Clinical trial NCT04086121
Conditions: Dermatitis, Atopic
Sponsor: Boehringer Ingelheim
Start date: 2019-09-24; Completion date: 2022-02-23
Enrollment: 14 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
To assess the long term safety and efficacy of treatment with BI 655130 in patients with AD who have completed and have responded to treatment in the parent study 1368-0032

Detailed description:

Arms: arm 1: 600 milligrams (mg) solution for subcutaneous (SC) injection of BI 655130 (Spesolimab) were to administered subcutaneously every 4 weeks.

All patients will return 16 weeks post the last treatment for an End of Study (EOS) visit.
Interventions: intervention 1: Spesolimab
Intervention descriptions: intervention 1: Solution for SC injection

Protocol documents:
Prot_000.pdf: 
001-MCS-40-106-RD-03 (16.0) / Saved on: 30 Aug 2018
Clinical Trial Protocol
TITLE PAGE
Document Number:
c26581385-02
EudraCT No.
EU Trial No.
N/A
BI Trial No.
1368-0037
BI Investigational
Medicinal Product(s)
BI 655130
Title
An open label extension study to assess the long term safety of 
treatment with BI 655130 administered subcutaneously in adult 
patients with moderate to severe atopic dermatitis.
Lay Title
A study to test the long-term safety of BI 655130 in patients with 
atopic eczema who took part in study 1368-0032
Clinical Phase
II
Clinical Trial Leader
Tel: 
Fax:
Coordinating 
Investigator
N/A
Status
Final Protocol (Revised Protocol based on Global Amendment 1)
Version and Date
Version: 2.0
Date: 23 March 2020
Page 1 of 73
Proprietary confidential information.
2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim 
Protocol date
07 May 2019
Revision date
23 Mar 2020
BI trial number
1368-0037
Title of trial
An open label extension study to assess the long term safety of 
treatment with BI 655130 administered subcutaneously in adult 
patients with moderate to severe atopic dermatitis.
Coordinating 
Investigator
N/A
Trial site(s)
Multi-centre trial 
Clinical phase
II
Trial rationale
To provide patients with moderate to severe atopic dermatitis
extended access to a potentially beneficial treatment and evaluate  
long-term tolerability and safety 
Trial objective(s)
The primary objective of this trial is to assess the long term safety and 
efficacy of treatment with BI 655130 in patients with atopic 
dermatitis who have completed and have responded to treatment in 
the parent study 1368-0032.
Trial endpoints
Primary Endpoint

Number of patients with treatment emergent adverse events 
(AEs) at week 48
Secondary endpoints

Percentage change from baseline in the Eczema Area and 
Severity Index (EASI) Score at Week 48

Percentage of patients with a 50% improvement from baseline 
in EASI (EASI50) at Week 48

Percentage of patients with a 75% improvement from baseline 
in EASI (EASI75) at Week 48

Change from baseline in SCORing of Atopic Dermatitis
(SCORAD) (%) at Week 48

Percentage of patients achieving at least a 2-grade reduction 
from baseline to clear (0) or almost clear (1) in Investigator 
Global Assessment (IGA) at Week 48
Trial design
An open label extension clinical trial consisting of approximately 4 
years of treatment and a 16 week follow-up
Total number of patients
randomised
Approximately 40 patients will enter this trial
Number of patients on 
each treatment
All patients will receive BI 655130
Diagnosis
Adult patients with moderate to severe atopic dermatitis
Main in- and exclusion 
Inclusion Criteria


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criteria

Signed and dated written informed consent in accordance with 
Good Clinical Practice (GCP) and local legislation prior to the 
start of any screening procedures

Patients who completed the 1368-0032 trial and did not 
prematurely discontinue treatment prior to week 16, and;
            In the 1368-0032 re-allocation period (V7 to V11) : 
If an original non-responder from week 16 (V7), attained at 
least an EASI 50 by last infusion (week 28) or by the EOS.
If an original responder from week 16 (V7) completed the last 
visit Week 28 (EOS) or dropped to an EASI 50 score prior to 
Week 28.
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 for the duration of the trial 
and 16 weeks after last administration. A list of contraception 
methods meeting these criteria is provided in the patient 
information. (Refer to Section 4.2.2.3)
1A woman is considered of childbearing potential (WOCBP), i.e. fertile, following 
menarche and until becoming post-menopausal unless permanently sterile. 
Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and 
bilateral oophorectomy.
Tubal ligation is NOT a method of permanent sterilisation.
A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. 
Exclusion Criteria

Women who are pregnant, nursing, or who plan to become 
pregnant while in the trial. (Refer to Section 4.2.2.3)

Any new documented active or suspected malignancy except 
appropriately treated basal cell carcinoma, squamous cell 
carcinoma of the skin or in situ carcinoma of uterine cervix.

Use of any restricted medication as specified in Section 
4.2.2.1 or any drug considered likely to interfere with the safe 
conduct of the study, as assessed by the investigator.

Active systemic infections during the last two weeks prior to 
first drug administration.

Currently enrolled in another investigational device or drug 
trial, except for 1368-0032.  

Any condition which would prevent the patient continuing on 
treatment in this trial 1368-0037


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
History of allergy/hypersensitivity to the systemically 
administered trial medication agent or its excipients
Test product(s)
BI 655130
dose
600 mg (4 syringes, 150 mg each) every 4 weeks
mode of 
administration
Subcutaneous (SC)
Comparator product(s)
N/A
dose
N/A
mode of
administration
N/A
Duration of treatment
Approximately 4 years
Statistical methods
Descriptive statistics only


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FLOW CHART- YEAR 1
Open Label Treatment Period- Year 1
Continue year 2 to 4 based on visit type (See Flow Chart for Years 2-4 and Flow Chart for end of treatment and end of study visits.
Visit Number
12
2
3
4
5
6
7
8
9
10
11
12
13
14
Day
1
29
57
85
113
141
169
197
225
253
281
309
337
365
Week
1
4
8
12
16
20
24
28
32
36
40
44
48
52
Visit Window 
(days)
n/a
±14
±14
±14
±14
±14
±14
±14
±14
±14
±14
±14
±14
±14
Visit Type
A
B
B
C
B
B
D
B
B
C
B
B
E
B
Informed 
consent 1
X
Demographics
X
Medical 
history
X
Inclusion/Exclu
sion/Eligibility
X
Smoking status/   
weight/height18
X
X
Physical exam
X8,
X9
X9
X9
X9
X9
X9
X9
X9
X9
X9
X9
X8
X9
Vital signs10
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12 lead-ECG 5
X
X
Safety Lab 
tests11             
X
X
X
Pregnancy 
Testing7
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Infection 
Testing12
X
X
VAS 
SCORAD 6
X
X
X
X
X
IGA6, EASI 6, 
SCORAD 6
X
X
X
X
X
 
 
 
 
All AEs/SAEs/ 
AESIs3
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
IRT Call
X16
X
X
X
X
X
X
X
X
X
X
X
X
X
Administer 
trial drugs
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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FLOW CHART- YEARS 2-4
The same visit schedule repeats yearly until the end of year four as follows.
These treatment visits will follow the same ±14 day visit window
Year 2
Visit
15
16
17
18
19
20
21
22
23
24
25
26
27
Day
393
421
449
477
505
533
561
589
617
645
673
701
729
Week
56
60
64
68
72
76
80
84
88
92
96
100
104
Visit Type 
B
B
C
B
B
D
B
B
C
B
B
E
B
Year 3*
Visit
28
29
30
31
32
33
34
35
36
37
38
39
40
Day
757
785
813
841
869
897
925
953
981
1009
1037
1065
1093
Week
108
112
116
120
124
128
132
136
140
144
148
152
156
Visit Type 
B
B
C
B
B
D
B
B
C
B
B
E
B
Year 4*
Visit
41
42
43
44
45
46
47
48
49
50
51
EOT
(52)
EOS
(53)
Day
1121
1149
1177
1205
1233
1261
1289
1317
1345
1373
1401
1429
1541
Week
160
164
168
172
176
180
184
188
192
196
200
204
220
Visit Type 
B
B
C
B
B
D
B
B
C
B
B
EOT
  EOS


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FLOW CHART: END OF TREATMENT AND END OF STUDY VISITS
Visit
EOT4 (52)
EOS4 (53)
Day
1429
1541
Week
204
EOT + 16 weeks
Visit Window
±14
+14
Physical examination
X8
X8
Vital signs
X10
X
Smoking status/ /weight
X
X
12 lead-ECG 5
X13
X
Safety Laboratory tests11               
X
X
Pregnancy Testing7
X
X
Infection Testing12
X13
X
 
VAS SCORAD6
X
X
IGA6, EASI6, SCORAD 6
X
X
All AEs/SAEs/ AESIs3
X
X
IRT call
X17
Administer study drugs
X15
Concomitant therapy
X
X
Completion of patient participation 
X
Flow Chart Visit Type Explanation
Visit types refer to the procedures required per Flow Chart. 
Visit Type
Procedures Required
A
Only performed per Flow Chart at Visit 1
B
Shorter visits and contain procedures that are consistently performed at every 
visit (targeted Physical exam, Vitals, pregnancy testing, IRT call, Trial drug 
administration,  AEs/SAEs/ AESIs, and Concomitant therapy
C
All “B” procedures plus IGA, EASI, SCORAD and VAS SCORAD
D
Approximately 6 month visit in each year.  All “B”, and “C” procedures plus 
safety labs,
 
E
Yearly visit. All “B”, “C”, and “D” procedures plus weight, smoking status, 
ECG and Infection Testing.  A complete physical rather than a targeted exam is 
to be performed.


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Footnotes to Flow Chart:
1.
Patients should sign consent on or prior to visit 1 (V1). 
2.
V1 of this extension trial should be preferably performed during the EOS of the preceding BI 
655130 parent trial. When the visits are performed on the same day duplicate procedures across 
studies are performed once during the EOS/V1. If these visits are not performed on the same day 
then all V1 procedures need to be performed at that visit. The only exception is Infection Testing 
which does not have to be repeated if performed at EOS of the parent trial and there is a <12 week 
gap from EOS of parent trial to V1 of this trial. Refer also to Section 6.2.1
3.
After the individual patient’s end of the trial the investigator should report only any cancers of new 
histology and exacerbations of existing cancer, study treatment related SAEs and study treatment 
related AESIs of which the investigator may become aware of and only via the BI SAE form. Refer 
to Section 5.2.6.2.1.
4.
All patients who receive at least one dose in the trial, including those who discontinue treatment 
prematurely, should complete the EOT visit as soon as possible and complete the EOS visit 16 
weeks after the date of last trial drug administration. 
5.
Where possible, electrocardiogram (ECG) measurements should precede blood sampling and drug 
administration. Refer to Section 5.2.4
6.
Body Surface Area (BSA) will be calculated from Part A of the SCORAD. All assessments must 
be done prior to trial drug administration. The questionnaires completed by patients should be done 
first before the investigator assessments. Refer to Section 6.2
7.
Only applicable for women of childbearing potential. Urine pregnancy tests will be performed at all 
visits indicated in the Flow Chart. Urine pregnancy testing should be done prior to administration 
of study drug. 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 performed at the central laboratory.
8.
Complete Physical Examination (PE) includes general appearance as well as evaluation of all organ 
systems.
9.
Targeted physical examination includes evaluation of organ systems associated with AE(s) 
symptoms or laboratory abnormalities.
10. Vital signs will be assessed pre dose as well as within 1 hour post dose. 
11. Safety laboratory tests include clinical chemistry, haematology, coagulation, and urinalysis, and 
will be performed centrally. Where possible, safety laboratory tests are to be drawn prior to dosing. 
12. Infection testing includes tuberculosis, hepatitis B, hepatitis C, and HIV assessments. Refer to 
Table 5.2.3:1 and Section 6.2.1. During a combined EOS/V1 only hepatitis C and HIV assesments 
will need to be done while results of tuberculosis and hepatits B will be used from the parent trial.
13. At EOT visit, infection testing and ECG are only required if not done within the past 6 months. 
14.
15. For patients who complete the trial, the EOT visit will be the last treatment administration. For 
patients who discontinue early, there will be no treatment administration at the EOT visit. 
16. There will be two IRT calls needed at Visit 1. The first is the study enrolment call performed after 
the patient signs consent; the second call is a “medication assignment” call performed after 
confirming eligibility to dispense the first dose of medication.
17. If a patient completes the trial and week 204 (Visit 52) is the EOT, then the site will need to make 
2 IRT transactions- one transaction to dispense last medication, and another transaction to complete 
treatment.  For patients who discontinue early, there will be 1 IRT call (transaction) to discontinue 
treatment.
18. Height is collected at Visit 1 only.


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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART- YEAR 1 .......................................................................................................5
FLOW CHART- YEARS 2-4..................................................................................................6
FLOW CHART:  END OF TREATMENT AND END OF STUDY VISITS ....................7
TABLE OF CONTENTS ........................................................................................................9
ABBREVIATIONS................................................................................................................13
1.
INTRODUCTION...............................................................................................16
1.1
MEDICAL BACKGROUND.............................................................................16
1.2
DRUG PROFILE................................................................................................17
1.2.1
Mode of Action ....................................................................................................17
1.2.1.1
Residual Effect Period ..........................................................................................17
1.2.1.2
Key pharmacokinetic characteristics ....................................................................17
1.2.3
Clinical Experience .............................................................................................18
1.3
RATIONALE FOR PERFORMING THE TRIAL.........................................19
1.4
BENEFIT - RISK ASSESSMENT.....................................................................20
1.4.1
Benefits.................................................................................................................20
1.4.2
Risks .....................................................................................................................20
1.4.3
Discussion.............................................................................................................23
2.
TRIAL OBJECTIVES AND ENDPOINTS......................................................24
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........24
2.1.1
Main objectives....................................................................................................24
2.1.2
Primary endpoint................................................................................................24
2.1.3
Secondary endpoints...........................................................................................24
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................26
3.1
OVERALL TRIAL DESIGN AND PLAN .......................................................26
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)......................................................................................27
3.3
SELECTION OF TRIAL POPULATION .......................................................27
3.3.1
Main diagnosis for trial entry ............................................................................27
3.3.2
Inclusion criteria .................................................................................................28
3.3.3
Exclusion Criteria ...............................................................................................29
3.3.4
Withdrawal of patients from treatment or assessments..................................29
3.3.4.1
Discontinuation of trial treatment .........................................................................30
3.3.4.2
Withdrawal of consent to trial participation .........................................................31


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3.3.4.3
Discontinuation of the trial by the sponsor...........................................................31
4.
TREATMENTS...................................................................................................32
4.1
INVESTIGATIONAL TREATMENTS ...........................................................32
4.1.1
Identity of the Investigational Medicinal Products..........................................32
4.1.2
Selection of doses in the trial and dose modifications......................................32
4.1.3
Method of assigning patients to treatment groups...........................................33
4.1.4
Drug assignment and administration of doses for each patient......................33
4.1.5
Blinding and procedures for unblinding...........................................................33
4.1.5.1
Blinding.................................................................................................................33
4.1.5.2
Unblinding and breaking the code ........................................................................34
4.1.6
Packaging, labelling, and re-supply...................................................................34
4.1.7
Storage conditions...............................................................................................34
4.1.8
Drug accountability.............................................................................................34
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ................................................................................................35
4.2.1
Other treatments and emergency procedures..................................................35
4.2.2
Restrictions ..........................................................................................................36
4.2.2.1
Restrictions regarding concomitant treatment ......................................................36
4.2.2.2
Restrictions on diet and life style..........................................................................37
4.2.2.3
Contraception requirements..................................................................................38
4.3
TREATMENT COMPLIANCE........................................................................38
5.
ASSESSMENTS..................................................................................................39
5.1
ASSESSMENT OF EFFICACY........................................................................39
5.2
ASSESSMENT OF SAFETY.............................................................................40
5.2.1
Physical examination ..........................................................................................40
5.2.2
Vital signs.............................................................................................................40
5.2.3
Safety laboratory parameters ............................................................................41
5.2.4
Electrocardiogram ..............................................................................................44
5.2.5
Other safety parameters.....................................................................................44
5.2.6
Assessment of adverse events.............................................................................44
5.2.6.1
Definitions of AEs ................................................................................................44
5.2.6.2
Adverse event collection and reporting ................................................................48
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS...................................................................................49
5.5
BIOBANKING ....................................................................................................51


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5.6
OTHER ASSESSMENTS...................................................................................51
5.7
APPROPRIATENESS OF MEASUREMENTS..............................................51
6.
INVESTIGATIONAL PLAN.............................................................................52
6.1
VISIT SCHEDULE.............................................................................................52
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................52
6.2.1
Visit 1....................................................................................................................53
6.2.2
Treatment period ................................................................................................55
6.2.3
End of Treatment  and Trial Completion.........................................................56
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................57
7.1
NULL AND ALTERNATIVE HYPOTHESES ...............................................57
7.2
PLANNED ANALYSES.....................................................................................57
7.2.1
General considerations .......................................................................................57
7.2.2
Primary endpoint analyses.................................................................................58
7.2.3
Secondary endpoint analyses .............................................................................58
7.2.5
Safety analyses.....................................................................................................59
7.2.7
Interim Analyses .................................................................................................60
7.3
HANDLING OF MISSING DATA ...................................................................61
7.4
RANDOMISATION ...........................................................................................61
7.5
DETERMINATION OF SAMPLE SIZE .........................................................61
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY, AND ADMINISTRATIVE STRUCTURE ........62
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT ...........................................................................................................62
8.2
DATA QUALITY ASSURANCE ......................................................................63
8.3
RECORDS...........................................................................................................63
8.3.1
Source documents ...............................................................................................63
8.3.2
Direct access to source data and documents.....................................................64
8.3.3
Storage period of records ...................................................................................65
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS ..................................65
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY........65
8.5.1
Collection, storage and future use of biological samples and corresponding 
data.......................................................................................................................65
8.6
TRIAL MILESTONES.......................................................................................66
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ...................................66
9.
REFERENCES....................................................................................................68
9.1
PUBLISHED REFERENCES............................................................................68
9.2
UNPUBLISHED REFERENCES......................................................................70
10.
APPENDICES.....................................................................................................71
10.1
INSTRUCTIONS FOR USE..............................................................................71
10.1.1
Clinical criteria for diagnosing anaphylaxis.....................................................71


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11.
DESCRIPTION OF  GLOBAL AMENDMENT (S) .......................................72
11.1
GLOBAL AMENDMENT 1 ..............................................................................72


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ABBREVIATIONS
                 
AD
Atopic Dermatitis
ADA
Anti-Drug Antibodies
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALT
Alanine Aminotransferase
ADCC
Antibody Dependent cellular cytotoxicity
ALQ
Above limit of Quantification
AP
Alkaline Phosphatase
aPTT
Activated Partial Thromboplastin Time
AST
Aspartate Aminotransferase
BI
Boehringer Ingelheim
BLQ
Below limit of Quantification
BSA
Body Surface area
CA
Competent Authority
CDC
Complement dependent cytotoxicity
CK
Creatine Kinase
CRA
Clinical Research Associate
CRF
Case Report Form, paper or electronic (sometimes referred to as 
“eCRF”)
CRO
Contract Research Organisation
CT Leader
Clinical Trial Leader
CT Manager
Clinical Trial Manager
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DBL
Database Lock
DILI
Drug Induced Liver Injury
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic acid
EASI
Eczema Area and Severity Index
EC
Ethics Committee


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ECG
Electrocardiogram
eCRF
Electronic Case Report Form
eDC
Electronic Data Capture
EDTA
Ethylendiaminetetraacetic acid
EOS
End of Study
EOT
End of Treatment
EudraCT
European Clinical Trials Database
FAS
Full Analysis set
GCP
Good Clinical Practice
GGT
Gamma-Glutamyl Transferase
GMP
Good Manufacturing Practice
GPP
Generalized pustular psoriasis
HA
Health Authority
HBV
Hepatitis B Virus
HCP
Health Care Proffessional
HIV
Human Immunodeficiency virus
IL
Interleukin
i.v.
intravenous
IB
Investigator’s Brochure
IBD
Inflammatory Bowel Disease
ICH
International Council on Harmonisation
IEC
Independent Ethics Committee
IGA
Investigator Global Assessment
INR
International Normalized Ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
ITE
Indirect Target Engagement
IUD
Intrauterine Device
IUS
Intrauterine Hormone-Releasing System
LDH
Lactate Dehydrogenase
LLOQ
Lower Limit of the Quantification
LPLT
Last Patient Last Treatment


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LPLV
Last Patient Last Visit
MedDRA
Medical Dictionary for Drug Regulatory Activities
Nab
Neutralizing Antibodies
NOAEL
No-observed-adverse-effect level
OPU
Operative Unit
PASI
psoriasis area and severity index
PBMC
Peripheral Blood Mononuclear Cells
PD
Pharmacodynamic
PK
Pharmacokinetics
PPP
Palmoplantar pustulosis
PRO
Patient Reported Outcome
RA
Regulatory Authority
RCTC
Rheumatology Common Toxicity Criteria
REP
Residual Effect Period
RNA
Ribonucleic acid
SC
Subcutaneous
SAE
Serious Adverse Event
SAF
Safety Analysis Set
SCORAD
SCORing of Atopic Dermatitis
SD
Standard Deviation
SoC
Standard of Care
SOP
Standard Operating Procedure
STORM
Storage Conditions for Trial Medications
SUSAR
Suspected Unexpected Serious Adverse Reactions
TB
Tuberculosis
TMDD
Target-Mediated Drug Disposition
TSAP
Trial Statistical Analysis Plan
ULN
Upper Level of Normal
ULOQ
Upper limit of quantification
VAS
Visual Analog Scale
WOCBP
Woman of childbearing potential


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Atopic Dermatitis (AD) is an immune-mediated skin disease characterized by chronic or 
relapsing red and inflamed skin (erythema) and an intense and unrelenting itch (pruritus). In 
common terminology AD is often referred to as Eczema, the term for a variety of skin 
conditions, of which AD is the most severe. Diagnosis is based on a patient’s medical history, 
characteristic clinical findings and exclusion of other skin conditions [P18-07868]. The 
hallmark of AD is pruritus that is responsible for much of the disease burden for patients and 
their families. Pruritus can be persistent and consequently can disrupt sleep and/or cause 
anxiety or depression [R18-2681, R18-2680]. Other clinical features of AD include skin 
dryness, erythema (redness), oozing, crusting, and lichenification (skin that has become 
thickened and leathery). 
Worldwide, the lifetime prevalence of AD has increased over the last 30 years occurring in 
10–20% of the population in developed countries. Prevalence is lower, but increasing, in 
developing countries [R18-2667]. Typically, AD develops during childhood with 
approximately 60% of cases occurring in the first year of life [P06-08156; R18-2668]. In 
about 70% of cases, the disease greatly improves or resolves in childhood, but the remaining 
30% of patients go on to have a remitting and relapsing condition with repeated flares [R18-
2668; R18-2663].
AD appears to have a more heterogeneous pathophysiology than previously thought. Unlike 
chronic plaque psoriasis that is almost exclusively driven by the Th17 pathway, AD involves 
multiple immune axes involving expression of multiple cytokines and chemokines, including 
Interleukin (IL)-13, IL-4, IL-33, and IL-22. 
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- β, IL12, IL17, IL23, TGF- β) and modulates the 
expression of tissue remodeling genes (e.g. MMPs, TGF- β). The link between IL36R and 
AD is based on data demonstrating upregulation of human IL36R and IL36 (and IL36α) 
expression in AD skin biopsies compared to normal control skin as well as data showing 
IL36R functionality in disease relevant primary human cells. In addition, there is data 
demonstrating enhanced IL-36 signaling in human macrophages via the TH2 cytokine (IL4) 
pathway. 
Recent data from a mouse model suggest that IL36R may also play a role in the pathogenesis 
of AD via a specific pathway related to S. aureus infection [R18-2666, R18-2669]. These 
papers show epicutaneous infection with S. aureus induces an inflammatory response 
mediated by IL-36 pathway and that IL36R deficiency or blockade results in a reduction of 
the skin inflammation induced by S. aureus derived virulent PSMα peptides [R18-2666, R18-
2669]. These studies demonstrated a clear link to the IL36 pathway suggesting IL36 pathway 
activation may represent an early and persistent event in the development of AD disease.


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1.2
DRUG PROFILE
1.2.1
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 activation of IL36R by 
cognate ligands (IL36 α, β and γ) and subsequent 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 AD, generalized pustular psoriasis 
(GPP), palmoplantar pustulosis (PPP) and inflammatory bowel disease (IBD).
1.2.1.1
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.
1.2.1.2
Key pharmacokinetic characteristics
PK data so far suggest target-mediated drug disposition (TMDD) kinetics for BI 655130. The 
saturation of the non-linear elimination pathway is likely occurring after 0.3 mg/kg and BI 
655130 seems to exhibit linear kinetics from the next dose-level onwards. Based on the PK in 
normal volunteers and GPP patients, the elimination half-life of BI 655130 in patients is 
approximately 3 weeks.
 
 
 
 
 
 
 


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1.2.3
Clinical Experience
As of September 2018, 212 subjects have been exposed to single or multiple doses of BI 
655130 in completed or ongoing clinical studies. The clinical safety data support the use of 
BI 655130 in clinical studies with repeat doses up to 20 mg/kg IV q week for 4 weeks. In 
phase I trials 1368-0001 and 1368-0002, single administration up to 20 mg/kg IV and repeat 
dosing up to 20 mg/kg IV have been tested. In trial 1368-0003, single doses of 150 or 300 mg 
SC and 300mg IV have been tested. In trial 1368-0029 single doses of up to 300 mg SC have 
been tested. All adverse events (AEs) reported were of mild or moderate intensity; drug-
related AEs of moderate intensity were only observed in 1 subject in the 20 mg/kg BI 655130 
treatment group (these AEs led to study drug withdrawal). All AEs were resolved by trial 
completion and no relevant changes were observed in safety laboratory tests, vital signs, or 
ECGs. No dose dependency was observed for all AEs. The incidences of drug related AEs 
were balanced across treatment groups up to 10 mg/kg dose, while higher incidences were 
reported in the 20 mg/kg dose group.
PK data suggest target-mediated drug disposition (TMDD) kinetics for BI 655130, with 
linear kinetics after 0.3 mg/kg. The effective half-life of BI 655130 is approximately 3 weeks 
in the linear dose range. Indirect target engagement (ITE) of IL36R by BI 655130, using an 
ex-vivo whole blood stimulation assay, indicates 94% inhibition of MIP-1β compared to 
baseline for up to 70 days after single dosing and at 90% inhibition for up to 22 weeks after 


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multiple dosing. Thus, the safety profile was established at doses corresponding with at least 
90% target saturation in peripheral whole blood up to 22 weeks after last dose.
In a study of BI 655130 in 7 patients with GPP (1368.0011) who received a single infusion of 
10 mg/kg of BI 655130, none of the reported AEs was severe, serious or led to 
discontinuation and no relevant abnormalities in laboratory values or vital signs were 
observed. Proof-of-concept was achieved with these 7 patients, who showed rapid clinical 
responses to single administrations of BI 655130 with good safety and tolerability. 
A placebo controlled Phase II study (1368-0015) has also been conducted to 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 patients with baseline disease scores > 16.7, a post-hoc subgroup analyses 
indicated efficacy for both doses of BI 655130. The mean percent reduction from baseline in 
pustular severity was 58%, 35% and 8% for the 900 mg BI 655130, 300 mg BI 655130 and 
placebo groups respectively, indicating a dramatic reduction in pustule severity with evidence 
of a dose response relationship.
Overall, BI 655130 was safe and well tolerated. Most AEs were of mild or moderate intensity 
and there were only 2 serious AEs, one of which occurred in a patient receiving placebo. No 
AE was considered to be dose-limiting and no AEs of special interest occurred. All AEs were 
resolved by the end of the trial. There were no relevant changes in safety laboratory tests, 
vital signs, or ECGs. No safety signals have been identified for BI 655130. There is 
preliminary, non-placebo controlled, efficacy in patients with an acute flare of GPP and a 
signal of efficacy in PPP patients with baseline disease scores above 16.7.
For further details and most up-to-date results refer to the current "Investigator`s Brochure" 
(IB) [c03320877-06].
1.3
RATIONALE FOR PERFORMING THE TRIAL
The purpose of the trial is to offer to all patients who completed the clinical trial 1368-0032 
as planned, the option to continue to receive BI 655130 treatment if they have responded to 
treatment and meet all criteria for study entry.


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This trial is designed to evaluate the long-term tolerability and safety of BI 655130 in patients 
with AD. The data generated from this extension trial is anticipated to provide additional 
safety data of up to approximately four years treatment in approximately 40 patients treated 
with BI 655130.
1.4
BENEFIT - RISK ASSESSMENT
1.4.1
Benefits
The parent study (1368-0032) is the first use of BI 655130 in patients with AD. 
Since this trial is ongoing the efficacy of BI 655130 in AD patients cannot be confirmed at 
this time. Nonetheless, if patients respond in the parent study they will receive the benefit of 
continued study medication.
The link between IL36R and AD is based on upregulation of human IL36R and its ligands in 
skin biopsies from AD patients, as well as data showing IL36R functionality in disease 
relevant primary human cells. In a mouse model, IL36R plays a role in the pathogenesis of 
AD via a specific pathway related to S. aureus infection [R18-2666, R18-2669]. These 
studies demonstrated a clear link to the IL36 pathway suggesting IL36 pathway activation 
may represent an early and persistent event in the development of AD disease. 
Patients in the parent trial (1368-0032) who do not achieve at least a 50% reduction in 
Eczema Area and Severity Index (EASI) following treatment with BI 655130 will not be 
enrolled in 1368-0037. Thus, all patients in 1368-0037 will be receiving BI 655130 and will 
have experienced some reduction in their disease in the parent trial. Since all patients will 
receive active treatment, most patients have a potential benefit from participating in this long 
term clinical trial.
1.4.2
Risks
There are no identified or potential safety risks for BI 655130, based on the toxicology 
programme or any clinical trials conducted for this product to date (Refer to Section 1.2). No 
other IL-36 receptor antagonist is currently approved, providing information on identified 
risks in molecules of this class. 
Currently there are no data available to suggest interactions of BI 655130 with other drugs 
[c03320877-06]. Since the drug exposure in this trial is expected to be lower than in the 
parent trial (1368-0032), there is a risk that some patients will lose response. Rules for 
discontinuation for these patients are outlined in Section 3.3.4.1.
The risks shown in the table below are hypothetical in nature; these are derived from general 
safety considerations of immunomodulatory drugs.
In order to protect the patient’s safety during conduct of this trial, an independent Data 
Monitoring Committee has been established for the periodic review of clinical trial safety 
data.


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Table 1.4.2:1
Study 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 Section 5.2.6
(AESI)
Systemic 
Hypersensitivity 
After administration of any 
biologic agent or protein there 
is a possibility of occurrence 
of adverse immune reactions 
which can be local (e.g. 
redness, pruritus, and or 
swelling at the injection site) 
or systemic (e.g. anaphylactic 
reactions). 
As patients have already been 
exposed in the parent trial, the 
risk of systemic 
hypersensitivity is low
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
(SoC) to interrupt and treat the 
condition. Systemic hypersensitivity 
reaction is defined as AESI. It is 
subject to close monitoring and 
investigators are requested assess 
these conditions using the criteria 
discussed in the statement paper 
from Sampson HA [R11-4890].
Infections
Inhibition of the immune 
response with an immune-
modulating biologic may 
increase the risk of infections.
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
Screening procedures for infections 
will be established for this trial. 
Patients with any relevant chronic 
or active 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 


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[R17-3632].
infections are considered AESI for 
this trial. These conditions and 
serious infections are subject to 
close monitoring.
Patients with active systemic 
infections during the parent 655130 
study must delay Visit 1 in this 
study until the infection has 
resolved for at least 2 weeks.
An independent data monitoring 
committee (DMC) is in place to 
periodically evaluate clinical trial 
safety data.
Malignancies
Inhibition of the immune 
response with an immune-
modulating biologic may 
increase the risk of a 
decreased immune defense 
against malignancies.
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].
Patients with a documented active 
or suspected malignancy 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 
BI655130.
Diagnostics and treatment have to 
be initiated according to local SoC.
Malignancies represent always 
serious adverse events and are 
subject to close monitoring.
Inclusion of 
paediatric,
pregnant and 
lactating patient
Currently there are no data 
available allowing the conduct 
of clinical trials in paediatric 
patients, pregnancy and 
lactation. 
Until such data are available, these 
patients will be excluded. 
Trial procedures


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Blood Sampling and 
SC injection
The risks of SC injection are 
expected to be lower than 
i.v. infusion used in parent 
trial (1368-0032)
There is a risk of mild pain, 
local irritation, erythema, or 
bruising at the injection/ 
puncture site. There is a 
small risk of lightheadedness 
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.
Frequent blood collection 
may cause anaemia (low red 
blood cell count), which may 
create a need for blood 
transfusions.
(a)
Close clinical monitoring of 
AEs
(b)
selection of experienced 
sites and site staff;
(c)
Training.
1.4.3
Discussion
Considering the unmet medical need for development of an effective and well tolerated drug
for the therapy of AD this benefit is considered to outweigh the potential risks and justifies 
the long term administration of BI 655130 to patients with AD.
Based on the limited data currently available, the risks to patients associated with 
administration of BI 655130 are considered acceptable.
In order to detect and mitigate any safety signals and potential risks described above as early 
as possible, an independent Data Monitoring Committee (DMC) will oversee this study. 


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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
The primary objective of this trial is to assess the long term safety and efficacy of treatment 
with BI 655130 in patients with AD who have completed and have responded to treatment in 
the parent study 1368-0032.
2.1.2
Primary endpoint
Number of patients with treatment emergent AEs at week 48
2.1.3
Secondary endpoints
Secondary endpoints are: 

Percentage change from baseline in the Eczema Area and Severity Index (EASI) 
Score at Week 48

Percentage of patients with a 50% improvement from baseline in EASI (EASI50) at 
Week 48

Percentage of patients with a 75% improvement from baseline in EASI (EASI75) at 
Week 48

Change from baseline in SCORing of Atopic Dermatitis (SCORAD) (%) at Week 48

Percentage of patients achieving at least a 2-grade reduction from baseline to clear (0) 
or almost clear (1) in Investigator Global Assessment (IGA) at Week 48


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This is a multi-centre, multi-national open label extension clinical trial. It is anticipated that 
approximately 40 patients with AD will complete the parent clinical trial 1368-0032 as 
planned and be eligible for enrolment in this extension trial. Patients who withdrew treatment 
prematurely in 1368-0032 will not be eligible for this extension trial. 
The purpose of the trial is to offer to all patients who completed the clinical trial 1368-0032 
as planned, the option to continue to receive BI 655130 treatment if they have responded to 
treatment and meet all criteria for study entry.
Response to treatment is defined as a 50% or more decrease in EASI in the parent trial. Refer 
to Section 3.3.1 and Section 3.3.2.
After signing informed consent, and if all eligibility criteria are met, patients will receive the 
first dose of BI 655130 for this extension trial. All patients will be assigned to receive active 
treatment, administered subcutaneously (SC). 
All patients will return 16 weeks post the last treatment for an End of Study (EOS) visit.
The trial is estimated to last approximately 4 years. The trial will end when all patients 
discontinue treatment, have another means to obtain treatment with BI 655130 or if the 
development of the drug is terminated. Individual treatment will be stopped if a reason for 
withdrawal is met.
Figure 3.1:1 Trial Design
N = 40
Treatment period
             16 week follow-up



……….…….................. 

V1
V2
V3
V4                 to                 V51
V52/EOT
V53/EOS
W1
W4
W8
W12              to                
W200
W204
         
Week220
V1 is eligibility and first SC injection
V1 should be preferably combined with EOS of trial 1368-0032.
Maximum gap for enrolling is 12 weeks from parent 1368-0032
V = Study Visit
W = Week (study weeks)
EOT = End-of-Treatment
EOS = End-of-Study
= BI 655130 600 mg SC once every 4 weeks


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3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
The trial will be conducted as a prospective, open-label design. The aim of the trial is to 
allow treatment continuation to individual patients who responded to treatment therefore, 
randomization, blinding and use or placebo would not be appropriate. 
This trial is designed as a long-term extension clinical trial and is expected to generate 
additional safety information to support registration submissions. Therefore the primary 
endpoint is focused on safety.  Patients who prematurely discontinued blinded treatment (up 
to Week 16) in the parent trial (1368-0032) are not eligible for this study.  In addition only 
patients who have met the definition of a completed patient and responded to treatment in the 
parent trial (1368-0032) will be eligible for this study. 
Our goal in this study is to obtain additional safety, tolerability and efficacy data following 
long-term drug administration. 
These parameters will be assessed in a descriptive manner, since the trial is open-label and 
there is no placebo control. Thus, there is no method of controlling observer bias. The 
duration of the trial is designed to provide additional long term safety data in patients 
receiving a dose that is at or above the potential to-be-marketed dose. In addition, the trial 
provides long term access to IP for patients that have responded prior to marketing approval.
3.3
SELECTION OF TRIAL POPULATION
It is anticipated that approximately 40 patients with AD from the parent trial 1368-0032 will 
be eligible for enrolment in this extension trial. This extension trial will utilize the same sites 
from the parent trial across the same countries.
A log of all patients enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the Investigator Site File (ISF) irrespective of whether they have been treated 
with investigational drug or not.
If a patient is enrolled in error (does not meet all inclusion criteria or meets one or more 
exclusion criteria on the day of enrolment), the sponsor should be contacted immediately.
3.3.1
Main diagnosis for trial entry
Patients with AD will be included in this trial if they fulfil all the inclusion and do not present 
any of the exclusion criteria. 
Patients who prematurely discontinued blinded treatment (up to Week 16) in the parent trial 
(1368-0032) are not eligible for this study.  In addition patients from 1368-0032 must have 


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shown a response in order to be eligible.  Patients from the 1368-0032 who were in the non-
responder category at week 16, which was defined as less than EASI 75, must have 
completed the EOS visit and must attain at least an EASI 50 by the last infusion of BI 655130 
(Week 28) or by the EOS in order to be eligible for this extension trial. 
Patients from the 1368-0032 who were in the responder category at week 16 (V7) which was 
defined as an EASI 75 or greater, are eligible as long as they have completed the (EOS) visit. 
If this patient drops to an EASI 50 score prior to the planned EOS at Week 28, they will 
immediately perform EOS in 1368-0032 and enter into this extension trial.
Patients should enrol into the extension trial as soon as possible after conclusion of the parent 
trial. It is preferred that the end of study (EOS) visit from parent trial (1368-0032) will be 
combined with Visit 1 of this trial which includes the first SC dose of trial drug.
The Sponsor must be notified if enrolment is delayed. Patients must be enrolled within a 
maximum of 12 weeks after the EOS visit from 1368-0032. (Refer to Section 6.2.1 for more 
detailed information on study procedures).  
The results of the safety labs as well as Infection Testing will be available/reported after the 
patient has entered and received the first dose of study medication in this trial. Refer to 
Section 3.3.4.1 for discontinuation of treatment rules.  
Please refer to Section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the in- and exclusion criteria.
3.3.2
Inclusion criteria
1. Signed and dated written informed consent in accordance with Good Clinical Practice 
(GCP) and local legislation prior to the start of any screening procedures
2. Patients who completed the 1368-0032 trial and did not prematurely discontinue 
treatment prior to week 16, and;
In the 1368-0032 re-allocation period (V7 to V11):
•
If an original non-responder from week 16 (V7), attained at least EASI 50 by last 
infusion (week 28) or by the EOS.
•
If an original responder from week 16 (V7) completed the last visit Week 28 (EOS) or 
dropped to a EASI 50 score prior to Week 28.
3. 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 for the duration of the trial and 16 
weeks after last study drug administration. A list of contraception methods meeting these 
criteria is provided in the patient information. (Refer to Section 4.2.2.3)
1A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-
menopausal unless permanently sterile. 
Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy.
Tubal ligation is NOT a method of permanent sterilisation.
A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. 


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3.3.3
Exclusion Criteria
1. Women who are pregnant, nursing, or who plan to become pregnant while in the trial. 
Refer to Section 4.2.2.3
2. Any new documented active or suspected malignancy except appropriately treated 
basal cell carcinoma, squamous cell carcinoma of the skin or in situ carcinoma of 
uterine cervix.
3. Use of any restricted medication as specified in Section 4.2.2.1 or any drug 
considered likely to interfere with the safe conduct of the study, as assessed by the 
investigator.
4. Active systemic infections during the last two weeks prior to first drug administration.
Refer to Section 1.4.2 and Section 4.2.1
5. Currently enrolled in another investigational device or drug trial, except for 1368-
0032.  
6. Any condition which would prevent the patient continuing on treatment in this trial 
1368-0037.
7. Evidence of a current or previous disease, medical condition (including chronic 
alcohol or drug abuse or any condition) other than AD, surgical procedure, psychiatric 
or social problems, medical examination finding (including vital signs and 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.
8. History of allergy/hypersensitivity to the systemically administered trial medication 
agent or its excipients.
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 Section 3.3.4.1 and 
Section 3.3.4.2.
Every effort should be made to keep the patients in the trial.
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. 


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The decision to discontinue trial treatment or withdraw consent to trial participation and the 
reason must be documented in the patient files and Electronic Case Report Form (eCRF). If 
the reason for discontinuation is death, this should be reported on the SAE form as well, 
regardless of causal relationship.
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 misses more thaan 3 consecutive doses of trial treatment.

The patient is unable to discontinue use of a restricted medication (Section 4.2.2.1) or 
requires other concomitant therapy that in the opinion of the investigator may interfere 
with trial treatment.

The patient requires rescue medication for the treatment of unstable or worsening of AD.
Refer to Section 4.2.2.1

The patient can no longer receive trial treatment for medical reasons (such as surgery, 
adverse events, and other diseases.) For individual stopping rules related to specific 
adverse events, please see Section 4.2.1 other treatments and emergency procedures.

Malignancies during the trial. Refer to Section 4.2.1

Severe, progressive, or uncontrolled hepatic disease during trial. 

The patient becomes pregnant during the trial.

Confirmed active tuberculosis during the trial.                                                      

The patient tests positive for HIV or Hepatitis B or C during the trial.  
If a patient permanently discontinues trial treatment, the patient should return for the end of 
treatment (EOT) procedures as well as the end of study (EOS) procedures as outlined in the 
Flow Chart and Section 6.2.3.
Discontinuation due to pregnancy
If a patient becomes pregnant during the trial the investigator must follow the AE reporting 
procedure as noted in Section 5.2.6.2.3. The patient must discontinue drug and perform EOT 
and EOS procedures accordingly.  The patient will be followed up until birth or otherwise 
termination of the pregnancy.
The data of the patient will be collected and reported in the clinical trial report (CTR) until 
last patient last visit (LPLV) and that any events thereafter will be reported in the BI 
Pharmacovigilance database.
It is per the Investigator opinion and judgment when trial medication can be temporarily 
interrupted and then reinstated for certain medical reasons such as surgery, adverse events 


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and other diseases.  In these cases of a temporary discontinuation/interruption of trial 
treatment, trial treatment should be restarted as soon as medically justified. (Refer to Section 
4.1.4 and Section 4.2.1).
3.3.4.2
Withdrawal of consent to trial participation
Patients may withdraw their consent to trial participation at any time without the need to 
justify the decision.
If a patient wants to withdraw consent, the investigator should be involved in the discussion 
with the patient and explain the difference between trial treatment discontinuation and 
withdrawal of consent to trial participation, as well as explain the options for continued 
follow-up after trial treatment discontinuation, please see Section 3.3.4.1 above.
3.3.4.3
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial
site at any time for the following reasons:
1. Failure to meet expected enrolment goals overall or at a particular trial site.
2. Emergence of any efficacy/safety information invalidating the earlier positive benefit-
risk-assessment that could significantly affect the continuation of the trial.
3. Deviations from GCP, the trial protocol, or the contract impairing the appropriate conduct
of the trial.
The investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).


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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
4.1.1
Identity of the Investigational Medicinal Products
Table 4.1.1: 1 Test product 
Substance:
BI 655130
Pharmaceutical formulation:
Solution for SC injection 
Source:
BI Pharma GmbH & Co. KG, Biberach,
Germany
Unit strength:
150mg/mL, 1mL prefilled syringe
Posology:
600mg once every 4 weeks
Method and route of administration:
Subcutaneous 
4.1.2
Selection of doses in the trial and dose modifications
The dose selected for this extension trial is 600 mg SC every 4 weeks. The exposure from a 
single dose of 600 mg SC.is expected to be approximately 60% of the 600 mg i.v. given in 
the parent trial. The rationale for this dose relates to the feasibility of administering more than 
600 mg (4 x 1mL syringe) at a single visit. Thus, it is expected that 600 mg SC will be at or 
above the to-be-marketed dose. If the data from the non-treatment portion of the parent trial 
indicates that a different posology is efficacious, the trial will be updated with this new 
posology, i.e. every 6 or 8 weeks.
For the parent trial, a fixed rather than weight-based dose regimen of single dose of 600 mg 
was selected. Early trials of therapeutic monoclonal antibodies often investigate body-
weight–based regimens to reduce the inter-subject variability in drug exposure. However, 
there is generally only a modest contribution of body weight to the overall pharmacokinetic 
(PK) and pharmacodynamic (PD) variability of monoclonal antibodies. Furthermore, 
monoclonal antibodies are highly target specific and offer a relatively large therapeutic 
window compared to new chemical entities. Therefore, most monoclonal antibodies are 
approved at fixed doses in antibody/target excess in order to cover target turnover and 
maximize efficacy [R10-6267; R13-4749; R13-4753; R13-4750; R13-4754].


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4.1.3
Method of assigning patients to treatment groups
An Interactive Response Technology (IRT) system will be used in this trial in order to dispense 
medication kits as well as manage initial/re-supply ordering of medication kits. The study site 
will be required to complete the appropriate module within the IRT system.
The investigator will receive all necessary instructions to access the IRT system from the
Sponsor or chosen provider. Detailed IRT transactions and procedures will be documented in
the user requirement specifications mutually agreed to by the sponsor and the IRT provider. 
All medication kit assignments will occur in an open label fashion.
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.
A total dose of 600 mg of BI 655130 will be administered to each patient every 4 weeks 
starting with Visit 1 until the End of Treatment (Week 204). IRT will dispense 4 medication 
kits at each drug administration. Each kit will contain one syringe. Each patient will receive 
all 4 syringes (4 injections) of study drug. Each of the four 1mL prefilled syringes will 
contain 150mg/mL of BI 655130 for a total dose of 600mg.
Study drug will be administered exclusively at the study site by a Health Care Professional 
(HCP) which will be the investigator or other authorized study personnel (e.g. study nurse).
Study drug will be administered as a SC injection in the abdomen or thighs. 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.
Dose modifications or adjustments are not permitted.
Interruption of trial treatment may be needed to treat AEs (ie. Infections) and trial treatment 
should be restarted as soon as medically justified. See Section 4.2.1.
Refer to Section 6.2.2 for rules for dosing limitations within a 14 day period
There are no dietary requirements needed.
In the eCRF, the study drug administration time is always the time of the first injection.
4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
This is an open label trial thus the patient, investigator and everyone involved in the trial 
conduct or analysis will be aware of the treatment assignment.


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The study treatment (BI 655130 or placebo) in which the patient received through Week 16 
in the parent trial will be blinded until the database lock (DBL) of the parent trial.
4.1.5.2
Unblinding and breaking the code
Not applicable.
4.1.6
Packaging, labelling, and re-supply
The investigational medicinal products will be provided by Boehringer Ingelheim (BI) or a 
designated Clinical Research Organization (CRO). They will be packaged and labelled in 
accordance with the principles of Good Manufacturing Practice (GMP). Re-supply to the
sites will be managed via an IRT system, which will also monitor expiry dates of supplies 
available at the sites. For details of packaging and the description of the label, refer to the 
ISF.
4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area according to the recommended storage conditions on the medication label. A 
temperature log must be maintained for documentation.
Trial medication must be securely stored, e.g. in a locked refrigerator or at a pharmacy. If the 
storage conditions are found to be outside the specified range, the Clinical Trial Manager 
(provided in the list of contacts) must be contacted immediately. Refer to the storage 
conditions for trial medications (STORM) document in the ISF for additional information.
The medication may only be dispensed to trial patients according to the Clinical Trial 
Protocol (CTP) by authorized personnel as documented in the trial staff list.
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 (EC)

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 (if applicable)

Availability of FDA Form 1572 (if applicable).


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Investigational drugs are not allowed to be used outside the context of this protocol. They 
must not be forwarded to other investigators or clinics unless there is Sponsor approval. All 
patients will be dosed in the clinic and will not be taking investigational product home. 
The investigator or designee must maintain records of the product’s delivery to the trial site, 
the inventory at the site, the use by each patient, and the return to the sponsor or warehouse / 
drug distribution centre or alternative disposal site of unused products. If applicable, the 
sponsor or warehouse / drug distribution centre will maintain records of the disposal. 
These records will include dates, quantities, batch / serial numbers, expiry (‘use- by’) dates, 
and the unique code numbers assigned to the investigational medicinal product and trial
patients. The investigator or designee will maintain records that document adequately that the 
patients were provided the doses specified by the Clinical Trial Protocol (CTP) and reconcile 
all investigational medicinal products received from the sponsor. At the time of return to the 
sponsor and/or appointed CRO, the investigator or designee must verify that all unused drug 
supplies have been returned by the clinical site staff and all used or partially used drug 
supplies have been destroyed on 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
Stable doses of concomitant therapies for chronic conditions, for which neither the condition 
nor the treatment are judged to exclude the patient from participation are permissible. All
concomitant medications should be carefully evaluated by the investigator and the Clinical 
Trial Manager should be contacted when there are questions regarding concomitant 
medications.
During the trial, if the severity and progression of the patients’ AD worsens the investigator 
can treat the patient with rescue treatment i.e.Standard of Care (SoC) of his/her choice.  The 
sponsor will not provide/supply SoC treatment(s) to the sites. Refer also to Section 4.2.2.1.
Patients with active systemic infections during the parent 655130 study must delay Visit 1 in 
this study until the infection has resolved for at least 2 weeks.
Severe infections according to Rheumatology Common Toxicity Criteria (RCTC ) grading, 
serious infections, and opportunistic or mycobacterium tuberculosis infections:
Treatment of the infection should be initiated promptly according to local SoC. No further 
trial 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, the 
investigator should discontinue treatment with the trial medication, and notify the Clinical 
Trial Manager (CT Manager). Diagnostics and treatment should be initiated according to 
local SoC.


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Systemic Hypersensitivity including anaphylactic reaction
In case of systemic hypersensitivity including anaphylactic reaction emerging during or after 
injection(s) of trial medication, the investigator should consider in accordance with severity 
of the reaction and local SoC to
1. Stop further injection(s)
2. 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 Antidrug antibodies (ADA) as detailed in the 
laboratory manual and consider the evaluation of histamine, serum tryptase, and complement 
components. 
In case of systemic hypersensitivity, based on patient’s clinical course and medical judgment, 
injections may be cautiously re-initiated or continued in case of mild or moderate systemic 
hypersensitivity (according to RCTC grading, provided in the ISF). 
In case of anaphylactic reaction based on the criteria discussed in the statement paper from 
Sampson HA (Appendix 10.1, R11-4890) suspected to be caused by the trial medication, the 
investigator should discontinue treatment with study drug. 
In case of potential systemic allergic reaction, blood samples for determination of serum 
tryptase will be collected 0.5 h, 2 h, 6 h, and 24 h after onset of the event.
There are no special emergency procedures to be followed.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
The medication (or classes of medications) listed in Table 4.2.2.1:1 are restricted for the 
entire study participation (V1 through to EOS). In the event that EOS/V1 cannot be done on 
the same day and a gap is needed from EOS of the 1368-0032 to visit 1 of this trial, restricted 
medication allowed and washout periods are noted in the right column of table.


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Table 4.2.2.1: 1
Restricted Medications
1 In case of worsening of the AD in the treatment period the use of a rescue medication is left at the 
discretion of the investigator. 
2No restriction on inhaled corticosteroids to treat asthma or corticosteroid drops administered in the eye or 
ear.
3Low potency topical steroids and non-urea containing moisturizers are allowed.
Restricted medication is defined as the use of any drugs listed in the Table 4.2.2.1:1 for any 
reason with the exception of unstable or worsening of AD).  If the restricted medication is 
taken during the trial, trial treatment discontinuation is not mandatory. The continuation of 
the treatment is left at the discretion of the investigator.
Rescue medication is defined as the use of highly potent topical corticosteroids, systemic 
immunomodulating treatments or biologics for the treatment of unstable or worsening of AD. 
The use of the rescue medication leads to the discontinuation of the trial treatment.   
4.2.2.2
Restrictions on diet and life style
There are no restrictions on diet and life style however patients should avoid prolonged 
exposure to sunlight and artificial UV light.
Medication or class of medications during study1
Washout periods prior to V1 
Dupilumab, UVB phototherapy, PUVA
Not allowed during gap
Hydroxyzine, diphenhydramine, doxepin 
Must be stopped 1 week before Visit 1
Any other topical medication particularly moisturizers
containing urea or high potency topical steroids3
Must be stopped at Visit 1
Methotrexate, cyclosporine, retinoids, azathioprine
Must be stopped 4 weeks prior to Visit 
1
IL36R inhibitors
Not allowed during gap
All other biologics, including but not limited to etanercept 
(Enbrel®) adalimumab (Humira®) infliximab (Remicade®) 
ustekinumab (Stelara®), secukinumab (Cosentyx®), 
brodalumab (Siliq®), guselkumab (Tremfya®), ixekizumab 
(Taltz®), tildrakizumab (Ilumya®), risankizumab (Skyrizi®), 
rituximab,
Not allowed during gap
live virus vaccinations
Not allowed during gap
other systemic immunomodulating treatments (e.g. 
corticosteroids2, cyclophosphamide), tofacitinib (Xeljanz®), 
apremilast (Otezla®)
Must be stopped 4 weeks prior to Visit 
1 
Any investigational device or product
Not allowed during gap


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4.2.2.3
Contraception requirements
Women of childbearing potential (WOCBP) 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 for the duration of the trial and 16 weeks after the last study drug 
administration. A list of contraception methods meeting these criteria is also provided in the 
patient information.
Female Patients:
Acceptable methods of birth control for this trial are:

Combined (estrogen and progestogen containing) hormonal birth control associated 
with inhibition of ovulation (oral, intravaginal, transdermal).

Progestogen-only hormonal birth control associated with inhibition of ovulation (oral, 
injectable, implantable).

Intrauterine device (IUD) and intrauterine hormone-releasing system (IUS).

Bilateral Tubal occlusion (blocking of the fallopian tubes).

Vasectomy of sexual partner (proven effective by documented absence of sperm on 
the ejaculation).

Complete sexual abstinence (not to have male-female vaginal sex). This is defined as 
being in line with the preferred and usual lifestyle of the patient. Periodic abstinence 
e.g. calendar, ovulation, symptothermal, post-ovulation methods; declaration of 
abstinence for the duration of exposure to study drug; and withdrawal are not 
acceptable.
As monoclonal antibodies can be secreted in milk, women must stop nursing once they 
receive study drug and up to 16 weeks after the last study drug administration.
4.3
TREATMENT COMPLIANCE
Administration of the trial medication will be done in the study centre under the supervision 
of the investigator or a designee. The measured plasma concentrations will provide additional 
confirmation of compliance.


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5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
Efficacy will be assessed using standard criteria that have been used in numerous AD studies, 
including the Eczema Area and Severity Index (EASI), the scoring of atopic dermatitis 
(SCORAD), Investigator Global Assessment (IGA)
 
EASI
The EASI scoring system is based on the psoriasis area and severity index (PASI) used 
routinely in patients with psoriasis to describe signs and severity of the disease. The principle 
of integrating disease extent and severity to describe disease led to the definition of the EASI 
[R18-2665]. The EASI score assesses the extent of disease at four body sites and measures 
four clinical signs: (1) erythema, (2) induration/papulation, (3) excoriation, and (4) 
lichenification, each on a scale of zero to three. The EASI score confers a maximum of 72 
and evaluates two dimensions of AD: disease extent and clinical signs. The suggested 
severity strata for the EASI are as follows: 0 = clear; 0.1–1.0 = almost clear; 1.1–7.0 = mild; 
7.1–21.0 = moderate; 21.1–50.0 = severe; 50.1–72.0 = very severe [R18-2851]. The EASI 
score does not assess symptoms like pruritus and sleep loss [R18-2670].
SCORAD
The SCORAD index will also be included in the clinical trials and has three elements: extent 
of disease, disease severity and subjective symptoms. These combine to give a maximum 
possible score of 103. The commonly used SCORAD strata to classify AD severity are mild 
= 0–25, moderate = 26–50 and severe = 51–103 [R18-2664, R18-2679].
IGA
The IGA scale allows investigators to assess overall disease severity at one given time point, 
and it consists of a five-point severity scale from clear to very severe disease (0= clear,1 
=almost clear, 2 = mild disease, 3 = moderate disease, 4= severe disease). The IGA scale uses 
clinical characteristics of erythema, infiltration, papulation, oozing and crusting as guidelines 
for the overall severity assessment [R18-2670].


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5.2
ASSESSMENT OF SAFETY
Safety will be assessed descriptively based on:
•
Adverse events (including drug-related AEs and AEs leading to discontinuation)
•
Adverse events of special interest (AESI)
•
Serious adverse events (SAEs)
•
Safety laboratory tests
•
Physical examination
•
Vital signs (blood pressure, pulse rate, body temperature)
•
12-lead ECG
•
Immunogenicity (ADA)
5.2.1
Physical examination
A complete physical examination will be performed at the visits as specified in the Flow
Chart. It includes at a minimum general appearance, neck, lungs, cardiovascular system, 
abdomen, extremities, and skin. 
A targeted physical examination will be performed at visits as specified in the Flow Chart.
This includes vital sign assessment as well as an evaluation of the organ systems associated 
with AE(s) symptoms or laboratory abnormalities.
The results must be included in the source documents available at the site. 
5.2.2
Vital signs
Vital signs will be performed pre-dose as well as within 1 hour post dose (Refer to Flow 
Chart). Vital signs include systolic and diastolic blood pressure, pulse rate (electronically or 
by palpation count for 1 minute) and body temperature. Vital signs will be measured after the 
patients has been sitting comfortably (resting)  for at least 5 minutes The results must be 
included in the source documents available at the site.


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5.2.3
Safety laboratory parameters
Safety laboratory parameters to be assessed are listed in Table 5.2.3:1. For the sampling time 
points please see the Flow Chart.
All analyses will be performed by a central laboratory, the respective reference ranges will be 
provided in the ISF. 
Patients do not have to be fasted for the blood sampling for the safety laboratory. 
Instructions regarding sample collection, sample handling/ processing and sample shipping 
are provided in the Laboratory Manual in the ISF. 
The central laboratory will send reports to the investigator. It is the responsibility of the 
investigator to evaluate the laboratory reports. Clinically relevant abnormal findings as 
judged by the investigator will be reported as adverse events (refer to Section 5.2.6).
In case the criteria for hepatic injury are fulfilled, a number of additional measures will be 
performed (Refer to Section 5.2.6.1.4) and the DILI Checklist provided in the ISF. The 
amount of blood taken from the patient concerned will be increased due to this additional 
sampling.
The central laboratory will transfer the results of the analysis to the sponsor.


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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 auto
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)
Alanine transaminase (ALT)
Alkaline phosphatase (AP)
Gamma-glutamyl transferase (GGT)
Creatine kinase (CK)
CK-MB, only if CK is elevated
Lactate dehydrogenase (LDH)
Substrates
C-Reactive Protein (CRP)
Serum albumin
Creatinine
Total bilirubin or  Direct bilirubin
Bilirubin Indirect (if total is elevated)
Total protein
Total cholesterol
Triglycerides
Plasma glucose
BUN (blood urea nitrogen)
Troponin (Reflex, in case of elevated CK)
LDL-Cholesterol (if total cholesterol is elevated)
HDL-Cholesterol (if total cholesterol is elevated)
Electrolytes
Sodium
Potassium
Chloride
Calcium


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Category
Test name
Urinalysis (Stix)
Urine nitrite
Urine protein
Urine glucose
Urine ketone
Urobilinogen
Urine bilirubin
Urine erythrocytes
Urine leukocytes
Urine pH
Urine-Sediment (only if urine analysis 
abnormal)
microscopic examination
Infection testing 1
Hepatitis B Surface Antigen (qualitative)
Hepatitis B core Antibody (qualitative)
Hepatitis B Virus (HBV)-DNA 
(quantitative)2
QuantiFERON®-TB3
Hepatitis C Antibodies (qualitative)
HIV-1, and HIV-2 Antibody (qualitative)
Urine Pregnancy test4 At the drug 
administration visits, the test will be 
performed prior to the administration of 
study drug
Human Chorionic Gonadotropin in urine
Serum Pregnancy test (only if urine 
pregnancy test is positive)
Human Serum Chorionic Gonadotropin
1 Refer to exclusion criteria Section 3.3.3 the Flow Chart and Section 6.2.1 for details 
regarding infection testing).
2 An HBV-DNA test should be conducted if Hepatitis B core Antibody is positive and 
Hepatitis B Surface Antigen is negative.
3 Patients with suspected false positive or indeterminate QuantiFERON TB result may be re-
tested once.  A PPD skin test may be performed locally in case of an indeterminate 
QuantiFERON TB result. 
4 Urine pregnancy testing will be performed as indicated in the Flow Chart.
NOTE:  See Section 4.2.1 and lab manual for lab procedures required for hypersensitivity and 
anaphylactic reactions.


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5.2.4
Electrocardiogram
A central laboratory will not be used for ECG recording and evaluation.  
The 12-lead ECGs must be administered by a qualified staff member and results will be 
recorded and reviewed prior to dosing as scheduled in the Flow Chart. Where possible, ECG 
measurements should precede blood sampling to avoid impact of sampling on the ECG 
results. The investigator or a designee will evaluate whether the ECG is normal or abnormal 
and assess clinical relevance if abnormal. ECGs may be repeated for quality reasons and the 
repeated recording used for analysis. 
Additional ECGs may be recorded for safety reasons. The 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 Visit 1) or as adverse events and will be followed up and/or treated as medically 
appropriate.
5.2.5
Other safety parameters
All cases of malignancies that are detected during the trial will be reported as SAEs. Patients 
with a documented active or suspected malignancy (except for specific cancers) will be 
excluded from this trial per the exclusion criteria (Section 3.3.3).
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.


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5.2.6.1.2 
Serious adverse event
A serious adverse event (SAE) is defined as any AE, which fulfils at least one of the 
following criteria:
-
results in death,
-
is life-threatening, which refers to an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe,
-
requires inpatient hospitalisation or prolongation of existing hospitalisation
-
results in persistent or significant disability or incapacity,
-
is a congenital anomaly / birth defect,
-
is deemed serious for any other reason if it is an important medical event when based 
on appropriate medical judgement which may jeopardise the patient and may require 
medical or surgical intervention to prevent one of the other outcomes listed in the 
above definitions. Examples of such events are intensive treatment in an emergency 
room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalisation or development of dependency or abuse. 
For Japan only: the following events will be handled as “deemed serious for any other 
reason”. AEs which possibly lead to disability will be reported as SAEs.
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 further AEs, which by their nature, can always be 
considered to be “serious” even though they may not have met the criteria of an SAE as 
defined above.
The latest list of “Always Serious AEs” can be found in the electronic data capture (eDC) 
system. A copy of the latest list of “Always Serious AEs” will be provided upon request. 
These events should always be reported as SAEs as described above.
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the time since discontinuation of the drug and must be reported as per 
Section 5.2.6.2, subsections “AE Collection” and “AE reporting to sponsor and timelines”.
5.2.6.1.4 
Adverse events of special interest
The term adverse events of special interest (AESI) relates to any specific AE that has been 
identified at the project level as being of particular concern for prospective safety monitoring 
and safety assessment within this trial, e.g. the potential for AEs based on knowledge from 
other compounds in the same class. AESIs need to be reported to the sponsor’s 
Pharmacovigilance Department within the same timeframe that applies to SAEs, please see 
Section 5.2.6.2.2. Refer also to Section 1.4.2 and Section 4.2.1


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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 (Aspartate Aminotransferase) and/or ALT (Alanine 
Aminotransferase) ≥3 fold ULN combined with an elevation of total bilirubin ≥2 fold 
ULN measured in the same blood draw sample, or

Aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN.
These lab findings constitute a hepatic injury alert and the patients showing these lab 
abnormalities need to be followed up according to the “DILI checklist” provided in the ISF.
In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without lab results 
(ALT, AST, total bilirubin) available, the investigator should make sure these parameters are 
analysed, if necessary in an unscheduled blood test. Should the results meet the criteria of 
hepatic injury alert, the procedures described in the DILI checklist should be followed.
Systemic hypersensitivity reactions including anaphylactic reaction
Any suspicion of severe systemic hypersensitivity reaction and of any potential cases of 
anaphylaxis should be defined and assessed using the criteria discussed in the statement paper 
from Sampson HA (Appendix 10.1, R11-4890).
Severe infections (according to RCTC grading in the ISF)
Opportunistic and mycobacterium tuberculosis infections
These include pneumocystis jirovecii, BK virus disease including PVAN, CMV, post-
transplant lymphoproliferative disorder (EBV), progressive multifocal leucoencephalopathy, 
bartonellosis (disseminated only), blastomycosis, toxoplasmosis, coccidioidomycosis, 
histoplasmosis, aspergillosis (invasive only), candidiasis (invasive or pharyngeal), 
cryptococcosis, other invasive fungi (mucormycosis zygomycosis, rhizopus, mucor, 
lichtheimia), scedosporium/pseudallescheria boydii, fusarium), legionellosis, listeria 
monocytogenes (invasive only), tuberculosis, nocardiosis, non-tuberculous mycobacterium, 
salmonellosis (invasive only), HBV reactivation, herpes simplex (invasive only), herpes 
zoster, strongyloides (hyperinfection syndrome and disseminated forms only), 
paracoccidioides, penicillium marneffei, sporothrix schenckii, cryptosporidium species 
(chronic only), microsporidiosis, leishmaniasis (visceral only), trypanosoma cruzi infection 
(Chagas’ disease) (disseminated only), campylobacteriosis (invasive only),  shigellosis 
(invasive only), vibriosis (invasive due to vibrio vulnificus), HCV progression [R17-2617].


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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 
 [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
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.


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
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:
•
From signing the informed consent onwards until the individual patient’s end of trial: 
all AEs (serious and non-serious) and all AESIs.
•
After the individual patient’s end of trial: 
the investigator does not need to actively monitor the patient for new AEs but should only 
report any occurrence of cancer and trial treatment related SAEs and trial treatment 
related AESIs of which the investigator may become aware of by any means of 
communication, e.g. phone call. Those AEs should be reported on the BI SAE form but 
not on the CRF.
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 via fax immediately (within 24 hours ) to the 
sponsor’s unique entry point (country specific contact details 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 fax 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
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 Studies (Part B).


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The ISF will contain the Pregnancy Monitoring Form for 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 Studies and not the SAE form is to be 
completed. If there is an SAE and/or AESI associated with the pregnancy an SAE form must 
be completed in addition.
5.2.6.2.4
Exemptions to SAE reporting
For this study there are no exemptions to SAE reporting.


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5.5
BIOBANKING
N/A
5.6
OTHER ASSESSMENTS
N/A
5.7
APPROPRIATENESS OF MEASUREMENTS
The safety assessments are standard, are accepted for evaluation of safety and tolerability of a 
SC 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 biomarker 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 AD 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.


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
All patients are to adhere to the visit schedule specified in the Flow Chart. Each visit date 
(with its window) is to be counted from Day 1 (V1).
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. 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.
Details relating to study drug administration and treatment interruptions are provided in 
Section 4.1.4.
Study measurements and assessments are scheduled to occur ‘before’ trial medication 
administration.  For planned individual plasma concentration sampling times refer to the 
Flow Chart.  Sampling times will be recorded and used for pharmacokinetic analysis.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
Study procedures to be performed at each visit are listed in the Flow Chart and respective 
sections of this protocol. Refer to Section 5.1 for explanations of the specified assessments 
and procedural details.
The patients’ questionnaires 
are to be 
completed by the patient him/herself, without any help from or interpretation by other people. 
.
Separate from the PROs above, the evaluation of efficacy assessments (IGA, EASI, and 
SCORAD) are to be conducted preferably by the same qualified assessor, whenever possible, 
throughout the study.
The following procedures should be completed in the following order prior to trial drug 
administration:
 
  
3.
IGA, EASI, SCORAD


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6.2.1
Visit 1
For the comprehensive list of the trial procedures required at Visit 1 please refer to the Flow 
Chart.
Visit 1 should preferably be performed in one visit combined with EOS visit of the preceding 
BI 655130 parent trial. These duplicate procedures across the two studies are performed only 
once when the visit is combined. When these two visits across both studies does not occur on 
the same day then all procedures will need to be performed at V1 of this trial. Refer to the 
Flow Chart for procedures that are identical across the two visits.
If a patient performs the EOS visit in the parent study but a newly observed medical finding 
(for example) prohibits the patient to immediately enrol into this study, the patient can come 
back for Visit 1 at a later date per the opinion of the investigator. The sponsor should be 
immediately notified if Visit 1 of this trial cannot be performed on the same day as the EOS 
in the parent study.
The maximum gap for enrolling into this trial is 12 weeks after the EOS in 1368-0032.
Informed Consent
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. 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.
Once consent is obtained, the patient is to be recorded on the enrolment log. The informed 
consent date will be reported in the eCRF.
IRT procedures and administration of study drug
Once consent is obtained an initial “enrolment call” must be made in the IRT system. At that 
time a patient number will be generated.
When confirmed at Visit 1 that the patient meets all criteria and can be administered study 
medication, a medication assignment call must be made in the IRT system in order to 
dispense the first dose of study medication. Medication assignment via the IRT system and 
administration of study drug should be the last activity at Visit 1.
Details of IRT procedures can be found in the IRT manual located in the ISF.
Demographics:
The gender, ethnicity and race (if allowed by local law) will be collected and reported in the 
eCRF.
Medical History and Baseline Conditions:
Information on clinically significant previous and concomitant illnesses, other than AD, 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 Visit 1 will be recorded as medical and surgical history.


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All ongoing AEs/SAEs at the end of the parent trial will be recorded on the Baseline
Condition eCRF page of this 1368-0037 study.
Height and Weight
Height and Weight will be collected and reported in the eCRF per the Flow Chart.
Smoking Status
Smoking status will be collected at and reported in the eCRF per the Flow Chart.
Infection screening:
Infection testing will include tuberculosis, hepatitis B, hepatitis C, and HIV assessments (see 
Table 5.2.3:1). The results of the Infection Testing will not be available until after the patient 
receives the first dose at Visit 1.  See Section 3.3.4.1 for Discontinuation Rules.
If there is less than 12 week gap from the EOS of the preceding trial to V1 of this trial, the 
Infection testing does not have to be repeated at Visit 1.
QuantiFERON TB testing
Patients with suspected false positive or indeterminate QuantiFERON TB result may have the 
test repeated once. If after repeat testing the QuantiFERON TB result is “indeterminate” A 
PPD skin test may be performed locally. A tuberculin skin test reaction ≥10mm (≥5mm if 
receiving ≥15mg/d prednisone or its equivalent) is considered positive.   
Patients who now test positive for QuantiFERON TB test may continue and receive treatment 
in this study if further work up (according to local practice/guidelines) establishes 
conclusively that the patient has no evidence of active tuberculosis.
If presence of latent tuberculosis is established, patients can receive anti-tuberculosis 
treatment (according to local practice/guidelines) and continue receiving study medication.
Pregnancy Testing
Urine pregnancy testing for all woman of childbearing potential will be conducted on-site 
prior to every dosing and must be negative to receive study drug. A positive urine test must 
be confirmed with a serum pregnancy test at the central laboratory
Concomitant medication review:
Any concomitant treatment taken since the last visit of previous study will be recorded in the
eCRF.
Review of inclusion/exclusion criteria:
Selection criteria will be reviewed carefully and patient eligibility confirmed prior to first 
dose.
Blood sampling
If EOS from the parent study and V1 from this study are performed on the same day, two lab 
kits will be required.  The EOS lab kit from the parent study will be used.  In addition a V1 


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lab kit from this trial will also need to be used as it contains labs not already included in the 
EOS from the previous parent trial. Details will be provided in the laboratory manual and the 
ISF.
For the comprehensive list of the trial procedures required at Visit 1 please refer to the Flow 
Chart.
6.2.2
Treatment period
After Visit 1, the patient will return for 51 additional visits during the treatment period. The 
duration between visits is 4 weeks.  At every visit study drug will be administered.
If the patient completes this 4 year study, the last study drug administration will be at Visit 52
(EOT).
Drug administration and rules for early/late visits
It’s important for the patient to adhere to the visit schedule per the Flow Chart.  The visit 
schedule should always align with Visit 1.
The IRT system has been set up to make sure that a patient does not receive 2 doses of 
medication in less than a 14 day period. 
In these scenarios, the patient should conduct the visit but skip the dose. The patient should 
be administered the dose at the next scheduled visit.
Pregnancy Testing
Urine pregnancy testing for all woman of childbearing potential will be conducted on-site 
prior to every dosing and must be negative to receive study drug. A positive urine test must 
be confirmed with a serum pregnancy test at the central laboratory.
See the Flow Chart for details of all procedures required at each visit.
Unscheduled visits
If a patient suspects that their AD is worsening 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
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.


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6.2.3
End of Treatment and Trial Completion
For all treated patients termination of trial medication and trial completion must be recorded 
on the corresponding eCRF.
For the comprehensive list of the trial procedures required at the EOT and the EOS visits
please refer to Flow Chart.
The EOS visit must be performed 16 weeks after the date of last drug administration.
Early Treatment and Trial Discontinuation:
If trial treatment is discontinued prematurely prior to the planned Flow Chart EOT visit, 
every effort should be made to have the patient return and undergo the procedures for the 
EOT visit as well as the EOS visit 16 weeks after the last study drug administration  as 
outlined in the Flow Chart.
Patients who are unable to physically return to the study site for the EOT and EOS visits 
should be contacted by the site by phone to collect information pertaining to adverse events 
and changes to concomitant therapy.
Trial Completion:
Trial completion is defined as a patient having reached the EOS visit within the specified 
window per protocol.
Treatment Completion:
Treatment completion is defined as a patient completing Visit 52 which is the EOT visit after 
receiving approximately 4 years of treatment 


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
This is an exploratory extension trial in patients with AD. It is designed as an open label 
study with one group of BI655130 150mg/mL (600mg once every four weeks).
The primary objective of this trial is to assess the long term safety and efficacy of treatment 
with BI 655130 in patients with AD who have completed and have responded to treatment in 
the parent study 1368-0032.
The primary endpoint is the number of patients with treatment emergent adverse events 
(AEs) at week 48. The efficacy will be assessed using secondary and further endpoints.
All analyses are planned to be descriptive in nature.
7.1
NULL AND ALTERNATIVE HYPOTHESES
No statistical testing is planned for this study. Only descriptive analyses are intended. 
Therefore, no statistical hypotheses are defined. 
7.2
PLANNED ANALYSES
7.2.1
General considerations
The efficacy analyses will be performed for the Full Analysis Set (FAS) that includes all 
patients who entered the study, received at least one dose of treatment, had a baseline 
measurement, and at least one post-baseline measurement.
All safety analyses will be performed on patients who entered the study and received at least
one dose of treatment during the trial. This set of patients is called Safety Analysis Set (SAF). 
With regard to efficacy and safety endpoints “baseline” refers to:
1. Baseline for the parent trial – the measurement recorded at randomisation visit (Visit 
2) of the parent trial (1368-0032). If the data at Visit 2 is missing, then the data from 
Visit 1 of the parent trial will be considered baseline.
2. Baseline for the extension trial – the last measurement before the BI655130 treatment 
intake in this extension trial.
Two separate analyses will be conducted – one including baseline from parent trial and the 
second including baseline form this extension trial.


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Important deviations of the protocol will include key inclusion and exclusion deviations, 
incorrect medication taken, concomitant use of restricted medications, and any other 
deviations from the protocol deemed important by the study team. 
This is an exploratory trial and sensitivity analyses may need to be done to investigate the 
effects of potential confounding factors.
Standard statistical parameters (number of non-missing values, mean, standard deviation 
(SD), median, quartiles, minimum and maximum) of frequency tables (including patient 
frequencies and percentages) will be calculated where appropriate.
The statistical parameters will be provided for the following groups:
1. By treatment received in the parent trial (1368-0032):

Placebo followed by BI655130 treatment

Placebo followed by no BI655130 treatment

BI655130 followed by BI655130 treatment

BI655130 followed by no BI655130 treatment

Total
2. By the response achieved at week 16 of the parent trial (1368-0032):

Responders – patients who attained at least 75% reduction in EASI score at week 
16 compared to baseline during the parent trial

Non-responders  - patients who attained less than 75% reduction in EASI score at 
week 16 compared to baseline during the parent trial;

Total
7.2.2
Primary endpoint analyses
The primary endpoint is the number of patients with treatment emergent AEs at week 48 and 
will be a part of the safety analysis (as described in Section 7.2.5). The primary analysis will 
be descriptive and will result in frequency table presenting the numbers and percentages of 
patients with treatment emergent AEs displayed per group as defined in Section 7.2.1 and 
also by the following subgroups:

Asian/Non-Asian

Age groups: <=30 years old/>30 years old
The primary analysis will be performed on the SAF.
7.2.3
Secondary endpoint analyses
All secondary analyses are planned to be descriptive. For continuous endpoints (change form 
baseline in EASI score and in SCORAD), standard statistical parameters (including number 
of non-missing values, mean, SD, median, quartiles, minimum, and maximum) will be 
presented per group as defined in Section 7.2.1 and also by the following subgroups:

Asian/Non-Asian

Age groups: <=30 years old/>30 years old


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For the EASI score, responder analyses will be performed. A patient is defined as EASI50 or 
EASI75 responder when percent change from baseline in EASI score is at least 50% or at 
least 75%, respectively. This results in binary variable with values of 1 (=responder) or 0 
(=non-responder). 
For binary endpoints (EASI50, EASI75, achieving at least a 2-grade reduction from baseline 
to clear (0) or almost clear (1) in IGA), frequency tables with numbers and percentages of 
patients will be used and display relevant categories in groups as defined in Section 7.2.1.
7.2.5
Safety analyses
Adverse events will be coded using the Medical Dictionary for Drug Regulatory Activities 
(MedDRA). Standard BI summary tables and listings will be produced. All adverse events 
with an onset between start of treatment and end of the REP, a period of 16 weeks after the 
last dose of trial medication, will be assigned to the on-treatment period for evaluation.
All treated patients will be included in the safety analysis. In general, safety analyses will be 
descriptive in nature and will be based on BI standards. No hypothesis testing is planned.
Statistical analysis and reporting of adverse events will concentrate on treatment-emergent 
adverse events, i.e. all adverse events occurring between start of treatment and end of the 
REP. Adverse events that start before first drug intake and deteriorate under treatment will 
also be considered as ‘treatment-emergent’.


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Frequency, severity, and causal relationship of adverse events will be tabulated by system 
organ class and preferred term after coding according to the Medical Dictionary for Drug 
Regulatory Activities (MedDRA).
Laboratory data will be analysed both quantitatively as well as qualitatively. The latter will 
be done via comparison of laboratory data to their reference ranges. Values outside the 
reference range as well as values defined as clinically relevant will be summarised. Groups
(defined in Section 7.2.1) 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 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.
 
7.2.7
Interim Analyses
In order to ensure the patient’s safety during the trial, an external DMC, independent of the 
trial and project teams, will be set-up to review all available safety data as well as selected 
efficacy data at regular intervals following first-patient-in. A DMC SAP which describes the 
analyses required for assessment by the DMC will be produced and finalised prior to first 
patient included into the trial. Further details will be provided in a DMC charter.
There will not be an interim analysis from a statistical standpoint. 
As the primary aim of this study is to collect long-term safety and efficacy data on the use of 
BI655130 in this population, multiple status reviews will be done over the approximate 4-
year conduct phase of this trial to support, for example, regulatory interactions, CTA and 
MAA/BLA submissions, but also to provide important safety and efficacy information to the 
sponsor to guide further development of the compound, and to investigators via IB updates 
and publications. Status review analyses will be performed on demand and are not feasible to 
be pre-defined.
A CTR describing all data collected within this trial will be produced once the last patient in 
the trial has completed the final End-of-Study (EOS) visit. 


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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.
With respect to safety or continuous efficacy evaluations, it is not planned to impute missing 
values.
For all binary endpoints (i.e. endpoints that are either 1 (patient responded) or 0 (patient did 
not respond)), the following rules apply:

If there are data at visits both before and after the visit with a missing outcome, 
then impute as responder only if both neighbouring visits also represent a 
responder;

Otherwise, impute as a non-responder.
For disease specific protein markers the following handling of data below or above the limit 
of quantification will be applied:
-
Below limit of quantification (BLQ) data will be replaced by 0.5 times the lower limit 
of the quantification (LLOQ)
-
Above limit of quantification (ALQ) data will be replaced by upper limit of 
quantification (ULOQ), if ULOQs are available. Otherwise, ALQ data will be 
excluded from the analysis. 
Further sensitivity analyses to assess the robustness of the results may be performed and as 
such will be described in the TSAP.
7.4
RANDOMISATION
Given the single arm nature of the trial, no randomisation will be performed.  
For packaging and labelling details, see Section 4.1.6.
7.5
DETERMINATION OF SAMPLE SIZE
This is an extension trial of the parent clinical trial 1368-0032 and given its descriptive 
nature, no sample size calculation has been performed. The sample size calculation for the 
parent trial can be found in the 1368-0032 CTP [c23806995-01].
Approximately 40 (but no more than 45) patients from the parent trial 1368-0032 who meet 
the entry criteria are planned for entry into this trial.


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


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


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Copies of source documents will be provided to the Sponsor. 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.
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)

Patient reported outcome forms and corresponding investigator assessment forms

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 Clinical Research Asociate (CRA), auditor 
and regulatory inspector (e.g. FDA). They may review all CRFs and informed consents. The 
accuracy of the data will be verified by direct comparison with the source documents 
described in Section 8.3.1. The sponsor will also monitor compliance with the protocol and 
GCP.


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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

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


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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 Suspected Unexpected Serious Adverse Reactions (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.
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim (BI).
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). 
While Regular DMC meetings will be held at specified intervals. The DMC will recommend 
continuation, modification or termination of the trial as detailed in the DMC charter. DMC 
recommendations as well as the final BI decision will be reported to the appropriate 
Regulatory Authorities (RAs)/Health Authorities (HAs), IRBs/ECs, and to investigators as 
requested by local law. The tasks and responsibilities of the DMC 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), CRAs, and investigators of participating countries.
The organisation of the trial in the participating countries will be performed by the respective 
local or regional BI-organisation (Operating Unit, OPU) in accordance with applicable 
regulations and BI SOPs, or by a CRO with which the responsibilities and tasks will have 
been agreed and a written contract filed before initiation of the clinical trial.


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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 and an IRT vendor will be used in this trial. The central 
laboratory will also manage the collection, storage and shipment of samples to the 
bioanalytical labs used in this study.  Details will be provided in the IRT Manual and Central 
Laboratory Manual, available in the ISF.


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9.
REFERENCES
9.1
PUBLISHED REFERENCES
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atopic dermatitis: A comparison of the Joint Task Force Practice 
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Nakagawa S, Matsumoto M, Katayama Y, Matsue H, Nunez G, Nakamura 
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systematic review of trends in disease severity and quality-of-life 
instruments 1985-2010. PLoS One. 2011. 6(4): e17520.
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Kunz B, Oranje AP, Labreze L, Stalder JF, Ring J, Taieb A. Clinical 
validation and guidelines for the SCORAD index: consensus report of the 
European Task Force on Atopic Dermatitis. Dermatology. 1997. 195(1): 
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Gadkari, A. Wei, W. Chao, J. Arnold, R. Yu, T. Vekeman, F. Suarez-
Farinas, M. Mastey, V. Chronicity, comorbidity and life course 
impairment in atopic dermatitis: Insights from a crosssectional study in US 
adults. European Academy of Dermatology and Venereology (EADV); 28 
September–2 October; Vienna, Austria 2016.
R18-2681
Weidinger S, Novak N. Atopic dermatitis. Lancet. 2016. 387(10023): 
1109-1022.
R17-3632
Mahil SK, Catapano M, Meglio PD, 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; eaan2514. 
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; 1012-1024.
R13-4749
Bai S, Jorga K, Xin Y, Jin D, Zheng Y, Damico-Beyer LA, Gupta M, 
Tang M, Allison DE, Lu D, Zhang Y, Joshi A, Dresser M J. A guide to 
rational dosing of monoclonal antibodies. Clin Pharmacokinet. 2012. 
51(2): 119-135.
R13-4750
Joos B, Trkola A, Kruster H, Aceto L, Fischer M, Stiegler G, Armbruster 
C, Vcelar B, katinger H, Guenthard HF. Long-term multiple-dose 
pharmacokinetics of human monoclonal antibodies (MAbs) against human 
immunodeficiency virus type 1 envelope gp120 (Mab 2G12) and gp41 
(MAbs 4E10 and 2F5). Antimicrob Agents Chemother. 2006. 50(5): 1773-
1779.
R13-4753
Deng R, Iyer S, Theil FP, Mortensen DL, Fielder PJ, Prabhu S. Projecting 
human pharmacokinetics of therapeutic antibodies from nonclinical data: 
what have we learned? mAbs. 2011. 3(1): 61-66.
R13-4754
Xin Y, Gordon MS, Jin D, Wakshull E, Chen DS, Rosen LS, Munster PN, 
Naumovski L, Bai S. Population pharmacokinetic (PK) analysis supports 
fixed dosing for the humanized monoclonal antibody (huMAb) anti-
EGFL7 (MEGF0444A) administered intravenously in patients with 
advanced solid tumors. 47th Ann Mtg of the American Society of Clinical 


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Oncology (ASCO), Chicago. Jun 2011. 3-7, J Clin Oncol. 2011. 29 (15) 
(Suppl). Abstr 2586.
R18-1988
DLQI instructions for use and scoring: information & conditions 
concerning use: clinical use of the DLQI. 
http://sites.cardiff.ac.uk/dermatology/quality-of-life/dermatology-quality-
of-li fe-index-dlqi/dlqi-instructions-for-use-and-scoring/ (access date: 11 
June 2018; Cardiff University (1993).
R13-3515
Woodworth T, Furst DE, Alten R, Bingham C, Yocum D, Sloan V, Tsuji 
W, Stevens R, Fries J, Witter J, Johnson K, Lassere M, Brooks P
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): 1401-1414.
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: 2107-2116.
P06-08156
Akdis CA, et al. Diagnosis and treatment of atopic dermatitis in children 
and adults: European Academy of Allergology and Clinical 
Immunology/American Academy of Allergy, Asthma and
Immunology/PRACTALL consensus report.
J Allergy Clin Immunol. 2006. 118(1): 152-169.
R18-2851
Leshem YA, Hajar T, Hanifin JM, Simpson EL. What the Eczema Area 
and Severity Index score tells us about the severity of atopic dermatitis: an 
interpretability study. Br J Dermatol. 2015. 172(5): 1353-1357.
9.2
UNPUBLISHED REFERENCES
c03320877-06
BI 655130 Investigator’s Brochure, Current Version 
c23806995-01
; Phase IIa, multicentre, randomized, 
double-blind, placebo-controlled,  study to evaluate the safety, 
tolerability and efficacy of  treatment with BI 655130 in adult patients 
with moderate to severe atopic dermatitis, 1368-0032, 05 Nov 2018
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, 1368.1, 07 
Apr 2017


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10.
APPENDICES
10.1
INSTRUCTIONS FOR USE
10.1.1
Clinical criteria for diagnosing anaphylaxis


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11.
DESCRIPTION OF  GLOBAL AMENDMENT (S)
11.1
GLOBAL AMENDMENT 1
Date of amendment
23 Mar 2020
EudraCT number 
EU number
NA
BI Trial number
1368-0037
BI Investigational Product(s)
BI 655130
Title of protocol
An open label extension study to assess the long 
term safety of treatment with BI 655130 
administered subcutaneously in adult patients 
with moderate to severe atopic dermatitis
Global amendment due to urgent safety reasons
Global amendment
X
    
Section to be changed
Flow chart footnote #2
Description of change
Administrative change to remove reference for 
completing procedures in the parent trial
Rationale for change
Clarification that procedures can be done as a 
combined visit (EOS/V1) as described 
throughout the protocol
Section to be changed
Flow chart footnote #12
Description of change
Hepatitis C and HIV assessment only, are to be 
completed for combined EOS/V1 visit 
Rationale for change
Clarification that during a combined EOS/V1 
visit only hepatitis C and HIV assessments are to 
be completed for this trial and the results of 
tuberculosis and hepatitis B testing will be used 
from the parent study
Section to be changed
Flow chart- End of Treatment and End of Study 
Visits
 


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Section to be changed
3.3.1 Main diagnosis for trial entry
Description of change
Gap period of 16 weeks between IV infusion and 
first SC injection removed
Rationale for change
Sentence is not consistent with the parent trial 
amendment as there will be a 4 week period as 
described in the parent trial amendment
Section to be changed
4.2.2.1 Restrictions regarding concomitant 
treatment
Description of change
Reference to use of restricted medication in the 
parent trial removed
Rationale for change
The criteria for use of restricted medication 
through to EOS of parent trial is described in the 
parent trial protocol and will not be reiterated for 
this extension trial.
Section to be changed
4.2.2.1:1 Restricted medication table
Description of change
Administrative change to remove paragraph
Rationale for change
Explanation is already provided under section 
4.2.2.1 and any reference to parent trial criteria is 
elaborated under the parent trial protocol
Section to be changed
4.2.2.1:1 Restricted medication table
Description of change
Column headings for medication or classes of 
medication in addition to washout period 
updated
Rationale for change
Administrative change for added clarity 
Section to be changed
Description of change
Rationale for change
Section to be changed
Description of change
Rationale for change


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c26581385
2.0
clinical-trial-protocol-version-02
An open label extension study to assess the long term safety of treatment with BI
655130 administered subcutaneously in adult patients with moderate to severe atopic
dermatitis
Author-Trial Clinical
Pharmacokineticist
24 Mar 2020 15:11 CET
Approval-Therapeutic Area 
24 Mar 2020 16:56 CET
Approval-Clinical Project 
24 Mar 2020 21:09 CET
Approval-Team Member Medicine
25 Mar 2020 00:48 CET
Approval-Biostatistics
25 Mar 2020 16:57 CET


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c26581385
2.0

SAP_001.pdf: 
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TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c37762870-01
BI Trial No.:
1368-0037
Title:
An open label extension study to assess the long term safety of 
treatment with BI 655130 administered subcutaneously in adult 
patients with moderate to severe atopic dermatitis
Including Protocol Amendment 1 [c26581385-02]
Investigational
Product(s):
BI 655130
Responsible trial 
statistician(s):
Phone: 
Fax:     
Date of statistical 
analysis plan:
20 Dec 2021 SIGNED
Version:
1.0
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Proprietary confidential information
2021 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                                                          
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1.
TABLE OF CONTENTS
TITLE PAGE............................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES ...................................................................................................................4
2.
LIST OF ABBREVIATIONS...............................................................................5
3.
INTRODUCTION.................................................................................................8
5.
ENDPOINT(S).......................................................................................................9
5.1
PRIMARY ENDPOINT(S)...................................................................................9
5.2
SECONDARY ENDPOINT(S).............................................................................9
5.2.1
Key secondary endpoint(s) ...................................................................................9
5.2.2
Secondary endpoint(s)...........................................................................................9
5.4.1
Safety ....................................................................................................................12
6.
GENERAL ANALYSIS DEFINITIONS...........................................................15
6.1
TREATMENT(S) ................................................................................................15
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................16
6.3
SUBJECT SETS ANALYSED ...........................................................................17
6.5
POOLING OF CENTRES..................................................................................18
6.6
HANDLING OF MISSING DATA AND OUTLIERS ....................................18
6.6.1
Withdrawals.........................................................................................................18
6.6.2
Efficacy data ........................................................................................................18
6.6.3
Safety data............................................................................................................18
6.6.4
Time since first diagnosis....................................................................................19
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS....................19
7.
PLANNED ANALYSIS ......................................................................................23
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS .........24
7.2
CONCOMITANT DISEASES AND MEDICATION......................................25
7.3
TREATMENT COMPLIANCE ........................................................................26
7.4
PRIMARY ENDPOINT(S).................................................................................26
7.4.1
Primary analysis of the primary endpoint(s)....................................................26
 


Boehringer Ingelheim                                                          
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7.5
SECONDARY ENDPOINT(S)...........................................................................26
7.5.1
Key secondary endpoint(s) .................................................................................26
7.5.2
(Other) Secondary endpoint(s)...........................................................................26
7.7
EXTENT OF EXPOSURE .................................................................................27
7.8
SAFETY ANALYSIS..........................................................................................27
7.8.1
Adverse Events ....................................................................................................28
7.8.2
Laboratory data...................................................................................................30
7.8.3
Vital signs.............................................................................................................31
7.8.4
ECG ......................................................................................................................32
7.8.5
Others ...................................................................................................................32
8.
TIMEPOINT OF RELEASE OF TREATMENT INFORMATION .............33
9. 
REFERENCES ....................................................................................................34
11.
HISTORY TABLE..............................................................................................36


Boehringer Ingelheim                                                          
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LIST OF TABLES
Table 6.1: 1
Flow chart of trial phases..................................................................................15
Table 6.3: 1
Subject sets analysed ........................................................................................17
Table 6.7: 1
Time windows for assignment of efficacy, safety lab, vital signs, and 
biomarker measurements to visits for statistical analysis.................................21
Table 7.1: 1
Categories for summary of continuous variables .............................................25
Table 7.8.1: 1 Project MedDRA search criteria for User Defined Adverse Event Concepts ..29
Table 11: 1
History table .....................................................................................................36


Boehringer Ingelheim                                                          
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2.
LIST OF ABBREVIATIONS
Term
Definition / description
ADA
Anti-drug antibodies
ADS
Analysis dataset
AE
Adverse event
AESI
Adverse event of special interest
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
ATC3
Anatomical-Therapeutic-Chemical classification level 3
BI
Boehringer Ingelheim
BIcMQ
Boehringer Ingelheim-customised MedDRA query
BM-SAP
Biomarker Statistical Analysis Plan
BMI
Body mass index
BSA
Body surface area
CARE
Clinical data analysis and reporting environment
CRP
C-reactive protein
CSAP
Cumulative statistical analysis plan
CTP
Clinical trial protocol
CTR
Clinical trial report
DBLM
Database lock meeting
DILI
Drug Induced Liver Injury
DLQI
Dermatology Life Quality Index
DMC
Data Monitoring Committee
DV
Protocol deviation
EASI
Eczema Area and Severity Index
ECG
Electrocardiogram
eCRF
Electronic case report form
eDISH
Evaluation of drug-induced serious hepatotoxicity
EDMS
Electronic document management system
EMA
European Medicines Agency
EoT
End of treatment
EoS
End of study
ES
Enrolled set


Boehringer Ingelheim                                                          
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Term
Definition / description
FAS
Full analysis set
HLT
High level term
HLGT
High level group term
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
IGA
Investigator Global Assessment
IgE
Immunoglobulin E
iPD
Important protocol deviation
ISF
Investigator site file
Max
Maximum
MedDRA
Medical Dictionary for Regulatory Activities
Min
Minimum
MQRM
Medical quality review meeting
N
Number of observations
NRI
Non-Responder imputation
PD
Pharmacodynamic(s)
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic parameter set
Q1
1st quartile
Q3
3rd quartile
q4w
every 4 weeks
RCTC
Rheumatology common toxicity criteria
RPM
Report planning meeting
SAE
Serious adverse event
SAF
Safety analysis set
SAP
Statistical analysis plan
SC
Subcutaneous
SCORAD
SCORing of Atopic Dermatitis
SD
Standard deviation
SDL
Subject data listing
SI
Système international d’unités
SMQ
Standardised MedDRA query
SOC
System Organ Class


Boehringer Ingelheim                                                          
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Term
Definition / description
TSAP
Trial statistical analysis plan
UDAEC
User-defined AE concepts
ULN
Upper limit of normal range
VAS
Visual analogue scale


Boehringer Ingelheim                                                          
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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 analyses described in the CTP and its amendments, 
and to include detailed procedures for executing the statistical analysis of the data.
This trial statistical analysis plan (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, planning of sample size, 
randomisation.
A separate Biomarker Statistical Analysis Plan (BM-SAP) will complement this TSAP.
Pharmacokinetic (PK) parameters are not planned to be analysed nor be the part of the CTR.
The statistical analyses will be performed within the validated working environment CARE, 
including SASTM (current Version 9.4, by
), and a number 
of 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). 
This TSAP will document the features of the data that will be performed for a final analysis. 
The specifications of the analyses for the status reviews at the time points within the requested 
timelines will be defined as requests in the Cumulative Statistical Analysis Plan (CSAP).
The results of the analyses defined in this SAP will be summarised in the abbreviated CTR.


Boehringer Ingelheim                                                          
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5.
ENDPOINT(S)
For all endpoints and unless explicitly specified otherwise, Week numbers refer to specific 
Visit numbers using extended time windows as defined in Table 6.7: 1.
For all endpoints and unless explicitly specified otherwise, End-of-Study visit refers to V53
(Week 220), using extended time windows as defined in Table 6.7: 1.
For handling of missing data and corresponding sensitivity analyses, see Section 6.6.
Definition of baseline is provided in Section 6.7.
5.1
PRIMARY ENDPOINT(S)
The primary endpoint is the number (and percentage) of patients with treatment emergent 
adverse events (AEs) at Week 48. This will be analysed as part of the Safety analysis (see 
Section 7.8)
5.2
SECONDARY ENDPOINT(S)
5.2.1
Key secondary endpoint(s)
Not applicable
5.2.2
Secondary endpoint(s)
The secondary endpoints are listed below.

Change from baseline in Eczema Area and Severity Index (EASI) Score at Week 48
The actual and percent change from baseline as well as the absolute values at visits 
will be analysed. 


Boehringer Ingelheim                                                          
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The EASI total score assesses the extent of disease (area affected) at four body regions: head, 
trunk, upper limb, and lower limb for which the following scoring will be used:
% involvement
0
1 to 
<10%
10 to 
<30%
30 to 
<50%
50 to 
<70%
70 to 
<90%
90 to 
100%
Region score
0
1
2
3
4
5
6
The severity of each of the four clinical signs: erythema, induration/papulation, excoriation, 
and lichenification using the following severity scale for each body region:

0 for “None”

0.5 for “None to Mild”

1 for “Mild”

1.5 for “Mild to Moderate”

2 for “Moderate”

2.5 for “Moderate to Severe”

3 for “Severe”
The following formula will be used to derive the EASI Total Score:
EASI Total Score = (ErythemaHead + Edema/papulationHead + ExcorationHead +
LichenificationHead)×(HeadRegion Score)×0.1 +
(ErythemaTrunk + Edema/papulationTrunk + ExcorationTrunk + 
LichenificationTrunk)×(TrunkRegion Score)×0.3 +
(ErythemaUpper limb + Edema/papulationUpper limb + ExcorationUpper limb + 
LichenificationUpper limb)×(Upper_limbRegion Score)×0.2 +
(ErythemaUpper limb + Edema/papulationLower limb + ExcorationLower limb + 
LichenificationLower limb)×(Lower_limbRegion Score)×0.4

50% improvement from baseline in EASI (EASI50) at Week 48
Numbers and percentages will be analysed.
Achievement of Decrease in EASI ≥ xx% (EASIxx)
Achieving an improvement of xx% or larger decrease from baseline in EASI score is 
denoted as EASIxx. The EASIxx represents a binary variable with values of 0 (= non-
response) or 1 (=response). 
It is calculated based on the following approach (with xx taking a value of 50 or 75):
If 
(
)()
(
)
× 100 ≥ then EASIxx=1,
else EASIxx = 0.

75% improvement from baseline in EASI (EASI75) at Week 48


Boehringer Ingelheim                                                          
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Numbers and percentages will be analysed.

Change from baseline in SCORing of Atopic Dermatitis (SCORAD) at Week 48 
The actual and percent change from baseline as well as the absolute values at visits 
will be analysed. 
The SCORAD consists of three elements: extent of disease, intensity of disease, and 
subjective symptoms (Pruritus and Sleep Loss). It sums up to a maximum of 103 
points. Two of the SCORAD items are subjective symptoms (C) assessed on Visual 
Analog Scales (VAS) from 0 to 10: Pruritus VAS and Sleep Loss VAS. 
The following formula will be used to calculate the SCORAD element assessing the 
Extent of the disease:
Extent Score(A) = (FaceFront×4.5 + Upper_LimbsFront×9 + TrunkFront×18 + 
Lower_limbsFront×18 + GenitalsFront×1 + HeadBack×4.5 + 
Upper_limbsBack×9 + TrunkBack×18 + Lower_limbsBack×18)/100
In the SCORAD element assessing the Intensity of the disease the following scoring 
will be used:
o
0 for “Absence”
o
1 for “Mild”
o
2 for “Moderate”
o
3 for ”Severe”
The SCORAD Intensity score element will be derived using the formula below:
Intensity Score(B) = (Erythema_Score + Edema/Papulation_Score + 
Oozing/crusts_Score + Excoriations_Score + 
Lichenification_Score + Dryness_Score)
For the SCORAD element subjective symptoms the following formula will be used:
Subjective symptoms(C) = Pruritus_VAS + Sleep_Loss_VAS
The following formula will be used to calculate the SCORAD Total Score:
SCORAD Total Score = (A/5) + (B×7/2) + C


Boehringer Ingelheim                                                          
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
Patients achieving at least a 2-grade reduction from baseline to clear (0) or almost 
clear (1) in the Investigator’s Global Assessment (IGA) at Week 48
Numbers and percentages will be analysed.
IGA score allows investigators to assess the overall disease severity at one given time 
point. It is a 5-point scale with: 0 = clear, 1 = almost clear, 2 = mild, 3 = moderate, and 
4 = severe. The overall IGA score includes the assessment of erythema, 
induration/papulation, lichenification, and oozing/crusting. For the first three sections 
the following scale will be used:
o
“None”
o
“Barely Perceptible” (“Minimal” for lichenification)
o
“Slight but Definite” 
o
“Clearly Perceptible”
o
“Marked”
For oozing/crusting the available answers are “None” or “Present.”
The following instructions will be used to derive the IGA Score:
-
IGA Score = 0 if the answers in all sections are “None”.
-
IGA Score = 1 if any of the following occurred: (erythema is barely 
perceptible OR induration/papulation is barely perceptible OR lichenification 
is minimal) AND no oozing/crusting is observed.
-
IGA Score = 2 if any of the following occurred: (erythema is slight but definite 
(pink) OR induration/papulation is slight but definite OR lichenification is 
slight but definite), AND no oozing/crusting is observed.
-
IGA Score = 3 if any of the following occurred: erythema is clearly perceptible 
(dull red) OR induration/papulation is clearly perceptible OR lichenification is 
clearly perceptible OR oozing/crusting is present.
-
IGA Score = 4 if any of the following occurred: erythema is marked (deep or 
bright red) OR induration/papulation is marked OR lichenification is marked. 
Note: For IGA score of 4, the oozing/crusting may be present.
5.4.1
Safety 
Safety will be assessed based on:


Boehringer Ingelheim                                                          
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Boehringer Ingelheim                                                          
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Boehringer Ingelheim                                                          
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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENT(S)
For basic study information on the treatment to be administered, assignment to treatment, and 
selection of dose, cf. Section 4 of the CTP.
All patients will receive subcutaneous doses of 600 mg of BI 655130 solution for SC injection
(every four weeks).
The following trial phases are defined:
Table 6.1: 1
Flow chart of trial phases 
Trial phase
Description
Start (included)
End (excluded)
Open label 
Treatment phase 
On-treatment 
period
Date of start of 
injection of first study 
drug (Day 1) 
EoT visit date + 1 day
Follow-up
phase 
Off-treatment 
follow-up 
period
EoT visit date + 1 day
Date of EoS Participation 
visit + 1 day
Dates are defined individually per patient. If more than one date is associated with a specific visit, measurements associated 
with a specific date are assigned to a study analysis phase according to the rules specified in the table. An analysis phase 
will not extend beyond the start date of the following phase. 
EoT = End of treatment; EoS = End of study;
Patients who discontinue the treatment but will continue on trial visits will be included in 
analyses with the available data. For patients who discontinue the trial prematurely only 
available data will be used in the analyses.
The time windows for data presentation in the analysis are described in Table 6.7: 1.
Treatment group will be labelled as follows: "Speso 600 mg SC q4w" (i.e., patients 
receiving BI 655130 600 mg). In addition, the descriptive statistics will be presented for the 
following groups:
1. By treatment received in the parent trial (1368-0032):

"Placebo" followed by "Speso 600 mg SC q4w" – patients who were 
randomised to receive placebo in the double-blind period of the parent trial and 
received Speso treatment in the open-label period of the parent trial

"Placebo" followed by "no Speso 600 mg SC q4w" – patients who were 
randomised to receive placebo in the double-blind period of the parent trial and 


Boehringer Ingelheim                                                          
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didn’t receive Speso treatment in the open-label period of the parent trial (but 
didn’t discontinue the parent study prematurely)

"Speso 600 mg SC q4w" followed by "Speso 600 mg SC q4w" – patients 
who were randomised to receive active treatment (Speso) in the double-blind 
period of the parent trial and received Speso treatment in the open-label period 
of the parent trial 

"Speso 600 mg SC q4w" followed by "no Speso 600 mg SC q4w" – patients 
who were randomised to receive active treatment (Speso) in the double-blind 
period of the parent trial and didn’t receive Speso treatment in the open-label 
period of the parent trial (but didn’t discontinue the parent study prematurely)

"Overall Total" – all patients from FAS, regardless of the treatment received 
in the parent trial.
2. By the response achieved at Week 16 of the parent trial (1368-0032):

"Responders" – patients who attained at least 75% reduction in EASI score at 
Week 16 compared to baseline during the parent trial

"Non-responders" – patients who attained less than 75% reduction in EASI 
score at Week 16 compared to baseline during the parent trial

"Overall Total" – all patients from FAS, regardless of the EASI response 
status at Week 16 in the parent trial.
More details on the technical implementation of these analyses are provided in the ADS Plan 
of this TSAP.
6.2
IMPORTANT PROTOCOL DEVIATIONS
Data discrepancies and deviations from the CTP will be identified for all patients in the 
database (i.e., enrolled patients). Consistency check listings (for identification of violations of 
time windows) and a list of protocol deviations will be provided to be discussed at the 
RPM/DBLM/MQRM. At meetings, it will be decided whether a discrepant data value can be 
used in analyses or whether it must be queried in the clinical database. Each protocol 
deviation must be assessed to determine whether it is an iPD. For definition of iPDs, and for 
the process of identification of these, refer to the BI reference document "Identify and 
Manage Important Protocol Deviations (iPD)" (2).
Handling of iPDs in the analysis is included in the DV domain specifications and stored 
within the TMF in EDMS. 


Boehringer Ingelheim                                                          
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6.3
SUBJECT SETS ANALYSED
The following analysis sets will be defined for this trial:

Enrolled set (ES)
This patient set includes all patients who signed informed consent. It will be used for 
display of patient disposition.

Safety analysis set (SAF)
This patient set includes all randomized patients who received at least one dose of 
study drug. It will be the main analysis set for presentation of safety. In addition, this 
set will be used for display of baseline and demographic characteristics, and patients 
with iPDs.

Full analysis set (FAS)
This patient set includes all patients in the SAF who had a baseline measurement and 
at least one post-baseline measurement for the secondary endpoint, EASI Total Score. 
It will be the main analysis set for presentation of efficacy results.
The discussion of all exceptional cases and problems and the decisions on the allocation of 
patients to populations will be made at latest at the DBLM.
Table 6.3: 1
Subject sets analysed
Subject set
Class of endpoint
ES
SAF
FAS
Primary and key secondary 
endpoints 
X
(other) Secondary and 
further endpoints 
X
Safety endpoints & 
treatment exposure
X
Patients disposition
X
Demographic/baseline 
endpoints
X
Note that the number of subjects with available data for an endpoint may differ. For details, see section 
“Handling of missing data”.


Boehringer Ingelheim                                                          
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6.5
POOLING OF CENTRES
Given the low number of patients per centre and the primarily descriptive nature of the 
statistical analysis, separate analyses by centre are not meaningful and will not be performed. 
6.6 HANDLING OF MISSING DATA AND OUTLIERS
6.6.1
Withdrawals
The reasons for withdrawal from treatment will be reported as indicated on the eCRF.
6.6.2
Efficacy data
Binary efficacy endpoints
The primary imputation approach for binary endpoints will be No Response Imputation (NRI) 
described below.
1. If a patient prematurely discontinues study medication administration for any reason, 
then all data subsequent to the discontinuation will be considered to be missing. The 
cut-off date to be used is the last dose of study medication administration + 4 weeks 
(including the extended time windows).
2. For endpoints which are measured at multiple visits, if there are data at visits both 
before and after the visit with a missing outcome, then impute as success (a responder) 
only if both neighbouring visits also represent a success (independent of whether the 
preceding and following observations were selected for analysis based on time 
windows described in Section 6.7).
For all patients with a missing visit outcome, it will be imputed as a failure to achieve a 
response (non-responder).
In addition, for all binary endpoints (i.e., endpoints that are either 1 (patient responded) or 0 
(patient did not respond)), frequency tables with observed data will be presented.
Categorical efficacy endpoints with more than two outcomes
Some endpoints or their subscores are categorical with more than two potential outcomes 
(e.g., IGA, DLQI). As a general rule, imputation will only be applied on the complete score. 
In case a categorical subscore is analysed separately, no imputation will be applied (only 
observed data will be analysed). 
Continuous efficacy endpoints
For efficacy endpoints which are continuous in nature, no imputation of missing data is 
planned. Only observed data will be used for analysis.
6.6.3
Safety data
From CTP Section 7.5: With respect to safety evaluations, it is not planned to impute 
missing values.


Boehringer Ingelheim                                                          
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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 (3)).
Partial start and stop dates for concomitant medications will be imputed to enable subsequent 
calculation (but not for display) by the following "worst case" approach:

If the day of the end date is missing, then the end date is set to last day of the month (or to 
the patient's trial completion date, if it is earlier than the last day of the month).

If the day and month of the end date are missing then the end date is set to 31st of 
December of the year (or to the patient's trial completion date, if it is earlier than the 
31st of December of the year).

If the day of the start date is missing the start date is set to first day of the month.

If the day and month of the start date are missing then the start date is set to 1st January of 
the year.

All other cases need to be assessed by the trial team on an individual basis, using the 
above points as guidance.
6.6.4
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. 
Note: Every effort should be made to have at least data on year of the first diagnosis 
populated.

If day and month of the first diagnosis are unknown, time since first diagnosis will be 
calculated as if diagnosed on the 30th June of that year.

If only the day of the first diagnosis is unknown, time since first diagnosis will be 
calculated as if diagnosed on the 15th of that month.
Information on the time since first diagnosis will be imported form the database of the parent 
trial (1368-0032).
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
Measurements reported with date and time and taken prior to start of administration of trial 
treatment will be considered pre-treatment values. Measurements reported with a date only 
(and no time) and taken on the day of first administration of trial treatment will also be 
considered pre-treatment values. These pre-treatment values will be assigned to visits 
according to the nominal visit number as recorded on the eCRF or as provided by the 
laboratory. For definitions used in Safety analyses, refer to Section 7.8.
There will be two different baseline definitions used in the analyses:
1. Baseline for this extension trial – defined as the last measurement recorded before the 
first trial medication administration in this study.


Boehringer Ingelheim                                                          
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2. Baseline for the parent trial (1638-0032) – defined as the measurement recorded at 
randomisation visit (Visit 2) of the parent trial. If the data at Visit 2 is missing, then 
the data from Visit 1 of the parent trial will be considered baseline.
Two separate analyses will be conducted, using the baselines as defined above.
Measurements taken after start of administration of trial treatment will be considered either 
on- or off-treatment values based on the definition in Section 6.1, and will be assigned to 
visits for statistical analysis, if applicable, as defined below.
Analysis of AE data, concomitant medication or non-drug therapies will not be based on 
visits. Therefore, no assignment to time windows will be necessary for such data.
For derivation of the last value on treatment, minimum value on treatment, and maximum 
value in the trial phase, all values from the relevant phase (whether or not collected in any 
time window; see Table 6.1: 1 for definition of the trial phases) will be considered; these will 
be derived for analysis of laboratory and vital signs data. For identification of potentially 
clinically significant abnormal laboratory values, all values (whether or not selected in any 
time window) before the date of EoS Participation visit will be considered.
A graphical analysis of the ALT and total bilirubin will be performed (so called eDISH plot) 
based on the available data obtained during the on-treatment period.
All other safety, efficacy and biomarker measurements will be assigned to visits based on 
extended time windows around the planned visit dates, defined relative to the day of first trial 
treatment (which is scheduled for Visit V2). These extended time windows are defined in 
Table 6.7: 1.


Boehringer Ingelheim                                                          
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Table 6.7: 1
Time windows for assignment of efficacy, safety lab, vital signs, and 
biomarker measurements to visits for statistical analysis
Visit 
number
/ name
Planned 
day
Time window (Days)
Visit label
Window 
(per 
CTP)
Start
(per CTP)
End
(per CTP)
Start 
(extended)
End 
(extended)
V1
Day 1
Day 1
n/a
1 A
1
   1 A
1
V2
Week 4
Day 29
+/- 14
15
43
         2
43
V3
Week 8
Day 57
+/- 14
44
71
44
71
V4
Week 12
Day 85
+/- 14
72
99
72
99
V5
Week 16
Day 113
+/- 14
100
127
100
127
V6
Week 20
Day 141
+/- 14
128
155
128
155
V7
Week 24
Day 169
+/- 14
156
183
156
183
V8
Week 28
Day 197
+/- 14
184
211
184
211
V9
Week 32
Day 225
+/- 14
212
239
212
239
V10
Week 36
Day 253
+/- 14
240
267
240
267
V11
Week 40
Day 281
+/- 14
268
295
268
295
V12
Week 44
Day 309
+/- 14
296
323
296
323
V13
Week 48
Day 337
+/- 14
324
351
324
351
V14
Week 52
Day 365
+/- 14
352
379
352
379
V15
Week 56
Day 393
+/- 14
380
407
380
407
V16
Week 60
Day 421
+/- 14
408
435
408
435
V17
Week 64
Day 449
+/- 14
436
463
436
463
V18
Week 68
Day 477
+/- 14
464
491
464
491
V19
Week 72
Day 505
+/- 14
492
519
492
519
V20
Week 76
Day 533
+/- 14
520
547
520
547
V21
Week 80
Day 561
+/- 14
548
575
548
575
V22
Week 84
Day 589
+/- 14
576
603
576
603
V23
Week 88
Day 617
+/- 14
604
631
604
631
V24
Week 92
Day 645
+/- 14
632
659
632
659
V25
Week 96
Day 673
+/- 14
660
687
660
687
V26
Week 100
Day 701
+/- 14
688
715
688
715
V27
Week 104
Day 729
+/- 14
716
743
716
743
…
…
…
…
…
…
…
…
V52
EoT
Day 1429
+/- 14
1415
1443
1415
1443
V53
EoS
Day 1541
+/- 14
1528
1555
1444
1555/EoT+
16weeks
Days are counted relative to the day of first treatment, which is defined as Day 1.
A Note that measurements made at Day 1 and assigned to the on-treatment period (because mistakenly made after start of 
injection of trial treatment) via assessment on date and time (i.e. safety laboratory) will not be assigned to Day 1. Such data 
will be listed only.
Repeated and unscheduled efficacy, safety and biomarker measurements will be handled 
similarly to scheduled measurements and will also be assigned to a time window depending 
upon the date of measurement. 
Only one observation per time window will be selected for statistical analysis at a particular 
visit – the value which is closest to the protocol planned visit day will be selected. If there are 
two observations which have the same difference in days to the planned day, the later value 
will be selected. If there are two observations on the same day, the worst value will be 
selected.


Boehringer Ingelheim                                                          
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Assignment of efficacy observations to visits based on time windows will be based on the 
non-imputed (observed) data. 
For visits without an assigned value based on time windows, a value will thereafter be 
imputed as defined in Section 6.6. Imputation of efficacy endpoints, when applicable, will be 
performed based on all available observations obtained during the on-treatment period, 
irrespective of whether the observation was selected in any time window. 
In addition, separate analyses will be performed using the parent trial baseline. Baseline value 
will then be defined the same way as in the parent trial (1368-0032) and will be taken from 
that parent trial.


Boehringer Ingelheim                                                          
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7.
PLANNED ANALYSIS
All efficacy and safety analyses will be purely exploratory in nature. The following analyses 
are planned throughout the trial.
o
Status review (at the requested timelines)
The status reviews will be performed periodically and on demand. The analyses will include 
all data available at the time of the snapshot. The analyses are planned to be defined for each 
time point as requests in the CSAP, depending on the requirements.
o
Final analysis (Week 220)
The analysis of the entire efficacy, safety, PK, and biomarker data collected through the full 
220 weeks of follow-up will be performed once all entered patients have completed the trial 
(up to EoS Visit); at that time point, a final database lock will be done and all data through 
week 220 will be reported. The majority of biomarkers will be reported outside the CTR.
General Remarks
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] (7) with the exception 
of those generated for PK.
The individual values of all patients will be listed, including those collected during the off-
treatment period. Listings will generally be sorted by country, centre number, patient number 
and visit (if visit is applicable in the respective listing). AE listings will be sorted by treatment 
(see Section 7.8.1 below for details).
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
The data format for descriptive statistics of concentrations will be identical with the data 
format of the respective concentrations.
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” (7). 


Boehringer Ingelheim                                                          
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Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category as well as the percentage (%) relative to the 
respective treatment. Percentages will be rounded to one decimal place. The category missing 
will be displayed if and only if there actually are missing values. Percentages will be based on 
all patients in the respective patient set whether they have non-missing values or not.
Disposition of the patient population participating in the trial (overall) will be summarised by 
presentation of the frequency of patients entered, treated, entered but not treated, who 
completed all doses of trial medication as planned (until the trial termination), who 
prematurely discontinued study drug administration by reason, who completed the 
observational period as planned, who prematurely discontinued study participation.
Disposition will be listed by country.
The frequency of patients with iPDs will be presented for the SAF, overall. The iPDs will be 
listed per patient indicating whether or not the iPD led to exclusion from patient sets analysed.
The frequency of patients in each of the different analysis sets will also be overall.
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the CTR.
Descriptive statistics will be presented overall for demographic parameters and baseline 
characteristics, based on the SAF. 
For the continuous variables described below, categories are defined in Table 7.1: 1. These 
variables will be presented according to the number and percentage of patients in each 
category.


Boehringer Ingelheim                                                          
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Table 7.1: 1
Categories for summary of continuous variables
Variable
Categories
Age
< 30 years
≥ 30 years
< 65 years
≥ 65 years
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
Age at disease onset
≤ 12 years old
> 12 years old
7.2
CONCOMITANT DISEASES AND MEDICATION
For this extension study, no information on historical medication is collected. For more 
details on that, please refer to the parent trial (1368-0032) results.
Analyses of concomitant diseases and medication will be based on the SAF.
Concomitant diseases will be coded according to the most recent version of MedDRA. 
Concomitant medication will be coded according to the most recent version of the World 
Health Organisation – Drug Dictionary.
Concomitant diseases which are present at start of the study, as well as characteristics of the 
trial disease, will be descriptively summarised overall. 
A medication will be considered concomitant to treatment, if it

is ongoing at the start of trial treatment or

starts within the on-treatment period (see Section 6.1 for a definition of study analysis 
phases).
Concomitant medication use will be summarised with frequency and percentage of patients by 
ATC3 class and preferred name, overall. 
Concomitant use of non-drug therapies will be summarized overall with frequency and 
percentage. 


Boehringer Ingelheim                                                          
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The relevance of the concomitant therapies to the evaluation of PK will be decided no later 
than at the RPM/DBLM.
7.3
TREATMENT COMPLIANCE
Treatment compliance will be summarised overall via total volume infused (as a % of 
planned) for the SAF using descriptive statistics (N, mean, SD, minimum, median, 
maximum). The volume injected (as a % of planned) is defined as the volume injected at a 
visit (in number of syringes as recorded in the eCRF), divided by 4 (the number of syringes
the patient should have received).
For the patients who discontinued the study treatment prematurely, only the visits on or 
before premature discontinuation will be used for the calculation of overall compliance.
The number of patients who received a dose will be tabulated per visit.
7.4
PRIMARY ENDPOINT(S)
The primary endpoint for this trial is the number of patients with treatment emergent adverse 
events at Week 48. 
7.4.1
Primary analysis of the primary endpoint(s)
The analysis of the primary endpoint will be descriptive in nature and will be a part of the 
Safety analyses described in detail in Section 7.8.
The primary analysis will be performed on the SAF. 
 
 
7.5
SECONDARY ENDPOINT(S)
7.5.1
Key secondary endpoint(s)
This section is not applicable as no key secondary endpoint has been specified.
7.5.2
(Other) Secondary endpoint(s)
All secondary efficacy endpoints will be analysed descriptively based on the FAS.


Boehringer Ingelheim                                                          
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For continuous secondary efficacy endpoints (EASI Score and SCORAD Score), standard 
statistical parameters (as defined in Section 7) will be presented per group defined in Section 
6.1. Both absolute and percent change from baseline will be analysed as an outcome as well 
as the values recorded at the respective time points.
For binary endpoints (EASI50, EASI75, achieving at least 2-grade reduction from baseline to 
clear (0) or almost clear (1) in IGA), frequency tables will be provided per group defined in 
Section 6.1.
7.7
EXTENT OF EXPOSURE
The number of subjects who received a dose of trial drug will be tabulated. The amount of 
treatment received will be summarised by descriptive statistics (N, mean, SD, minimum, 
median, maximum) per visit and overall. Additionally, number of injections administered (as 
defined in Section 5.4.4) overall will be displayed. 
7.8
SAFETY ANALYSIS
All safety analyses will be performed based on the SAF following BI standards. No 
hypothesis testing is planned.


Boehringer Ingelheim                                                          
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7.8.1
Adverse Events
AEs will be coded with the most recent version of MedDRA. 
The analyses of AEs will be descriptive in nature. All analyses of AEs will be based on the 
number of patients with AEs and not on the number of AEs. System organ classes (if 
applicable) will be sorted according to the standard sort order specified by the EMA, preferred 
terms (if applicable) will be sorted by total frequency (within system organ class) across all 
treatment arms.
For further details on summarization of AE data, please refer to “Analysis and Presentation of 
Adverse Event Data from Clinical Trials” [BI-KMED-BDS-HTG-0066] (4) and “Handling of 
missing and incomplete AE dates” [BI-KMED-BDS-HTG-0035] (3). 
The analysis of AEs will be based on the concept of treatment emergent AEs. If only the start 
date of an AE is collected (without start time), any AE occurrence on the same day as the first 
BI 655130 administration will be assigned to the on-treatment phase.
An overall summary of AEs will be presented by treatment. 
This overall summary will include summary statistics for the class of other significant AEs 
(sponsor definition based on ICH E3 (6)) and for the class of AESIs. 
The following are considered an AESI in this trial:
-
Hepatic injury
-
Systemic hypersensitivity reactions including anaphylactic reaction
-
Severe infections (according to RCTC grading in the ISF)
-
Opportunistic and mycobacterium tuberculosis infections
The investigator has to classify on the eCRF whether an observed AE was an AESI or not. 
Only those AEs that are indicated by the investigator as AESI in the eCRF will be analysed in 
this category.
Based on the specification provided in ICH E3 (6), the sponsor has defined AEs which are to 
be classified as ‘other significant’. These will include those non-serious AEs which were 
reported with ‘action taken = Drug withdrawn’ or ‘action taken = Dose reduced’.
The frequency of patients with AEs will be summarised by treatment, primary system organ 
class and preferred term. AEs which were considered by the investigator to be drug related 
will be summarised separately (secondary safety endpoint of this trial). Separate tables will 
also be provided for patients with SAEs, patients with drug-related SAEs, patients with 
AESIs, patients with AE leading to discontinuation of the trial, and patients with other 
significant AEs (as described previously). AEs will also be summarized by maximum RCTC 
grade.
A summary of user-defined AE concepts (UDAEC) will be presented by treatment group. The 
UDAEC are presented in the table below.


Boehringer Ingelheim                                                          
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Table 7.8.1: 1 Project MedDRA search criteria for User Defined Adverse Event Concepts
User Defined AE Concepts
Categories
Hypersensitivity ALL
Combined search strategy based on the three individual 
UDAECs described below (Anaphylactic reaction, 
Angioedema, Hypersensitivity)
Anaphylactic reaction
Narrow SMQ “Anaphylactic reaction”
Angioedema
Narrow SMQ “Angioedema”
Hypersensitivity
Narrow SMQ “Hypersensitivity”
Infections ALL
Combined search strategy based on the individual 
UDAECs described below (Severe infections, 
Opportunistic infections, Tuberculosis infections, and 
Serious infections); Severe infections investigator-defined 
will be disregarded for this search.
Severe infections (according 
to RCTC grading)
SOC Infections and infestations of at least severe RCTC 
grade, by HLGT
Serious infections
SOC Infections and infestations reported as serious AEs
Opportunistic infections
SMQ Opportunistic Infections (narrow)
Tuberculosis infections
BIcMQ sub-search 8.2 “Tuberculosis related terms”, 
narrow
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 tumors” excluding HLT 
skin melanomas (excl. ocular)
Malignancies excluding 
NMSC
Sub-SMQ “Malignant tumours” excluding NMSC, 
whereas NMSC is defined above 
Torsades de pointes
Broad sub-SMQ “Torsades de pointes/QT prolongation”


Boehringer Ingelheim                                                          
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Table 7.8.1:1 Project MedRDA dearch criteria for User Defined Adverse Event Concepts 
(cont.)
DRESS (Drug reaction with 
eosinophilia and systemic 
symptoms syndrome),
narrow
SMQ "Drug reaction with eosinophilia and systemic 
symptoms syndrome", narrow
DRESS (Drug reaction with 
eosinophilia and systemic 
symptoms syndrome), broad
Algorithmic SMQ on "Drug reaction with eosinophilia 
and systemic symptoms syndrome", broad
Algorithm:
A or (B and C and D) or (B and C and E) or (B and D and 
E)
Depression
sub-SMQ "Depression (excl suicide and self-injury)", 
broad
Suicidal ideation and 
behavior (SIB)
sub-SMQ "Suicide/self-injury"
For disclosure of AE data on ClinicalTrials.gov, the frequency of patients with non-serious 
AEs occurring with an incidence of greater than 5% (in preferred terms) will be summarised 
by treatment, primary system organ class and preferred term. The frequency of patients with 
SAEs will also be summarised.
7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI standards 
(5). Note that data from the central Laboratory will be used for all displays described below, 
unless otherwise specified.
For continuous safety laboratory parameters, normalized values will be derived.
Normalisation means transformation to a standard unit and to a standard reference range. The 
process of normalisation, handling of repeat values at the same visit for by-visit displays, as 
well as standard analyses for safety laboratory data are described in the BI guidance for the 
“Handling, Display and Analysis of Laboratory Data” (5). All analyses considering multiple 
times of the ULN (as described below) will be based on standardized and not normalized 
values. For continuous safety laboratory parameters, differences to baseline will be calculated.
Only patients with at least one available post-baseline value will be included in the analysis of 
an individual laboratory parameter. All individual laboratory data will be listed. Values 
outside the reference range will be flagged.
Descriptive statistics of laboratory values over time and for the difference from baseline (see
Section 6.7) will be based upon normalised values and provided by visit, including summaries 
of the last value on treatment, the minimum value on treatment and maximum value on 
treatment.


Boehringer Ingelheim                                                          
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Laboratory values will be compared to their reference ranges; shift tables will be provided for 
the number of patients with a specific RCTC grade at baseline versus the grade at the last 
measurement on treatment, as well as the worst grade on treatment. These analyses will be 
based on standardized laboratory values.
Potentially clinically significant abnormalities will be identified based on BI standard rules 
which are based on normalized converted lab values, i.e. using SI units. These rules will be 
listed in the SDL appendix of the CTR. Frequency tables will summarize the number of 
patients with potentially clinically significant abnormalities. Patients having an abnormal lab 
value at baseline will be presented separately. A separate listing will present potentially 
clinically significant abnormal lab values.
The frequency of patients with AST or ALT elevations ≥ 3xULN, ≥ 5xULN, ≥ 10xULN, and 
≥ 20xULN will be displayed based on standardized laboratory values. To support analyses of 
liver related adverse drug effects, the frequency of patients with AST and/or ALT ≥ 3xULN 
combined with a total bilirubin ≥ 2xULN in a 30 day period after AST/ALT elevation will be 
displayed, stratified by alkaline phosphatase < 2xULN and ≥ 2xULN (a patient can potentially 
be in both alkaline phosphatase strata in case of multiple AST/ALT and bilirubin elevations). 
The start of the 30 day time span is triggered by each liver enzyme elevation above the 
defined thresholds. This analysis will be based on standardized laboratory values. A graphical 
analysis of the ALT and total bilirubin during the on-treatment period will also be performed; 
the so called eDISH plot. In the graph, for each subject, the peak total bilirubin is presented as 
a fold increase over the ULN against the peak ALT as a fold increase over the ULN, on a 
log10 scale. The measurements displayed or total bilirubin and ALT may, or may not, occur 
on the same date. Two reference lines, 2xULN for total bilirubin and 3xULN for ALT, are 
drawn onto the graph in order to divide the plane into four quadrants. Normal cases are in the 
lower left quadrant, potential DILI cases are in the upper right quadrant (Hy’s Law quadrant), 
while the lower right quadrant is known as the Temple’s corollary range (ALT ≥ 3xULN and 
total bilirubin < 2xULN).
Clinically relevant findings in laboratory data will be reported as baseline conditions (at 
screening) or as AEs (during the trial) if judged clinically relevant by the investigator, and 
will be analysed as such.
7.8.3
Vital signs
The analyses of vital signs (blood pressure, pulse rate, body temperature and body weight) 
will be descriptive in nature.
Descriptive statistics of vital signs over time and for the difference from baseline (see Section 
6.7) will be provided by treatment, including summaries of the last value during the on-
treatment period, the minimum value during on-treatment period, and the maximum value 
during on-treatment period (see Table 6.1: 1 for definition of the on-treatment period).
Clinically relevant findings in vital signs data will be reported as baseline conditions (at 
screening) or as AEs (during the trial) if judged clinically relevant by the investigator, and 
will be analysed as such.


Boehringer Ingelheim                                                          
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7.8.4
ECG
Abnormal findings in 12-lead ECG will be reported as baseline conditions (at screening) or as 
AEs (during the trial) if judged clinically relevant by the investigator, and will be analysed as 
such.
No separate listing or analysis of ECG data will be prepared.
7.8.5
Others
Injection reactions including anaphylactic reaction
Injection reactions will be summarized overall, with the frequency and percentage of patients 
who experienced any injection reaction, both overall and specifying anaphylactic reaction as 
part of the table presenting patients with adverse events of special interest (AESI).
Immunogenicity
The frequency and percentage of patients with ADAs to BI 655130 will be presented by 
treatment, by visit and overall, if sufficient data is available. 
Further exploratory assessments of the ADA data (e.g., relationship between ADA and PK) 
might be performed once data is available and these will be described, if done, in the 
abbreviated CTR.
Handling of DMC Analyses
A partially external DMC, independent of the trial and project teams, was set-up on project 
level to review all available safety data as well as selected efficacy data in an unblinded 
manner at regular intervals following first-patient-in. A separate DMC SAP which describes 
the analyses required for assessment by the DMC was produced and finalised prior to first 
patient randomised into the trial. Further details were provided in a DMC charter.


Boehringer Ingelheim                                                          
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8.
TIMEPOINT OF RELEASE OF TREATMENT 
INFORMATION
This is an open-label trial with a single arm and the treatment information will be loaded into 
the trial database.


Boehringer Ingelheim                                                          
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9.
REFERENCES
1
CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline 
Topic E9; Note For Guidance on Statistical Principles for Clinical Trials, current 
version
2
001-MCS-40-413: "Identify and Manage Important Protocol Deviations (iPD)", 
current version; Group “Clinical Operations”, IDEA for CON
3
BI-KMED-BDS-HTG-0035: "Handling of missing and incomplete AE dates", 
current version; IDEA for CON
4
BI-KMED-BDS-HTG-0066: "Analysis and Presentation of Adverse Event Data 
from Clinical Trials", current version; IDEA for CON
5
BI-KMED-BDS-HTG-0042: "Handling, Display and Analysis of Laboratory Data", 
current version; IDEA for CON
6
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
7
BI-KMED-BDS-HTG-0045: "Standards for Reporting of Clinical Trials and Project 
Summaries", current version; IDEA for CON


Boehringer Ingelheim                                                          
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Boehringer Ingelheim                                                          
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11.
HISTORY TABLE
Table 11: 1
History table
Version
Date
(DD-MMM-
YY)
Author
Sections 
changed
Brief description of change
1 
20-DEC-21
None
This is the final TSAP