Conditions: Dermatitis, Atopic
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 51
Healthy volunteers: no

Brief summary:
The primary objective of this trial is to investigate the safety, tolerability and efficacy of BI 655130 in patients with Atopic Dermatitis (AD) following repeated intravenous administrations compared to placebo.

Detailed description:

Arms:
arm 1: i.v. arm 2: i.v.

Interventions: intervention 1: BI 655130 intervention 2: Placebo
Intervention descriptions: intervention 1: Solution for infusion intervention 2: Solution for infusion

Protocol document:
Prot_000.pdf: 
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Clinical Trial Protocol
TITLE PAGE
Document Number:
c23806995-04
EudraCT No.
EU Trial No.
N/A
BI Trial No.
1368-0032
BI Investigational
Medicinal Product(s)
BI 655130
Title
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
Lay Title
A study in patients with atopic eczema to test how effective BI 
655130 is and how well it is tolerated
Clinical Phase
Phase IIa
Clinical Trial Leader
Tel:
  Fax:
Coordinating 
Investigator
N/A
Status
Final Protocol (based on Global Amendment 03)
Version and Date
Version: 4.0
Date: 12 Feb 2020
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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
05 Nov 2018
Revision date
12 Feb 2020
BI trial number
1368-0032
Title of trial
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
Coordinating 
Investigator
N/A
Trial site(s)
Multi-centre trial
Clinical phase
IIa
Trial rationale
Although the pre-clinical data and rationale for the use of an IL-36R 
antagonist in atopic dermatitis (AD) are strong, there are no data on 
the use of an IL-36 receptor antagonist in patients with AD. Thus, a 
small proof of clinical concept study is planned to assess safety, 
tolerability and efficacy in patients with moderate to severe AD.
Trial objective(s)
The primary objectives of this trial are to investigate the safety, 
tolerability and efficacy of BI 655130 in adult patients with moderate 
to severe atopic dermatitis following repeated intravenous 
administrations of 600 mg compared to placebo.
Trial endpoints
Primary endpoint

Percentage change from baseline in EASI at Week 16 
Secondary endpoint

Number of patients with drug related AEs

Absolute and percentage change from baseline in EASI at
Week 4 

Proportion of patients with a 50% improvement from baseline 
in EASI (EASI50) at Week 4 and 16

Proportion of patients with a 75% improvement from baseline 
in EASI (EASI75) at Week 4 and 16

Change from baseline in SCORAD at Week 4 and 16 

Proportion of patients achieving at least a 2-grade reduction 
from baseline to clear (0) or almost clear (1) in IGA at Week 4 
and 16
Trial design
Double-blind, randomised, placebo-controlled comparison of two 
groups over 16 weeks
Total number of patients
randomised
Approximately 45 patients will be entered in the study
Number of patients on 
each treatment
30 patients in the active group
15 patients in the placebo group
Diagnosis
Adult patients with moderate to severe atopic dermatitis


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Main in- and exclusion 
criteria
Inclusion Criteria (for complete list refer to Section 3.3.2)

Male or female patients, 18 to 75 years of age at screening

Diagnosis of atopic dermatitis for at least 1 year

Moderate to severe atopic dermatitis defined as:
o
At least 10% Body Surface Area (BSA) of atopic 
dermatitis involvement at screening and baseline
o
Eczema Area and Severity Index (EASI) of at least 12 
at screening and at least 16 at baseline,
o
Investigator Global Assessment (IGA) of at least 3 at 
screening and baseline

Documented history of inadequate response to topical 
corticosteroid as judged by the investigator

Willing to use a standard emollient for the duration of the study

Women of childbearing potential (WOCBP)1 must be ready and 
able to use highly effective methods of birth control per
International Council on Harmonization (ICH) M3 (R2) that 
result in a low failure rate of less than 1% per year when used 
consistently and correctly. A list of contraception methods 
meeting these criteria is provided in the patient information.
Exclusion Criteria (for complete list refer to Section 3.3.3)

Use of topical corticosteroids or other agents for atopic 
dermatitis within 7 days prior to first dose of trial treatment.

Use of systemic corticosteroids or other agents for atopic 
dermatitis within 4 weeks prior to first dose of trial treatment
(for more details refer to Table 4.2.3.1: 1)

Women who are pregnant, nursing, or who plan to become 
pregnant while in the trial. 

Any documented active or suspected malignancy or history of 
malignancy within 5 years prior to the screening visit, except 
appropriately treated basal cell carcinoma of the skin, squamous 
cell carcinoma of the skin or in situ carcinoma of uterine cervix.
Use of any restricted medication as specified in Table 4.2.3.1: 1
or any drug considered likely to interfere with the safe conduct 
of the study, as assessed by the investigator.

History of allergy/hypersensitivity to the systemically 
                                                
1 A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-
menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and 
bilateral oophorectomy. Tubal ligation is NOT a method of permanent sterilisation. A postmenopausal state is defined as no 
menses for 12 months without an alternative medical cause.


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administered trial medication agent or its excipients.

Active systemic infections (Fungal and bacterial disease) during 
the last 2 weeks prior to first drug administration, per 
investigator assessment.

Relevant chronic or acute infections (exception: common cold) 
including human immunodeficiency virus (HIV) or viral 
hepatitis. A patient can be re-screened if the patient was treated 
and is cured from the acute infection. 

Active or Latent TB:

Patients with active tuberculosis are excluded.

Patients with a positive QuantiFERON TB test during 
screening are excluded, unless:
o
Patient had previous diagnosis of active or latent TB 
and has completed appropriate treatment per local 
practice/guidelines within the last 3 years and at least  
6 months before first administration of trial medication 
under this protocol (patients may be re-screened once 
to meet this criterion)
o
Patients with suspected false positive or indeterminate 
QuantiFERON TB result may be re-tested once 
o
If QuantiFERON TB test result is not available or 
providing indeterminate results after repeat testing: A 
tuberculin skin test reaction ≥10mm (≥5mm if 
receiving ≥15mg/d prednisone or its equivalent) is 
considered positive.

Evidence of a current or previous disease, medical condition 
other than atopic dermatitis, surgical procedure, psychiatric or 
social problems, medical examination finding, or laboratory 
value at 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.

Major surgery (major according to the investigator) performed 
within 12 weeks prior to first study drug adminstration or
planned during the study (e.g. hip replacement, aneurysm 
removal, stomach ligation).

Severe, progressive, or uncontrolled hepatic disease, defined as 
>3-fold Upper Limit of Normal (ULN) elevation in AST or 
ALT or alkaline phosphatase, or >2-fold ULN elevation in total 
bilirubin.
Test product(s)
BI 655130


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dose
600 mg every 4 weeks
method and route of 
administration
Intravenous (i.v)
Comparator product(s)
Placebo
dose
Matching placebo
method and route of
administration
Intravenous (i.v.)
Duration of treatment
Up to 32 weeks
Statistical methods
Restricted maximum likelihood estimation based on a mixed-effect 
model for repeated measures analysis will be used to obtain adjusted 
means for the treatment effects of the primary endpoint percent 
change in EASI Score. This model will include discrete fixed effects 
for treatment at each visit and stratification factor Asian/Non-Asian, 
and continuous fixed effects for baseline at each visit. The primary 
treatment comparisons will be the contrast between treatments at 
Week 16.
To compare proportion of patients reaching EASI 50 or 75, or having 
IGA 0 and 1, the Cochran-Mantel-Haenszel test will be used.
Safety data will be presented using descriptive methods.
An interim analysis will be conducted when 75% of the patients have 
completed at least 4 weeks of treatment.


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FLOW CHART
Randomised Treatment Period
Trial Periods
Screening 
Visit
1
21*
3
4
5
6
717
Re-allocation
8
9
10
(EoS for R)2
11
End of Study
(EoS)/FU1
(NR) 3,18
End of Study
Safety Phone 
Call (NR)20
Day 
-28 to -7
1
15
29 
57
85 
113
141
169
197
228 - 309
309
Week
-4 to -1
2
4
8
12
16
20
24
28
32 - 44
44
Time window for visits
±3
days
±3 days
±3 days
±3days
±3 days
±3 days
±3 days
±3 days
±3 days
+/- 3 days
Screening/baseline
Informed consent for main study  
X
Informed consent for PGx Sampling 
X
Demographics
X
Smoking History
X
Medical history
X
Review of in-/exclusion criteria
X
X
Randomisation
X
Physician and Patient Assessments
Investigator Global Assessment 
(IGA)17
X
X
X
X
X
X
X
X
X
X
X
EASI17
X
X
X
X
X
X
X
X
X
X
X
SCORAD17
X19
(BSA only)
X
X
X
X
X
X
X
X
X
X
DLQI17
X
X
X
X
X
X
X
X
X
X
All AEs/SAEs/AESIs**
X
X
X
X
X
X
X
X
X
X
X
X
Treatment
Administer trial drugs
X
X
X
X
X16
X16
X16
X16
Concomitant therapy
X
X
X
X
X
X
X
X
X
X
X
X
Treatment Re-allocation
X
End of Study Completion Call in 
IRT
X (R)
X22 (NR)
X22 (NR)
Safety
Physical examination4
XC
XT
XT
XT
XT
XT
XC
XT
XT
XC,T
XC


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Trial Periods
Screening 
Visit
1
21*
3
4
5
6
717
Re-allocation
8
9
10
(EoS for R)2
11
End of Study
(EoS)/FU1
(NR) 3,18
End of Study
Safety Phone 
Call (NR)20
Day 
-28 to -7
1
15
29 
57
85 
113
141
169
197
228 - 309
309
Week
-4 to -1
2
4
8
12
16
20
24
28
32 - 44
44
Time window for visits
±3
days
±3 days
±3 days
±3days
±3 days
±3 days
±3 days
±3 days
±3 days
+/- 3 days
Vital signs5
X
X
X
X
X
X
X
X
X
X
X
Safety Laboratory tests (blood and 
urine)6
X
X
X
X
X
X
X
X
X
X
X
Pregnancy testing7
XS
XU, (S)
X U, (S)
X U, (S)
X U, (S)
X U, (S)
X U, (S)
X U, (S)
X U, (S)
X U, (S)
X21
12 lead-ECG (local)8
X
X
X
X
X
X
X
X
X
X
X
Infection Testing9
X
X
X
Biomarker and PK sampling
Skin Biopsies -Lesional (L) and non 
lesional  (NL)10
X
(L;NL)
X (L)
X (L)
X(L 
optional)
X(L optional)
Photographs of skin lesion11
X
X
X
X
X
Skin Tape stripping12
X 
(L;NL)
X(L)
X(L)
X (L 
optional)
X (L 
optional)
ADA/Nab13
X
X
X
X
X
X
X
X
X
X
PK Sampling13
X
X
X
X
X
X
X
X
X
X
Blood sample for RNA 
sequencing13
X
X
X
X
X
Blood sample for DNA 
resequencing13
X
Microbiome sample for 16S 
sequencing 14
X 
(L,NL)
X (L,NL)
X (L,NL)
Blood sample – soluble protein13
biomarker
X
X
X
X
X
X
X
X
X
Blood sample – Optional PGx 
Sampling15
X15
ADA, anti-drug antibody; AE, adverse events; AESI, adverse event of special interest; C, complete physical examination; DLQI, dermatology life quality index; EASI, 
Eczema Area and Severity Index; ECG, electrocardiogram; EOS, End of Study; L, lesional; PGx, pharmacogenomics; NL, non lesional; PK, pharmacokinetic; SAE, serious 
adverse event; SCORAD, SCORing of Atopic Dermatitis; T, targeted physical examination; TB, tuberculosis


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(*)
Day of Randomisation / Day of first intake of randomised medication = Day 1. 
(**)
After the individual patient’s end of the trial the investigator should report only any occurrence of cancer, related SAEs and related AESIs of which the investigator 
may become aware of and only via the SAE form. Please refer to Section 5.2.5.2.
1- Initiation of randomized treatment at Visit 2 can only begin if the patient meets the criteria for Initiation of Treatment. Please refer to Sections 3.3.2 and 3.3.3.
2- At Visit 10, Non- Responders (NR) will receive their last study drug administration and Responders (R) will have their End of Study (EoS) visit. 
3- Should a patient prematurely discontinue before their scheduled EoS every effort should be made to keep the patient in the trial and complete all of the remaining study 
visits or at a minimum an early EoS visit. Patients who prematurely discontinue before V7/Wk16 are considered Non-Responders.
4- C = Complete Physical Examination (PE) includes general appearance as well as evaluation of all organ systems; T = Targeted physical examination includes evaluation of 
organ systems associated with AE(s) symptoms or laboratory abnormalities. At Visit 10 complete physical examination will be performed for Responders (EOS), targeted 
physical examination will be performed for Non-Responders. Please refer to Section 5.2.1.
5- Vital signs will be assessed at predose, at approximately 5 minutes after the end of infusion, and 60 mins after the end of infusion at visits with i.v. administration.
6- Safety laboratory tests include clinical chemistry, haematology, coagulation, and urinalysis, and will be performed centrally. Local Labs may to be used for dosing 
decisions prior to i.v. administration. Please refer to Section 5.2.3.
7- Only applicable for women of childbearing potential. S – serum pregnancy test (performed at screening). U – urine pregnancy tests will be performed at all other visits 
indicated 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. (S) - in case of a positive urine pregnancy test, a serum pregnancy test will be done. Please refer to Section 5.2.5.2.
8- ECG measurements should always precede blood sampling and drug administration. Clinically significant abnormal findings should be reported as AEs in the eCRF.
9- Infection testing includes tuberculosis, hepatitis B, hepatitis C, and HIV assessments. Please refer to Table 5.2.3: 1. For the EoS visit only tuberculosis and hepatitis B 
testing will be performed. For Responders the Infection testing will be conducted at V10 (Week28) which corresponds to their EoS. For Non Responders the Infection testing 
will be conducted at V11.
10- One (1) lesional (L) and One (1) non-lesional (NL) biopsy will be collected at V2 (baseline), One (1) lesional (L) biopsy will be collected at V4 (Week 4) and at V7 
(Week 16). One (1) optional lesional (L) will be collected at EoS (V10 for Responders or V11 for Non-Responders). Each skin biopsy of 4.5 mm punch (split into half for 
IHC and RNASeq) should be collected prior to trial drug infusion.
11- Photographs of skin lesions are to precede skin biopsies and study drug administration. Please refer to Section 5.6.
12- Skin tape stripping samples will be collected as close as possible to the site of the skin biopsy and at the same timepoint. Skin tape stripping samples must be taken before 
biopsies are taken and before trial drug infusion.  One (1) L and one (1) NL at V2; one (1) L at V4 (Week 4) and V7 (Week 16); and one (1) optional lesional (L) at EoS(V10
for Responders or V11 for Non-Responders) .
13- pre dose PK and ADA and Nab samples will be collected within 2 hour period prior to infusion. In addition, all biomarkers samples will be collected prior to trial drug
infusion. Please refer to Section 5.3.
14- Microbiome samples must be taken before biopsies are taken and before trial drug infusion.
15- Deoxyribonucleic acid (DNA) banking sample is optional. Participating patients are required to give informed consent specifically for this banking. Blood sample will be 
collected in a PAX-gene Blood DNA tube at day 1 (Visit 2). If not possible at Visit 2, this sample may also be collected during a later visit. The DNA banking sample must 
be collected prior to infusion of the trial drug infusion.
16- At V7 (Week 16) all patients will be evaluated with the EASI score. Non-responders will be re-allocated to receive BI open label trial drug from V7 (Week 16) onward 
until V10 (Week 28). Responders will be re-assigned to no treatment from V7 (Week 16) onward until V10 (Week 28) but will be expected to come to all visits.


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17- All assessments must be done prior to trial drug infusion.  The questionnaires completed by patients should be done first before the investigator assessments. Please refer 
to Section 6.2.
18- For Responders (R) the EoS visit must be completed 16 weeks after last treatment, which is at the latest at Week 28 (V10). Responders (R) may complete EOS at any 
point after V7 (Week 16) if the patient drops to an EASI 50 score prior to the planned EOS. For Non Responder (NR) patients who have achieved EASI 50 and plan to 
participate in the extension trial, the EoS visit will be completed no earlier than Week 32. Non Responder patients not participating in the extension trial will complete a 
V11/FU1 visit between Week 32-44. If a patient should discontinue treatment prematurely every effort should be made to keep the patient in the trial and complete all of the 
remaining study visits or at a minimum an early EoS visit 16 weeks after last treatment.
19- At V1 (Screening) BSA will be assessed for eligibility. From V2 (baseline) onward BSA will be completed as part of SCORAD assessment.
20- Only Non-Responders not participating in the open label extension trial must complete an End of Study Safety Phone Call. V11 and End of Study Safety Phone call can 
occur on the same day only if the Residual Effect Period (16 weeks after last trial drug infusion) has been reached (WK44). The phone call cannot be performed before the 
V11.
21- Patients will be asked about their pregnancy status at the End of Study Safety Phone Call.
22- For Non-Responders participating in the open label extension trial, End of Study completion IRT call is registered at V11 as the End of Study Safety Phone Call is not 
required. For Non-Responders not participating in the open label extension trial, End of Study completion IRT call is registered only at End of Study Safety Phone Call 
(WK44). V11 is not registered in IRT.


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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART........................................................................................................................6
TABLE OF CONTENTS ......................................................................................................10
ABBREVIATIONS................................................................................................................13
1.
INTRODUCTION...............................................................................................16
1.1
MEDICAL BACKGROUND.............................................................................16
1.2
DRUG PROFILE................................................................................................17
1.2.1
Mode of Action ....................................................................................................17
1.2.2
Nonclinical pharmacology..................................................................................17
1.2.3
Clinical experience..............................................................................................18
1.3
RATIONALE FOR PERFORMING THE TRIAL.........................................20
1.4
BENEFIT - RISK ASSESSMENT.....................................................................20
2.
TRIAL OBJECTIVES AND ENDPOINTS......................................................22
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........22
2.1.1
Main objectives....................................................................................................22
2.1.2
Primary endpoint................................................................................................22
2.1.3
Secondary endpoint(s) ........................................................................................22
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................24
3.1
OVERALL TRIAL DESIGN AND PLAN .......................................................24
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)......................................................................................25
3.3
SELECTION OF TRIAL POPULATION .......................................................25
3.3.1
Main diagnosis for trial entry ............................................................................25
3.3.2
Inclusion criteria .................................................................................................25
3.3.3
Exclusion criteria ................................................................................................26
3.3.4
Withdrawal of patients from treatment or assessments..................................27
3.3.4.1
Discontinuation of trial treatment .........................................................................27
3.3.4.2
Withdrawal of consent to trial participation .........................................................28
3.3.4.3
Discontinuation of the trial by the sponsor...........................................................28
4.
TREATMENTS...................................................................................................29
4.1
INVESTIGATIONAL TREATMENTS ...........................................................29
4.1.1
Identity of the Investigational Medicinal Products..........................................29
4.1.2
Selection of doses in the trial and dose modifications......................................30
4.1.3
Method of assigning patients to treatment groups...........................................30
4.1.4
Drug assignment and administration of doses for each patient......................30
4.1.5
Blinding and procedures for unblinding...........................................................31


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4.1.5.1
Blinding.................................................................................................................31
4.1.5.2
Unblinding and breaking the code ........................................................................31
4.1.6
Packaging, labelling, and re-supply...................................................................31
4.1.7
Storage conditions...............................................................................................31
4.1.8
Drug accountability.............................................................................................32
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ................................................................................................32
4.2.1
Other treatments and emergency procedures..................................................32
4.2.2
Emergency procedures .......................................................................................33
4.2.3
Restrictions ..........................................................................................................34
4.2.3.1
Restrictions regarding concomitant treatment ......................................................34
4.2.3.2
Restrictions on diet and life style..........................................................................35
4.2.3.3
Contraception requirements..................................................................................36
4.3
TREATMENT COMPLIANCE........................................................................36
5.
ASSESSMENTS..................................................................................................37
5.1
ASSESSMENT OF EFFICACY........................................................................37
5.2
ASSESSMENT OF SAFETY.............................................................................38
5.2.1
Physical examination ..........................................................................................38
5.2.2
Vital signs.............................................................................................................38
5.2.3
Safety laboratory parameters ............................................................................39
5.2.4
Electrocardiogram (ECG)..................................................................................41
5.2.5
Assessment of adverse events.............................................................................42
5.2.5.1
Definitions of AEs ................................................................................................42
5.2.5.2
Adverse event collection and reporting ................................................................45
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS...................................................................................47
5.3.1
Assessment of pharmacokinetics .......................................................................47
5.3.2
Methods of sample collection .............................................................................47
5.3.2.1
Plasma sampling for pharmacokinetic analysis ....................................................47
5.3.2.2
Sampling for ADA/Nab assessment .....................................................................48
5.3.4
Pharmacokinetic – pharmacodynamic relationship........................................48
5.5
BIOBANKING ....................................................................................................50
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
Screening..............................................................................................................53
6.2.2
Randomization Visit and Treatment Visits ......................................................54
6.2.2.1
Clinical monitoring after study drug administration.............................................54
6.2.2.2
Unscheduled visits ................................................................................................55


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6.2.2.3
End of Study Visit and Safety Phone Call ............................................................55
6.2.3
Trial Completion and End of Residual Period.................................................55
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................57
7.1
STATISTICAL DESIGN - MODEL.................................................................57
7.2
NULL AND ALTERNATIVE HYPOTHESES ...............................................57
7.3
PLANNED ANALYSES.....................................................................................58
7.3.1
Primary endpoint analyses.................................................................................58
7.3.2
Secondary endpoint analyses .............................................................................59
7.3.4
Safety analyses.....................................................................................................60
7.3.5
Pharmacokinetic and pharmacodynamic analyses..........................................60
7.4
INTERIM ANALYSES ......................................................................................61
7.5
HANDLING OF MISSING DATA ...................................................................61
7.6
RANDOMISATION ...........................................................................................62
7.7
DETERMINATION OF SAMPLE SIZE .........................................................62
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY, AND ADMINISTRATIVE STRUCTURE ........64
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT ...........................................................................................................64
8.2
DATA QUALITY ASSURANCE ......................................................................65
8.3
RECORDS...........................................................................................................65
8.3.1
Source documents ...............................................................................................65
8.3.2
Direct access to source data and documents.....................................................66
8.3.3
Storage period of records ...................................................................................66
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS ..................................67
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY........67
8.5.1
Collection, storage and future use of biological samples and corresponding 
data.......................................................................................................................67
8.6
TRIAL MILESTONES.......................................................................................67
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ...................................68
9.
REFERENCES....................................................................................................70
9.1
PUBLISHED REFERENCES............................................................................70
9.2
UNPUBLISHED REFERENCES......................................................................73
10.
APPENDICES.....................................................................................................74
10.1
INSTRUCTIONS FOR USE..............................................................................74
10.1.1
Diagnosis of Anaphylaxis....................................................................................74
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .........................................75
11.1
GLOBAL AMENDMENT 1 ..............................................................................75
11.2
GLOBAL AMENDMENT 2 ..............................................................................75
11.3
GLOBAL AMENDMENT 3 ..............................................................................82


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ABBREVIATIONS
AD
Atopic Dermatitis
ADA
Anti-Drug Antibodies
ADCC
Antibody-Dependent Cellular Cytotoxicity
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALQ
Above limit of quantification
ALT
Alanine Aminotransferase
AST
Aspartate Transaminase 
BI
Boehringer Ingelheim
BLQ
Below limit of quantification
CA
Competent Authority
CDC
Complement Dependent Toxicity
CI
Confidence Interval
CMH
Cochran-Mantel-Haenszel
CRA
Clinical Research Associate
CRF
Case Report Form, paper or electronic (sometimes referred to as “eCRF”)
CRO
Contract Research Organization
CTL
Clinical Trial Leader
CTP
Clinical Trial Protocol
CTM
Clinical Trial Manager
DBL
Database Lock
DILI
Drug Induced Liver Injury
DLQI
Dermatology Life Quality Index
DMC
Data Monitoring Committee
EASI
Eczema Area and Severity Index
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
eDC
Electronic Data Capture
EoS
End of Study
EudraCT
European Clinical Trials Database
FAS
Full Analysis Set
GCP
Good Clinical Practice


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GMP
Good Manufacturing Practice
GPP
Generalised Pustular Psoriasis
HA
Health Authority
i.v.
intravenous
IBD
Inflamatory Bowel Disease
ICH
International Council on Harmonization
IEC
Independent Emmittee
IGA
Investigator's Global Assessment
IHC
Immunohistochemistry
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
IUD
Intrauterine Device
IUS
Intrauterine Hormone-Releasing System
LLOQ
Lower limit of quantification
LPLT
Last Patient Last Treatment
MedDRA
Medical Dictionary for Drug Regulatory Activities
MMRM
Mixed model with repeated measurements
Nab
Neutralizing Antibody
NOAEL
No-observed-adverse-effect level
OPU
Operative Unit
PBMC
Peripheral blood mononuclear cell
PK
Pharmacokinetics
PPP
Palmoplantar Pustulosis
RA
Regulatory Authority
RCTC
Rheumatology Common Toxicity Criteria
REML
Restricted maximum likelihood
REP
Residual Effect Period
s.c.
subcutaneous
SAE
Serious Adverse Event
SAF
Safety Analysis Set
SD
Standard Deviation
SCORAD
SCORing of Atopic Dermatitis
SoC
Standard of Care


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SOP
Standard Operating Procedure
SUSAR
Suspected Unexpected Serious Adverse Reactions
TMDD
Target-Mediated Drug Disposition
TSAP
Trial Statistical Analysis Plan
ULN
Upper Level of Normal
ULOQ
Upper limit of quantification
WHO
World Health Organization
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 (prutitis). 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 
IL-13, IL-4, IL-33, IL-17 and IL-22. IL-36 is thought to have a pivotal role in amplifying 
these immune pathways and may be a critical link between S. aureus infection and 
exacerbation of AD inflammation.
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 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).
1.2.2
Nonclinical pharmacology
Preclinical studies
BI 655130 binds to human IL36R with a binding avidity of less than 1 pM. BI 655130
inhibits IL36 ligand-stimulated NF-B activation in HT29 and transformed epithelial cells
and in primary human dermal fibroblasts or intestinal myofibroblasts with IC90 values in a 
consistent range of 0.7 to 3.7 nM. BI 655130 also inhibits IL8 release in primary human 
intestinal myofibroblasts and IFNγ secretion in human peripheral blood mononuclear cell
(PBMC) stimulated with IL36α, IL36β, or IL36γ combined with IL12.
Mutations of two key residues (L234 and L235) to alanine were made to BI 655130 to 
abrogate FcR binding activity and function. Direct assessment of the impact of the mutations 
in the IgG1 FcR binding sites on both antibody-dependent cellular cytotoxicity (ADCC) and 
complement-dependent cytotoxicity (CDC) effector functions revealed that the mutations 
abrogate both ADCC and CDC effector functions and indicate that BI 655130 will be a non-
depleting therapy in vivo.
Toxicology studies
As BI 655130 does not demonstrate adequate pharmacological activity in common
toxicology species, a surrogate antibody (BI 674304) specific for mouse IL36R was
developed and used for toxicology assessments. In a 13-week intravenous toxicity study of BI 
674304 in mice, no adverse effects of IL36R antagonism were seen at a dose (50 mg/kg, 
twice weekly) that was 5 fold higher than the dose that was protective in an experimental 
mouse colonic inflammation model. The in vitro cytokine release and tissue cross-reactivity 
assays demonstrate that the risk of transient cytokine release in humans is low and that, as 
expected, BI 655130 stains epithelium in a variety of tissues. There were no signs of local 
irritation after single, 1 mL injections of the subcutaneous formulation in rabbits. 
In intravenous toxicity studies of up to 26 weeks in duration in mice, no adverse effects of 
IL36R antagonism were seen at a dose that was 5 fold higher than the dose predicted for 
human studies. Based on these results, the no-observed-adverse-effect level (NOAEL) was 
considered to be 50 mg/kg/dose.


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In developmental and reproductive toxicity studies there was no evidence of effects on 
fertility or embryonic development in mice after administration of 50 mg/kg/dose of BI 
674304 in directed fertility and embryonic development studies.
1.2.3
Clinical experience
As of April 2019, five clinical phase I trials and one clinical phase II trial have been 
completed for BI 655130; 4 phase I trials were conducted in healthy volunteers (HV), 1 phase 
I trial in GPP patients and 1 phase II trial in PPP patients. 
A total of 187 healthy volunteers have been exposed to single or multiple doses of BI 655130 
in 4 phase I studies which assessed safety, tolerability, PK and PD of BI 655130 in healthy 
volunteers [c09985235-01]. 

Study 1368.1 was a single escalating dose trial with i.v. infusions of placebo or BI 
655130 up to 10 mg/kg [c09985235-01]. The most frequently reported treatment-
emergent AEs were nasopharyngitis (BI 655130: 20.7%; placebo: 15.0%), headache 
(BI 655130: 8.6%; placebo: 15.0%), influenza like illness (BI 655130: 6.9%; placebo: 
10.0%), and diarrhoea (BI 655130: 3.4%; placebo: 10.0%). All AEs were of mild or 
moderate intensity and were resolved by the end of the trial.There were no serious 
AEs and no AEs that led to discontinuation of trial drug.

Study 1368.2 was a multiple rising dose trial with subjects receiving up to 20 mg/kg 
in a single intravenous infusion weekly for 4 weeks. The incidence of nervous system 
disorders (especially headache) appeared to be higher in the 20 mg/kg BI 655130 
group than in the other treatment groups. Two subjects experienced dyspnoea only in 
the 20 mg/kg group. Additionally, gastrointestinal disorders (diarrhoea and nausea) 
and nasopharyngitis appeared to occur more often in subjects who received BI 655130 
than in subjects who received placebo. Infusion related reaction, decreased appetite, 
and anxiety were reported for 1 subject in the 20 mg/kg BI 655130 treatment group.

Study 1368.3 was a relative bioavailability trial in 36 subjects of a subcutaneous (s.c.) 
formulation of BI 655130 at two different dose strengths (150 mg and 300mg). The 
most frequent local events reported were redness and swelling at the injection site, all 
were mild in intensity, occurred within 30 minutes after injection and completely 
resolved within 4 hours. There were no reports of injection site pain.

Study 1368.9 was a single rising dosing trial in 32 Japanese healthy volunteers 
receiving different i.v. doses of BI 655130 (300 mg, 600 mg, and 1200 mg) or one 
subcutaneous dose (300 mg). Adverse events by preferred term reported on placebo 
were vomiting, chest incomfort, and allergic rhinitis, while AEs reported on BI 
655130 were upper respiratory infection (300 mg i.v.), contusion (600 mg i.v.), 
gastroenteritis (1200 mg i.v.), and temporomandibular joint syndrome (1200 mg i.v.). 
None of the observed AEs were judged by the investigator as related to the trial 
medication.
The first study in patients was conducted as an open-label, single arm phase I study to 
explore the safety, tolerability, PK and efficacy of BI 655130 in GPP (1368.11). A total of 7 
patients with acute GPP were enrolled and treated with a single intravenous dose of BI 
655130 (10 mg/kg). Proof-of-concept was achieved with the first 7 patients treated, who 
showed rapid clinical responses to single administrations of BI 655130 with good safety and 


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tolerability. The early response in the skin was also accompanied by an early and rapid 
response in systemic components (C-Reactive Protein [CRP] approaching normalization 
within 4 weeks). All patients (7/7) reported at least 1 AE while on-treatment and in 4 patients 
(57.4%) AEs considered drug-related by the investigators were reported. None of the reported 
AEs was severe, serious or led to discontinuation.The most frequently reported treatment-
emergent AE was arthralgia (3 out of 7 patients [42.9%]). Eosinophilia, chills, oedema 
peripheral, pyrexia, upper respiratory tract infection, and eczema were each reported in 2 
patients [28.6%]
Study 1368.15, a randomised placebo controlled study investigated the safety, tolerability, 
pharmacokinetics, pharmacogenomics and efficacy of 2 intravenous doses of BI 655130 in 59 
patients with palmoplantar pustulosis psoriasis. Patients were randomized in a 1:1:1 
allocation ratio and received either 900 mg BI 655130, 300 mg BI 655130 or placebo 
intravenously every 4 weeks over a period of 12 weeks. 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). However, post-hoc subgroup analyses indicated efficacy of both doses of BI 655130 in 
patients with more severe PPP disease at baseline (above the median PPPASI value of 16.7). 
In particular, the results on pustule severity were pronounced with a rapid reduction in 
pustule severity with evidence of a dose response relationship.
In total, 85.7% in the placebo arm and 89.5% in each of the BI 655130 arms (300 mg and 900 
mg) reported at least 1 AE while on treatment. There were 3 AEs leading to discontinuation 
of trial drug in the placebo arm (14.3%), whereas 1 patient in the 300 mg dosing arm (5.3%) 
and 3 patients in the 900 mg dosing arm (15.8%) discontinued trial medication due to an 
adverse event. The most frequently reported treatment-emergent AE were nasopharyngitis 
(placebo 38.1%, 300 mg BI 655130 26.3%, 900 mg BI 655130 42.1%) and headache 
(placebo 33.3%, 300 mg BI 655130 21.1%, 900 mg BI 655130 31.6%).
PK data indicate target-mediated drug disposition (TMDD) of BI 655130. The saturation of 
the non-linear elimination pathway is likely occurring after 0.3 mg/kg and BI655130 exhibits 
linear kinetics at dose-level greater than 0.3 mg/kg. The half-life of BI655130 is 
approximately 4 weeks in the linear dose range and thus similar to otherIgG1 molecules. 
In one patient an infusion related reaction was reported. The patient felt “heat” after the 
infusion of the trial medication during Visit 3. The event was not accompanied by other 
symptoms, in particular vital signs remained stable. The patient recovered without treatment. 
There were no clinically relevant abnormalities on treatment with BI 655130 with respect to
safety laboratory and vital signs.
Summary 
BI 655130 has been tested and found safe and tolerable in humans in single and multiple 
rising dose trials 1368.1, 1368.2, 1368.3 and 1368.9 in healthy male and female subjects and 
in trial 1368.11 in GPP patients and in trial 1368.15 in PPP patients. The most frequently 
reported treatment-emergent AEs were viral upper respiratory tract infection, 
nasopharyngitis, headache, influenza like illness and injection site erythema, without any 
dose-dependency. One potential infusion reaction has been reported in a subject who 


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discontinued his third infusion of BI 655130 in 1368.2. All AEs were resolved by the end of 
the trial. There were no relevant changes in safety laboratory tests, vital signs, or ECGs
For further details and most up-to-date results refer to the current "Investigator`s Brochure" 
[c03320877-05].
1.3
RATIONALE FOR PERFORMING THE TRIAL
Although the pre-clinical data and rationale for the use of an IL-36R antagonist in AD are 
strong, there are no clinical data on this mechanism of action in AD. Thus, a small proof of 
clinical concept study is planned to assess safety, tolerability and efficacy in patients with 
moderate to severe AD. 
In order to be able to address future scientific questions, patients will be asked to voluntarily 
donate biospecimens for banking (please see Section 5.4). If the patient agrees, banked 
samples may be used for future biomarker research and drug development projects, e.g. to 
identify patients that are more likely to benefit from a treatment or experience an adverse 
event (AE), or to gain a mechanistic or genetic understanding of drug effects and thereby 
better match patients with therapies.
1.4
BENEFIT - RISK ASSESSMENT
The positive efficacy data obtained in GPP (trial 1368.11) confirms BI 655130's mechanism 
of action of effectively blocking the IL36 pathway thereby providing support for potential 
benefit in diseases where the IL36 pathway appears to contribute to disease. Furthermore, the 
clinical safety data support clinical studies in patients with repeat doses up to 20mg/kg
IV qw.
There is no direct benefit for individual participants in this study, because efficacy of BI 
655130 has not been demonstrated in AD and because some patients will initially be 
randomised to the placebo arm. Participation in this study may help to generate future benefit 
for larger groups of patients with atopic dermatitis if BI 655130 proves to be successful in 
treating this disease. In order to assess any future benefit for atopic dermatitis patients, it is 
critical to have a placebo control to address potential confounding factors, such as placebo 
effect, regression to the mean in endpoint scoring or potential investigator bias in safety and 
efficacy assessments. Patients who are initially randomized to placebo and do not respond 
will be given the opportunity to receive BI 655130 after the Week 16 primary analysis.
One subject in trial 1368.2 appeared to have an infusion reaction at a dose of 20 mg/kg, thus 
patients in this trial will be closely monitored for infusion reactions, including measurement 
of pulse and blood pressure prior to infusion and approximately 5 and 60 minutes after the 
end of infusion.
Humans with congenital absence of IL36R have no adverse clinical signs or symptoms, 
including susceptibility to infection or reactivation of chronic infections. Nonetheless, given 
this is the first trial in patients with atopic dermatitis, patients with active infection or certain 
chronic infections (HIV, HBV, TB) will be excluded.


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The mouse specific analogue of BI 655130 has been tested in embryo-fetal and fertility and 
early embryonic development studies. There was no evidence of effects on fertility or 
embryonic development (teratogenicity) in mice after administration of 10 or 50 mg/kg/dose.
Thus, men and women of child bearing potential with appropriate birth control can be 
included in clinical trials with BI 655130. Women of child bearing potential with appropriate 
birth control can be included in clinical trials with BI 655130 but must maintain a highly 
effective method of contraception throughout the course of trials with BI 655130 and up to 16
weeks after the last study drug infusion. Contraception of male trial precipitants and female 
partners of male trial participants are not required based on the toxicity studies conducted in 
mice. Due to the outcome of the completed teratogenicity study a double barrier method of 
contraception is not required.
Currently there are no data available allowing the conduct of clinical trials in pediatric
patients, pregnancy and lactation. Until such data are available, these patients will be
excluded from this study (1368-0032).
Currently there are no data available to suggest interactions of BI 655130 with other drugs 
[c03320877-05].
Considering the medical need for development of an effective and well tolerated drug for the 
therapy of AD, the benefit of this trial is considered to outweigh the potential risks and 
justifies the administration of multiple doses of BI 655130 to patients with AD to investigate
safety, tolerability and efficacy.


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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 investigate the safety, tolerability and efficacy of BI 
655130 in patients with AD following multiple intravenous administrations of 600 mg
compared to placebo.
While the main objective is to assess safety and tolerability of BI55130 in patients with AD, 
these endpoints can only be analyzed descriptively. Thus, the endpoints to be discussed 
below will focus on efficacy endpoints that are more amenable to other statistical analyses 
and where sample size considerations may be more relevant.
A description of the endpoints to be determined, and the observations along with specific 
information as how to collect the data for that information, is provided in Section 5.
2.1.2
Primary endpoint
The primary efficacy endpoint for this trial is the percentage change from baseline in the 
Eczema Area and Severity Index (EASI) Score at Week 16.
2.1.3
Secondary endpoint(s)
Secondary efficacy endpoints are

Number of patients with drug related AEs

Absolute and percentage change from baseline in EASI at Week 4 

Proportion of patients with a 50% improvement from baseline in EASI (EASI50) at 
Week 4 and 16

Proportion of patients with a 75% improvement from baseline in EASI (EASI75) at 
Week 4 and 16

Change from baseline in SCORAD at Week 4 and 16 

Proportion of patients achieving at least a 2-grade reduction from baseline to clear (0) 
or almost clear (1) in IGA at Week 4 and 16


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This is a double-blind, placebo-controlled study assessing the safety, tolerability and efficacy 
of 600 mg BI 655130 compared to placebo given intravenously every 4 weeks in patients 
with moderate to severe atopic dermatitis. Safety and tolerability will be evaluated based on 
AE data collected and physical examination at every visit. At W16 patients will be evaluated 
for response to treatment by the change in EASI score compared to baseline. Patients who 
have responded, defined as having attained at least 75% reduction in EASI score compared to 
baseline will no longer receive treatment and will be followed at W 20, 24 and 28 to evaluate 
the sustainability of their response. If this patient reaches a 50% reduction in EASI score 
compared to baseline prior to the planned EOS at Week 28, they will immediately perform
EOS and will be given the opportunity to receive treatment in an open label extension trial. 
Patients who have not responded, defined as attained less than 75% reduction in EASI score 
compared to baseline will receive 600 mg BI 655130 at W16, 20, 24 and 28. Patients re-
allocated to treatment, who reach EOS will be offered participation in the extension trial if 
they meet the eligibility criteria.
After re-allocation at Week 16, a patient will know what treatment they are on but will 
remain blinded to the treatment received until Week 16.
Figure 3.1.1 Trial design
600 mg i.v.
Placebo i.v.
Treatment period
No Treatment
600 mg i.v.
screening
V1
V2
W4
V5
V6
V7/W16
Treatment 
re-allocation period
Patient 
assessment
V7
V8
V9
V10
V11
N=30
N=15
W0
V4
W8
W12
W16
Open 
label 
Extension
Trial
W20
W24
W28
Primary efficacy endpoint
Change in EASI at week 16
BI 655130 600 mg i.v.
Placebo i.v.
Study drug administration
V – Study Visit 
W – Week  (study visits)
Responders
(EASI ≥ 75)
Non-Responders
(EASI<75)
V3
W2
End of Study 
Safety Call †
W32 
or 
later*
W44†


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3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
The placebo control is required to control for investigator bias and/or beneficial effects of 
being in a clinical trial. The 2:1 randomization (active: placebo) is warranted in order to 
maximize the number of patients receiving active treatment and is being controlled for from a 
statistical standpoint. The rationale for switching responding patients to follow-up with no-
treatment at Week 16 is to evaluate the duration of clinical response off treatment. In addition, 
patients who have not attained at least a 75% reduction in EASI score compared to baseline
will have the opportunity to receive (or continue) active treatment.
3.3
SELECTION OF TRIAL POPULATION
3.3.1
Main diagnosis for trial entry
This study will include adult patients diagnosed with atopic dermatitis for at least 1 year who 
developed moderate to severe atopic dermatitis with documented inadequate response to 
topical corticosteroid and be willing to discontinue topical corsticosteroid 7 days or systemic 
corticosteroid 4 weeks before first administration of trial treatment.
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. Male or female patients, 18 to 75 years of age at screening
3. Diagnosis of atopic dermatitis for at least 1 year
4. Moderate to severe atopic dermatitis defined as:

At least 10% Body Surface Area (BSA) of atopic dermatitis involvement at screening
and baseline

Eczema Area and Severity Index (EASI) of at least 12 at screening and at least 16 at 
baseline

Investigator Global Assessment (IGA) of at least 3 at screening and baseline
5. Documented history of inadequate response to topical corticosteroid as judged by the 
investigator
6. Willing to use a standard emollient for the duration of the study
7. Women of childbearing potential (WOCBP)2 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 
                                                
2 A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-
menopausal unless permanently sterile. 
Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy.
Tubal ligation is NOT a method of permanent sterilisation.


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than 1% per year when used consistently and correctly. A list of contraception methods 
meeting these criteria is provided in the patient information.
3.3.3
Exclusion criteria
1. Use of topical corticosteroids or other agents for atopic dermatitis within 7 days prior to 
first dose of trial treatment.
2. Use of systemic corticosteroids or other agents for atopic dermatitis within 4 weeks prior 
to first dose of trial treatment (for more details refer to Table 4.2.3.1: 1).
3. Women who are pregnant, nursing, or who plan to become pregnant while in the trial. 
Women who stop nursing before the study drug administration do not need to be excluded 
from participating; they should refrain from breastfeeding up to 16 weeks after the last 
study drug administration (see Section 4.2.3.3)
4. Patient with a transplanted organ (with exception of a corneal transplant > 12 weeks prior 
to screening) or who have ever received stem cell therapy (e.g., Prochymal).
5. Any documented active or suspected malignancy or history of malignancy within 5 years 
prior to the screening visit, except appropriately treated basal cell carcinoma of the skin,
squamous cell carcinoma of the skin or in situ carcinoma of uterine cervix.
6. Use of any restricted medication as specified in Table 4.2.3.1: 1 or any drug considered 
likely to interfere with the safe conduct of the study, as assessed by the investigator.
7. History of allergy/hypersensitivity to the systemically administered trial medication agent 
or its excipients.
8. Active systemic infections (Fungal and bacterial disease) during the last 2 weeks prior to 
first drug administration, per investigator assessment.
9. Relevant chronic or acute infections (exception: common cold) including human 
immunodeficiency virus (HIV) or viral hepatitis. A patient can be re-screened if the 
patient was treated and is cured from the acute infection. 
10. Active or Latent TB:
Patients with active tuberculosis are excluded.
Patients with a positive QuantiFERON TB test during screening are excluded, unless:

Patient had previous diagnosis of active or latent TB and has completed 
appropriate treatment per local practice/guidelines within the last 3 years and at 
least  6 months before first administration of trial medication under this protocol 
(patients may be re-screened once to meet this criterion)

Patients with suspected false positive or indeterminate QuantiFERON TB result 
may be re-tested once 

If the QuantiFERON TB test result is not available or provides indeterminate 
results after repeat testing: A tuberculin skin test reaction ≥10mm (≥5mm if 
receiving ≥15mg/d prednisone or its equivalent) is considered positive.
                                                                                                                                                       
A postmenopausal state is defined as no menses for 12 months without an alternative medical cause.


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11. Currently enrolled in another investigational device or drug trial, or less than 30 days or 5 
half lives, whichever is longer since ending another investigational device or drug trial(s), 
or receiving other investigational treatment(s).
12. 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.
13. Major surgery (major according to the investigator) performed within 12 weeks prior to 
first study drug adminstration or planned during the study (e.g. hip replacement, 
aneurysm removal, stomach ligation).
14. Severe, progressive, or uncontrolled hepatic disease, defined as >3-fold Upper Limit of 
Normal (ULN) elevation in AST or ALT or alkaline phosphatase, or >2-fold ULN 
elevation in total bilirubin.
3.3.4
Withdrawal of patients from treatment or assessments
Patients may discontinue trial treatment or withdraw consent to trial participation as a whole
(“withdrawal of consent”) with very different implications; please see Sections 3.3.4.1 and 
3.3.4.2 below.
Every effort should be made to keep the patients in the trial: if possible on treatment, or at 
least to collect important trial data.
Measures to control the withdrawal rate include careful patient selection, appropriate 
explanation of the trial requirements and procedures prior to trial enrolment, as well as the
explanation of the consequences of withdrawal. 
The decision to discontinue trial treatment or withdraw consent to trial participation and the 
reason must be documented in the patient files and 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 needs to take concomitant medication that interferes with the investigational 
medicinal product or other trial treatment, please see Section 4.2.3.

The patient can no longer receive trial treatment for medical reasons (such as surgery, 
adverse events, other diseases, or pregnancy).


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
For individual stopping rules related to specific adverse events, please see Section 4.2.
In case of a temporary discontinuation of trial treatment, trial treatment should be restarted as 
soon as medically justified, please see Section 4.1.4, 4.2.2. Even if the trial treatment is 
discontinued, the patient remains in the trial and, given his/her agreement, will undergo the 
procedures for early treatment discontinuation and follow up as outlined in the Flow Chart
and Section 6.2.3.
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 (BI) 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. Violation of 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
The investigational product has been manufactured by BI Pharma GmbH & Co. KG, 
Biberach, Germany. The BI 655130 molecule is an anti-human IL36 receptor monocloncal 
antibody heterodimer with a molecular weight of approximately 146 kDa.
BI 655130 solution for infusion (i.v. administration) is formulated at 60 mg/mL presented in 
a 10 mLvial with a nominal fill volume of 7.5 mL (450 mg).
4.1.1
Identity of the Investigational Medicinal Products
Table 4.1.1: 1 
Study Compound
Substance:
BI 655130
Pharmaceutical formulation:
Solution for infusion
Source:
BI Pharma GmbH & Co. KG, Biberach,
Germany
Unit strength:
BI 655130 450 mg/vial (60 mg/mL), 7.5 mL
fill volume
Posology:
600 mg i.v. infusion once every 4 weeks 
Method and route of administration:
i.v. infusion
Table 4.1.1: 2 
Placebo comparator
Substance:
Placebo
Pharmaceutical formulation:
Solution for infusion
Source:
BI Pharma GmbH & Co. KG, Biberach,
Germany
Unit strength:
Placebo to BI 655130 450 mg/vial (60
mg/mL), 7.5 mL fill volume
Posology:
0 mg i.v. infusion once every 4 weeks
Method and route of administration:
i.v. infusion
At the time of use the i.v. solutions for dosing will be prepared as detailed in the instruction 
in the ISF.


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4.1.2
Selection of doses in the trial and dose modifications
A fixed rather than weight-based dose regimen of single dose of 600 mg has been 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].
4.1.3
Method of assigning patients to treatment groups
An Interactive Response Technology (IRT) will be used to screen and randomise eligible 
patients, perform subsequent drug assignment, manage initial/re-supply ordering of drug
supplies and handle emergency un-blinding. The investigator will receive all necessary
instructions to access IRT from the Sponsor or chosen provider. Detailed IRT functions and 
procedures will be documented in the user requirement specifications mutually agreed to by
the sponsor and the IRT vendor. Patients will be randomly assigned to one of the treatment
groups through the assignment of medication which will be treatment group-specific (Section 
3.1). For technical and statistical features of the treatment allocation process, please see.
Sections 4.1.4 and 7.6.
During Visit 2 (W0) and after the patient’s eligibility has been confirmed, the treatment will 
be assigned via IRT. Patients will be randomized to receive BI 655130 600 mg or placebo in 
a ratio of 2:1. The assignment will occur in a blinded fashion via IRT. 
During Visit 7 (W16) patients will be evaluated with the EASI scoring system (see Section 
5.1) and based on the response will be reassigned via IRT to receive BI 655130 600 mg or no 
treatment at all.  The re-assignement will occur in an open label fashion.
4.1.4
Drug assignment and administration of doses for each patient
In all patients, the infusion solution is intended to be intravenously administered over a 
period of 90 minutes. In case of safety concerns, e.g. due to infusion reactions, it is at the 
discretion of the investigator or his/her designee to adapt the infusion scheme, including but 
not limited to slowing down the infusion rate, stopping the infusion, and provided no further 
safety concern exists, restarting at a slower rate. Regardless, the total duration of infusion 
should not exceed 180 minutes (3 hours). Further based on his/her medical judgment the 
investigator will provide medications as needed.
The administration of the trial medication will be done under the supervision of the 
investigating physician or a designee. The so-called four-eye principle (two-person rule) 
should be applied for administration of trial medication and – if applicable – its preparation, 
if correct dosage cannot be ensured otherwise.


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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.
4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
Patients, investigators and everyone involved in trial conduct or analysis or with any other
interest in this double-blind trial will remain blinded with regard to the randomised treatment 
assignments until after the data base lock (DBL) for the primary analysis. The randomisation
code will be kept secret by Clinical Trial Support up to the interim database lock at Week 16.
The randomisation codes will be provided to bioanalytics prior to last patient completed to 
allow for the exclusion from the analyses of pharmacokinetic (PK) samples taken from 
placebo patients. Bioanalytics will not disclose the randomisation code or the results of their 
measurements until the trial is officially unblinded.
4.1.5.2
Unblinding and breaking the code
Emergency unblinding will be available to the investigator via IRT. It must only be used in
an emergency situation when the identity of the trial drug must be known to the investigator
in order to provide appropriate medical treatment or otherwise assure safety of trial
participants. The reason for unblinding must be documented in the source documents and/or 
appropriate CRF page.
Due to the requirements to report Suspected Unexpected Serious Adverse Reactions 
(SUSARs), it may be necessary for a representative from BI’s Pharmacovigilance group to 
access the randomisation code for individual patients during trial conduct. The access to the 
code will only be given to authorised Pharmacovigilance representatives and not be shared 
further. 
4.1.6
Packaging, labelling, and re-supply
The investigational medicinal products will be provided by BI or a designated CRO. They 
will be packaged and labelled in accordance with the principles of Good Manufacturing 
Practice (GMP). Re-supply to the sites will be managed via an IRT system, which will also 
monitor expiry dates of supplies available at the sites. 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


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(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 Institutional Review Board (IRB) / ethics 
committee,

Availability of a signed and dated clinical trial contract between the sponsor and the 
investigational site,

Approval/notification of the regulatory authority, e.g. competent authority (CA),

Availability of the curriculum vitae of the Principal Investigator,

Availability of a signed and dated clinical trial protocol,

Availability of the proof of a medical license for the Principal Investigator,

Availability of FDA Form 1572 (if applicable).
Investigational drugs are not allowed to be used outside the context of this protocol. They 
must not be forwarded to other investigators or clinics. 
The investigator or designee must maintain records of the product’s delivery to the trial site, 
the inventory at the site, the use by each patient, and the return to the sponsor or warehouse / 
drug distribution centre or alternative disposal of unused products. If applicable, the sponsor 
or warehouse / drug distribution centre will maintain records of the disposal. 
These records will include dates, quantities, batch / serial numbers, expiry (‘use- by’) dates, 
and the unique code numbers assigned to the investigational medicinal product and trial
patients. The investigator or designee will maintain records that document adequately that the 
patients were provided the doses specified by the CTP and reconcile all investigational 
medicinal products received from the sponsor. At the time of return to the sponsor or
appointed CRO, the investigator or designee must verify that all unused or partially used drug 
supplies have been returned by the clinical trial patient and that no remaining supplies are in
the investigator’s possession.
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
Stable doses of concomitant therapies for chronic conditions, for which neither the condition 
nor the treatment are judged to exclude the patient from participation (see Section 3.3), 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.


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During the trial, if the severity and progression of the disease worsens, the investigator can 
treat the patient with Standard of Care (SoC) of his/her choice. All efforts should be made to 
inform the patient of the importance of coming to the protocol specified visits (See Flow 
Chart) up to the EoS visit. Patients refusing to return to the study site for scheduled visits 
after the end of treatment should at least provide safety information by phone at the 
respective visits.
Overall, the choice of the escape treatment i.e Standard of Care treatment will be left at the 
discretion of the investigator. The sponsor will not provide/supply SoC treatment(s) to the 
sites. If a patient receives escape treatment the decision to maintain the patient on trial 
treatment will be decided with discussion between the investigator and sponsor.
4.2.2
Emergency procedures
Infusion reactions including anaphylactic reaction
In case of infusion reactions including anaphylactic reaction emerging during or after 
infusion of trial medication, the investigator should consider in accordance with severity of 
the reaction and local standard of care to:
-
Immediately interrupt the infusion
-
Treat with systemic anti-histamines, i.v. steroids, and in case of a severe allergic 
reaction (eg, anaphylactic reaction) epinephrine
Also draw a plasma sample for IgE and ADA as detailed in the Lab Manual (Central 
laboratory). Consider also the evaluation of histamine, serum tryptase, and complement 
components.
In case of infusion reaction, based on patient’s clinical course and medical judgment, the 
infusion may be re-initiated in case of mild or moderate infusion reactions (according to 
Rheumatology Common Toxicity Criteria (RCTC) V2) at lower speed with gradual increase 
to complete the infusion as detailed in the Instructions for Preparation and Handling of BI 
655130 in the ISF. In any case, the total duration of infusion should not exceed 180 minutes 
(3 hours).
In case of potential systemic allergic reaction, blood samples for determination of serum 
tryptase will be collected 0.5 h, 2 h, 6 h, 24 h after onset of the event.
In case of suspected drug related anaphylactic reaction (Appendix 10.1.1) the investigator 
should discontinue treatment permanently with BI 655130.
Severe infections (according to RCTC V2), serious infections, opportunistic or 
mycobacterium tuberculosis infections.
Treatment of the infection should be initiated promptly according to local standard of care. 
No further trial medication should be administered until the active infection has resolved. 
Treatment with BI 655130 may be restarted when the patient has recovered according to 
investigator’s assessment.


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Overall, the choice of Standard of Care treatment will be left at the discretion of the 
investigator. The sponsor will not provide/supply SoC treatment (s) to the sites.
4.2.3
Restrictions
4.2.3.1
Restrictions regarding concomitant treatment
The medications (or classes of medications) listed in Table 4.2.3.1: 1 must not have been 
taken before inclusion for the time periods as specified, and are not permitted throughout the 
study participation.
Patients are prohibited from receiving the following therapies, during trial treatment and prior 
to Visit 2 for the duration specified in the Table below.
Patients who are re-allocated as Non-Responders at Visit 7 (Week 16) and have not reached a 
50% reduction in EASI score compared to baseline at End of Treatment are prohibited from 
receiving the following therapies through to End of Study:
Table 4.2.3.1: 1
Restricted medications
Medication or class of medications1, 2
Restriction duration prior to Visit 2
UVB phototherapy (including self-treatment 
with tanning beds or therapeutic sunbathing), 
PUVA
4 weeks
Hydroxyzine, diphenhydramine, doxepin3
1 week
Any other topical medication than the 
provided emollient (e.g. moisturizers 
containing urea, calcineurin inhibitors, 
topical corticosteroids)4
1 week
Azathioprine
4 weeks
Investigational products (including biologics)
30 days or 5 half-lives (whichever is 
longer)
IL36R inhibitors
before and during trial participation
All other biologics, including but not limted 
to: 
secukinumab (Cosentyx®)
tildrakizumab (Ilumya®)
rituximab, ustekinumab (Stelara®),
3 months or 5 half-lives (whichever is 
longer)
5.5 months prior to Visit 2
5 months priot to Visit 2
4 months prior to Visit 2


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Medication or class of medications1, 2
Restriction duration prior to Visit 2
talizumab, alemtuzumab, guselkumab
(Tremfya), ixekizumab (Taltz®), 
adalimumab (Humira®)
brodalumab (Siliq®), efalizumab, 
visilizumab, briakinumab, infliximab 
(Remicade®)
etanercept (Enbrel®)
3 months prior to Visit 2
2 months prior to Visit 2
6 weeks
live virus vaccinations
6 weeks 
Any other systemic immunomodulating 
treatments (e.g. corticosteroids, 
cyclophosphamide), tofacitinib (Xeljanz®), 
apremilast (Otezla®)
Any systemic immunomodulating treatments 
for atopic dermatitis including JAK 
inhitibors, PDE4 inhibitors, systemic steroids
30 days 
retinoids
4 weeks no treatment initiation or dose 
escalation
Must be discontinued prior to receiving 
the first dose of BI 65513/placebo
1In case of disease worsening, the use of standard of care (physician’s choice) is left at the 
discretion of the investigator (refer to Section 4.2.1). Patient continuation on trial treatment 
will be reassessed based on the medication used for the disease worsening.
2This list is not all inclusive, for any medications that are not listed, contact the Clinical Trial 
Manager (CTM) for restriction duration
3 Other antihistamines for indications other than atopic dermatitis can be prescribed on an as-
needed basis. Dose should, preferably, be stable within one week prior to V2 and during the 
course of the study. 
4 No restriction on corticosteroid drops administered in the eye or ear; nasal corticosteroids to 
treat rhinitis;inhaled corticosteroids to treat asthma; Montelukast (systemic) to treat asthma or 
allergic rhinitis - if these medications were on stable maintenance dose for 3 months prior to 
Visit 2.
4.2.3.2
Restrictions on diet and life style
No specific restrictions on diet or life style of the patients are required
Patients should avoid prolonged exposure to sunlight and artificial UV light. Patients should 
only be using supplied emollient as instructed by the trial physician, instruction will be 
provided (see Section 6.2.2).


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4.2.3.3
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. A list of contraception methods meeting these criteria is 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.

Progestogen-only hormonal birth control associated with inhibition of ovulation.

Intrauterine device (IUD) and intrauterine hormone-releasing system (IUS).

Bilateral Tubal occlusion (blocking of the fallopian tubes).

Vasectomy of sexual partner (proven effective by absence of sperm on the 
ejaculation).

Complete sexual abstinence (not to have male-female vaginal sex).
As monoclonal antibodies can be secreted in milk, women should refrain from breastfeeding 
once they receive the study drug and up to 16 weeks after, i.e. until BI 655130 is eliminated. 
They can start nursing again after this period.
4.3
TREATMENT COMPLIANCE
Administration of the trial medication will be done in the study center 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) and Dermatology Quality of Life Index 
(DLQI).
The primary efficacy endpoint for this trial is percent change in EASI Score at Week 16 
compared to Baseline. Secondary endpoints include EASI 50, EASI 75, SCORAD and IGA. 
An interim analysis of change in EASI at Week 4 will be conducted when 75% of patients 
have completed the Week 4 visit. The details of these assessments are described below.
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 severe disease (0= clear,1 =almost 
clear, 2 = mild, 3 = moderate, 4= severe). 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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DLQI
The DLQI is a patient-administered, ten-question, quality of life questionnaire that covers six
domains including symptoms and feelings, daily activities, leisure, work and school, personal
relationships and treatment [R05-2548]. The DLQI has a one-week recall period. Response
categories include “not relevant” (score of 0), “not at all” (score of 0), “a little” (score of 1),
“a lot” (score of 2) and “very much” (score of 3). Question 7 is a “yes”/ “no” question where
“yes” is scored as 3. DLQI total score is calculated by summing the scores of each question 
resulting in a range of 0 to 30 where 0-1 = no effect on patient’s life, 2-5 = small effect, 6-10 
= moderate effect, 11-20 = very large effect, and 21-30 = extremely large effect on patient’s 
life. The higher the score, the more the quality of life is impaired. A 4-point change from 
baseline is considered a clinically important difference [R18-1988].
5.2
ASSESSMENT OF SAFETY
Safety will be assessed descriptively based on:
•
Adverse events (including drug-related AEs)
•
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
•
Infusion site reactions
•
Immunogenicity (ADA)
5.2.1
Physical examination
Complete and targeted physical examinations will be performed at visits as described in the 
Flow Chart. Height and weight of the patient will be recorded at the Screening Visit only.
Complete physical examination will include general appearance as well as evaluation of all 
organ systems. Targeted physical examination will evaluation of organ systems associated 
with AE(s) symptoms or laboratory abnormalities.
Clinically relevant abnormal findings will be reported as baseline conditions or AEs.
5.2.2
Vital signs
Vital signs evaluations will be performed at visits as shown in the Flow Chart. This includes
measuring temperature, pulse rate and systolic/diastolic blood pressure. Vital signs will be 
measured after patients have been sitting comfortably for at least 5 minutes. All recordings 
should be made using the same type of blood pressure recording instrument on the same arm 
if possible. Measurement of vital signs should precede blood sampling to avoid the impact of 
blood sampling on the vital measurements.


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At visits with i.v. administration, vital signs will be assessed pre-dose, at approximately 5 
minutes after the end of infusion and 60 minutes after the end of infusion.
During i.v. drug administration, patients should be closely monitored for signs and symptoms 
of hypersensitivity reactions for approximately 1 hour after the end of study drug 
administration.
Hypersensitivity reactions should be treated according to medical standards. Pre-medications 
for further infusions might be considered and will be agreed on between investigator and BI 
CTM.
5.2.3
Safety laboratory parameters
For the assessment of laboratory parameters, blood and urine samples will be collected by the 
trial site at the time points indicated in the Flow Chart.
The parameters that will be determined are listed in Table 5.2.3: 1. The laboratory tests will 
be performed at a central laboratory.
However, local labs may be used for dosing decisions at visits involving i.v. administration of
BI 655130 or placebo. The lab tests listed in Table 5.2.3: 1 can be collected and assessed 
locally by the investigator prior to study drug infusion to allow for immediate subject 
management; however, split or concurrent samples will be drawn and sent to the central 
laboratory for analysis.
In case the criteria for hepatic injury are fulfilled, a number of additional measures will be 
performed (please see Section 5.2.5.2 and the Drug Induced Liver Injury (DILI) Checklist 
provided in the ISF and the electronic data capture (eDC) system). The amount of blood 
taken from the patient concerned will be increased due to this additional sampling.
Clinically relevant abnormal findings (e.g. anemia, hypoproteinemia, hypoalbuminemia, 
hypocalcemia etc.) will be reported as baseline conditions or AEs. A clinically relevant value 
may be either in- or outside the reference range. Clinically relevant abnormal laboratory test 
results must be confirmed using an unscheduled visit laboratory kit and should be repeated 
until normalization or stabilization or until an alternative explanation has been found. 
Abnormal laboratory values will also be graded for intensity by using RCTC Version 2.0 
criteria [R13-3515].
Instructions regarding sample collection, sample handling/processing and sample shipping 
are included in the laboratory manual in ISF.


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Table 5.2.3: 1 
Safety laboratory tests (Central lab Assessment)
Category
Test Name
Haemtology
Haematocrit
Haemoglobin
Red blood cell count (RBC)
White blood cell count (WBC)
Platelet count
Automatic WBC differential
(relative and absolute)
Neutrophils, eosinophils, basophils, monocytes, 
lymphocytes
Manual differential WBC (if
automatic differential WBC is 
abnormal)
Neutrophils (stabs), eosinophils, basophils, monocytes, 
lymphocytes
Coagulation
Activated partial thromboplastin time (aPTT)
Prothrombin time (Quick’s test and International 
Normalized Ratio [INR])
Fibrinogen
Enzymes
Aspartate transaminase (AST/GOT)
Alanine transaminase (ALT/GPT)
Alkaline phosphatase (AP)
Gamma-glutamyl transferase (GGT)
Creatine kinase (CK)
CK-MB, only if CK is elevated
Lactate dehydrogenase (LDH)
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 (qualitative7
Hepatitis B core Antibody7
HBV-DNA (quantitative) at baseline and EoS2
QuantiFERON®-TB3,4,7
Hepatitis C Antibodies (qualitative)
HIV-1, and HIV-2 Antibody (qualitative)
Specific gamma-globulin
quantification IgE
IgE5
Urine Pregnancy test6. At the 
drug administration visits, the 
test will be performed prior to the 
administration of study drug
Human Chorionic Gonadotropin in urine
Serum Pregnancy test6 (only if 
urine pregnancy test is positive)
Human Serum Chorionic Gonadotropin
1 For eligibility refer to exclusion criteria Section 3.3.3 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. These evaluations should be conducted at screening and EOS.
3 If the 1st QuantiFERON®-TB test result is indeterminate, a retest should be performed.
4 In patients with a negative QuantiFERON®-TB test, the test should be repeated at EOS.
5 IgE will be taken in case of infusion reaction together with ADA (anti-drug antibodies) sample.
6 Urine and serum pregnancy testing will be performed as indicated in the Flow Chart.
7 Also performed at EoS visit 
5.2.4
Electrocardiogram (ECG)
ECG measurements will always precede blood sampling to avoid impact of sampling on the 
ECG results. The 12-lead ECGs will be recorded and reviewed prior to dosing as scheduled 
in the Flow Chart. The investigator or a designee will evaluate whether the ECG is normal or 
abnormal and whether it is clinically relevant, if abnormal. ECGs may be repeated for quality 
reasons and the repeated recording used for analysis. No central laboratory will be used for 
ECG recording. 


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Additional ECGs may be recorded for safety reasons. The electronic version, if applicable, or 
dated and signed printouts of the ECG, will be regarded as source data and will be stored in 
the patient’s medical file.
Clinically relevant abnormal findings will be reported either as baseline condition (if 
identified at the screening visit) or as adverse events and will be followed up and/or treated as 
medically appropriate.
Other Safety Parameters:
In case of an infusion reaction, monitor the patient per standard of care, grade the intensity of 
the reaction according to RCTC V2 grading (cf. ISF) and proceed as described in Section 
4.2.1.
All cases of malignancies that are detected during the trial will be reported as SAEs. 
5.2.5
Assessment of adverse events
5.2.5.1
Definitions of AEs 
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.
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,
-
requires 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.


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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. 
AEs considered “Always Serious”
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the duration between discontinuation of the drug and must be reported as 
described in Section 5.2.5.2, subsections “AE Collection” and “AE reporting to sponsor and 
timelines”.
In accordance with the European Medicines Agency initiative on Important Medical Events,
Boehringer Ingelheim has developed a list of further AEs, which by their nature, can always 
be considered to be “serious” even though they may not have met the criteria of an SAE as 
defined above.
The latest list of “Always Serious AEs” can be found in the eDC system.
Adverse events of special interest (AESIs)
The term 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 below.
The following are considered as AESIs:
Hepatic injury
Hepatic Injury, is defined by the following alterations of hepatic laboratory parameters:

An elevation of AST and/or ALT ≥3-fold ULN combined with an elevation of total 
bilirubin ≥2-fold ULN measured in the same blood sample, or

Aminotransferase (ALT, and/or AST) elevations ≥ 10 fold ULN
Any patients with these lab abnormalities need to be followed up according to the DILI 
Checklist provided in the ISF. In case of a DILI, it will be up to the investigator to keep the 
patient in the trial as long as he considers he/she can perform all planned procedures. 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.


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Infusion reactions including anaphylactic reaction
Any suspicion of severe infusion reaction and of any potential cases of anaphylaxis should be 
defined and assessed using the criteria discussed in the statement paper from Sampson HA et 
al [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].
Protocol-specified AESI can be classified as serious or non-serious but all AESI must be 
reported in an expedited manner similar to serious adverse events on a SAE form (i.e. non 
serious AESI must be reported on the SAE form and follow the same reporting timelines as 
for serious AEs).
Intensity (severity) of AEs
The intensity grading of AEs will be performed according to RCTC Version 2.0 developed 
by the Outcome Measures in Rheumatology (OMERACT) organization [R13-3515]. Refer to 
the ISF for intensity/severity classification.
Intensity options are:
Grade 1 mild
Grade 2 moderate
Grade 3 severe
Grade 4 life-threatening
Causal relationship of AEs
Medical judgement should be used to determine the relationship, 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. 


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Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:

The event is consistent with the known pharmacology of the drug.

The event is known to be caused by or attributed to the drug class.

A plausible time to onset of the event relative to the time of drug exposure.

Evidence that the event is reproducible when the drug is re-introduced.

No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications).

The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome).

An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is reduced).
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:

No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks 
of drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned).

Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives).
Of note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger.

Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned).

Disappearance of the event even though the trial drug treatment continues or remains 
unchanged.
5.2.5.2
Adverse event collection and reporting
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:
o
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 related SAEs and related AESIs of which the 
investigator may become aware of by any means of communication, e.g. phone call.
Those AEs should however not be reported in the CRF.


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AE reporting to the sponsor and timelines
The investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form immediately (within 24 hours) to the sponsor’s 
unique entry point (country specific reporting process will be provided in the ISF). The same 
timeline applies if follow-up information becomes available. In specific occasions, the 
investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete and send the BI SAE form.
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information the same rules and timeline apply as for initial 
information.
Information required
For each AE, the investigator should provide the information requested on the appropriate 
eCRF pages and, if applicable, the BI SAE form. The investigator should determine the 
causal relationship to the trial medication.
The following should also be recorded as an (S)AE in the CRF and, if applicable, BI SAE 
form:

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 pre-exist prior to trial inclusion they will be considered as 
baseline conditions and should be collected in the eCRF only. All (S)AEs, including those 
persisting after a 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.
Pregnancy
Urine pregnancy testing should be done prior to study drug administration. Study drug should 
only be administered in case of a negative test result. In case of a positive urine pregnancy 
test, a serum pregnancy test will be done. Women who underwent tubal ligation are still 
considered of childbearing potential and pregnancy testing is necessary as well. The testing 
schedule is specified in the Flow Chart. The patient will also be asked about their pregnancy 
status at the End of Study Safety Phone Call.
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.
Exemptions to SAE reporting
For this study there are no exemptions to SAE reporting.
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
5.3.1
Assessment of pharmacokinetics
BI 655130 concentrations will be reported descriptively. It is not intended to calculate PK 
parameters; however, if appropriate PK parameters might be calculated. PK data may be 
incorporated into a larger pharmacometric analysis with other trials of the BI 655130 project.
Also, ADAs and neutralizing antibody (Nabs) will be measured and their impact on PK will 
be assessed. The relationship between PK and selected efficacy endpoints, biomarkers and 
AEs may be assessed. PK and demographic data together with treatment assignments and 
dosing information may be made available to individuals outside of the trial team for the 
purpose of PK dataset generation in accordance with sponsor’s standard procedures.
Refer to the Flow Chart for the time points of PK, ADA and Nab. Date and exact time of 
drug administration and PK, ADA and Nab will be recorded on CRFs. On visits with study 
medication dosing, PK, ADA and Nab should be collected within 2 hour period prior to 
administration of study drug.
5.3.2
Methods of sample collection
5.3.2.1
Plasma sampling for pharmacokinetic analysis
For quantification of BI 655130 plasma concentrations, blood will be taken from a forearm 
vein into a K2EDTA (ethylendiaminetetraacetic acid) anticoagulant blood-drawing tube at the 
time points listed in the Flow Chart under PK sampling.
Samples will be stored in a freezer set at the analytical laboratory until the finalization of the 
clinical trial report (CTR). The plasma samples may be used for further methodological 
investigations (e.g. for stability testing) however, only data related to the analyte will be 
generated by these additional investigations. The study samples will be discarded after 
completion of the additional investigations but not later than 5 years upon the final study 
report has been signed.


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5.3.2.2
Sampling for ADA/Nab assessment
For ADA assessment, blood will be taken from a forearm vein into a K2EDTA anticoagulant 
blood-drawing tube at the time points listed in the Flow Chart. For Nab assessment, blood 
will be taken from a forearm vein into a serum blood drawing tube at the time points listed in 
the Flow Chart.
Samples will be stored in a freezer set at the analytical laboratory until they are analyzed. The
Plasma/serum samples may be used for further methodological investigations, e.g. for 
stability testing, however only data related to the anti-drug antibodies will be generated by 
these additional investigations. The study samples will be discarded after completion of the 
additional investigations but not later than 5 years after the final study report has been signed.
5.3.4
Pharmacokinetic – pharmacodynamic relationship
No formal analysis of pharmacokinetic/pharmacodynamic relationships is planned.
If the data suggest a pharmacokinetic/pharmacodynamic relationship of special parameters, 
e.g. an exploratory analysis may be performed.
Correlation between drug concentration and response may be made if adequate data are 
available. In addition, exploratory correlations may also be made between drug concentration 
and AEs. It is not intended to include these data into the final report. However, the data may 
be part of the report if the available data allows for such correlation.
Data may also be used to develop pharmacokinetic/pharmacodynamic models using nonlinear 
mixed effect modeling techniques, if feasible. For this purpose data may also be combined 
with data from other trials. Modeling activities will be planned and documented separately 
according to internal and external guidelines and Standard Operating Procesures (SOP).


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5.5
BIOBANKING
Participation in biobanking is voluntary and not a prerequisite for participation in the 
trial. Sample collection and biobanking will only occur after a separate biobanking informed 
consent has been given in accordance with local ethical and regulatory requirements.
One (1) blood sample will be used for DNA Banking which will be stored at Boehringer 
Ingelheim. The stored DNA may be retrospectively analysed, e.g. to identify whether there 
are other genetic factors that could contribute to a better therapeutic outcome or a higher risk
of developing treatment related adverse drug reactions. 
This blood sample will be collected in a PAXgene Blood DNA tube at Visit 2. If not possible 
at Visit 2, this sample may also be collected at a later visit.


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5.7
APPROPRIATENESS OF MEASUREMENTS
The scheduled measurements will allow monitoring of changes in vital signs, standard 
laboratory values, and ECG variables that might occur as a result of administration of trial 
medication. The safety assessments are standard, are accepted for evaluation of safety and 
tolerability of an intravenously administered drug, and are widely used in clinical trials. The 
pharmacokinetic parameters and measurements outlined in Section 5.3 are generally used 
assessments of drug exposure. The biomarkers and pharmacogenomic parameters are 
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 atopic dermatitis 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 (V2).
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 are provided in Section 4.1.4.
Study measurements and assessments are scheduled to occur ‘before’ trial medication
administration at dosing visits and are to be performed and completed prior to the trial drug
administration (including pre-dose on Day 1 for PK, ADA, Nab and biomarkers). For planned
individual plasma concentration sampling times refer to the Flow Chart. At non-dosing visits
sampling should be done after other study procedures have concluded. 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 for explanations of the specified assessments and 
procedural details.
Based on the investigator’s clinical judgment, patients may be hospitalized prior to, during or
following first study drug administration. Subsequent visits will be conducted in accordance 
with the protocol and the investigator’s judgment (For details, see Flow Chart and Section 
3.1).
The patients’ questionnaires (DLQI, VAS for pruritus and Sleep loss in SCORAD) are to be 
completed by the patient him/herself, without any help from or interpretation by other people.
The VAS SCORAD should be completed before the DLQI.
Separate from the PROs above, the evaluation of efficacy assessments (EASI, SCORAD, and 
IGA) are to be conducted preferably by the same physician, whenever possible, throughout 
the study.


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The following procedures should be completed in the following order prior to trial drug 
infusion:
1. Pruritus and Sleep Loss SCORAD VAS
2. DLQI  
3. SCORAD, EASI and IGA
4. Photographs of skin lesions
5. Tape stripping
6. Skin biopsies
Refer to ISF (applicable processing manual) for sample preparation and shipment instructions. 
6.2.1
Screening 
Screening Period
After patients have been informed about the trial, written informed consent in accordance 
with GCP and the local legislation must be obtained prior to performing any study related 
procedures.
Once consent is obtained, the patient is considered to have started the screening process, and 
is assigned a unique patient number by the IRT system. The patient is to be recorded on the 
enrolment log and be registered in the IRT system as a screened patient. Study requirements, 
including the procedure for the follow-up of prematurely withdrawn patients, must be fully 
explained to the patient and written informed consent obtained prior to initiating any study-
related evaluation. The importance of staying in the study until completion of all 
requirements is to be emphasized. No study procedures are to be done unless the patient has 
provided consent to take part in the study.
Demographics:
Informed consent date, gender, ethnicity and race (if allowed by local law) will be collected 
and reported in the eCRF.
Baseline Conditions:
Chronic diseases, current observable conditions, any new clinically relevant findings 
discovered from the physical examination, ECG, safety labs, and any condition requiring 
therapy (excluding AD) will be reported on the Baseline Condition eCRF page.
Infection screening:
Infection testing will include tuberculosis, hepatitis B, hepatitis C, and HIV assessments (see 
Table 5.2.3: 1). 
Medical History:
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 the screening visits will be recorded as medical and surgical history at screening. 


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Regarding AD, a detailed history of the disease will be collected and reported in the eCRF. 
Also, previous and concomitant treatment for AD will be recorded.
Re-screening:
If a patient results in a screen failure (i.e. does not meet the eligibility criteria) the patient 
must be registered as a screen failure in IRT system. However, re-screening of a previously 
screen failed patient will be permitted once. Details of IRT procedures can be found in the 
IRT manual located in the ISF.
For the comprehensive list of the trial procedures required at the Screening Visit (Visit 1) 
please refer to the Flow Chart.
6.2.2
Randomization Visit and Treatment Visits
Patients will be randomized to receive 600 mg BI 655130 or placebo in a 2:1 randomisation 
ratio (2:1) at Visit 2. Patients will be stratified according to race i.e Asian vs non-Asian.
The first study drug administration is at Visit 2 (Day 1). Thereafter, patients will receive 
blinded trial drug at V4, V5 and V6. At V7 patients will be evaluated with EASI scrore and 
responders will be re-assigned to no treatment whereas non-responders will be re-assigned to 
BI 655130 600 mg. The re-assignement will be un-blinded.
For information pertaining to PK, ADA, Nab and biomarkers, see Sections 5.3 and 5.4.
Fasting is not required for blood sampling. For information pertaining to laboratory tests, 
ECG, vital signs, and physical examination, see Sections 5.2.1 to 5.2.5.
DNA banking is optional and is only to be done for patients who have provided informed 
consent for this specific procedure.
Skin lesion photographs will be taken at all visits on site and are to be taken prior to any skin 
biopsies or study drug administration.
At Visit 1, patients will be provided with emollient and instructions on how to apply. 
Emollient will be provided to each patient as required for the duration of the study.
Study drug allocation via the IRT system and administration of study drug should be the last 
activity at Visit 2 with the exception of post dose vital signs assessments. 
For women of child-bearing potential, pregnancy testing will be done as specified in the Flow 
Chart. The patient will also be asked about their pregnancy status at the End of Study Safety 
Phone Call.
6.2.2.1
Clinical monitoring after study drug administration
During i.v. drug administration, vital signs will be assessed pre-dose, at approximately 5 
minutes after the end of infusion, and 60 minutes after the end of infusion. Patients should be 
closely monitored for signs and symptoms of hypersensitivity reactions for approximately 1


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hour after the end of infusion. Hypersensitivity reactions should be treated according to 
medical standards (See Section 4.2.2).
6.2.2.2
Unscheduled visits
During the treatment period patients may be seen at an unscheduled visit if they experience 
worsening of the disease or have AEs that in the opinion of the investigator need intervention 
(e.g. escape or rescue treatment) or repeated laboratory testing.
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 that were missed at a 
previous visit. All unscheduled visits (including the reason for the visit) should be described 
and documented in the medical/source record, and in the eCRF.
6.2.2.3
End of Study Visit and Safety Phone Call
For the list of trial procedures required at the End of Study visit, please refer to the Flow 
Chart.
For Non-Responder patients:
At Visit 11, if the patient has any ongoing or newly diagnosed clinical relevant changes in 
safety laboratory tests, vital signs, ECG or AEs/SAEs/AESIs, the patient should be followed-
up as deemed necessary based on medical judgement of the investigator.  
An End of Study Safety Phone Call will be completed for Non-Responder patients not 
participating in the open label extension trial. At any time from Visit 11 to the End of Study 
Safety Phone Call, if the patient reports any new or ongoing AEs/SAEs/AESIs that based on 
medical judgement of the investigator require further follow-up, an unscheduled visit should 
be planned for follow-up or patient referral.
6.2.3
Trial Completion and End of Residual Period
For all randomized patients termination of trial medication and trial completion must be 
recorded on the corresponding eCRF.
For the comprehensive list of the trial procedures required following the end of treatment, 
please refer to Flow Chart.
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 receiving four (4) infusions of trial drug (BI 
655130 or placebo) at V2, V4, V5 and V6.


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In the re-allocation period (V7 to V11) treatment completion is defined as:

non-responder patient receiving 4 infusions of BI 655130 at V7, V8, V9, V10 and 
continuing in the trial until the last visit (V11) – End of Study/FU1 (Week 32 - 44).

responder continuing in the trial until the last visit (V10) – Week 28 or until they 
reach a 50% reduction in EASI score compared to baseline 
Early Treatment Discontinuation:
In case the infusion of study drug is permanently discontinued before the whole amount of 
prepared solution has been administered to the patient, every effort should be made to keep 
the patient in the trial and complete all of the remaining study visits. If this is not possible, 
assessments of the primary endpoint V7 (Week16), should be completed or at a minimum an 
early EoS visit. Please refer to the Flow Chart.
Early Trial Discontinuation:
A patient not having reached the EoS visit within the specified window per protocol (e.g. due 
to withdrawal of consent, lost to follow-up, death etc.).


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN - MODEL
This is an exploratory trial in patients with atopic dermatitis. It is designed as a 2:1 
randomised, double-blind, placebo-controlled trial with 2 parallel groups (1 dose of BI
655130 and placebo (2:1)).
The primary objective of this trial is to explore the safety, tolerability and efficacy of BI 
655130 in comparison to placebo in patients with atopic dermatitis.
The primary efficacy endpoint for this trial is Percent change in Eczema Area and Severity 
Index (EASI) Score at Week 16 compared to Baseline.
Due to the potential for different pathophysiology in different ethnic groups, randomisation 
will be stratified by race (Asian vs. Non-Asian patients). The primary endpoint will be 
analysed using a restricted maximum likelihood estimation based on a mixed-effect model for 
repeated measures analysis to obtain adjusted means for the treatment effects. This model 
will include discrete fixed effects for treatment at each visit and stratification factor 
Asian/Non-Asian, and continuous fixed effects for baseline at each visit. The primary 
treatment comparisons will be the contrast between treatments at Week 16.
After Week 16 there will be a treatment re-allocation based on EASI75 outcome. In case of 
EASI75 reached, no treatment will be given, otherwise BI 655130.
7.2
NULL AND ALTERNATIVE HYPOTHESES
One of the aims of this trial is to investigate whether BI 655130 has any therapeutic effect in 
atopic dermatitis patients, in other words to have the proof of clinical concept. Superiority of 
BI 655130 to placebo will be tested by the comparison of mean percentage change in the 
EASI score for BI 655130 and placebo, at Week 16.
The following hypothesis testing will be performed having an alpha level of 10% (two-sided), 
or α = 0.05 (one-sided):
H0:  Mean percent change of EASI score at Week 16 (BI 655130)
≤ Mean percent change EASI score at Week 16 (Placebo)
H1:  Mean percent change EASI score at wWeek 16 (BI 655130)
> Mean percent change EASI score at Week 16 (Placebo)
As this is an exploratory trial, the result of this hypothesis testing will be discussed in the 
context with all results, both safety and efficacy.


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7.3
PLANNED ANALYSES
The efficacy analyses will be performed for the Full Analysis Set (FAS), which is based on 
the intent-to-treat principle, and comprises all participants who were randomised, received at 
least one dose during the trial, and had a baseline measurement for the primary endpoint. 
Efficacy analyses will be based on the planned treatment (i.e., the treatment assigned at 
randomisation). Safety analyses on patients who were randomised, and received at least one 
dose during the trial will be based on the actual treatment received at the randomisation visit; 
this set of patients is called the Safety Analysis Set (SAF). All efficacy analyses will be 
conducted on the FAS. All safety analyses will be conducted on the SAF. With regard to 
efficacy and safety endpoints, “baseline” refers to the measurement recorded at 
randomisation (Visit 2), if data at Visit 2 is missing, then data from Visit 1 will be considered 
baseline.
Important deviations of the protocol will include key inclusion and exclusion deviations, 
incorrect medications taken, compliance with study medication, concomitant use of restricted 
medications, and any other deviations of the protocol deemed important by the study team. 
All decisions concerning important protocol deviations will be made prior to un-blinding of 
the database for the primary week 16 analysis. 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) or frequency tables (including patient 
frequencies and percentages) will be calculated where appropriate.
7.3.1
Primary endpoint analyses
The primary analysis is a restricted maximum likelihood (REML) based approach using a 
mixed model with repeated measurements (MMRM) comparing the percent change from 
baseline of the EASI score after 16 weeks of treatment.
The analysis will include the fixed, categorical effects of treatment at each visit, stratification 
factor Asian/Non-Asian and the fixed continuous effects of baseline at each visit. Visits will 
be treated as the repeated measure with an unstructured covariance structure used to model 
the within-patient measurements.
The Kenward-Roger approximation will be used to estimate denominator degrees of freedom 
and adjust standard errors. Significance tests will be based on least-squares means using a 
two-sided α = 0.10 (two-sided 90% confidence intervals (CI)). The primary treatment 
comparison will be the contrast between treatments at Week 16.
The primary analysis will be performed on the FAS. Patients will be analysed according to 
the stratum to which they belong (regardless of any miss-assignment to treatment based on 
identification of the wrong stratum), as such an error occurs before randomisation.
Procedures to follow if the analysis fails to converge will be described in the TSAP.


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To assess the homogeneity of the treatment effect on the primary endpoint across the levels 
of Asian/Non-Asian, the same MMRM model will be fitted but replacing the treatment-by-
visit term by a treatment-by-Asian/Non-Asian-by-visit term. A descriptive p-value of 
treatment effect homogeneity at Week 16 will be calculated. No overall treatment effect will 
be estimated from this model, as it is not interpretable.
7.3.2
Secondary endpoint analyses
The endpoint change from baseline in SCORAD will be analysed using the same model as 
used for the primary endpoint (MMRM).
For the primary endpoint variable, the EASI score, responder analyses will be performed. A 
patient is defined as EASI50/75 responder when percent change from baseline of the EASI 
score is ≥50% or ≥75%, resulting in binary variable with values of 1 (=response) or 0 (=non-
response). A logistic regression model will be used to predict the response rates and to 
calculate the risk difference for BI 655130 versus placebo. As a sensitivity analyses, the
Cochran-Mantel-Haenszel (CMH) test adjusted by randomization stratum (Asian/Non-Asian) 
will be used.
For the proportion of patients with IGA 0 or 1 at weeks 4 and 16, also the CMH test will be 
used.


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7.3.4
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 residual effect period (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’.
Frequency, severity, and causal relationship of adverse events will be tabulated by system 
organ class and preferred term after coding according to the current version of the Medical 
Dictionary for Drug Regulatory Activities (MedDRA) at database lock.
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. Treatment 
groups will be compared descriptively with regard to distribution parameters as well as with 
regard to frequency and percentage of patients with abnormal values or clinically relevant 
abnormal values.
Vital signs, physical examinations, or other safety-relevant data observed at screening, 
baseline, during the course of the trial and at the end-of-trial evaluation will be assessed with 
regard to possible changes compared to findings before start of treatment.
7.3.5
Pharmacokinetic and pharmacodynamic analyses
Refer to Section 5.3.1 and Section 5.3.4.


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7.4
INTERIM ANALYSES
An interim analysis will be conducted when 75% of the patients have completed at least 4 
weeks of treatment. The results of the analysis will be used for internal decision making only 
and individuals involved in the conduct of the trial will not be made aware of the results.
There will be no changes of the design of the trial because of this interim analysis at Week 4. 
The time-point of this interim analysis is triggered by the availability of all EASI and 
SCORAD data in the database on the first 75% of the patients. For this interim analysis an 
interim analysis SAP and an interim analysis logistics plan will be developed, including a list 
with individuals and roles who will have access to unblinding information.
7.5
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.


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With respect to safety evaluations, it is not planned to impute missing values.
If a patient misses a visit, for continuous endpoints the missing data will not be imputed. The 
mixed effect model will handle missing data based on a likelihood method under the "missing 
at random” assumption.
For all binary endpoints (i.e. endpoints that are either 1 (patient responded) or 0 (patient did 
not respond)), the following will be performed:

If there are data at visits both before and after the visit with a missing outcome, then 
impute as success only if both neighbouring visits also represent a success;

Otherwise, impute as a non-responder
Further sensitivity analyses to assess the robustness of the results may be performed and as 
such will be described in the TSAP.
7.6
RANDOMISATION
The trial will be performed as a double-blind design with respect to placebo and the active 
dose group of BI 655130. Patients will be randomised in blocks to the 2 trial treatments in a 
2:1 at baseline visit. The randomisation will be stratified by race (Asian versus Non-Asian 
patients). If necessary, and depending upon global distribution, entry of patients into a 
stratum may be capped.
The randomisation of patients to the treatment groups will be performed via IRT. BI will 
arrange for the randomisation as well as packaging and labelling of trial medication. The 
randomisation list will be generated using a validated system, which involves a pseudo-
random number generator and a supplied seed number so that the resulting allocation of 
medication numbers to treatment is both reproducible and non-predictable. The block size 
will be documented in the CTR. Access to the codes will be controlled and documented.
7.7
DETERMINATION OF SAMPLE SIZE
Based on experience with Dupilumab, it is estimated that the standard deviation of percent 
change from baseline in EASI Score after 16 weeks of treatment is 30%. The delta used for 
sample size calculation is 25%. Source for the estimate of the the standard deviation is 
clinicaltrials.gov, searching was performed using the following condition ‘Dupilumab | 
Studies With Results | Atopic Dermatitis’.


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The other parameters for sample size calculation are a power of 80% and a two-sided alpha of 
10%. With these parameters, a sample size of at least 42 patients is needed, with at least 28 
patients on BI 655130 600mg and 14 patients on placebo.
Table 7.7: 1
Several scenarios for sample size calculation (10% two-sided alpha), based 
on change from baseline for EASI Score
Delta (%)
SD (%)
Power (%)
N total (active/placebo)
25
25
80
30 (20/10)
30
25
80
21 (14/7)
35
25
80
18 (12/6)
25
30
80
42 (28/14)
30
30
80
30 (20/10)
35
30
80
24 (16/8)
25
35
80
57 (38/19)
30
35
80
42 (28/14)
35
35
80
30 (20/10)
25
35
69
24 (16/8)
25
40
59
24 (16/8)
20
30
63
24 (16/8)
22.5
30
72
24 (16/8)
In addition, with the chosen sample size, the following probabilities we have with this trial. 
Assuming a treatment effect of 35% in the population, the probability to observe a difference 
of 25% or more in our study is 85% and the probability to observe a difference of 20% or less 
in our study only is 6%. 
If there would be no difference (delta=0%), the probability to observe a difference of 25% or 
more in our study only is 1%, also almost 98% to observe a difference of 20% or less.


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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) and other 
relevant regulations. Investigators and site staff must adhere to these principles.
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains the 
responsibility of the treating physician of the patient.
The investigator will inform the sponsor immediately of any urgent safety measures taken to 
protect the 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 finalization of the Clinical Trial Report.
The certificate of insurance cover is made available to the investigator and the patients, and is
stored in the ISF.
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB) / Independent Ethics Committee 
(IEC) and CA according to national and international regulations. The same applies for the 
implementation of changes introduced by amendments.
Prior to patient participation in the trial, written informed consent must be obtained from each 
patient (or the patient’s legally accepted representative) according to ICH-GCP and to the 
regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional patient-
information form retained by the investigator as part of the trial records. A signed copy of the 
informed consent and any additional patient information must be given to each patient or the 
patient’s legally accepted representative.”
The investigator or delegate must give a full explanation to trial patients based on the patient
information form. A language understandable to the patient should be chosen, technical terms 
and expressions avoided, if possible. 
The patient 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 his delegate must sign (or place a seal on) and date the informed consent form. 


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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. See Section 4.1.5.2 for rules 
about emergency code breaks. For drug accountability, refer to Section 4.1.8.
8.3.1
Source documents
In accordance with regulatory requirements, the investigator should prepare and maintain 
adequate and accurate source documents and trial records that include all observations and 
other data pertinent to the investigation on each trial patient. Source data as well as reported 
data should follow the “ALCOA principles” and be attributable, legible, contemporaneous, 
original and accurate. Changes to the data should be traceable (audit trail). Data reported on 
the CRF must be consistent with the source data or the discrepancies must be explained.
The current medical history of the patient may not be sufficient to confirm eligibility for the 
trial and the investigator may need to request previous medical histories and evidence of any 
diagnostic tests. In this case, the investigator must make three documented attempts to 
retrieve previous medical records. If this fails, a verbal history from the patient, documented 
in their medical records, would be acceptable.
Copies of patients’ 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


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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)

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 Associate (CRA), auditor 
and regulatory inspector (e.g. FDA). They may review all CRFs and informed consents. The 
accuracy of the data will be verified by direct comparison with the source documents 
described in Section 8.3.1. The sponsor will also monitor compliance with the protocol and 
GCP.
8.3.3
Storage period of records
Trial site(s):
The trial site(s) must retain the source and essential documents (including Investigator Site 
File (ISF)) according to contract or the local requirements valid at the time of the end of the 
trial (whichever period is longer).
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.


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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
Individual patient data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the exceptions noted in Section 8.7. 
Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principles 6 and 12 of the Wolrd Health 
Organization (WHO) GCP handbook.
Personalised treatment data may be given to the patient’s personal physician or to other 
appropriate medical personnel responsible for the patient’s welfare. Data generated at the site
as a result of the 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
8.6
TRIAL MILESTONES
The start of the trial is defined as the date when the first patient in the whole trial signs 
informed consent. The end of the trial is defined as the date of the last visit of the last 
patient in the whole trial (“Last Patient Completed”). The “Last Patient Last Treatment”
(LPLT) date is defined as the date on which the last patient in the whole trial is administered 
the last dose of trial treatment (as scheduled per protocol or prematurely). Individual 
investigators will be notified of SUSARs occurring with the trial medication until 30 days 
after LPLT at their site. Early termination of the trial is defined as the premature 
termination of the trial due to any reason before the end of the trial as specified in this 


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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 (HA) request.
The IEC / CA in each participating EU member state will be notified about the trial
milestones according to the respective laws. A final report of the clinical trial data will be 
written only after all patients have completed the trial in all countries (EU or non-EU) to 
incorporate and consider all data in the report. The sponsor will submit to the EU database a 
summary of the final trial results within one year from the end of a clinical trial as a whole, 
regardless of the country of the last patient (EU or non-EU).
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim.
A project-independent external Data Monitoring Committee (DMC) will be established to 
assess the safety and efficacy of BI 655130 in this clinical trial at specified intervals through 
the final time-point (End of Study Visit). Measures will be put in place to ensure blinding of 
the sponsor and all other trial participants. The tasks and responsibilities of the DMC will be 
specified in a charter. The DMC will maintain written records of all its meetings. 
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 are 
specified in a charter.
Relevant documentation on the participating (Principal) Investigators (e.g. their curricula 
vitae) will be filed in the ISF. The investigators will have access to the BI clinical trial portal 
(Clinergize) to facilitate document exchange and maintain electronic ISF. 
BI has appointed a Clinical Trial Leader (CTL), responsible for coordinating all required 
activities, in order to 
-
manage the trial in accordance with applicable regulations and internal SOPs,
-
direct the clinical trial team in the preparation, conduct, and reporting of the trial,
-
ensure appropriate training and information of Clinical Trial Manager (CTM), 
Clinical Research Associates (CRAs), and investigators of participating countries.
The organisation of the trial in the participating countries will be performed by the respective 
local or regional BI-organisation (Operating Unit, OPU) in accordance with applicable 
regulations and BI SOPs, or by a Contract Research Organisation (CRO) with which the 
responsibilities and tasks will have been agreed and a written contract filed before initiation 
of the clinical trial.


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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. 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
R05-2548
Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI)--a simple 
practical measure for routine clinical use. Clin Exp Dermatol. 1994. 
19(3): 210-216.
R11-4890
Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson NF, Jr., Bock 
SA, Branum A, et al. Second symposium on the definition and 
management of anaphylaxis: summary report--Second National Institute 
of Allergy and Infectious Disease/Food Allergy and Anaphylaxis 
Network symposium. J Allergy Clin Immunol. 2006. 117(2): 391-397.
R18-2663
Bieber T. Atopic dermatitis. N Engl J Med. 2008. 358(14): 1483-94.
R18-2664
Chopra R, Vakharia PP, Sacotte R, Patel N, Immaneni S, White T, et al. 
Severity strata for EASI, mEASI, oSCORAD, SCORAD, ADSI and 
BSA in adolescents and adults with atopic dermatitis. Br J Dermatol. 
2017. 177: 1316-1321.
R18-2665
Hanifin JM, Thurston M, Omoto M, Cherill R, Tofte SJ, Graeber M. The 
eczema area and severity index (EASI): assessment of reliability in 
atopic dermatitis. EASI Evaluator Group. Exp Dermatol. 2001. 10(1): 
11-18.
R18-2666
Liu H, Archer NK, Dillen, CA, Stibitz S, Geha R, Miller LS. 
Staphylococcus aureus epicutaneous exposure drives skin inflammation 
via IL-36 mediated T cell responses. Cell Host Microbe. 2017. 22(5): 
653-666.e5.
R18-2667
Deckers IA, McLean S, Linssen S, Mommers M, van Schayck CP, 
Sheikh A. Investigating international time trends in the incidence and 
prevalence of atopic eczema 1990-2010: a systematic review of 
epidemiological studies. PLoS One. 2012. 7(7): e39803.
P18-07868
Eichenfield LF, Ahluwalia J, Waldman A, Borok J, Udkoff J, 
Boguniewicz M. Current guidelines for the evaluation and management 
of atopic dermatitis: A comparison of the Joint Task Force Practice 
Parameter and American Academy of Dermatology guidelines. J Allergy 
Clin Immunol. 2017. 139(4s): S49-57.


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R18-2668
Garmhausen D, Hagemann T, Bieber T, Dimitriou I, Fimmers R, 
Diepgen T, et al. Characterization of different courses of atopic 
dermatitis in adolescent and adult patients. Allergy. 2013. 68(4): 498-
506.
R18-2669
Nakagawa S, Matsumoto M, Katayama Y, Matsue H, Nunez G, 
Nakamura Y. Staphylococcus aureus virulent PSM peptides induce 
keratinocyte alarmin release to orchestrate IL-17-dependent skin 
inflammation Cell Host Microbe. 2017. 22(5): 667-677.e5.
R18-2670
Rehal B, Armstrong AW. Health outcome measures in atopic dermatitis: 
a systematic review of trends in disease severity and quality-of-life 
instruments 1985-2010. PLoS One. 2011. 6(4): e17520.
R18-2679
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): 10-19.
R18-2680
Simpson EG-Y, E. Margolis, DJ. Feldman, S. Qureshi, A. Eckert, L. 
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 


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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 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: 


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an interpretability study. Br J Dermatol. 2015. 172(5): 1353-1357.
9.2
UNPUBLISHED REFERENCES
c03320877-05
BI 655130 Investigator’s Brochure, Current Version 
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
Diagnosis of Anaphylaxis
Clinical criteria for diagnosing anaphylaxis [R11-4890]


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Date of amendment
05 Nov 2018
EudraCT number
EU number
NA
BI Trial number
1368-0032
BI Investigational Product(s)
BI 655130
Title of protocol
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
Global Amendment due to urgent safety reasons
Global Amendment
X
Section to be changed
Title Page
Description of change
Administrative change to Lay Title
Rationale for change
To provide a more accurate description of the 
protocol title
11.2
GLOBAL AMENDMENT 2
Date of amendment
05 Jul 2019
EudraCT number
EU number
NA
BI Trial number
1368-0032
BI Investigational Product(s)
BI 655130
Title of protocol
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
Global Amendment due to urgent safety reasons
Global Amendment
X
Section to be changed
All Sections
Description of change
Participants in this trial will be refered to as 
patients instead of subjects. This has been corrected 
throughout the protocol
Rationale for change
Correction
Section to be changed
Title Page
Description of change
Administrative changes for CTL, document 
number, version and date


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Rationale for change
To reflect the change in CTL for the study, 
document number, version number and date of new 
version 
Section to be changed
Clinical Trial Protocol Synopsis
Description of change
Removed striked-through text.
Exclusion Criteria 

Use of systemic corticosteroids or other 
agents for atopic dermatitis within 4 weeks 
prior to first dose of trial treatment (for more 
details refer to Table 4.2.3.1: 1)

Any documented active or suspected 
malignancy or history of malignancy within 5 
years prior to the screening visit, except 
appropriately treated basal cell carcinoma of 
the skin, squamous cell carcinoma of the skin 
or in situ carcinoma of uterine cervix.

Active or Latent TB:

Patients with active tuberculosis are 
excluded.

Patients with a positive QuantiFERON TB 
test during screening are excluded, unless:
o
Patient had previous diagnosis of 
active or latent TB and has 
completed appropriate treatment per 
local practice/guidelines within the 
last 3 years and at least  6 months 
before first administration of trial 
medication under this protocol 
(patients may be re-screened once to 
meet this criterion)
o
Patients with suspected false 
positive or indeterminate 
QuantiFERON TB result may be re-
tested once 
o
If QuantiFERON TB test result is 
not available or providing 
indeterminate results after repeat 
testing : A tuberculin skin test 
reaction ≥10mm (≥5mm if receiving 
≥15mg/d prednisone or its 
equivalent) is considered positive
and patients will be excluded.
Rationale for change
To clarify some sections of the criteria and align 
with project standard


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Section to be changed
Flow Chart
Description of change
Added section headers and grouped assessments; 
Added “X” for Investigator Global Assessment 
(IGA), EASI and SCORAD – BSA only) at 
Screening Visit; Added ‘C’ for Physical 
examination at V10; Added ‘S’ for Pregnancy 
testing at all visits after Screening; 
Added ‘X’ for Blood sample-soluble protein 
biomarker at V11
Footnotes: Added clarifications for Physical 
Examination, Vital Signs, ECG measurements, 
Blood Sampling – Optional PGx Sampling, End of 
Study Visit for Responders (V10) and Non-
Responders (V11)
Added footnote 19 to reflect collection of BSA 
assessment at all visits 
Rationale for change
Assessments were rearranged to more accurately 
reflect the order of assessments performed in the 
clinic. Assessments remained unchanged.
Timepoints where procedures are to be completed 
were updated to be aligned throughout study 
protocol
Added protein biomarker at V11 as this was 
omitted in error in the initial protocol
Footnotes:
Clarifications and corrections made to be aligned 
throughout study protocol. Removal of rescue visits 
which are not applicable to the study.
Footnote 15: Reinforce that this sample is optional 
and separate consent is required.
Section to be changed
Section 1.1
Description of change
Added IL-17 to list of cytokines and chemokines 
that are expressed by AD.  Added statement:
IL-36 is thought to have a pivotal role in 
amplifying these immune pathways and may be a 
critical link between S. aureus infection and 
exacerbation of AD inflammation.
Rationale for change
To provide further clarification on the medical 
background of AD
Section to be changed
Section 1.2.3
Description of change
Updated information to include more recent clinical 


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trial experience
Rationale for change
To be in alignment with the Investigator Brochure 
v6.0 dated 04Apr2019 
Section to be changed
Section 1.4
Description of change
Added information from recent BI clinical trials. 
Removed the word ‘minimal’ from the following 
sentence:
Considering the medical need for development of 
an effective and well tolerated drug for the therapy 
of AD, the benefit of this trial is considered to 
outweigh the potential minimal risks and justifies 
the administration of multiple doses of BI 655130 
to patients with AD to investigate safety, 
tolerability and efficacy.
Rationale for change
To be in alignment with the Investigator Brochure 
v6.0 dated 04Apr2019
Section to be changed
Section 3.1
Description of change
Added clarification on when patients may be 
withdrawn from the trial or complete End of Study 
Visit before being given the opportunity to enrol in 
the extension trial.
Rationale for change
Provided more clarification on the trial design
Section to be changed
Section 3.3.3
Description of change
Exclusion Criteria
2. Use of systemic corticosteroids or other 
agents for atopic dermatitis within 4 weeks 
prior to first dose of trial treatment (for 
more details refer to Table 4.2.3.1)
5. Any documented active or suspected 
malignancy or history of malignancy within 
5 years prior to the screening visit, except 
appropriately treated basal cell carcinoma of 
the skin, squamous cell carcinoma of the 
skin or in situ carcinoma of uterine cervix.
10. Active or Latent TB:
Patients with active tuberculosis are excluded.
Patients with a positive QuantiFERON TB test 
during screening are excluded, unless:

If the QuantiFERON TB test result
is not available or provides
indeterminate results after repeat 
testing: A tuberculin skin test 
reaction ≥10mm (≥5mm if receiving 
≥15mg/d prednisone or its 
equivalent) is considered positive 


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and patients will be excluded.
11. Currently enrolled in another investigational 
device or drug trial, or less than 30 days or 
5 half lives, whichever is longer since 
ending another investigational device or 
drug trial(s), or receiving other 
investigational treatment(s).
Rationale for change
Clarification of criteria; removed inaccurate 
information
Section to be changed
Section 4.1.5.2
Description of change
The following text was removed from Section 
4.1.5.2 :
An emergency code break (envelope) will be 
available to the investigator. This code break may 
only be opened in an emergency situation when the 
identity of the trial drug must be known to the 
investigator in order to provide appropriate medical 
treatment or otherwise assure safety of trial 
participants. If the code break for a patient is 
opened, the sponsor must be informed immediately 
about the unblinding. The treatment allocation 
should not be disclosed to the sponsor unless this is 
explicitly requested. The reason for opening the 
code break must be documented on the envelope 
and/or appropriate CRF page.
Rationale for change
Removed inaccurate information 
Section to be changed
Section 4.2.1
Description of change
The following text was revised: 
Patients refusing to return to the study site (during 
the follow-up period) for scheduled visits after the 
end of treatment should at least provide safety 
information by phone at the respective visits.
The following text was added:
If a patient receives escape treatment the decision 
to maintain the patient on trial treatment will be 
decided with discussion between the investigator 
and sponsor.
Rationale for change
Reinforce the requirement for patients to complete 
all study visits. Provided clarification on how 
decisions will be made if patients use escape 
treatment during the trial 
Section to be changed
Section 4.2.3.1:1
Table 4.2.3.1:1


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Description of change
Added the following sentence:
Patients are prohibited from receiving the following 
therapies, during trial treatment and prior
to Visit 2 for the duration specified in the Table 
below:
Washout periods for restricted medications were 
updated or added
Footnote: Added the following:

Clarification that patients receiving standard 
of care treatment for disease worsening will 
be reassessed to continue on trial treatment

This list is not all inclusive, for any 
medications not listed, contact the Clinical 
Trial Manager for restricted duration

Antihistamines for indications other than 
atopic dermatitis can be prescribed on an as 
needed basis. Dose should, preferably, be 
stable within one week prior to V2 and 
during the course of the study

No restriction on use of corticosteroid drops, 
nasal and inhaled corticosteroids, 
Montelukast to treat conditions listed – if 
medications are on stable dose for 3 months 
prior to Visit 2.
Rationale for change
Clarify how patient treatment administration will be 
managed in patients who use standard of care in 
case of worsening disease. Added restricted 
medications and clarified washout periods to 
include common treatments for AD which may be 
used by patients.
Section to be changed
Section 5.1
Description of change
Removed striked-through text.
The EASI Instrument is provided in Appendix 
10.1.2.
The SCORAD Instrument is provided in Appendix 
10.1.3.
The IGA Instrument is provided in Appendix 
10.1.4  
The DLQI Instrument is provided in Appendix 
10.1.5.
IGA: Removed ‘disease’after each classification
Rationale for change
To prevent confusion for sites over which format to 


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use; Removed inaccurate information
Section to be changed
Section 5.7
Description of change
Information about race should be obtained from all 
study participants as allowed by local regulations. 
This is because the prevalence and characteristics 
of psoriasis atopic dermatitis may differ between 
patients of different racial origin. It will thus be
worthwhile to assess if patients of different race 
will respond differently to the study treatment.
Rationale for change
Correction of the disease
Section to be changed
Section 6.2.2
Description of change
Removed striked-through text:
At Visit 21before study drug administration, 
patients will be provided with emollient and 
instructions on how to apply. Emollient will be 
provided to each patient as required for the duration 
of the study.
Rationale for change
To correct the timing for when emollient is to be 
provided to the patient
Section to be changed
Section 6.2.3
Description of change
For the comprehensive list of the trial procedures 
required following the end of treatment please refer 
to Flow Chart.
Rationale for change
Accurately describe the period between end of 
treatment and end of study
Section to be changed
Description of change
Rationale for change
Section to be changed
Section 10.1.2


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Description of change
Removed Eczema Area and Severity Index (EASI)
Rationale for change
To prevent confusion for sites over which format to 
use
Section to be changed
Section 10.1.3
Description of change
Removed SCOring of Atopic Dermatitis 
(SCORAD)
Rationale for change
To prevent confusion for sites over which format to 
use
Section to be changed
Section 10.1.4
Description of change
Removed Investigator Global Assessment (IGA)
Rationale for change
To prevent confusion for sites over which format to 
use
Section to be changed
Section 10.1.5
Description of change
Removed Dermatology Life Quality Index (DLQI)
Rationale for change
To prevent confusion for sites over which format to 
use
11.3
GLOBAL AMENDMENT 3
Date of amendment
12 Feb 2020
EudraCT number
EU number
NA
BI Trial number
1368-0032
BI Investigational Product(s)
BI 655130
Title of protocol
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
Global Amendment due to urgent safety reasons
Global Amendment
X
COMMENT: The main purpose of this amendment is to give patients re-allocated as 
Non-Responders at V7 (Week 16) an opportunity to participate in the open label 
extension trial earlier after treatment completion.
Section to be changed
Flow 
Chart
Description of change
Renamed V11 End of Study
Reduced time for when V11 End of Study visit 
should be completed after treatment completion, 
for Non-Responder patients.
Added End of Study Safety Phone call for Non-
Responder patients who do not continue in open 
label extension trial.


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Updated Footnotes 3 and 9
Updated footnote 18 to include End of Study and 
Follow-up visit for Non-Responder patients.
Footnotes 20-22 added
Added line item for End of Study Completion 
Call in IRT
Infection Testing: Removed HBV DNA at V10 
and V11
Section header: Physician and Patient 
Assessments removed
Rationale for change
To distinguish visit for Non-Responder patients, 
depending on if they continue in open label 
extension trial
To allow Non-Responders to complete End of 
Study visit sooner after treatment and if eligible, 
continue in the open label extension trial.
To ensure patients re-allocated as Non-
Responders and not continuing in open label 
extension trial, complete a safety assessment at 
the end of the residual period.
Footnote 3 updated to clarify status of patients 
who discontinue treatment prematurely
Footnote 9 updated to explain which infection 
tests are performed at EoS visits.
Footnotes 18, 20-22 added/revised to clarify when 
the V11 End of Study/Follow-Up 1 visit and End 
of Study Safety Phone call should be completed 
for Non-Responder patients 
End of Study Completion Call in IRT added to 
clarify when EoS should be registered for the 
patient
HBV DNA removed from Infection Testing for 
correction
Section header removed to prevent confusion


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Section to be changed
Description of change
Rationale for change
Section to be changed
3.1
Overall Trial Design and Plan
Description of change
Updated Figure 3.1.1 Trial design with new time 
point for when V11 should be completed and 
added Safety Follow-up Phone Call
Rationale for change
To remain consistent with all protocol amendment 
changes
Section to be changed
4.2.3
Table 4.2.3.1:1 Restricted Medications
Description of change
Duration of restricted medication extended to End 
of Study Visit for Non-Responders under the 
specified condition
Rationale for change
Ensures Non-Responder patients who reach EASI 
50 (while only on active treatment) by End of 
Study Visit, are eligible to continue in the open 
label extension trial
Section to be changed
5.2
Assessment of Safety
Description of change
Table 5.2.3:1 Footnote 1 updated and 7 added
Rationale for change
Footnote 1 updated for correction
Footnote 7 added to clarify Infection tests 
performed at EoS visit
Description of change
5.2.5.2 Adverse event collection and Reporting:
Updated instructions on the method of reporting 
SAEs, AESIs and non-serious AEs
Updated Pregnancy section to include collection 
of pregnancy status at the Safety Follow-up phone 
call
Rationale for change
To allow an alternative method of SAE report 
transmission (instead of fax) if implemented in 
this trial
To ensure an appropriate safety assessment is 
completed at the end of the residual period
Section to be changed
6.2
Details of Trial Procedures at Selected Visits
Description of change
6.2.2 Randomization Visit and Treatment Visits:
For women of child-bearing potential, added the 
collection of pregnancy status at the Safety 
Follow-up call.
6.2.2.3 End of Study Visit and Safety Follow-up 
Phone Call added 
Trial Completion:
Updated the time point (week) when V11 – End 
of Study should be completed 


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Rationale for change
To remain consistent with all protocol amendment 
changes 
To include details on the safety assessment for 
Non-Responder patients after treatment 
completion
Section to be changed
7.3
Planned Analysis
Description of change
Rationale for change
Correction and clarification on endpoint analysis 


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c23806995
4.0
clinical-trial-protocol-version-04
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
Author-Trial Clinical
Pharmacokineticist
14 Feb 2020 16:47 CET
Approval-Translational Medicine
Expert
14 Feb 2020 17:18 CET
Approval-Team Member Medicine
14 Feb 2020 17:56 CET
Approval-
Medicine
14 Feb 2020 19:32 CET
Approval-Clinical Trial Leader
16 Feb 2020 15:39 CET
Approval-Biostatistics
18 Feb 2020 16:49 CET


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c23806995
4.0

SAP_001.pdf: 
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c27696306-02
BI Trial No.:
1368-0032
Title:
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
Including Revised Protocol Amendment #3 [c23806995-04]
Investigational
Product:
BI 655130
Responsible trial 
statisticians:
Phone: 
Fax:     
Date of statistical 
analysis plan:
20 Aug 2020 SIGNED
Version:
2.0
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reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES...................................................................................................................4
2.
LIST OF ABBREVIATIONS ..............................................................................5
3.
INTRODUCTION.................................................................................................8
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY......................9
5.
ENDPOINTS .........................................................................................................9
5.1
PRIMARY ENDPOINT .......................................................................................9
5.2
SECONDARY ENDPOINTS.............................................................................10
Key secondary endpoint .....................................................................................10
5.2.1
Secondary endpoints...........................................................................................10
5.2.2
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................17
6.1
TREATMENTS...................................................................................................17
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................20
6.3
SUBJECT SETS ANALYSED...........................................................................30
6.5
POOLING OF CENTRES .................................................................................32
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................32
Withdrawals ........................................................................................................32
6.6.1
Efficacy data........................................................................................................32
6.6.2
Safety data ...........................................................................................................33
6.6.3
Time since first diagnosis ...................................................................................34
6.6.6
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................34
7.
PLANNED ANALYSIS......................................................................................37
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........38
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................39
7.3
TREATMENT COMPLIANCE........................................................................41
7.4
PRIMARY ENDPOINT .....................................................................................41
Primary analysis of the primary endpoint........................................................41
7.4.1


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7.5
SECONDARY ENDPOINTS.............................................................................44
Key secondary endpoint .....................................................................................44
7.5.1
Secondary endpoints...........................................................................................44
7.5.2
7.5.2.1
Secondary efficacy endpoints ...............................................................................44
7.5.2.2
Secondary safety endpoints...................................................................................44
7.7
EXTENT OF EXPOSURE.................................................................................47
7.8
SAFETY ANALYSIS..........................................................................................47
Adverse events.....................................................................................................48
7.8.1
Laboratory data ..................................................................................................49
7.8.2
Vital signs.............................................................................................................51
7.8.3
ECG......................................................................................................................51
7.8.4
Others...................................................................................................................51
7.8.5
7.8.5.1
Infusion reactions including anaphylactic reaction...............................................51
7.8.5.2
Immunogenicity ....................................................................................................51
7.8.5.3
Handling of DMC Analyses..................................................................................51
8.
REFERENCES....................................................................................................53
10.
HISTORY TABLE..............................................................................................55


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LIST OF TABLES
Table 6.1: 1
Flow chart of trial period/phases .............................................................................................. 17
Table 6.1: 2
AE assignment to analysis treatment groups............................................................................ 18
Table 6.2: 1
Important protocol deviations................................................................................................... 21
Table 6.7: 1
Time windows for assignment of efficacy, safety lab, vital signs, and  biomarker 
measurements to visits for statistical analysis of the double-blind treatment period................ 35
Table 6.7: 2
Time windows for assignment of efficacy, safety lab, vital signs, and  biomarker 
measurements to visits for statistical analysis after Week 16 visit date ................................... 36
Table 7.1: 1
Categories for summary of continuous variables ..................................................................... 39
Table 7.8.1: 1 Project MEDDRA search criteria for User Defined Adverse Event Concepts.............................. 49
Table 10: 1
History table ............................................................................................................................. 55


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
AD
Atopic dermatitis
ADA
Anti-drug antibodies
ADS
Analysis dataset
AE
Adverse event
AESI
Adverse event of special interest
ALT
Alanine aminotransferase
ALQ
Above limit of quantification
AST
Aspartate aminotransferase
ATC3
Anatomical-Therapeutic-Chemical classification level 3
BI
Boehringer Ingelheim
BIcMQ
Boehringer Ingelheim-customised MedDRA query
BLQ
Below the lower limit of quantification
BM-SAP
Biomarker Statistical Analysis Plan
BMI
Body mass index
BSA
Body surface area
CARE
Clinical data analysis and reporting environment
CI
Confidence interval
CMH
Cochran-Mantel-Haenszel
CRP
C-reactive protein
CTP
Clinical trial protocol
CTR
Clinical trial report
CV
Arithmetic coefficient of variation
DBLM
Database lock meeting
DILI
Drug Induced Liver Injury
DLQI
Dermatology Life Quality Index
DMC
Data Monitoring Committee
ECG
Electrocardiogram
eCRF
Electronic case report form
eDISH
Evaluation of drug-induced serious hepatotoxicity
EASI
Eczema Area and Severity Index
EMA
European Medicines Agency


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Term
Definition / description
EoS
End of study
ES
Enrolled set
EX
Exclusion
FAS
Full analysis set
FAS-C
Full analysis set including completers
gCV
Geometric coefficient of variation
gMean
Geometric mean
HIV
Human immunodeficiency virus
HLT
High level term
HLGT
High level group term
IC
Informed consent
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
IGA
Investigator Global Assessment
IgE
Immunoglobulin E
IN
Inclusion
iPD
Important protocol deviation
IQR
Interquartile range
IQRMP
Integrated Quality and Risk Management Plan
IRT
Interactive response technology
LD
Last dose
LLOQ
Lower limit of quantification
Max
Maximum
MedDRA
Medical Dictionary for Regulatory Activities
Min
Minimum
MMRM
Mixed Model Repeated Measures
MQRM
Medical quality review meeting
N
Number of observations
NA
Not applicable
NR
Non-Responder
OL
Open label
PD
Pharmacodynamic(s)
PE
Primary endpoint


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Term
Definition / description
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic parameter set
PPS
Per protocol set
Q1
1st quartile
Q3
3rd quartile
R
Responder
RAGe
Report appendix generator
RCTC
Rheumatology common toxicity criteria
REML
Restricted maximum likelihood
RPM
Report planning meeting
RS
Randomized set
SAE
Serious adverse event
SAF
Safety analysis set
SAF-OL
Safety analysis set in the open-label treatment period
SAP
Statistical analysis plan
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
TB
Tuberculosis
TSAP
Trial statistical analysis plan
UDAEC
User-defined AE concepts
ULN
Upper limit of normal range
ULOQ
Upper limit of quantification
VAS
Visual analogue scale


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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 primary and 
secondary variables and other 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.
Pharmacokinetic (PK) parameters will be calculated using WinNonlinTM software (version
6.3, Certara USA Inc., Princeton, NJ, USA).
The statistical analyses will be performed within the validated working environment CARE, 
including SASTM (current Version 9.4, by SAS Institute Inc., Cary, NC, USA), 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 primary week 16 analysis (to be performed once 
all randomized patients have completed through the week 16 visit), as well as the final trial 
analysis including data beyond week 16 (to be performed once all patients have completed 
the trial). A separate Interim Statistical Analysis Plan describes the analyses that were 
performed once 75% of patients had completed at least 4 weeks of treatment.


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
NA
5.
ENDPOINTS
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 and Table 6.7:2.
For all endpoints and unless explicitly specified otherwise, End-of-Study visit refers to V10
(Week 28) for Responders and V11 (Week 44) for Non-Responders, using extended time 
windows as defined in Table 6.7: 1 and Table 6.7:2.
Responders are defined as patients who attain at least 75% reduction in Eczema Area and 
Severity Index (EASI) score compared to baseline at Week 16. Non-Responders are defined 
as patients who do not achieve at least 75% improvement from baseline in EASI score at 
Week 16.
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
The primary efficacy endpoint is change from baseline in EASI Score at Week 16.
The absolute and percent change from baseline will be analysed as well as the absolute values 
at visits. 
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”


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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 
5.2
SECONDARY ENDPOINTS
Key secondary endpoint
5.2.1
Not applicable.
Secondary endpoints
5.2.2
The secondary endpoints are listed below.

Drug-related Adverse Events (AEs)
Numbers and percentages of patients with drug-related AEs will be presented.

Change from baseline in EASI Score at Week 4 
The absolute and percent change from baseline as well as the absolute values at visits 
will be analysed. 

EASI50/75 responders at Week 4 and 16
Numbers and percentages will be analysed.
Achievement of Decrease in EASI ≥ xx% (EASIxx)
Achieving a response 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.


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
Change from baseline in SCORing of Atopic Dermatitis (SCORAD) at Week 4 and 
16 
The absolute 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


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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 4 and 16
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.”
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.


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Safety will be assessed based on:

Adverse events

Serious adverse events (SAEs)


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
For basic study information on the treatment to be administered, assignment to treatment, and 
selection of dose, cf. Section 4 of the CTP.
In the blinded treatment phase, all patients will receive either intravenous doses of 600mg of 
BI 655130 solution for infusion (at weeks 0, 4, 8, and 12), or Placebo.
At Week 16, all patients will be evaluated with the EASI Score. Non-responders (EASI < 75) 
will be re-allocated to receive BI open label trial drug from Week 16 through Week 28; they 
will be followed until Week 44. Responders (EASI >= 75) will be re-assigned to receive no 
further trial treatment but will be expected to come to all visits up to Week 28, when EOS 
visit is planned.
The following trial periods/phases are defined:
Table 6.1: 1
Flow chart of trial period/phases
Trial phase
Description
Start (included)
End (excluded)
Screening phase
Screening
Date of informed consent 
Date of start of first infusion of 
study drug (day 1).
Blinded Treatment 
phase
Randomised 
On-treatment 
period
Date of start of infusion of 
first study drug (Day 1) 
Week 16 visit date + 1 day
Open label
Treatment phase1
Re-allocation
period (Either 
open label 
BI655130 or No 
treatment)
Week 16 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. 
1 Non-responders (i.e. EASI<75) at Week 16 will be re-allocated to BI655130 600mg IV open label and will continue in the 
trial until Week 44. Responders (EASI>=75) at Week 16 will be re-allocated to no treatment and will be observed
until Week 28 or the day when they return to a 50% reduction in EASI score (EASI50) and start the treatment in 
the extension trial.
Patients who discontinue the treatment but will continue on trial visits will be included in 
analyses with the available data. For patients who discontinue trial prematurely only available 
data will be used in the analyses.


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For the final analysis of the trial to be performed once all patients have completed through the 
planned period, results will be summarized including the data from the reallocation period 
(Open-label Treatment phase). Results will be presented separately and in descriptive 
manner. The time windows for data presentation in this analysis are described in Table 6.7: 1.
In addition, analyses including the data from the double-blind period (initially used for the 
Primary Analysis) will be re-run after the final database lock.
To distinguish between assignment to trial periods/phases and AE assignments, please, refer
to Table 6.1:2.
Table 6.1: 2
AE assignment to analysis treatment groups
Randomised 
treatment
EASI75 response
at Week 16
Open-label
period
AE assignment to analysis
treatment group
PLACEBO
Responder
No Treatment
AE that occurred between first 
randomised study drug intake and
min[(EoS visit date), (last randomised 
study drug administration date + 112 
days)] will be analysed under 
PLACEBO. AEs occurring later will 
be listed only.
PLACEBO
Non-Responder
BI 655130 Treatment
AE that occurred between first
randomised study drug intake and
Week 16 visit date (excluding) will be 
analysed under PLACEBO. AEs 
occurring later will be analysed under 
Open-label BI Treatment.
BI 655130
Responder
No Treatment
AE that occurred between first 
randomised study drug intake and 
min[(EoS visit date), (last randomised 
study drug administration date + 112 
days)] will be analysed under BI 
655130. AEs occurring later will be 
listed only.
BI 655130
Non-Responder
BI 655130 Treatment
AE that occurred between first 
randomised study drug intake and 
Week 16 visit date (excluding) will be 
analysed under BI 655130. AEs 
occurring later will be analysed under 
Open-label BI Treatment.
Treatment groups up to Week 16 will be labelled as follows:

"Speso 600 mg IV q4w" (i.e., patients randomised to BI 655130 600 mg) 

"Placebo" (i.e., patients randomised to Placebo)

"Overall Total" (across treatments: Placebo and BI 655130 600 mg), where appropriate.


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Treatment groups for the efficacy analysis after week 16 will be labelled as follows:

"Open-label treatment: No Treatment"
-
“Placebo” (i.e., patients randomised to Placebo in the double-blind treatment period 
and who did not receive an open-label BI 655130 treatment starting from Week 16 
(V7))
-
“Speso 600 mg IV q4w” (i.e., patients randomised to BI 655130 in the double-blind 
treatment period and who did not receive and open-label BI 655130 treatment starting 
from Week 16 (V7)) 
-
“Total” (i.e., patients randomised either to Placebo or BI 655130 in the double-blind 
treatment period and who did not receive an open-label BI 655130 treatment starting 
from Week 16 (V7))

"Open-label treatment: Speso 600 mg IV q4w"
-
“Placebo” (i.e., patients randomised to Placebo in the double-blind treatment period 
and received an open-label BI 655130 treatment starting from Week 16 (V7))
-
“Speso 600 mg IV q4w” (i.e., patients randomised to BI 655130 in the double-blind 
treatment period and received and open-label BI 655130 treatment starting from Week 
16 (V7))
-
“Total” (i.e., patients randomised either to Placebo or BI 655130 in the double-blind 
treatment period and received an open-label BI 655130 treatment starting from Week 
16 (V7))
Treatment groups for the safety analysis for the whole trial will be labelled as follows:

"Speso 600 mg IV q4w" (i.e., patients randomised to BI 655130 600 mg) 

"Placebo" (i.e., patients randomised to Placebo)

"Total Speso 600 mg IV q4w OL" (i.e., patients randomised either to Placebo or BI 
655130 600mg and assigned to BI 655130 600 mg open-label treatment at Week 16)
More details on the technical implementation of these analyses are provided in the ADS Plan 
of this TSAP.


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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).
If any iPDs are identified, they are to be summarised into categories and will be captured in 
the Integrated Quality and Risk Management Plan (IQRMP) (3). The following table contains 
the categories which are considered to be iPDs in this trial. If the data show other iPDs, this 
table will be supplemented accordingly by the time of the RPM/DBLM/MQRM. Not all iPDs 
will lead to exclusion from analysis sets. iPDs are indicated as such in Table 6.2: 1.
iPDs will be summarised and listed.


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Table 6.2: 1
Important protocol deviations
Category / 
Code
Description
Comments*
Excluded 
from1
A
Entrance criteria violated
A1
Inclusion criteria not met
A1.01
Age out of range
LABEL:
Age < 18
IN02
Also check versus derived
age for patient.
None
A1.01a
Age out of range
LABEL:
Age > 75
IN02
Also check versus derived
age for patient.
None
A1.02
Moderate to severe atopic
dermatitis per CTP not
confirmed, ie.:
BSA of
atopic dermatitis involvement
at screening < 10% OR
BSA of atopic dermatitis
involvement at baseline < 10%
OR
EASI at screening < 7.1 (12 in the CTP 
as inclusion criterion)
OR
EASI at baseline < 16 
OR
IGA at screening
< 3 OR IGA at baseline < 3
LABEL:
Disease severity out of range (moderate-
severe).
IN04
Also check versus BSA, 
IGA, and EASI 
None


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Table 6.2: 1 (cont’d) Important protocol deviations
Category / 
Code
Description
Comments
Excluded 
from1
A1.03
Diagnosis of AD for less than 1 year.
LABEL:
Disease duration too short.
IN03
Also check versus derived 
disease duration
None
A1.04
History of inadequate response to topical 
corticosteroid as judged by the 
investigator not documented or 
documented response to topical 
corticosteroid.
LABEL:
Lack of inadequate response to topical 
corticosteroid
IN05
Also manual review versus 
listing of concomitant 
therapies (eCRF page, form: 
Atopic Dermatitis Therapy 
History (Topical)) and 
listing of reasons for 
discontinuation
None
A1.05
Patient is not willing to use a standard 
emollient for the duration of the study
LABEL:
Lack of willingness to use an emollient
IN06
None
A1.06
Women of childbearing potential are not 
ready or 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.
LABEL:
Not sufficient or no contraception 
method used 
IN07
None
A2
Exclusion criteria violated 
General Exclusion Criteria
A2.03
Use of topical corticosteroids
(or agent) for atopic dermatitis within 7 
days prior
to first dose of trial treatment
LABEL: 
Use of topical corticosteroids – wash-out 
period too short.
EX01
Also manual review versus 
listing of concomitant 
therapy used
None


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Table 6.2: 1 (cont’d) Important protocol deviations
Category / 
Code
Description
Comments
Excluded 
from1
A2.04
Use of systemic corticosteroids
(or agent) for atopic dermatitis
within 4 weeks prior to first
dose of trial treatment.
LABEL: 
Use of systemic corticosteroids – wash-
out period too short.
EX02
Also manual review versus 
listing of concomitant 
therapy used
None
A2.05
Women who are pregnant or
plan to become pregnant while
in the trial. 
LABEL: 
Pregnancy.
EX03
None
A2.06
Currently enrolled or less than 30 days 
or 5half lives since participation in
another
investigational device or drug trial, or 
receiving other investigational 
treatment(s).
LABEL:
Participation in another drug 
development program.
EX11
None
A2.07
Patient with a transplanted organ (with 
exception of a corneal transplant > 12 
weeks prior to screening) or who have 
ever received stem cell therapy.
LABEL:
History of transplantation or stem cell 
therapy.
EX04
None
A2.08
Any documented active or suspected 
malignancy or history of malignancy 
within 5 years prior to the screening 
visit, except appropriately treated 
squamous cell carcinoma of the skin or 
in situ carcinoma of uterine cervix.
LABEL:
Malignancy.
EX05
Also manual review versus 
listing of AEs and listing of 
medical history
None


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Table 6.2: 1 (cont’d) Important protocol deviations
Category / 
Code
Description
Comments
Excluded 
from1
A2.09
Use of any restricted medication as 
specified in CTP, Table 4.2.3.1:1 or any 
drug considered likely to interfere with 
the safe conduct of the study, as assessed 
by the investigator.
LABEL:
Restricted medication use.
EX06
Also manual review versus 
listing of concomitant 
therapy
None
A2.10
History of allergy/hypersensitivity to the 
systematically administered trial 
medication agent or its excipients.
LABEL:
History of allergy/hypersensitivity
EX07
Also manual review versus 
listing of medical history
None
A2.11
Active systemic infections (Fungal and 
bacterial disease) during the last 2 weeks 
prior to first drug administration, per 
investigator assessment.
LABEL:
Washout after systemic infection too 
short.
EX08
Also manual review versus 
listing of AEs and listing of 
medical history
None
A2.12
Relevant chronic or acute infections 
(exception: common cold) including 
HIV or viral hepatitis. A patient can be 
re-screened if the patient was treated and 
is cured from the acute infection.
LABEL:
Chronic or acute infection.
EX09
Also manual review versus 
listing of medical history
None


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Table 6.2: 1 (cont’d) Important protocol deviations
Category / 
Code
Description
Comments
Excluded 
from1
A2.13
Patients with active TB.
Patients with a positive QuantiFERON 
TB test during screening, if patient had 
previous diagnosis of active or latent TB 
and has not completed appropriate 
treatment per local practice/guidelines 
within the last 3 years and at least 6 
months before first administration of 
trial medication under this protocol 
(patients may be re-screened once to 
meet this criterion).
Patients with suspected false positive or 
indeterminate QuantiFERON TB result 
may be retested once.
If the QuantiFERON TB test result is not 
available or provides indeterminate 
results after repeat testing: A tuberculin 
skin test reaction ≥10mm (≥5mm if 
receiving ≥15mg/d prednisone or its 
equivalent) is considered positive.
LABEL:
Tuberculosis.
EX10
Also manual review versus 
listing of medical history
None
A2.14
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 data.
LABEL:
General health condition.
EX12
Also manual review versus 
listing of medical history, 
vital signs, laboratory results
None


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Table 6.2: 1 (cont’d) Important protocol deviations
Category / 
Code
Description
Comments
Excluded 
from1
A2.15
Major surgery (major according to the 
investigator) performed within 12 weeks 
prior to first study drug administration or 
planned during the study.
LABEL:
Time since major surgery <12 weeks 
before start of treatment or planned 
during the study.
EX13
Also manual review versus 
listing of medical history 
and AEs
None
A2.16
Severe, progressive, or uncontrolled 
hepatic disease, defined as >3-fold ULN 
elevation in AST or ALT or alkaline 
phosphatase, or >2-fold ULN elevation 
in total bilirubin.
LABEL:
Hepatic disease.
EX14
Also manual review versus 
listing of AEs and laboratory 
results
None
B
Informed consent
B1
Date of informed consent missing
OR
No signature available
LABEL:
IC not available.
IN01
In this case: Patient’s data 
will not be used for the 
reporting in CTR
All analyses
#
B2
Informed consent too late.
LABEL:
IC too late.
Informed consent date was 
after V1
None


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Table 6.2: 1 (cont’d) Important protocol deviations
Category / 
Code
Description
Comments
Excluded 
from1
C
Trial medication and randomisation
C1
Incorrect trial medication
C1.01
Randomisation order not
followed
Different medication administered at 
randomization visit,
than the patient was
randomised to (i.e. drug kit
recorded in eCRF is from a
different treatment group than
the drug kit assigned by IRT)
LABEL:
Wrong treatment dispensed at 
randomisation visit.
Usually in this case patient
should continue with the 
first medication 
administered for the whole 
trial.
None
C1.02
Wrong kit assigned to the
patient.
LABEL:
Wrong medication assigned.
After unblinding check the 
numbers of kits assigned by 
IRT system versus the 
randomised treatment.
None
C1.03
Patient treated without
randomisation. 
LABEL:
Treatment without randomisation.
Patient treated according to 
eCRF, but not randomised 
according to IRT.
None
C2
Non-compliance
C2.01
Non-compliance with study
drug administration - administered dose
too high
LABEL:
Too high dose taken
The dose administered 
above 600 mg
None
#
C2.02
Non-compliance with study
drug administration - administered dose
too low
LABEL:
Too low dose taken
The dose administered 
below 600 mg
Check versus total infusion 
volume reported on the 
eCRF
None


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Table 6.2: 1 (cont’d) Important protocol deviations
Category / 
Code
Description
Comments
Excluded 
from1
C3
Incorrect trial medication dispensed
C3.01
Incorrect trial medication dispensed
LABEL:
Incorrect trial medication dispensed
This could be e.g. the case 
if wrong medication was 
dispensed by investigator 
at any visit after 
randomisation visit. After 
unblinding it needs to be 
checked whether this is an 
iPD.
None
D
Concomitant medication
D1
Previous medication
D1.01
Washout of previous medication too 
short
LABEL:
Washout too short.
Check versus concomitant 
medication end date
None
#
D2
Prohibited medication use
D2.01a
Use of restricted medication (other than 
steroid) with potential influence on 
efficacy data
LABEL:
Restricted medication other than steroid.
Manual review versus listing 
of concomitant medication
None
#
D2.01b
Use of restricted medication (systemic 
steroid) with potential influence on 
efficacy data
LABEL:
Restricted medication (systemic steroid).
Manual review versus listing 
of concomitant medication
None
#
D2.01c
Use of restricted medication (skin-
related steroid) with potential influence 
on efficacy data
LABEL:
Restricted medication (skin-related 
steroid).
Manual review versus listing 
of concomitant medication
None
#


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Table 6.2: 1 (cont’d) Important protocol deviations
Category / 
Code
Description
Comments
Excluded 
from1
F
Study specific analysis
F1
Other trial specific violation
F1.01
Study drug intake too early (i.e., <14 
days after the previous intake)
LABEL: 
Study drug intake outside time window 
(<14 days)
Check actual visit dates 
None
F1.02
Primary endpoint (PE) assessment more 
than 1 week before planned day
LABEL:
PE assessment >1 week before planned.
Check actual visit dates 
versus the scheduled ones
None
F2
Certain violations of procedures used 
to measure primary or secondary 
efficacy data
F2.01
Missing data entries of EASI
for Week 4.
LABEL:
Missing EASI at Week 4.
Missing data for EASI 
Score– interim analysis.
None
F2.02
Missing data entries of EASI
for Week 16.
LABEL:
Missing EASI at Week 16.
Missing data for PE.
None
F2.03
Patient incorrectly assigned as 
responder/non-responder for EASI at V7 
(in IRT system)
Manual review vs. data 
entered into the IRT system
None
#


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Table 6.2: 1 (cont’d) Important protocol deviations
Category / 
Code
Description
Comments
Excluded 
from1
G
Other safety related violations
G1.01
Pregnancy test not done for woman of 
child bearing potential per CTP 
flowchart
LABEL:
Pregnancy test not done.
Pregnancy test not done at 
any visit where such is 
scheduled and the patient 
did not yet complete follow-
up.
None
G1.02
Pregnancy or nursing
LABEL:
Pregnancy or nursing.
Medical review: Pregnancy 
or nursing during the trial up
to 16 weeks after the last 
study drug administration
None
#
# PD will be detected manually; PE = Primary endpoint; IC = Informed consent; IN = Inclusion criterion; EX = Exclusion 
criterion
Source: BI reference document: “Identify and Manage Important Protocol Deviations (iPD)” [001-MCS-40-413] (2).
1 See Section 6.3 for population definitions 
* tick box on eCRF page and derived data will be checked.
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.

Randomized set (RS)
This patient set includes all patients who were randomized into the trial. 
It will be used for display of patient disposition, baseline and demographic 
characteristics, and patients with IPDs.

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. Treatment 
assignment will be based on the actual treatment administered. Actual treatment refers 
to the actual treatment administered at the first dosing. This treatment should be 
followed through the whole trial, regardless of the initially randomised treatment.


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
Safety analysis set in the open-label treatment period (SAF-OL)
This patient set includes all randomized patients who received at least one dose of 
study drug and received study medication after re-allocation visit (i.e., after Week 16 
visit). Treatment assignment will be based on the actual treatment administered
starting from Week 16 visit. This analysis set will the main set for presentation of the 
safety data for the treatment re-allocation period.

Full analysis set (FAS)
This patient set includes all patients in the SAF who had a baseline measurement for 
the primary endpoint. It will be the main analysis set for presentation of efficacy 
results. Treatment assignment will be as randomized.

Full analysis set including completers (FAS-C)
This analysis set includes all patients in the FAS who completed double-blind 
treatment, i.e., did not prematurely discontinue treatment up to (and including) Week 
12. 

Pharmacokinetic parameter set (PKS)
This patient set includes all patients in the SAF who provide at least one evaluable 
observation for the BI 655130 concentration, which was not flagged for exclusion. 
This patient set will be used for the display of concentrations.
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.
Handling of Treatment Misallocations in Analysis Sets
If a patient was administered incorrect treatment during the study, then for safety the 
following will be used in addition:
-
If a patient is planned to receive multiple dose administrations of BI 
655130 (i.e. randomized to BI 655130 600 mg IV every 4 weeks), then 
patients will be reported under their actual treatment from the 
randomisation visit for safety analyses because the overall safety profile is 
expected to be driven by the amount of drug received in totality over the 
entire treatment duration. It is not expected that the safety profile will 
deviate from the planned treatment regimen if the subject receives only 
one or two vials of the incorrect medication at only some dosing 
occasions.
-
If a patient is planned to receive multiple dose administrations of placebo, 
then patients will be reported under their randomized treatment group for 
safety analysis if the patient was administered no vials of BI 655130 at any 
visit. If the patient was administered at least one vial of BI 655130 during 
the treatment period, then the patient will be assigned to BI 655130 600 
mg IV treatment group.


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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 not desirable. 
6.6
HANDLING OF MISSING DATA AND OUTLIERS
Withdrawals
6.6.1
The reasons for withdrawal from treatment will be reported as indicated on the eCRF.
Efficacy data
6.6.2
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).


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For all patients with a missing visit outcome, impute 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 if 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, the use of a restricted maximum 
likelihood (REML)-based mixed model repeated measures (MMRM) approach, if applicable, 
will ensure that missing data are handled implicitly, via a missing at random assumption, by 
the statistical model.
Safety data
6.6.3
From CTP Section 7.5: With respect to safety evaluations, it is not planned to impute 
missing values.
The only exceptions where imputation might be necessary for safety evaluation are AE dates 
and start and stop dates for concomitant medications. Missing or incomplete AE dates are 
imputed according to BI standards (see BI-KMED-BDS-HTG-0035 (4)).
Partial start and stop dates for concomitant medications 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.


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Time since first diagnosis
6.6.6
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.
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.
Baseline, unless otherwise specified, is defined as the last measurement collected prior to the 
start of administration of the trial treatment.
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.


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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 periods/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.
Table 6.7: 1
Time windows for assignment of efficacy, safety lab, vital signs, and 
biomarker measurements to visits for statistical analysis of the double-blind treatment period
Visit 
number
/ name
Planned 
day
Time window (Days)
Visit label
Window 
(per 
CTP)
Start
(per CTP)
End
(per CTP)
Start 
(extended)
End 
(extended)
V1
Screening
- 28 to -7
n/a
-∞
0
V2
Day 1
Day 1
n/a
1 A
1
1 A
1
V3
Week 2
Day 15
+/- 3
12
18
2
21
V4
Week 4
Day 29
+/- 3 
26
32
22
42
V5
Week 8
Day 57
+/- 3 
54
60
43
70
V6
Week 12
Day 85
+/- 3 
82
88
71
98
V7
Week 16
Day 113
+/- 3 
110
116
99
Week 16 
visit date
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 
infusion 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.
Table 6.7:1 needs to be taken only when the measurement occurs between randomisation date 
and primary endpoint visit date (Week 16 visit date). Any unscheduled visits after Week 16 
visit date will not be taken into account in Table 6.7:1.
For measurements after the primary endpoint visit date (Week 16 visit date), including 
unscheduled visits, refer to the Table 6.7:2. 


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Table 6.7: 2
Time windows for assignment of efficacy, safety lab, vital signs, and  
biomarker measurements to visits for statistical analysis after Week 16 visit date
Visit 
number/ 
name
Planned 
day
Time window (Days)
Visit label
Window 
(per 
CTP)
Start
(per CTP)
End
(per CTP)
Start 
(extended)
End 
(extended)
V7.1*
Week 
16OL
Week 16 
visit date+1
126
V8
Week 20
Day 141
+/- 3 
138
144
127
154
V9
Week 24
Day 169
+/- 3 
166
172
155
182
V10**
EoS for R
Day 197
+/- 3 
194
200
183
210/
LD+16 
weeks/EoS 
visit date
V11a***
EoS for 
NR
Day 228
+/- 3 
225
231
211
238/
LD+16weeks
/EoS visit 
date
V11b***
EoS for 
NR
Day 309
+/- 3 
306
312
239
LD+16weeks
/EoS visit 
date
Days are counted relative to the day of first treatment, which is defined as Day 1.
LD = Last dose of treatment
EoS = End of Study
R = Responder
NR = Non-Responder
* For vital signs, measurements after EASI responder-non-responder assessment are assigned to Week 16 (V7), after first 
open-label (OL) treatment
** V10 EoS applies to patients who responded at Week 16 (up to LD+16 weeks); Non-responders receive the last dose of the 
BI655130 at that Week 28 visit (up to day 252)
*** V11a and V11b apply to patients who did not respond at Week 16 and were re-allocated to BI655130 treatment
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.
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.


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7.
PLANNED ANALYSIS
All efficacy analyses will be purely exploratory in nature. The following analyses are planned
at different stages throughout the trial.
o
Primary Analysis (Week 16)
The primary analysis is planned to be performed when all patients complete week 16 visit of 
the trial.
A memorandum is planned to summarize the results of the primary analysis at Week 16. 
o
Final analysis (Week 44)
The analysis of the entire efficacy, safety, PK, and biomarker data collected through the full 
44 weeks of follow-up will be performed once all entered patients have completed the trial 
(up to EoS for Non-Responders/Week 44 Visit); at that time point, a final database lock will 
be done and all data through week 44 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] (10) 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
For PK analyte concentrations, the following descriptive statistics will additionally be 
calculated:

CV arithmetic coefficient of variation

gMean geometric mean

gCV geometric coefficient of variation
The data format for descriptive statistics of concentrations will be identical with the data 
format of the respective concentrations.


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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” (10). 
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category as well as the percentage (%) relative to the 
respective treatment. Percentages will be rounded to one decimal place. The category missing 
will be displayed if and only if 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 will be summarised by 
presentation of the frequency of patients screened, entered/randomised, screened but not 
entered, treated, entered but not treated, who completed all doses of trial medication as 
planned (overall, in the double-blind treatment period, and in the BI open-label treatment 
period), who prematurely discontinued study drug administration by reason (overall, in the 
double-blind treatment period, and in the BI open-label treatment period), patients still on-
going in the study, those, who completed the observational period as planned, who 
prematurely discontinued study participation, who completed Week 4 visit (V4), who 
completed the re-allocation visit at Week 16 (V7), number of patients reallocated to BI open-
label treatment. Disposition will be listed by country.
The frequency of patients with iPDs will be presented for the RS by treatment. 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 presented by 
treatment.
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the CTR.


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Descriptive statistics will be presented by treatment for demographic parameters and baseline 
characteristics, based on the RS. 
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.
Table 7.1: 1
Categories for summary of continuous variables
Variable
Categories
Age
< 30 years
≥ 30 years
< 50 years
50 to < 65 years
65 to < 75 years
≥ 75 years
< 65 years
≥ 65 years
Weight
≤70 kg
>70 to ≤80 kg
>80 to ≤ 90 kg
>90 kg
BMI
< 25 kg/m2
25 to < 30 kg/m2
≥ 30 kg/m2
Time since first diagnosis
≤ 1 year
> 1 to ≤ 5 years
> 5 to ≤ 10 years
> 10 years
Disease severity based on 
EASI total score
>7  to ≤ 21 (moderate)
>21            (severe)
Disease severity based on 
IGA score
= 3 (moderate)
= 4 (severe)
Age at disease onset 
≤12 years old
>12 years old
<18 years old
≥18 years old
7.2
CONCOMITANT DISEASES AND MEDICATION
Analyses of concomitant diseases and medication will be based on the RS.
Concomitant diseases will be coded according to the most recent version of MedDRA. 


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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 summarized by treatment. 
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. Summaries will be presented for:

historical medication taken before the first study drug administration of the double-
blind period (i.e., the start and stop dates are before the date of the first study 
medication infusion)

concomitant medication that started before the double-blind treatment (i.e., 
concomitant medication start date was prior to first study treatment administration)

concomitant medication started and taken within the double-blind period (from the 
day of the first treatment administration to the date of the Week 16 visit – 1 day)

concomitant medication that started on or after the Week 16 (V7) visit date (i.e., 
concomitant medication start date was on the Week 16 visit date or thereafter)
The frequency and percentage of patients with previous medication for AD will be displayed
as per data collected in the eCRF (i.e., separately for topical, non-topical, and non-
topical/non-drug therapies). Frequencies by preferred name and treatment arm will be 
displayed.
Concomitant use of non-drug therapies will be summarized with frequency and percentage. 
Summaries will be presented for

historical non-drug therapies taken before the first study drug administration of the 
double-blind period (i.e., the start and stop dates are before the date of the first study 
medication infusion)

concomitant non-drug therapies that started before the double-blind treatment (i.e., 
concomitant non-drug therapy start date was prior to first study treatment 
administration)

concomitant non-drug therapies started and taken within the double-blind period 
(from the day of the first treatment administration to the date of the Week 16 visit – 1 
day)

concomitant non-drug therapies that started on or after the Week 16 (V7) visit date
(i.e., concomitant non-drug therapy start date was on the Week 16 visit date or 
thereafter)


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In addition, the frequency and percentages of patients with concomitant AD medication used 
during the double-blind period (i.e., starting at baseline visit or thereafter) will be displayed 
by ATC3 and preferred name and by treatment.
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 infused (as a % of planned) is defined as the volume infused at a 
visit (in ml as recorded in the eCRF), divided by 100 ml (the volume the patient should have 
received).
In case the total volume administered (including saline) is greater than 100 mL (including 
flushing volume), 100mL i.e., full infusion will be used in the analysis.
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 and percentage of patients with the following overall compliance categories will 
be presented:

"< 80% of planned",

"80 to 100% of planned" 
The number of patients who received a dose will be tabulated per visit.
7.4
PRIMARY ENDPOINT
The primary endpoint for this trial is the percentage change from baseline in EASI Score at 
Week 16. 
Primary analysis of the primary endpoint
7.4.1
The analysis of the primary endpoint will be based on Section 7.3.1 of the CTP: 
From CTP Section 7.3.1: The primary analysis is a restricted maximum likelihood (REML) 
based approach using a mixed model with repeated measurements (MMRM) comparing the 
percent change from baseline of EASI score after 16 weeks of treatment. 
The analysis will include the fixed, categorical effects of treatment-by-visit interaction, 
stratification factor Asian/Non-Asian, and the fixed continuous effects of baseline-by-visit 
interaction. Visits will be treated as the repeated measure with an unstructured covariance 
structure used to model the within-patient measurements. The Kenward-Roger approximation 
will be used to estimate denominator degrees of freedom and adjust standard errors. 
Significance tests will be based on least-squares means using a two-sided α=0.10 (two-sided 


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90% confidence intervals (CI)). The primary treatment comparison will be the contrast 
between treatments at Week 16.
SAS code for the above model will be based on the following structure:
PROC MIXED DATA=alldat cl method=reml; 
  CLASS visit trt stratum subject; 
  MODEL ept = base visit trt stratum visit*trt base*visit / ddfm=kr s CL; 
  REPEATED visit / subject= subject type=un r rcorr; 
  LSMEANS visit*trt / pdiff=all om cl alpha=0.10 slice=visit; 
RUN;
For handling of non-convergence see Section 9.1.
The following hypothesis testing will be performed having an alpha level of 10% (two-sided) 
or 5% (one-sided):
H0: Mean percent change from baseline in EASI score at Week 16 (BI 655130) 
≤ Mean percent change from baseline in EASI score at Week 16 (Placebo)
H1: Mean percent change from baseline in EASI score at Week 16 (BI 655130) 
> Mean percent change from baseline in EASI score at Week 16 (Placebo)
The primary analysis will be performed on the FAS with patients analysed according to the 
stratum to which they belong (regardless of any miss-assignment to treatment based on 
identification of the wrong stratum). 


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7.5
SECONDARY ENDPOINTS
Key secondary endpoint
7.5.1
This section is not applicable as no key secondary endpoint has been specified.
Secondary endpoints
7.5.2
7.5.2.1 Secondary efficacy endpoints
All secondary efficacy endpoints will be analysed on FAS.
The continuous secondary efficacy endpoints (change from baseline in EASI at Week 4 and 
change from baseline in SCORAD at Week 4 and 16) will be analysed using the same 
MMRM model as defined for the primary endpoint. Both absolute and percent change from 
baseline will be analysed as an outcome.
A responder analysis based on the EASI Score will be performed at Week 4 and 16.
The binary endpoints defined above will be analysed with a logistic regression model 
including treatment and Asian/Non-Asian as explanatory variables. Risk difference for 
BI655130 versus placebo will be obtained as well as the response rates for the treatment 
groups.
As a sensitivity analyses, the Cochran-Mantel-Haenszel (CMH) test adjusted by Asian/Non-
Asian will be performed. 
The proportion of patients who achieved at least a 2-grade reduction from baseline in IGA to 
clear (0) or almost clear (1) at Week 4 and 16 will be analysed with CMH test.
7.5.2.2 Secondary safety endpoints
The secondary safety endpoint is defined as the number of patients with drug related adverse 
events (AEs). This will be a part of the Safety analyses described in detail in Section 7.8.


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7.7
EXTENT OF EXPOSURE
The number of subjects who received a dose of trial drug will be tabulated. The amount of 
treatment received (actual and weight based) will be summarised by descriptive statistics (N, 
mean, SD, minimum, median, maximum) per visit and overall. Additionally, number of 
infusions administered overall per treatment arm will be displayed. Also, the duration of the 
infusion will be provided for each visit.
7.8
SAFETY ANALYSIS
All safety analyses will be performed based on the SAF following BI standards. No 
hypothesis testing is planned.
In addition, overall AE table and the frequency table of patients with at least one AE by 
MedDRA System Ogran Class and Preferred Term will be prepared for AEs occurring 
between start date of study medication and Week 16 visit data (not including residual effect 
period). 
All safety data analyses beyond Week 16 (for patients not receiving BI open-label treatment) 
will be based on SAF-OL.


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Adverse events
7.8.1
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.
The analyses of AEs will be performed for double-blind period and for the re-allocation 
period separately.
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] (7) and “Handling of 
missing and incomplete AE dates” [BI-KMED-BDS-HTG-0035] (4). 
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 (9)) and for the class of AESIs.
The following is considered an AESI in this trial:
-
Hepatic injury
-
Infusion reactions including anaphylactic reaction
-
Severe infections 
-
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 (9), 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.


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A summary of user-defined AE concepts (UDAEC) will be presented by treatment group. 
The UDAEC are presented in the table below.
Table 7.8.1: 1 Project MEDDRA search criteria for User Defined Adverse Event Concepts
User Defined AE Concepts
Categories
Infusion/Systemic hypersensitivity 
reactions including anaphylactic 
reactions
Narrow SMQ “Anaphylactic reaction”
Narrow SMQ “Angioedema”
Narrow SMQ “Hypersensitivity”
Severe infections (according to 
RCTC grading)
SOC Infections and infestations of at least severe RCTC grade, by 
HLGT
Opportunistic infections
MedDRA SMQ Opportunistic Infections (narrow)
Hepatic injuries
See Section 7.8.2
Tuberculosis infections
BIcMQ sub-search 8.2 “Tuberculosis related terms”
Malignant tumours
(SMQ “Malignancies”)
(Sub-SMQ “Malignant or unspecified tumours”)
Narrow Sub-SMQ “Malignant tumours”
          Narrow Sub-SMQ “Haematological malignant   
              tumours”
          Narrow Sub-SMQ “Non-Haematological malignant   
              tumours”
Torsades de pointes
Broad SMQ “Torsades de pointes/QT prolongation”
Malignant skin tumours
(SMQ “Skin neoplasms, malignant and unspecified”)
          Broad Sub-SMQ “Skin malignant tumours”
Skin melanomas
HLT Skin melanomas (excl. Ocular)
Non-melanoma skin cancer 
(NMSC)
Broad Sub-BIcMQ “Skin Malignancies excluding melanomas”
Malignancies excluding NMSC
Sub-SMQ “Malignant tumours” excluding broad sub-BIcMQ “Skin 
Malignancies excluding melanomas”
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.
Laboratory data
7.8.2
The analyses of laboratory data will be descriptive in nature and will be based on BI 
standards (8). Note that data from the central Laboratory will be used for all displays 
described below, unless otherwise specified.
The analyses of safety laboratory parameters will be performed for the double-blind period 
and re-allocation period separately.
For continuous safety laboratory parameters, normalized values will be derived.


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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” (8). 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 in the respective period (double-blind or re-allocation).
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.
In addition, box and whiskers plots will be presented for the laboratory parameters.
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).


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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.
Vital signs
7.8.3
The analyses of vital signs (blood pressure, pulse rate, body temperature and body weight)
will be descriptive in nature and will be performed for double-blind period and re-allocation 
period separately.
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 
respective period (double-blind or re-allocation), the minimum value during respective 
period, and the maximum value during respective period (see Table 6.1: 1 for definition of 
the trial periods/phases).
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.
ECG
7.8.4
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.
Others
7.8.5
7.8.5.1 Infusion reactions including anaphylactic reaction
Infusion reactions will be summarized overall, with the frequency and percentage of patients 
who experienced any infusion reaction, both overall and specifying anaphylactic reaction as 
part of the table presenting patients with adverse events of special interest (AESI).
7.8.5.2 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 CTR.
7.8.5.3 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 


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the analyses required for assessment by the DMC was produced and finalized prior to first 
patient randomised into the trial. Further details were provided in a DMC charter.


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8.
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
001-MCS-40-135_RD-01: "Integrated Quality and Risk Management Plan", current 
version; Group “Clinical Operations”, IDEA for CON
4
BI-KMED-BDS-HTG-0035: "Handling of missing and incomplete AE dates", 
current version; IDEA for CON
5
001-MCS-36-472_RD-01: "Noncompartmental Pharmacokinetic / 
Pharmacodynamic Analyses of Clinical Studies", current version; IDEA for CON
6
001-MCS-36-472_RD-03: “Description of Analytical Transfer Files and PK/PD 
Data Files”, current version; IDEA for CON
7
BI-KMED-BDS-HTG-0066: "Analysis and Presentation of Adverse Event Data 
from Clinical Trials", current version; IDEA for CON
8
BI-KMED-BDS-HTG-0042: "Handling, Display and Analysis of Laboratory Data", 
current version; IDEA for CON
9
CPMP/ICH/137/95: "Structure and Content of Clinical Study Reports", ICH 
Guideline Topic E3; Note For Guidance on Structure and Content of Clinical Study 
Reports, current version
10 BI-KMED-BDS-HTG-0045: "Standards for Reporting of Clinical Trials and Project 
Summaries", current version; IDEA for CON
11 001-MCS-36-472: "Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics", current version; IDEA for CON


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10.
HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-MMM-YY)
Author
Sections 
changed
Brief description of change
1.0 
12-Feb-20
This is the first version of the TSAP
2.0
20-Aug-20
7.1
6.2
7.4.2
6.7
7.8
7.8.1
This is the second version of the 
TSAP, including CTP Amendment 3
The following changes to the TSAP 
were made:
Disease severity based on EASI 
Score, disease severity based on IGA 
Score, and age at disease onset were 
added as part of the baseline 
characteristics 
“Nursing” iPD (G1.02) was changed 
to “Pregnancy or nursing”
Time windows for visit 11 were 
updated as per CTP amendment 
(Table 6.7:2)
Additional outputs for AEs 
occurring between study treatment 
start date and Week 16 visit date 
(not including REP) were added.
List of user-defined AE concepts 
was updated as per new MedDRA 
version (Table 7.8.7:1).
Information on disclosure in 
EudraCT was removed since it is not 
applicable in this study.