for CON 
9 
CPMP/ICH/137/95: "Structure and Content of Clinical Study Reports", ICH Guideline 
Topic E3; Note For Guidance on Structure and Content of Clinical Study Reports, 
current version 
10 BI-KMED-BDS-HTG-0045: "Standards for Reporting of Clinical Trials and Project 
Summaries", current version; IDEA for CON. 
11 R20-2984: Hodges Jr J L, Lehmann E L. Estimates of location based on rank tests[J]. 
The Annals of Mathematical Statistics, 1963: 598-611. 
12 001-MCS-40-413_RD-00: "List of References to SOP Identify and Mange 
Important Protocol Deviations (iPD)", current version; IDEA for CON 
13 R16-0029: Cella D, Yount S, Sorensen M, Chartash E, Sengupta N, Grober J. 
Validation of the Functional Assessment of Chronic Illness Therapy Fatigue Scale 
relative to other instrumentation in patients with rheumatoid arthritis. J Rheumatol. 
2005;32(5):811-9. 


Boehringer Ingelheim  
TSAP for BI Trial No: 1368.0027 
c39181950-02 
Page 66 of 84 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
 
001-MCS-50-415_RD-01 (3.0) / Saved on 18 Jan 2021 
14 R18-1989: Hawker GA, Mian S, Kendzerska T, French M. Measures of adult pain: 
Visual Analog Scale for Pain (VAS Pain), Numeric Rating Scale for Pain (NRS Pain), 
McGill Pain Questionnaire (MPQ), Short-Form McGill Pain Questionnaire (SF-MPQ), 
Chronic Pain Grade Scale (CPGS), Short Form-36 Bodily Pain Scale (SF-36 BPS), and 
Measure of Intermittent and Constant Osteoarthritis Pain (ICOAP). Arthritis Care Res 
(Hoboken). 2011;63 Suppl 11:S240-52. 
15 R18-1990: Rentz AM, Skalicky AM, Burslem K, Becker K, Kaschinski D, Esser D, et al. 
The content validity of the PSS in patients with plaque psoriasis. J Patient Rep 
Outcomes. 2017;1(1):4. 
16 R05-2548: Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI)--a simple 
practical measure for routine clinical use. Clin Exp Dermatol. 1994;19(3):210-6. 
17 Anne Lott & Jerome P. Reiter (2020) Wilson Confidence Intervals for Binomial  
Proportions With Multiple Imputation for Missing Data, The American Statistician, 
74:2, 109-115,  
DOI: 10.1080/00031305.2018.1473796  
18 Rubin, D. B. (1976), “Inference and Missing data” (with discussion),  
Biometrika, 63, 581–592.[109]  
19 Pinheiro J, Bornkamp B, Bretz F. Design and analysis of dose-finding 
studies combining multiple comparisons and modeling procedures. J 
Biopharm Stat 16 (5), 639 - 656 (2006) 
20 Model-based dose finding under model uncertainty using general parametric 
models”. Pinheiro et al. 2014 
21 Firth D. Bias reduction of maximum likelihood estimates. Biometrika 1993; 80(1):27–
38 
22 Heinze G. The application of Firth’s procedure to Cox and logistic regression, 
Technical Report 10/1999, update in January 
23 Heinze G, Schemper M. A solution to the problem of monotone likelihood in Cox 
regression. Biometrics 2001; 57(1): 114–119 
24 Greenland S, Robins M. Estimation of a common effect parameter from 
sparse follow-up data, Biometrics 41, 55-68, 1985 
25 Sato T. On the Variance Estimator of the Mantel-Haenszel Risk 
Difference, Biometrics, 45, 1323–1324, 1989, letter to the editor. 
26 Klein, J. P. and Moeschberger, M. L. (1997), Survival Analysis: Techniques for 
Censored and Truncated Data, New York: Springer-Verlag. 


Boehringer Ingelheim  
TSAP for BI Trial No: 1368.0027 
c39181950-02 
Page 67 of 84 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
 
001-MCS-50-415_RD-01 (3.0) / Saved on 18 Jan 2021 
27 Ware JE, Snow KK, Kosinski M, Gandek B. SF-36 Health Survey: Manual and 
Interpretation Guide. Boston: The Health Institute, New England Medical Center. 
1993. 
28 Ware JE. SF-36 Health Survey Update. Spine. 2000. 25(24): 3130-3139. 
29 Frendl DM, Ware JE. Patient-reported Functional Health and Well-Being 
Outcomes with Drug Therapy: A Systematic Review of Randomized Trials Using 
the SF-36 Health Survey. Medical Care. 2014. 52(5): 439-445. 
30 001-MCG-741: "Clinical subgroup analyses for local and regional Populations in Asia 
- Clinical Bridging Study Waiver (BSW) and Descriptive Subgroup Analysis (SGA) 
Reports”, current version; IDEA for CON. 
31 BI-KMED-COPS-HTG-0141 “CTR writing guidance for trials impacted by the 
COVID-19 pandemic” 
32 001-MCS-40-135_RD-01: “Integrated Quality and Risk Management Plan”, current 
version, Group “Clinical Operations”, IDEA for CON. 
33 BI-KMED-COPS-HTG-0117 “IQRM and Centralized Monitoring during COVID-19 - 
Guidance for Trial Teams” 
 


Boehringer Ingelheim  
TSAP for BI Trial No: 1368.0027 
c39181950-02 
Page 68 of 84 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
001-MCS-50-415_RD-01 (3.0) / Saved on 18 Jan 2021 


Boehringer Ingelheim  
TSAP for BI Trial No: 1368.0027 
c39181950-02 
Page 69 of 84 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
 
001-MCS-50-415_RD-01 (3.0) / Saved on 18 Jan 2021 
 


Boehringer Ingelheim  
TSAP for BI Trial No: 1368.0027 
c39181950-02 
Page 70 of 84 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
001-MCS-50-415_RD-01 (3.0) / Saved on 18 Jan 2021 


Boehringer Ingelheim  
TSAP for BI Trial No: 1368.0027 
c39181950-02 
Page 71 of 84 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
001-MCS-50-415_RD-01 (3.0) / Saved on 18 Jan 2021 
 
 
 
 
 
 
 


Boehringer Ingelheim  
TSAP for BI Trial No: 1368.0027 
c39181950-02 
Page 72 of 84 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
 
001-MCS-50-415_RD-01 (3.0) / Saved on 18 Jan 2021 


Boehringer Ingelheim  
TSAP for BI Trial No: 1368.0027 
c39181950-02 
Page 73 of 84 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
 
001-MCS-50-415_RD-01 (3.0) / Saved on 18 Jan 2021 


Boehringer Ingelheim  
TSAP for BI Trial No: 1368.0027 
c39181950-02 
Page 74 of 84 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
 
001-MCS-50-415_RD-01 (3.0) / Saved on 18 Jan 2021 


Boehringer Ingelheim  
TSAP for BI Trial No: 1368.0027 
c39181950-02 
Page 75 of 84 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
001-MCS-50-415_RD-01 (3.0) / Saved on 18 Jan 2021 


Boehringer Ingelheim  
TSAP for BI Trial No: 1368.0027 
c39181950-02 
Page 76 of 84 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
 
001-MCS-50-415_RD-01 (3.0) / Saved on 18 Jan 2021 


Boehringer Ingelheim  
TSAP for BI Trial No: 1368.0027 
c39181950-02 
Page 77 of 84 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
 
001-MCS-50-415_RD-01 (3.0) / Saved on 18 Jan 2021 
 
 
 
 
 
 
 
 
 
 
 


Boehringer Ingelheim  
TSAP for BI Trial No: 1368.0027 
c39181950-02 
Page 78 of 84 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
001-MCS-50-415_RD-01 (3.0) / Saved on 18 Jan 2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Boehringer Ingelheim  
TSAP for BI Trial No: 1368.0027 
c39181950-02 
Page 79 of 84 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
001-MCS-50-415_RD-01 (3.0) / Saved on 18 Jan 2021 
 
 
 
 
 
 
 
 
 
 
 


Boehringer Ingelheim  
TSAP for BI Trial No: 1368.0027 
c39181950-02 
Page 80 of 84 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
001-MCS-50-415_RD-01 (3.0) / Saved on 18 Jan 2021 
 
 


Boehringer Ingelheim  
TSAP for BI Trial No: 1368.0027 
c39181950-02 
Page 81 of 84 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
001-MCS-50-415_RD-01 (3.0) / Saved on 18 Jan 2021 
 


Boehringer Ingelheim  
TSAP for BI Trial No: 1368.0027 
c39181950-02 
Page 82 of 84 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
 
001-MCS-50-415_RD-01 (3.0) / Saved on 18 Jan 2021 


Boehringer Ingelheim  
TSAP for BI Trial No: 1368.0027 
c39181950-02 
Page 83 of 84 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
001-MCS-50-415_RD-01 (3.0) / Saved on 18 Jan 2021 
 


Boehringer Ingelheim  
TSAP for BI Trial No: 1368.0027 
c39181950-02 
Page 84 of 84 
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
 
001-MCS-50-415_RD-01 (3.0) / Saved on 18 Jan 2021 
11. 
HISTORY TABLE 
Table 11: 1 
History table 
Version 
Date 
(DD-MMM-
YY) 
Author 
Sections 
changed 
Brief description of change 
1  
1-Jul-22 
 
None 
This is the final TSAP  
2 
2-Dec-22 
 
Section 6.6.2 
Multiple imputation algorithm is 
elaborated for clarity 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 7.5.2 
Eligibility of time-to-event analysis for 
DLQI worsening/ PSS worsening is 
elaborated for subjects without a 
baseline or with a high baseline  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 6.7 
Analysis time window of randomized 
maintenance treatment period is 
updated to capture the status of early-
onset flare 
 
 
 
Section 7.4 
Section 7.5 
Primary method to estimate the 
treatment effect i.e., hazard ratio, for 
secondary objective is changed to be 
consistent with treatment effect 
estimation in primary objective. 
 
 
 
Section 7.8.1 
UDAEC is modified to align with 
project-level standard 
 
 
 
 
 
 
 
 
 
Section 3 
Version of R software is updated