A Randomized, Placebo-controlled, Double-blind, Parallel-group, Multicenter Phase 2a Study to Investigate Efficacy and Safety of Zabedosertib (BAY 1834845) for the Treatment of Adult Patients With Moderate-to-severe Atopic Dermatitis
Phase: PHASE2
Conditions: Atopic Dermatitis
Sponsor: Bayer

 
Document Type: 
Clinical Study Protocol 
Official Title: 
A randomized, placebo-controlled, double-blind, parallel-
group, multicenter Phase 2a study to investigate efficacy 
and safety of zabedosertib (BAY 1834845) for the treatment 
of adult patients with moderate-to-severe atopic dermatitis 
NCT Number: 
NCT05656911 
Document Date: 
18-Jul-2023 
 

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Title Page 
Protocol Title: 
A randomized, placebo-controlled, double-blind, parallel-group, multicenter Phase 2a study to 
investigate efficacy and safety of zabedosertib (BAY 1834845) for the treatment of adult 
patients with moderate-to-severe atopic dermatitis  
Protocol Number: 
22158 
Protocol Version:  
2.0 
Amendment Number: 
1.0 
Compound Number: 
Zabedosertib (BAY 1834845) 
Short Title: 
Proof-of-concept of efficacy and safety of zabedosertib in the 
treatment of moderate-to-severe atopic dermatitis in adults 
Study Phase: 
2a 
Acronym: 
Damask 
Sponsor Name: 
Bayer AG 
Legal registered address:  
Non-US: Bayer AG, 51368 Leverkusen, Germany 
US territory: Bayer HealthCare Pharmaceuticals Inc., 100 Bayer Boulevard, P.O. Box 915, 
Whippany NJ 07981-0915, USA 
Regulatory Agency Identifier Number(s): 
EudraCT Number: 2022-000520-38 
Protocol Date: 
18 JUL 2023 
Name: 
 
 
Role: 
 
This is an electronically generated document that does not bear any sponsor signatures. The 
signature of the sponsor’s medically responsible person is filed in the TMF and available on 
request. 
Medical Monitor name and contact information will be provided separately. 
Confidential 
The information provided in this document is strictly confidential and is intended solely for the performance of 
the clinical investigation. Reproduction or disclosure of this document, whether in part or in full, to parties not 
associated with the clinical investigation or its use for any other purpose without the prior written consent of the 
sponsor is not permitted.  
Throughout this document, symbols indicating proprietary names (®, TM) may not be displayed. Hence, the 
appearance of product names without these symbols does not imply that these names are not protected. 
PPD
PPD
PPD

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Document History Table 
DOCUMENT HISTORY 
Document 
Version 
Date 
Comments (if applicable) 
Amendment 1  
2.0 
18 JUL 2023 
Global amendment that includes changes 
applicable to all countries 
FRA-1 
FRA-1 
15 FEB 2023 
To include changes specific for France 
(request from local ethics committee [EC]) 
Clinical Study Protocol 
1.0 
08 JUL 2022 
 
Protocol Amendment Summary of Changes 
Amendment 1 (18 JUL 2023) 
This amendment/modification is considered to be non-substantial based on the relevant 
criteria of the European Union clinical trial legislation. 
Overall Rationale for the Amendment 
Section # and Name 
Description of Change 
Brief Rationale 
9.4 Interim Analysis 
Text added to describe the 
possibility of conducting an 
interim analysis during the 
ongoing study. 
Original text of this section 
(“No formal interim analysis 
using unblinded data is 
planned for this study, due to 
the short study duration” 
deleted. 
Depending on recruitment 
progress, an interim analysis 
may be performed using the 
data of all study participants 
having either regularly 
completed or prematurely 
discontinued study 
intervention at a certain 
cutoff date, when a 
minimum of 80% of patients 
are evaluable. The further 
study conduct or study 
design will not be affected 
by the results of the interim 
analysis. 
Throughout the document 
Minor mainly editoral 
clarifications 
 
 
 
 
 

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Table of contents 
Title Page ............................................................................................................................... 1 
Document History Table ...................................................................................................... 2 
Protocol Amendment Summary of Changes ..................................................................... 2 
Table of Tables ..................................................................................................................... 6 
Table of Figures .................................................................................................................... 6 
List of Abbreviations ............................................................................................................ 7 
1 
Protocol summary ....................................................................................................... 10 
1.1 
Synopsis ..................................................................................................................... 10 
1.2 
Schema ....................................................................................................................... 13 
1.3 
Schedule of activities (SoA) ...................................................................................... 14 
2 
Introduction ................................................................................................................. 16 
2.1 
Study Rationale .......................................................................................................... 16 
2.2 
Background ................................................................................................................ 16 
2.2.1 
Disease Background ..................................................................................... 16 
2.2.2 
Current Treatment Options and Unmet Medical Need ................................. 16 
2.2.3 
Rationale for IRAK4 inhibitors as an AD treatment option ......................... 18 
2.2.4 
Zabedosertib (BAY 1834845) ...................................................................... 18 
2.3 
Benefit/risk assessment .............................................................................................. 19 
2.3.1 
Risk Assessment ........................................................................................... 19 
2.3.2 
Benefit Assessment ....................................................................................... 22 
2.3.3 
Overall Benefit/Risk Conclusion .................................................................. 23 
3 
Objectives, Endpoints, and Estimands ...................................................................... 23 
3.1 
Objectives and Endpoints .......................................................................................... 23 
3.2 
Estimand .................................................................................................................... 24 
4 
Study Design ................................................................................................................ 26 
4.1 
Overall Design ........................................................................................................... 26 
4.2 
Scientific Rationale for Study Design ....................................................................... 27 
4.3 
Participant Input into Design ..................................................................................... 27 
4.4 
Justification of Dose .................................................................................................. 28 
4.5 
End of Study Definition ............................................................................................. 28 
5 
Study Population ......................................................................................................... 29 
5.1 
Inclusion Criteria ....................................................................................................... 29 
5.2 
Exclusion Criteria ...................................................................................................... 31 
5.3 
Lifestyle Considerations ............................................................................................ 34 
5.3.1 
Meals and Dietary Restrictions ..................................................................... 34 
5.3.2 
Caffeine, Alcohol, and Tobacco ................................................................... 34 
5.3.3 
Activity ......................................................................................................... 34 
5.3.4 
Other Restrictions ......................................................................................... 34 
5.4 
Screen Failures ........................................................................................................... 35 
5.5 
Criteria for Temporarily Delaying Enrollment/Randomization/Study Intervention 
Administration ........................................................................................................... 35 
6 
Study intervention(s) and Concomitant Therapy .................................................... 35 
6.1 
Study Intervention(s) Administered ........................................................................... 36 

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6.2 
Preparation, Handling, Storage, and Accountability ................................................. 36 
6.3 
Assignment to Study Intervention ............................................................................. 37 
6.4 
Blinding ..................................................................................................................... 37 
6.5 
Study Intervention Compliance ................................................................................. 38 
6.6 
Dose Modification ..................................................................................................... 38 
6.7 
Continued Access to Study Intervention after the End of the Study ......................... 38 
6.8 
Treatment of Overdose .............................................................................................. 38 
6.9 
Prior and Concomitant Therapy ................................................................................. 39 
6.9.1 
Background Therapy with Emollients / Moisturizers ................................... 39 
6.9.2 
Rescue Medication ....................................................................................... 40 
6.9.3 
Prohibited Medication and Therapies ........................................................... 41 
7 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal ...................................................................................... 41 
7.1 
Discontinuation of Study Intervention ....................................................................... 41 
7.1.1 
Liver Chemistry Stopping Criteria ............................................................... 43 
7.1.2 
QTc Stopping Criteria .................................................................................. 43 
7.1.3 
Temporary Discontinuation .......................................................................... 43 
7.1.4 
Temporary Discontinuation and Restart of Study Medication ..................... 44 
7.2 
Participant Discontinuation/Withdrawal from the Study ........................................... 44 
7.3 
Lost to Follow Up ...................................................................................................... 45 
8 
Study Assessments and Procedures ........................................................................... 46 
8.1 
Administrative and General Procedures .................................................................... 46 
8.2 
Efficacy Assessments ................................................................................................ 47 
8.2.1 
Clinician-Reported Outcomes (ClinROs) ..................................................... 48 
8.2.1.1 
Eczema Area and Severity Index (EASI) .................................... 48 
8.2.1.2 
Validated Investigator’s Global Assessment for Atopic Dermatitis 
(vIGA-AD) .................................................................................. 48 
8.2.1.3 
Assessment of Body Surface Area (BSA) Affected by Atopic 
Dermatitis .................................................................................... 48 
8.2.2 
Patient-Reported Outcomes (PROs) – General Information ........................ 49 
8.3 
Safety Assessments .................................................................................................... 51 
8.3.1 
Physical Examinations .................................................................................. 51 
8.3.2 
Vital Signs .................................................................................................... 51 
8.3.3 
Electrocardiograms ....................................................................................... 51 
8.3.4 
Clinical Safety Laboratory Tests .................................................................. 52 
8.3.5 
Pregnancy Testing ........................................................................................ 52 
8.3.6 
Suicidal Ideation and Behavior Risk Monitoring ......................................... 53 
8.4 
Adverse Events (AEs), Serious Adverse Events (SAEs) and Other Safety Reporting
 ................................................................................................................................... 53 
8.4.1 
Time Period and Frequency for Collecting AE and SAE Information ......... 53 
8.4.2 
Method of Detecting AEs and SAEs ............................................................ 53 
8.4.3 
Follow-up of AEs and SAEs ........................................................................ 54 
8.4.4 
Regulatory Reporting Requirements for SAEs ............................................ 54 
8.4.5 
Pregnancy ..................................................................................................... 54 
8.4.6 
Cardiovascular and Death Events ................................................................. 55 
8.4.7 
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs ................................................................................................. 55 
8.4.8 
Adverse Events of Special Interest ............................................................... 55 

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8.5 
Pharmacokinetics ....................................................................................................... 56 
8.5.1 
PK measurements of zabedosertib and its metabolite M-5 .......................... 56 
8.5.2 
Population pharmacokinetic (popPK) evaluation ......................................... 56 
8.6 
Pharmacodynamics .................................................................................................... 57 
8.7 
Genetics ..................................................................................................................... 57 
8.8 
Biomarkers ................................................................................................................. 57 
8.8.1 
Biomarkers Monitoring Disease Activity ..................................................... 58 
8.8.2 
Other Biomarkers ......................................................................................... 58 
8.9 
Immunogenicity Assessments .................................................................................... 58 
8.10 Health Economics ...................................................................................................... 58 
8.11 Other Procedures ........................................................................................................ 59 
9 
Statistical Considerations ........................................................................................... 59 
9.1 
Statistical Hypothesis ................................................................................................. 59 
9.2 
Analysis Sets .............................................................................................................. 60 
9.3 
Statistical Analyses .................................................................................................... 60 
9.3.1 
General Considerations ................................................................................. 60 
9.3.2 
Efficacy Analyses ......................................................................................... 61 
9.3.2.1 
Primary Efficacy Endpoint .......................................................... 61 
9.3.2.2 
Secondary Efficacy Endpoints ..................................................... 62 
9.3.3 
Safety Analyses ............................................................................................ 63 
9.3.3.1 
Secondary Endpoint - Safety ....................................................... 63 
9.3.3.2 
Other Safety Endpoints ................................................................ 63 
9.3.4 
Pharmacokinetic Analyses ............................................................................ 63 
9.3.5 
Exploratory/Other Endpoint(s) ..................................................................... 64 
9.3.6 
Other Analyses ............................................................................................. 64 
9.4 
Interim Analysis ......................................................................................................... 64 
9.5 
Sample Size Determination ....................................................................................... 64 
10 Supporting documentation and operational considerations ................................... 66 
10.1.1 Appendix 1: Regulatory, ethical, and study oversight considerations ......... 66 
10.1.2 Regulatory and ethical considerations .......................................................... 66 
10.1.3 Financial disclosure ...................................................................................... 66 
10.1.4 Informed consent process ............................................................................. 67 
10.1.5 Recruitment strategy ..................................................................................... 67 
10.1.6 Data protection ............................................................................................. 67 
10.1.7 Committees structure .................................................................................... 68 
10.1.8 Dissemination of clinical study data ............................................................. 68 
10.1.9 Data quality assurance .................................................................................. 69 
10.1.10 Source documents ......................................................................................... 69 
10.1.11 Study and site start and closure .................................................................... 70 
10.1.12 Publication policy ......................................................................................... 70 
10.2 Appendix 2: Clinical laboratory tests ........................................................................ 71 
10.2.1 Guidance for management of muscle symptoms and CK elevations ........... 73 
10.3 Appendix 3: Adverse events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting .......................................................................................... 74 
10.3.1 Definition of AE ........................................................................................... 74 
10.3.2 Definition of SAE ......................................................................................... 76 
10.3.3 Recording and follow-up of AE and/or SAE ................................................ 77 
10.3.4 Reporting of SAEs ........................................................................................ 78 

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10.4 Appendix 4: Contraceptive guidance and collection of pregnancy information ....... 79 
10.5 Appendix 5: Skin biopsy assessment (substudy) ....................................................... 83 
10.6 Appendix 6: Prohibited medications .......................................................................... 84 
10.7 Appendix 7: Questionnaires ....................................................................................... 85 
10.7.1 ClinROs scoring ........................................................................................... 85 
10.7.1.1 Eczema Area and Severity Index (EASI) .................................... 85 
10.7.1.2 Validated Investigator Global Assessment for Atopic Dermatitis 
(vIGA-AD) .................................................................................. 86 
10.7.1.3 Assessment of body surface area (BSA) affected by atopic 
dermatitis ..................................................................................... 87 
10.7.2 PROs scales and questionnaires ................................................................... 88 
10.8 Appendix 8: Country-specific Requirements ............................................................ 88 
10.8.1 France (FRA) ................................................................................................ 88 
10.8.1.1 FRA-1: Country-specific requirements for France only .............. 88 
11 References .................................................................................................................... 90 
 
Table of Tables 
Table 2–1: Risk overview ........................................................................................................ 21 
Table 6–1: Study interventions ................................................................................................ 36 
Table 6–2: Study Arms ............................................................................................................ 36 
Table 8–1: Sample types for biomarkers.................................................................................. 57 
Table 9–1: Analysis sets ........................................................................................................... 60 
Table 10–1: Protocol-required safety laboratory assessments at visits V1 (screening), V3 
(randomization), V 4 (Day 14), V5 (Day 28), V6 (Day 56), V7 (Day 84) and EOS 
(Day 112) ............................................................................................................... 72 
Table 10–2: Substrates (X) for breast cancer resistance proteins (BCRP) and organic-anion-
transporting polypeptides (OATP) 1B1 and 1B3 .................................................. 84 
 
Table of Figures 
Figure 1–1: Detailed schema .................................................................................................... 13 
Figure 10–1: EASI scoring table .............................................................................................. 86 
Figure 10–2: COA instrument: vIGA-AD ............................................................................... 87 
Figure 10–3: Peak Pruritus 0-10 NRS ...................................................................................... 88 
 
 

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List of Abbreviations 
 
AD 
atopic dermatitis 
AE 
adverse event 
AESI 
adverse event of special interest 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
aPTT  
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
BCRP 
breast cancer resistance protein 
BID 
twice daily 
BM 
biomarker 
BMI 
body mass index 
BSA 
body surface area 
CAD 
canine atopic dermatitis 
CAIA 
collagen antibody-induced arthritis 
CCl17/18 
chemokine (C-C motif) chemokine ligand 17 and 18 
CI 
confidence interval 
CK 
creatine kinase 
ClinRO 
clinician-reported outcome 
COVID-19 
corona virus disease 2019 
(e)CRF 
(electronic) case report form 
CRP 
C-reactive protein 
CTCAE 
Common Terminology Criteria for AEs 
CV 
coefficient of variation 
EASI 
Eczema Area and Severity Index 
EASI x response x% reduction from baseline in the EASI, e.g. EASI 75 response 
ECG 
electrocardiogram or electrocardiography 
eDiary  
electronic diary 
eGFR 
estimated glomerular filtration rate 
ePRO 
electronic patient-reported outcome 
EMA 
European Medicines Agency 
EOS 
end of study 
EOT 
end of treatment 
EU 
European Union 
FDA 
Food and Drug Administration 
FiM 
First-in-Man 
FSH 
follicle stimulating hormone 
FU 
follow-up 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
HBcAb  
hepatitis B core antibody 
HBsAb 
hepatitis B surface antibody 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
hCG  
human chorionic gonadotropin 

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HCV 
hepatitis C virus 
HDL 
high-density lipoprotein 
HRQoL 
health-related quality of life  
HIV 
human immunodeficiency virus 
HRT 
hormonal replacement therapy 
hsCRP  
high sensitivity C-reactive protein 
IB 
investigator’s brochure 
IBD 
inflammatory bowel disease 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
ICU 
intensive care unit 
IEC 
independent ethics committee 
Ig 
immunoglobulin 
IL 
interleukin 
IMQ 
imiquimod 
INR 
international normalized ratio 
LPS 
lipopolysaccharide 
IRAK4 
interleukin1 receptor-associated kinase 4 
IRB 
institutional review board 
IUD 
intrauterine device 
IRT 
Interactive Response Technology 
JAK 
Janus kinase 
LDH 
lactate dehydrogenase 
LLOQ 
lower limit of quantification 
M&S 
Modelling and Simulation 
MCP mod 
Multiple Comparisons Procedure combined with modeling  
MDRD 
modification of diet in renal disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMF 
mycophenolate mofetil 
MTX 
methotrexate 
NRS 
numerical rating scale 
NYHA 
New York Heart Association 
OATP 
organic-anion-transporting polypeptides 
PCR 
polymerase chain reaction 
PD 
pharmacodynamic(s) 
PE 
physical examination 
PG 
pharmacogenetic(s) 
PID 
participant identification 
PK 
pharmacokinetic(s) 
PMDA 
Pharmaceuticals and Medical Devices Agency 
popPK 
population pharmacokinetics 
PPS 
per protocol set 
PT 
preferred term 
Q4 
fourth quarter 
QC 
quality control 
QD 
once daily 
q.i.d. 
4 times daily 

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QoL 
quality of life 
R 
software environment for statistical computing and graphics 
RA 
rheumatoid arthritis 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SAF 
safety analysis set 
SAP 
statistical analysis plan 
SAS 
Statistical Analysis System 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SoA 
schedule of activities 
SoC 
standard-of-care 
SOC 
System Organ Class 
SOP 
standard operating procedure 
TB 
tuberculosis 
TBL 
total bilirubin 
TCI 
topical calcineurin inhibitor 
TCS 
topical corticosteroids 
TEAE(s) 
treatment-emergent adverse event(s) 
TEAESI 
treatment-emergent adverse events of special interest 
TESAE 
treatment-emergent serious adverse event 
TLR 
toll like receptor 
TSH 
thyroid stimulating hormone 
TSLP 
thymic stromal lymphopoietin 
ULN 
upper limit of normal 
vIGA-AD 
validated Investigator Global Assessment for Atopic Dermatitis 
vIGA-AD 
response 
 
vIGA-AD of 0 or 1 with at least a 2-grade reduction from baseline  
VRS 
verbal rating scale 
WBC 
white blood cell 
WOCBP 
women of child-bearing potential 
 

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1 
Protocol summary 
1.1 Synopsis  
Protocol Title: 
A randomized, placebo-controlled, double-blind, parallel-group, multicenter Phase 2a study to 
investigate efficacy and safety of zabedosertib (BAY 1834845) for the treatment of adult 
patients with moderate-to-severe atopic dermatitis  
Short Title: 
Proof-of-concept of efficacy and safety of zabedosertib in the treatment of moderate-to-severe 
atopic dermatitis in adults 
Regulatory Agency Identifier Number(s): 
EudraCT Number: 2022-000520-38 
 
Envisaged indication:  
Moderate-to-severe atopic dermatitis in adults 
 
Rationale: 
Based on scientific considerations and preclinical observations, zabedosertib may provide a 
safe and effective treatment option for atopic dermatitis (AD) by its anti-inflammatory 
properties. 
The aim of this Phase 2a study is to explore for the first time whether the interleukin-1 receptor-
associated kinase 4 (IRAK4) inhibitor zabedosertib can safely provide a therapeutic benefit in 
patients with moderate-to-severe AD and to achieve a proof of concept for further development 
steps of the compound (or the compound class).  
 

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Objectives, Endpoints and/or Estimands: 
Objectives 
Endpoints 
Primary objectives 
• To assess the efficacy of 
zabedosertib vs. placebo in adult 
patients with moderate-to-severe 
atopic dermatitis (AD) with 
inadequate response to topical 
corticosteroids or if topical 
treatments are medically not 
advisable 
 
 
Primary endpoint: 
• Achievement of 75% reduction from baseline in the Eczema Area and 
Severity Index (EASI 75 response) at Week 12 (Day 84)  
 
Primary endpoint is the composite variable defined as follows: 
• an EASI 75 response at Week 12 (Day 84), 
• no stop of study intervention for reasons related to lack of efficacy, 
• no rescue medication use during the 4 weeks before Day 84 and 
• no use of systemic AD treatment  
 
 
 
Secondary endpoints: 
• Percent change from baseline in EASI at Week 12 (Day 84)  
• Achievement of EASI 50 response at Week 12 (Day 84) 
• Achievement of EASI 90 response at Week 12 (Day 84) 
• Achievement of a vIGA-AD response (score 0 or 1 and ≥ 2 points 
improvement) at Week 12 (Day 84) 
• Absolute change from baseline in body surface area (BSA) affected by 
AD at Week 12 (Day 84)  
• Absolute values and percent change of weekly average of the Peak 
Pruritus 0-10 NRS score from baseline at Week 12 (Day 84) 
• Achievement of a ≥ 4 point-improvement (reduction) in the weekly 
average of the Peak Pruritus 0-10 NRS score from baseline to Week 
12 (Day 84) for participants with Peak Pruritus 0-10 NRS score ≥ 4 at 
baseline 
Secondary objectives 
 
• To assess the safety and 
tolerability of zabedosertib vs. 
placebo 
Secondary endpoints: 
• Frequency and severity of treatment-emergent adverse events 
(TEAEs) 
Other safety endpoints: 
• Frequency and severity of TEAEs of special interest 
• Changes in vital signs from baseline 
• Changes in clinical laboratory test results from baseline (e.g., 
chemistry, lipid panel, hematology, urinalyses) 
• Changes in electrocardiogram (ECG) parameters from baseline and 
frequency of ECG findings 
 
Exploratory objectives and other pre-specified endpoints are listed in Section 3. 
Overall Design Synopsis: 
Disclosure Statement: This is a randomized, placebo-controlled, double-blind, parallel-group 
multicenter, Phase 2a study to investigate efficacy and safety of zabedosertib for the treatment 
of adult patients with moderate-to-severe atopic dermatitis.  
 

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Short Summary 
The purpose of this study is to assess the efficacy and safety of zabedosertib compared with 
placebo in participants with moderate-to-severe AD. The study consists of an up to 28-day 
screening period (Visits 1 and 2), a 12-week intervention period consisting of 5 visits (Visits 3 
to 7), and a 4-week follow-up (FU) period with one visit (Visit 8 ).  
A total of 72 participants are planned to be randomly allocated to 1 of the 2 treatment groups 
with a 2:1 allocation ratio to achieve a total of 57 participants valid for efficacy analysis: 
Zabedosertib at a dose of 120 mg BID: 
48 randomized / 38 valid for the efficacy analysis 
Matching placebo BID: 
 
 
24 randomized / 19 valid for the efficacy analysis. 
Efficacy parameters will be assessed prior to study intervention, during the 12-week 
intervention period and at follow-up according the Schedule of Activities (SoA).  
All participants will be closely monitored for safety throughout the study.  
To gain most accurate dosing data and to ensure adherence to study intervention, the data of 
participant’s daily intake of study intervention will be collected as daily questions on an 
electronic patient handheld device. Participants are required to use additive-free emollients 
twice a day throughout the study. Participants will be reminded once a week about this 
requirement by the electronic hand held device. 
Blood sampling for pharmacokinetic and pharmacodynamic evaluations will be obtained in 
accordance with the SoA.  
At selected study sites in a subset of participants, skin biopsy samples will be taken for the 
assessment of gene expression and immunohistochemistry as indicated in the SoA.  
Number of Participants: 
Approximately 72 participants will be randomly assigned to the study to obtain 57 evaluable 
participants overall (2:1 randomization zabedosertib versus placebo). 
Study Arms and Duration: 
The total study duration per participant will be 17 to 20 weeks (approximately 140 days), with 
8 study visits at intervals of 8 to 28 days with 2 study arms: 
Zabedosertib at a dose of 120 mg BID orally: 
 
48 randomized participants 
Matching placebo BID orally: 
 
 
 
24 randomized participants. 
Dose changes and/or adjustments are not planned. Decisions regarding dose interruptions will 
be made by the investigator in consultation with the Medical Monitor based on the clinical 
evaluation of the participant. 
 
Data Monitoring/Other Committee:  
No 
 

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1.2 Schema 
 
Figure 1–1: Detailed schema 
 

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1.3 Schedule of activities (SoA) 
 
 
 
(For footnotes, see next page.) 
 
Screening 
Intervention period 
Follow-up 
 
 
 
Randomization 
 
 
 
EOT1 
Days after last 
dose 
 
 
 
 
 
 
 
282 
 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 (EOS) 
 
Day 
-28 
-8 
1 
14 
28 
56 
84 
112 
 
 
to -14 
+ 1 
 
± 2 
± 2 
± 3 
± 3 
± 3 
Initiation 
General Informed Consent 
● 
 
 
 
 
 
 
 
Consent Skin Biopsy3 
● 
 
 
 
 
 
 
 
Consent Photography3 
● 
 
 
 
 
 
 
 
Demography  
● 
 
 
 
 
 
 
 
Quantiferon TB Gold Plus test  
● 
 
 
 
 
 
 
 
HIV, hepatitis B and C  
● 
 
 
 
 
 
 
 
SARS-CoV-2 RNA test4 
 
● 
 
 
 
 
 
 
Medical history / history of AD 
● 
 
 
 
 
 
 
 
Prior medication / prior AD 
therapy 
● 
 
● 
 
 
 
 
 
Height 
● 
 
 
 
 
 
 
 
Weight 
● 
 
● 
● 
● 
● 
● 
● 
Check of in-/exclusion criteria  
● 
● 
● 
 
 
 
 
 
Medication 
Randomization  
 
 
● 
 
 
 
 
 
IRT registration 
● 
● 
● 
● 
● 
● 
 
Study intervention dispensation 
 
 
● 
● 
● 
● 
 
 
Study int. return / accountability 
 
 
 
● 
● 
● 
● 
 
Study intervention intake 
 
 
0⎯−−−−− ongoing −−⎯→ 
 
Enter intervention intake into 
eDiary 
 
 
 ⎯−−−−− ongoing −⎯−→ 
 
 
Concomitant medication  
● 
● 
● 
● 
● 
● 
● 
● 
Efficacy 
ClinROs 
- EASI  
 
● 
 
 
● 
 
● 
 
● 
 
● 
 
● 
 
● 
- vIGA-AD 
● 
 
● 
● 
● 
● 
● 
● 
- BSA affected by AD 
● 
 
● 
● 
● 
● 
● 
● 
ePRO 
- Dispense and training of 
patient handheld device 
 
 
● 
 
 
 
 
 
 
 
- Daily Peak Pruritus 0-10 NRS6 
 
     ⎯−⎯⎯−−−−⎯−− ongoing ⎯⎯⎯⎯−−−−−−−−−→ 
 
- Return handheld device 
 
 
 
 
 
 
 
● 
 
Other procedure: photograph0  
 
 
● 
 
 
 
● 
● 
Safety 
Complete physical examination  
● 
 
● 
 
 
 
● 
● 
Symptom-directed 
PE/inspection 
 
● 
 
● 
● 
● 
 
 
AE/SAE assessment  
●8 
●8 
● 
● 
● 
● 
● 
● 
AESI assessment 
●8 
●8 
● 
● 
● 
● 
● 
● 
Pregnancy test – S(erum) / 
U(rine) 
●S 
●S 
●U 
 ●U 
●U 
 ●U 
 ●U 
●S 
 
Safety panel (central lab)9 
● 
●10 
● 
● 
● 
● 
● 
● 
Lipid profile (central lab) 
 
 
● 
 
 
 
● 
 
Urinalysis 
● 
●10 
● 
 
● 
 
● 
● 
12-lead ECG11 
● 
 
 
● 
 
 
● 
● 
Vital signs 
● 
● 
● 
● 
● 
● 
● 
● 
PK/PD 
BM blood samples12 
 
 
● 
 
 
 
● 
 
BM on-study skin biopsy 13,14 
 
 
● 
 
 
 
● 
 
PK blood sample 
 
 
●15 
●16 
●16 
●16 
●15, 16 
 
 
Footnotes for schedule of activities (see next page) 
 
 

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Footnotes for schedule of activities 
AD = atopic dermatitis; AE(SI) = adverse event (of special interest); BM = biomarker; BSA = body 
surface area; ClinROs = clinician-reported outcomes; CRP = C-reactive protein; EASI = Eczema 
Area and Severity Index; ECG = electrocardiogram; eDiary = electronic diary (= patient handheld 
device); EOS = end of study; EOT = end of treatment; HIV = human immunodeficiency virus; 
IRT = Interactive Response Technology; NRS = numerical rating scale; PD = 
pharmacodynamc(s); PE = physical examination; PK = pharmacokinetic(s); PRO = patient-
reported outcome; RNA = ribonucleic acid; SAE = serious adverse event; SARS-CoV-2 = severe 
acute respiratory syndrome coronavirus 2; v = visit; vIGA-AD = validated Investigator’s Global 
Assessment for Atopic Dermatitis 
Early Discontinuation: Visit 7 (EOT) and Visit 8 (EOS) assessments should be performed  
Performed 28 days after last dose of study intervention 
Optional, should be obtained for participants taking part in the skin biopsy subgroup or the photograph 
subgroup. Consent can be obtained up to Visit 3. 
In exceptional cases, e.g., if test results are not available in time, SARS-CoV-2 test (PCR test or 
similar test) may be performed locally. 
First dose of study intervention should only be taken after all baseline assessments are completed. 
Daily assessment should start 7 days before randomization visit. 
At select study sites (optional): Photographs of a representative area of AD involvement (e.g., the 
lesioned area used for EASI assessments). Instructions for taking the photographs will be 
provided in a photography manual. 
Only (S)AEs which are related to protocol-required study procedures should be recorded before start 
of study intervention (all other events should be recorded as medical history). 
Safety panel (central lab) will include parameters listed in Appendix 10.2 (Table 10-1) 
Only CRP, blood count, and urinalysis must be re-assessed at Visit 2 to rule out asymptomatic 
infections; further lab values only in case results from screening lab (Visit 1) require re-testing for 
eligibility or clinically indicated control-analyses. 
May be performed + 3 days of visit. All ECG reports are to be assessed for clinical significance by a 
physician.  
Blood samples (plasma and whole blood) for molecular biomarkers (optional analysis) 
In total 2, BM samples will be collected: 1x biomarker blood plasma and 1x biomarker whole 
blood. See Table 8–1 for further details to BM samples. 
At select study sites (optional): Skin lesion biopsy samples (2 x 3 mm punch biopsies per timepoint) in 
approximately 40 participants for assessment of gene expression (e.g., inflammation and skin 
barrier markers) and immunohistochemistry (e.g., immune cells; optional analysis).  
Two BM samples each at baseline and at EOT will be collected: biomarker on-study skin biopsy 
for mRNA expression and 1x biomarker on-study skin biopsy for IHC expression. See Table 8–1 
for further details to BM samples. 
Optional procedure requiring a separate informed consent 
Post-morning dose blood samples for pharmacokinetics between 0.5 to 1.5 hours post-dose, and 
between 2 to 5 hours post-dose with at least 1 hour difference between the 2 post-dose samples. 
NOTE: At visits with PK, study drug intake of the morning dose should occur at the study site. The 
participants should bring their handheld devices to these visits as well. 
Blood samples for pharmacokinetics should be taken pre-dose. NOTE: At visits with PK, study drug 
intake of the morning dose should be taken at site. The participants should bring their handheld 
devices to these visits as well. 
 

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2 
Introduction 
2.1 
Study Rationale 
Despite the abundance of topical and systemic therapeutic options, disease management in 
patients with moderate to severe AD is often difficult. The available drugs have either 
unsatisfactory efficacy, require parenteral application or their safety profile contains an 
increased risk for significant adverse events. Based on scientific considerations and 
preclinical observations, zabedosertib may offer a new treatment option for patients suffering 
from moderate to severe AD and inadequately responding to topical therapy due to its anti-
inflammatory properties.  
The aim of this Phase 2a study is to explore whether the IRAK4 inhibitor zabedosertib can 
safely provide a therapeutic benefit in patients with moderate-to-severe AD and to achieve a 
proof of concept for further development steps of the compound.  
2.2 
Background 
2.2.1 
Disease Background 
AD, also known as atopic eczema, is a common, chronic and relapsing inflammatory skin 
disorder with increasing incidence especially in developed countries. The adult prevalence of 
AD varies in published literature between 2.1% in Japan, 3.5% in Canada, 4.9% in the US and  
in the EU with individual ranges of 2.2% for Germany to 8.1% for Italy (Barbarot et al, 2018). 
The prevalence generally is lower for males compared to females and decreases with age. 
AD causes high health-care costs and has become a global health issue with considerable 
morbidity and quality of life (QoL) impairment with limited treatment options for moderate-
to-severe AD (Silverberg et al, 2017). AD is often the first step in the development of other 
atopic diseases such as allergic rhinitis, allergic asthma and food allergy, the so-called atopic 
march.  
AD is characterized by a chronic or relapsing course with acute flares of eczematous pruritic 
lesions over dry skin, with the tendency to bacterial superinfections, lichenification and 
prurigo nodules. Itch may cause mental symptoms (Patel et al, 2019), and, if experienced at 
night may result in sleep disturbances with the result of daytime fatigue, irritability, decreased 
motor performance and negative impact on health-related quality of life (HRQoL) (Bawany et 
al, 2021). There is no specific test or biomarker (BM) for AD, however, the most typical 
laboratory parameter is the elevation of total or allergen-specific IgE levels in serum (Torres 
et al, 2019). 
2.2.2 
Current Treatment Options and Unmet Medical Need 
AD is currently managed with topical and systemic treatments, as well as phototherapy. For 
mild and moderate AD topical therapy is mainly the most frequent option: emollients / 
moisturizers as background therapy promote the hydration of the skin by at least twice daily 
application and topical corticosteroids (TCS) are a first-line anti-inflammatory treatment, 
applied on inflammatory skin according to the needs (pruritus, sleeplessness, new flare). 
Topical calcineurin inhibitors (TCI) are effective for acute and chronic treatment, especially 
in selected anatomical areas (Wollenberg et al, 2018). 
Although mild and moderate AD may be managed appropriately with TCSs, TCIs and/or 
phototherapy, a considerable part of patients with AD requires systemic treatments to allow 
for adequate symptom control (Suga H, Sato S. 2019). Conventionally, the main systemic 

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treatment for AD has been cyclosporine; however, relapse is frequently seen soon after 
treatment withdrawal. Moreover, nephrotoxicity and hypertension are the most significant 
side effects of cyclosporine limiting long term use and usability for some patient populations.  
Although other immunosuppressive drugs, such as methotrexate and azathioprine, have also 
been used to treat severe AD, methotrexate’s exact mechanism of action in inflammatory 
diseases, including AD, is not fully understood and azathioprine can cause myelosuppression 
and carries an increased risk of infection, lymphoma and non-melanoma skin cancers 
(Wollenberg et al, 2018). 
Dupilumab, a fully human monoclonal antibody that blocks the common α-chain of the recep-
tor for interleukin-4 and interleukin-13, modulating both the interleukin-4 and interleukin-13 
pathways, has been approved alone or in combination with TCSs by the European Medicines 
Agency (EMA), the US Food and Drug Administration (FDA) and the Pharmaceuticals and 
Medical Devices Agency (PMDA) as a first-line biologic treatment for moderate-to-severe 
AD. Limited efficacy and side effects such as conjunctivitis as well as the parenteral route of 
administration limit its use in AD.  
In 2020, the first in-class oral selective Janus kinase (JAK) inhibitor, baricitinib, was 
approved in the EU and in Japan. This was followed by approvals of other oral, selective and 
reversible JAK inhibitors, upadacitinib and abrocitinib by EMA and FDA by the end of 2021 
and January 2022 for patients with moderate to severe AD. 
For mild to moderate AD, ruxolitinib cream was approved by the FDA in September 2021. 
All JAK inhibitors have a rapid onset of action and were shown to be at least as efficient as 
dupilumab (Papp et al, May 2021; Bieber et al, June 2021). However, they potentially 
increase the risk of serious infections, non-melanoma skin cancer and thromboembolism 
(Reich et al, 2020; Silverberg et al, 2020; Simpson et al, 2020). Moreover, the need for 
continuous blood monitoring, possible pre-vaccination for herpes zoster in susceptible 
patients and drug to drug interactions might restrict their use to some patients (Thyssen & 
Thomson, 2021). In addition, a safety review of JAK inhibitors in the treatment of 
inflammatory disorders has been initiated at the request of the European Commission (EC) 
under Article 20 of Regulation (EC) No 726/2004 in February 2022. 
In 2021 tralokinumab, a monoclonal Interleukin (IL)-13 antibody was approved by EMA, 
MHRA and FDA for patients with moderate to severe AD who are candidates for systemic 
therapy. Although, vIGA-AD and EASI response rates were lower compared to dupilumab at 
Week 16, as an advantage over dupilumab approximately 50% of the tralokinumab responders 
did not need any rescue medication including topical steroids up to Week 52 (Wollenberg et 
al, 2021, Silverberg et al, 2021).  
Other biologics targeting IL-13 such as lebrikizumab and the IL-31 receptor anatagonist 
nemolizumab are in an advanced stage of drug development (Guttman-Yasky et al, 2020; 
Silverberg et al, 2020). However, their parenteral application with potential injection site 
reaction as well as increased occurrence of upper respiratory tract infections and 
conjunctivitis may limit their use. 
Despite the mentioned therapeutic options, the treatment of moderate-to-severe AD remains 
challenging and novel, efficacious, safe and targeted treatment alternatives are urgently 
needed (Hon et al, 2020).  

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2.2.3 
Rationale for IRAK4 inhibitors as an AD treatment option 
IRAK4, is the key isoform of a 4-kinase family regulating the production of proinflammatory 
cytokines. IRAK4 is the first of the 4 kinases mediating the intracellular signal transduction 
pathway utilized by the innate immune cell receptors e.g., IL-1R, IL-18 receptor (IL-18R), IL-
33 receptor (IL-33R) and Toll-like receptors (TLRs) except TLR3.  
When these receptors are bound with multiple exogenous ligands, endogenous stimuli or 
proinflammatory cytokines, they initiate the first wave of inflammatory signals and innate 
immune responses propagating and amplifying these signals. These receptors are 
constitutionally expressed on a variety of innate immune cells and other cell types including 
macrophages, fibroblasts, monocytes and endothelial cells. The role of IRAK4 as a key 
component of Toll/Interleukin-1 receptor signaling and potential inhibition being associated 
with a low rate of infectious complications (Wiese et al, 2020) constitutes a promising 
therapeutic option in AD management.  
Based on the following observations, theoretical considerations and scientific knowledge, 
there is good scientific rationale to assume positive effects on AD by inhibition of the IRAK4 
enzyme: 
• Genetic loci associated with the susceptibility to develop AD encompasses components 
of the IRAK4 signaling including IL1β and IL-18 receptor (Dainichi et al, 2018). 
• Epidermal barrier disruption is one of the key mechanism promoting inflammation in 
AD that is associated with members of the IL-1R family (e.g., IL-1β and IL-33) 
(Weidinger et al, 2018). 
• Specific overexpression of IL-18 in the skin leads to the spontaneous development of 
AD-like inflammatory skin lesion in a murine animal model (Konishi et al, 2002). 
• The lack of components of the IRAK4 pathway like MyD88 (Myeloid differentiation 
primary response 88, component of the IRAK4 signaling complex), IL-1 and IL-33 
improves characteristic of AD in different murine disease models (Didovic et al, 2016; 
Imai et al, 2019; Li et al, 2017; Sun et al, 2019).  
• Reduction in skin lesions (CADESI) and pruritus achieved after 28 days of treatment 
with BAY 1834845 (an IRAK4 inhibitor with comparable potency) in 2 pilot field 
studies in privately owned dogs (treating > 70 dogs in total) with canine atopic 
dermatitis (CAD) (data on file). 
2.2.4 
Zabedosertib (BAY 1834845) 
BAY 1834845 is a potent and highly selective interleukin-1 receptor-associated kinase 4 
(IRAK4) inhibitor and provides a new approach for the treatment of AD and other inflamma-
tory diseases such as rheumatoid arthritis. IRAK4 is a pro-inflammatory kinase that is essen-
tial for nuclear factor-B (NF-kB) and mitogen-activated protein kinase (MAPK) activation in 
toll like receptor (TLR, except TLR3) and interleukin-1 receptor (IL-1R, including IL-1, IL-
18 and IL-33) family-driven processes leading to inflammatory skin lesions. IRAK4 induces 
the production and activation of a variety of pro-inflammatory cytokines such as tumor 
necrosis factor alpha (TNF α), interleukin-1 beta (IL-1β), IL-6, interferon gamma (IFN-) and 
IL-17, all cytokines that play a critical role in various inflammatory conditions. 
Further information can be found in the Investigator’s Brochure (IB). 

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2.3 
Benefit/risk assessment 
Emerging safety issues which affect the benefit/risk assessment of the study will be communi-
cated as soon as possible between the sponsor, all study sites and investigators, trial 
participants, health authorities and ethics committees.  
This Benefit-Risk-Assessment takes into account safety information from the development 
compound zabedosertib and a competitor IRAK4 inhibitor program (development candidate 
PF-06650833 for RA and emavusertib (GS-5718) for cancer). 
More detailed information about the known and expected benefits and risks of BAY 1834845 
can be found in the Section 5.3 of the IB. 
2.3.1 
Risk Assessment 
Risks in relation to pharmacological IRAK4 inhibition 
It is known that IRAK4-deficient persons are prone to pyogenic infections in childhood, a risk 
which vanishes after maturation of the adaptive immune system during puberty. However, to 
reduce the risk for the adult study population participants with scheduled (elective) surgery, 
planned hospitalization or dental treatment will be excluded from participation in this Phase 
2a study to avoid an iatrogenic bacteremia that could pose a potential risk for infection.  
Additionally, during the study, participants will be carefully examined regarding early signs 
of infectious diseases during the study visits, measurement of vital signs and inflammatory 
parameters such as C-reactive protein. All confirmed severe invasive bacterial infections, 
systemic hypersensitivity reactions and non-invasive infections (skin) will be required to be 
reported as adverse events of special interest.  
Information related to zabedosertib  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
CCI

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In addition, a mechanistic study (#21329) in healthy volunteers was conducted with a 
topically applied TLR7/8 activator (imiquimod = Aldara cream) as well as in a systemic 
challenge with intravenous lipopolysaccharides (LPS). Topline results of the mechanistic 
study with zabedosertib (BAY 1834845 120 mg BID for 7 days, N=12) showed that the 
IRAK4 inhibitor had a distinct and significant effect over placebo in the skin (i.e., alleviation 
erythema) as well as systemically, assessed by significant reduction in pro-inflammatory 
cytokines. PK concentrations of zabedosertib in skin suction blisters as a surrogate for skin 
exposure showed approx. 50% of plasma concentration. No safety concerns were observed 
during the study (data on file). 
For further details refer to the IB. 
 
 
 
 
 
 
For further details refer to the IB. 
 
CCI
CCI

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Table 2–1: Risk overview 
Potential risk of 
clinical significance 
Summary of data / 
rationale for risk 
Mitigation strategy 
 
Study intervention 
 
Infections 
Based on the mode of action, 
therapeutic inhibition of IRAK4 
may result in a modified innate 
immune response to infections.  
Clinical effects of IRAK4 
inhibition may therefore, in 
theory, include increased 
susceptibility or modified course 
of infections.  
Congenital IRAK4 deficiency is 
associated with pyogenic 
infections caused by 
Staphylococcus aureus, and 
Pseudomonas aeruginosa, but 
not from other bacterial, fungal, 
or viral infections that have 
been reported to require TLR/ 
IRAK-4 signaling in animal 
experimental models (Picard C 
et al 2003).  
Current preclinical and clinical 
data with zabedosertib and 
other compounds inhibiting 
IRAK4 currently do not indicate 
an increased infection risk by 
the pharmacological inhibition 
of IRAK4. 
The effect of Zabedosertib on 
immune function (potential 
susceptibility to infections) is 
regarded to be of low relevance 
in immunocompetent 
participants within this study 
due to the limited inhibition of 
the IRAK4 pathway-related 
signaling by zabedosertib.  
 
• 
Exclusion of patients with active, 
latent, chronic, recurrent 
infections (see Exclusion criteria 
#2)  
• 
Only immunocompetent 
participants will be enrolled in 
the study. 
• 
Regular clinical examination and 
laboratory assessment of 
infections  
• 
Reporting of infections 
(AEs/SAEs, TEAEs, AESIs)  
• 
Only SARS-CoV-2-virus-RNA-
test-negative participants without 
any symptoms of COVID-19 
prior to randomization to 
treatment. As part of the clinical 
study procedures, participants 
will be closely monitored for 
signs symptoms of COVID-19 
during the entire study duration. 
Study intervention will be 
terminated for all study 
participants with a SARS-CoV-2 
positive test result. During the 
entire study, all 
recommendations issued by the 
health authorities as well as local 
guidelines with respect to 
minimizing the risk of disease 
spreading, e.g., social 
distancing, disinfection, hygiene, 
and wearing of mouth-nose 
masks need to be followed and 
further measures according to 
recommendations and 
requirements from local health 
authorities may become 
necessary and will be followed 
within the context of this study 
as far as applicable in order to 
ensure full implementation of the 
principles of GCP with priority on 
subject safety. 
 
 
Embryotoxicity and 
teratogenicity  
BAY 1834845 was embryotoxic 
and, at the highest tested dose, 
also teratogenic in the studies on 
embryofetal development in mice 
with safety margins of less than 1 
when looking at total exposure. 
With regard to unbound exposure, 
the safety margin for 
teratogenicity was 10 to 14. 
• 
Exclusion of pregnant women  
• 
Appropriate contraception measures 
for women of child-bearing potential 
(WOCBP) and study participants with 
WOCBP as partners are required. 
• 
Serum pregnancy test will be 
performed for WOCBP at screening 
Visit 1 and Visit 2 and at end of study 
visit (EOS, 28 days after the last drug 
dose intake). In addition, regular urine 
pregnancy tests will be carried out at 
randomization (Visit 3) and at Visit 4 

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Potential risk of 
clinical significance 
Summary of data / 
rationale for risk 
Mitigation strategy 
(Day 14), Visit 5 (Day 28), Visit 6 (Day 
56) including the end-of-treatment visit 
(Day 84). 
 
Rhabdomyolysis 
In an ongoing clinical study in 
which a research molecule of the 
same drug class as BAY 1834845 
was tested, a case of severe 
muscle damage (rhabdomyolysis) 
with lethal outcome was observed 
in a patient with a malignant 
disease. 
Although this case refers to a different 
molecule and the relationship to the study 
drug is yet under investigation, some 
measures to identify any myopathies are 
implemented in this study: 
• 
Frequent testing of CK in serum 
• 
Discontinuation in case of elevated 
CK or suspicion of 
myopathy/rhabdomyolysis 
• 
Instruction of participants to 
abstain from intensive exercise 
and to report symptoms of 
myopathy (e.g., muscle weakness, 
muscle pain), change of color of 
urine or urinary retention 
• 
Guidance for management of 
muscle symptoms and CK 
increase 
• 
Unexplained cases of 
rhabdomyolysis defined as AESI. 
 
Study procedures 
 
Blood sampling (by single vein 
puncture and/or indwelling 
cannula) may be accompanied 
by mild pain, hematoma and in 
rare cases inflammation of the 
vessel wall or injury of a nerve. 
This presents minimal risk as 
related documented AEs 
observed in prior studies are mild 
and were completely resolved. 
All study assessments will be carried out by 
trained clinical staff. 
Complications from skin biopsy Participants who consent to 
participate in the skin biopsy 
substudy may experience minor 
complications such as pain, 
bleeding, bruising, and/or scarring 
from the skin biopsy, infection or 
damage of the structures in the 
vicinity of the biopsy site (e.g., 
vessels and skin nerves). 
Only sites with experience in skin biopsy 
sample collection will participate in the skin 
biopsy substudy. 
 
Other 
 
Not applicable.  
Not applicable. 
Not applicable. 
AE = adverse event; AESI = adverse event of special interest; CK = creatine kinase, COVID-19 = corona virus 
disease 2019; GCP = Good Clinical Practice; IRAK4 = interleukin1 receptor-associated kinase 4; SARS-CoV-2 = 
severe acute respiratory syndrome coronavirus 2; WOCBP = women of childbearing potential 
2.3.2 
Benefit Assessment 
Participation in this study with the administration of zabedosertib may be associated with the 
following benefits:  
• Overall improvement of the skin condition, reduction of pruritus and improvement 
of AD-related symptoms and signs, e.g., pain, sleep disturbances with resulting 
positive impact on reduced HRQoL. 
• Contributing to the process of developing new therapies in an area of unmet need. 
• Close medical and treatment monitoring including regular investigations 
associated with study procedures (e.g., physical examinations, electrocardiogram 
(ECG), laboratory evaluations) can be regarded as beneficial. 

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In addition, the data obtained from this study in regard to safety, tolerability, and PK will 
form the basis for further development of zabedosertib in AD and other inflammatory 
conditions. 
2.3.3 
Overall Benefit/Risk Conclusion 
Taking into account the measures taken to minimize risk to participants in this study, the 
potential risks identified in association with zabedosertib are acceptable by the anticipated 
benefits that may be afforded to participants with AD during the study, and the benefit for 
patients with AD by a potential continued development of zabedosertib in this indication. 
3 
Objectives, Endpoints, and Estimands 
3.1 
Objectives and Endpoints 
 
Objectives 
Endpoints  
Primary objective 
• To assess the efficacy of zabedosertib vs. 
placebo in adult patients with moderate-to-
severe atopic dermatitis (AD) with inadequate 
response to topical corticosteroids or if topical 
treatments are medically not advisable 
 
Primary endpoint: 
• Achievement of 75% reduction from baseline in the 
Eczema Area and Severity Index (EASI 75 response) at 
Week 12 (Day 84)  
 
Primary endpoint (see Section 3.2) is the composite 
variable defined as follows: 
•  an EASI 75 response at Week 12 (Day 84), 
• no stop of study intervention for reasons related to lack 
of efficacy, 
• no rescue medication use during the 4 weeks before 
Day 84 and 
• no use of systemic AD treatment.  
 
 
 
Secondary endpoints: 
• Percent change from baseline in EASI at Week 12 (Day 84) 
• Achievement of EASI 50 response at Week 12 (Day 84) 
• Achievement of EASI 90 response at Week 12 (Day 84) 
• Achievement of a vIGA-AD response (score 0 or 1 and 
≥ 2 points improvement) at Week 12 (Day 84)  
• Absolute change from baseline in body surface area (BSA) 
affected by AD at Week 12 (Day 84)  
• Absolute values and percent change of the weekly average 
of the Peak Pruritus 0-10 NRS score from baseline at 
Week 12 (Day 84) 
• Achievement of a ≥ 4 point-improvement (reduction) in the 
weekly average of the Peak Pruritus 0-10 NRS score from 
baseline at Week 12 (Day 84) for participants with Peak 
Pruritus 0-10 NRS score ≥ 4 at baseline 

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Objectives 
Endpoints  
Secondary objectives 
 
 
• To assess the safety and tolerability of 
zabedosertib vs. placebo 
Secondary endpoints: 
• Frequency and severity of TEAEs 
Other safety endpoints: 
• Frequency and severity of TEAEs of special interest 
• Changes in vital signs from baseline 
• Changes in clinical laboratory test results from baseline 
(e.g., chemistry lipid panel, hematology, urinalyses) 
• Changes in ECG parameters from baseline and frequency 
of ECG findings 
Other pre-specified / Exploratory objectives  
 
Other Pre-Specified Endpoints 
• To further assess the efficacy of zabedosertib 
vs. placebo 
• Achievement of EASI 75 response up to Week 8 (Day 56) 
• Achievement of EASI 100  response at Week 12 (Day 84) 
• Achievement of a ≥ 3 point- improvement (reduction) in the 
weekly average of the Peak Pruritus 0-10 NRS from 
baseline at Week 12 (Day 84) 
• Absolute values and percent change from baseline in 
weekly averages of Peak Pruritus 0-10 NRS scores over 
time 
 
• Exploration of the pharmacokinetics of 
zabedosertib 
• Plasma concentrations of zabedosertib and metabolite BAY 
28822815 (M-5) and population pharmacokinetic (popPK) 
evaluation derived PK parameters (will be reported 
separately, if applicable) 
• Pharmacodynamics disease-monitoring 
biomarkers by: 
 
• Assessment of treatment response by 
analysis of blood biomarkers (BM) 
• Plasma levels of inflammatory markers (optional analysis) 
 
• Evaluation of skin biopsies (subset of 
participants) 
• Measurement of molecular changes in AD transcriptome 
reg. inflammatory cytokines, chemokines (e.g., IL-1β, IL-4, 
IL-33, TSLP) and immunohistochemistry (e.g., epidermal 
barrier markers; optional analysis).  
3.2 
Estimand 
The estimand for the primary endpoint is shown below. 
Primary Objective: See Section 3.1 
Estimand label: primary 
Endpoint:  
Achievement of 75% reduction from baseline in the Eczema Area and Severity Index (EASI)  at 
Week 12 (Day 84) – EASI 75 response 
 
Population: 
Adult patients with moderate-to-severe atopic dermatitis (for at least one year and inadequate 
response to topical treatment or if topical treatments are medically not advisable) 
Treatment condition:  
Zabedosertib vs placebo  
Population-level summary: 
The estimated difference in the proportion of responders between interventions. 

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Intercurrent event(s) 
• Use of topical rescue medication: 
At Day 56 (Visit 6) or later: 
analyze study participant as non-responder (composite strategy) 
Before Day 56 (Visit 6): 
disregard use of topical rescue medication (treatment policy strategy) 
• Use of systemic standard of care: 
analyze study participant as non-responder (composite strategy) 
• Discontinuation of treatment due to lack of efficacy: 
analyze study participant as non-responder (composite strategy) 
• Discontinuation of treatment due to reasons not related to lack of efficacy (including Covid-19 
related reasons): 
At Day 56 (Visit 6) or later: 
imputation of response information (hypothetical strategy) 
Before Day 56 (Visit 6): 
exclusion from analysis as adequate imputation of response information is considered not possible 
  
• Non-compliance with study intervention (general), defined as actual drug intake lower than 80% of 
the planned drug intake. Actual drug intake will be calculated from the date of first drug intake until 
end of treatment or start of rescue medication (at or after Day 56 (Visit 6)), whatever comes first:  
exclusion from analysis as adequate imputation of response information is considered not possible 
• Non-compliance with study intervention (last 4 weeks) defined as actual drug intake lower than 
 80% of the planned drug intake during the last 4 weeks. Reference point for determination of the 
time period will be either the end of treatment or the start of rescue medication (at or after Day 56 
(Visit 6)), whatever comes first.: 
exclusion from analysis as adequate imputation of response information is considered not possible 
• Non-compliance with emollients / moisturizers: 
regardless of non-compliance with emollients / moisturizers (treatment policy) 
• Missing baseline value EASI assessment: 
exclusion from analysis as adequate imputation of response information is considered not possible 
• Missing Day 84 (Visit 7) EASI assessment: 
 
imputation of response information using data from Day 56 (Visit 6) or later (hypothetical strategy), 
if none of the conditions applies which are described above. 
• Missing Day 56 (Visit 6) and later EASI assessment: 
exclusion from analysis unless participant is a non-responder due to use of rescue medication, 
SOC or treatment discontinuation due to lack of efficacy 
 
 

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4 
Study Design 
4.1 
Overall Design 
Study 22158 is a Phase 2a proof of concept (PoC) study. 
Randomized, placebo-controlled, double-blind, 2-arm, parallel-group, multi-center Phase 2a 
study. The study consists of  
• a 28-day screening period (Visits 1 and 2),  
• a 12-week intervention period consisting of 5 visits (Visits 3, 4, 5, 6, and 7),  
• and a 4-week follow-up (FU) period with one visit (Visit 8).  
Thus, the total study duration per participant will be 17 to 20 weeks (approximately 140 
days), with 8 study visits at intervals of 8  to 28  ± 3 days. 
 
Screening period 
During the screening period, potential study participants will be identified, and informed 
consent will be obtained prior to the initiation of any study-related procedures. Participants 
will then be evaluated for eligibility against the study-specific inclusion and exclusion criteria.  
Emollients used by the participant before entering the study should be continued with the 
same frequency/intensity. At least 7 days before the randomization visit, participants are 
required to use a stable amount (i.e., approximately the same amount for each application) of 
topical drug-free emollient to moisturize the skin applied to the whole body twice a day, 
which should continue during the study.  
During the same 7-day period, participants will daily record the intensity of their peak pruritus 
using a 0-10 numerical rating scale (NRS) [Peak Pruritus 0-10 NRS] displayed on the 
electronic patient handheld device.  
Randomization 
Randomization will be done at the randomization visit on Day 1, i.e. at the end of the 
screening period.  
A total of 72 participants are planned to be randomly allocated to 1 of the 2 treatment groups 
with a 2:1 allocation ratio to achieve a total of 57 participants valid for efficacy analysis: 
zabedosertib at a dose of 120 mg BID: 
48 randomized / 38 valid for the efficacy 
analysis 
Matching placebo BID: 
 
 
24 randomized / 19 valid for the efficacy  
 
 
analysis. 
Intervention period 
During the intervention period, participants will take the study intervention twice daily. The 
participants will receive two tablets per day, one tablet of zabedosertib or placebo in the 
morning and in the evening. 
Skin condition will be assessed regularly using validated ClinROs in AD, such as the Eczema 
Area and Severity Index (EASI), validated Investigator’s Global Assessment scale for atopic 
dermatitis (vIGA-AD), and the assessment of the BSA affected by AD.  

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In addition, the patient-reported outcome Peak Pruritus 0-10 NRS will be used to investigate 
further efficacy of zabedosertib. 
All participants will be closely monitored for safety throughout the study.  
To gain most accurate dosing data and to ensure adherence to study intervention, the data of 
participant’s daily intake of study intervention will be collected as daily questions on an 
electronic patient handheld device. 
Blood sampling for pharmacokinetic and pharmacodynamic evaluations will be done in all 
participants. 
At selected study sites in a subset of participants, skin biopsy samples will be taken for the 
assessment of gene expression and immunohistochemistry. 
To control worsening of AD symptoms, topical rescue treatment is defined and may be 
provided to study participants at the discretion of the investigator, if required.  
If additional systemic treatment for AD is initiated, the participant needs to stop the study 
treatment and should undergo safety and efficacy assessments as scheduled for the end-of-
treatment (EOT) visit and complete the FU visit. 
Follow-up period 
After the end of study intervention, participants will be followed up for safety and any 
changes in efficacy parameters for further 28 days. 
4.2 
Scientific Rationale for Study Design 
This Phase 2a study protocol was designed to explore the effects of zabedosertib on moderate-
to-severe AD. 
A randomized, double-blind, placebo-controlled design is considered appropriate to assess the 
study objectives listed in Section 3 in the population of interest, which are adult patients with 
moderate-to-severe AD. The EASI was chosen as the primary endpoint measure and is a well-
established and frequently used instrument in clinical studies to assess the severity and extent 
of AD.  
An intervention duration of 12 weeks (84 days) is considered appropriate to observe efficacy 
in this study population and to investigate potential changes in safety parameters.  
4.3 
Participant Input into Design 
Participant involvement in the design of the clinical study was collected via several structured 
feasibility processes interacting with study sites interested in taking part in the clinical study. 
AD patients were also consulted via 2 different methods: 
• A sponsor internal patient questionnaire making use of the input of 114 individuals 
with AD (sponsor employees), (data on file).  
• A patient advisory board conducted with AD patients, interviewed according to a 
questionnaire provided by the study team.  
These consultations provided patients feedback about their disease, treatments and some of 
the study processes. 
Processes were adapted whenever it was possible where concerns were identified during the 
feasibility with sites and through patient's consultations. 

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4.4 
Justification of Dose 
This study aims to generate first evidence of efficacy of the IRAK inhibitor zabedosertib in 
AD. Specifically, this study assesses whether, and if so, to what extent treatment with 
zabedosertib is associated with a reduction of AD symptoms in adult patients suffering from 
moderate-to-severe AD over a timeframe of 12 weeks. Based on its mode of action and 
preclinical information, IRAK4 inhibition is expected to reduce skin inflammation and 
pruritus in patients with AD. In addition, a mechanistic study (21329) to assess the 
pharmacological activity of oral administrations of zabedosertib on the inhibition of IRAK4 
pathway mediated reactions upon local and systemic challenges is operationally completed 
and data showed a positive and promising outcome. 
The dose was selected because the results from Phase 1-Studies 18384 and 18385 
demonstrate that plasma concentrations achieved with 120 mg BID are expected to reach the 
anticipated therapeutic exposure levels (see below) and a higher dose resulted in only slight 
respectively no increase in exposure (a dose of 200 mg BID was tested in Study 18385 (part 
1, healthy volunteers) and was safe and well tolerated but resulted in no exposure increase). 
Also, this dose is considered well suited since single doses up to 480 mg zabedosertib were 
well tolerated by healthy male participants in Study 18384. Similarly, results from Study 
18385 (part 2, patients with psoriasis) showed acceptable tolerability of 120 mg zabedosertib 
BID for 8 weeks. For details please refer to IB zabedosertib. 
The estimated human efficacious exposure for the indication rheumatoid arthritis was based 
on experimental data from a mouse collagen antibody-induced arthritis (CAIA) model in 
female Balb/C mice. The unbound AUC (AUCu) to achieve 50% efficacy was determined as 
20 mg h/L. Due to species differences in potency between mouse and human, this translates to 
an AUCu in human of 4.7 mg h/L, which was considered as therapeutic human AUCu. The 
dose of 120 mg BID in humans resulted in a coverage of 136% of the estimated human 
efficacious exposure.  
Also, clear evidence for pharmacological activity of the dose of 120 mg BID in the skin and 
systemically was demonstrated in the Mechanistic Study 21329 in a human imiquimod skin 
challenge model and in a systemic LPS challenge (data on file) suggesting efficacy in AD. 
Relevant concentrations of zabedosertib were further detected in skin suction blisters, 
indicating a skin exposure of about 43% in relation to the systemic exposure. 
12 weeks are considered to be adequate to show an effect in this patient population and to 
assess safety and tolerability in patients with AD to decide on the further development in this 
indication as well as to benchmark against other development drugs. 
Only one active dose is used in this study to limit the number of participants who are exposed 
in reflection of the fact that there is no clinical experience with the IRAK inhibitor 
zabedosertib in patients suffering from AD. 
 
No dose modification is intended in this study (see Section 6.6). 
4.5 
End of Study Definition 
A study participant is considered to have completed the study, if the participant has completed 
all phases of the study including the FU visit. 
The end of the study is defined as the date of the clean database. 

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Primary completion 
The primary completion is defined as the date of the last treatment of the last participant.  
5 
Study Population 
The study population consists of adult patients with a clinical diagnosis of AD for ≥ 1 year 
and moderate-to-severe disease intensity at study entry. For details of eligibility criteria see 
Section 5.1 and 5.2.  
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known 
as protocol waivers or exemptions, is not permitted. 
 
5.1 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
1. 18 to 65 years of age inclusive, at the time of signing the informed consent. 
2. Diagnosis of AD for ≥ 1 year at the screening visit. 
3. Moderate-to-severe AD at randomization visit as defined by  
- 
EASI score ≥ 16,  
- 
BSA affected by AD ≥ 10%,  
- 
vIGA-AD score ≥ 3, and  
- 
Peak Pruritus 0-10 NRS ≥ 4 (average score of the daily scores of the 7 days 
before randomization, with ≥ 4 scores required). 
4. Documented history (within 6 months prior to the first screening visit) of inadequate 
response to treatment with topical corticosteroids (TCS), or if TCS are medically not 
advisable (e.g., due to important side effects or safety risks). 
− Inadequate response is defined as failure to achieve and maintain remission or a 
low disease activity state (comparable to vIGA-AD 0 = clear to 2 = mild) in spite of 
treatment with a daily regimen of TCS of moderate or higher potency, see 
WHOCC, ATC/DDD Index as a guidance ( ± TCI as appropriate), applied for at 
least 28 days or for the maximum duration recommended if less than 28 days by the 
product prescribing information (e.g., 14 days for super-potent TCS), whichever is 
shorter. 
− Documented systemic treatment for AD in the past 6 months also qualifies as 
inadequate response to topical treatments. 
− Important side effects or safety risks are considered to be those risks that outweigh 
the potential treatment benefits. They include intolerance to treatment, 
hypersensitivity reactions, significant skin atrophy, and systemic effects, as 
assessed by the investigator or by the patient’s treating physician. 
− Acceptable documentation must be obtained, which includes concurrent chart notes 
that record topical medication prescription and treatment outcome, or investigator 
documentation based on communication with the patient’s treating physician. If 
documentation is insufficient, potential patients may be re-screened after such 
documentation is obtained (i.e., patients are shown to fail a 28-day course of 
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5. Stable amount of emollient applied to skin over the whole body twice daily for at least 
the 7 consecutive days before the randomization visit (NOTE: further instructions 
regarding emollients / moisturizers can be found in Section 6.9.1). 
6.  Body mass index (BMI) within the range of 18.5 to 35.0 kg/m2 (inclusive) at 
screening (Visit 1) and randomization visits. 
7. Women of childbearing potential (WOCBP; for definition, see Section 10.4) and male 
subjects able to father children must agree to use adequate contraception when sexual-
ly active. This applies since the signing of the informed consent form until 30 days 
after the last study intervention administration. Contraceptive use by men or women 
should be consistent with local regulations regarding the methods of contraception for 
those participating in clinical studies. 
Male Participants: 
Male participants are eligible to participate if they agree to the following during the 
study intervention period and for at least 30 days after the last dose of study 
intervention: 
• Must agree to use contraception / barrier as detailed below: 
- 
Agree to use a male condom with female partner use of an additional 
highly effective contraceptive method with a failure rate of < 1% per year 
as described in Appendix 4 Contraceptive and Barrier Requirements (see 
Section 10.4). 
or 
• Be abstinent from heterosexual intercourse as their preferred and usual lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent. 
• Refrain from donating sperm. 
 
Female Participants:  
• A female participant is eligible to participate if she is not pregnant or 
breastfeeding, and one of the following conditions applies: 
- 
Is a woman of nonchildbearing potential (WONCBP) as defined in 
Appendix 4 (see Section 10.4). Contraception and Barrier Guidance. 
- 
Is a WOCBP and using a contraceptive method that is highly effective 
(with a failure rate of < 1% per year), preferably with low user dependency, 
as described in Appendix 4 (see Section 10.4). Contraception and Barrier 
Guidance during the study intervention period and for at least 30 days after 
the last dose of study intervention. The investigator should evaluate the 
potential for contraceptive method failure (e.g., noncompliance, recently 
initiated) in relationship to the first dose of study intervention. 
• A WOCBP must have a negative highly sensitive pregnancy test (urine) as 
required by local regulations within 24 hours before the first dose of study 
intervention, see Section 8.3.5 Pregnancy Testing. 
- 
If a urine test cannot be confirmed as negative (e.g., an ambiguous result), a 
serum pregnancy test is required. In such cases, the participant must be 
excluded from participation if the serum pregnancy result is positive.  

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- 
Additional requirements for pregnancy testing during and after study 
intervention are located in Section 8.3.5 Pregnancy Testing. 
- 
The investigator is responsible for review of medical history including 
menstrual history and recent sexual activity to decrease the risk for 
inclusion of a woman with an early undetected pregnancy. 
8. Capable of giving signed informed consent as described in Section 10.1.4, which 
includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol. See country-specific requirement for France 
(FRA-1) in Section 10.8. 
5.2 
Exclusion Criteria  
Participants are excluded from randomization if any of the following criteria apply: 
Medical Conditions 
1. 
History of any major surgery within 8 weeks prior to screening or scheduled (elective) 
surgery, planned hospitalization and/or planned dental treatment during the study that 
could constitute a risk when participating in a study. 
2. 
Severe invasive infections in medical history and/or active clinically significant viral, 
bacterial, fungal, or parasitic infection (systemic or severe skin infection) ≤ 3 months 
prior to the randomization visit.  
− Patients with a positive SARS-CoV-2-virus-RNA-test at Visit 2 (Day -8) or with 
any symptoms suspicious of COVID-19 or with contact to any SARS-CoV-2-
positive patient/individual within 2 weeks prior to the SARS-CoV-2-virus-RNA-
test at Visit 2 (Day -8).   
If a SARS-CoV-2 viral RNA test is indicated between Visit 2 (Day -8) and  
Visit 3 (randomization visit), start of study intervention should be delayed until test 
results exclude an infection. 
− Patients with a history of severe COVID-19 infection (i.e., requiring a hospital 
admission) independent of the time point. 
− Patients with a history of non-severe COVID-19 infection (i.e., not requiring 
hospital admission) ≤ 3 months prior to screening and/or without a full recovery 
(i.e., patients with clinically significant sequelae).  
− Symptomatic herpes zoster infection within 12 weeks prior to randomization visit 
or any history of disseminated/complicated herpes zoster (e.g., multi-dermatomal 
involvement, ophthalmic zoster, central nervous system involvement, or 
postherpetic neuralgia). 
3. 
A presence of uncontrolled condition including cardiovascular, respiratory, hepatic 
(see exclusion criterion 22), renal (see exclusion criterion 23), gastrointestinal, 
endocrine, hematological, neurological, or neuropsychiatric disorders or any other 
unstable illness that, in the opinion of the investigator, could constitute a risk when 
taking investigational product, study conduct or could interfere with the interpretation 
of data. Patients with stable asthma may be enrolled (stable asthma medication 
throughout study expected, see exclusion criterion 11). 

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4. 
Any clinically relevant abnormal findings in medical condition or history thereof or 
any deviation from normal laboratory values, physical examination, vital signs, 12-
lead ECG at screening or randomization which in the opinion of the investigator, may 
put the participant at risk by participation in the study or provide difficulties in 
interpreting the trial data. 
5. 
Participants with any of the following within 12 weeks of study entry: myocardial 
infarction, unstable ischemic heart disease or cerebrovascular accident. 
6. 
Current or history of lymphoproliferative disease; or signs or symptoms suggestive of 
possible lymphoproliferative disease, including lymphadenopathy or splenomegaly; or 
active primary or recurrent malignant disease; or been in remission from clinically 
significant malignancy for < 5 years. 
The following exceptions to the above are acceptable for enrollment: 
a. Cervical carcinoma in situ that has been resected with no evidence of recurrence or 
metastatic disease for ≥ 3 years and 
b. Basal cell or squamous epithelial skin cancers that have been completely resected 
with no evidence of recurrence for ≥ 3 years. 
7. 
Known immunodeficiency disorder or immunocompromised state or, in the opinion of 
the investigator, unacceptable risk for participating in the study. 
Prior/Concomitant Therapy 
8. 
Use of topical or systemic antihistamines within 7 days before Visit 3 
9. 
Use of topical treatments for AD (i.e., topical glucocorticosteroids [TCSs] or topical 
calcineurin-inhibitors [TCIs] or topical JAK inhibitors) within 7 days before the 
randomization visit. 
10. 
Start use of prescription emollients / moisturizers or emollients / moisturizers 
containing additives such as urea, ceramides, hyaluronic acid, heparinoid or any other 
active substances during the screening period or during the study. 
11. 
Systemic immunosuppressive/ immunomodulating therapy (e.g., systemic 
glucocorticoids, cyclosporine, mycophenolate mofetil [MMF], methotrexate, 
azathioprine or oral Janus kinase (JAK)-inhibiting agents) or phototherapy within 
4 weeks before the randomization visit. A stable daily dose of max. 1200 µg inhalative 
glucocorticosteroid (budesonide or equivalent) is allowed; this includes ‘reliever 
treatment’ expected to be required by the patient during the study. 
12. 
Therapy with biologic drugs within 5 half-lives of the biologic drug (e.g. dupilumab or 
tralokinumab) or 12 weeks before randomization visit – whatever is longer –, except 
cell depletion therapy (within 6 months before the randomization visit). For vaccines, 
see “Other exclusions” below.  
13. 
Use of drugs which might affect absorption of the study intervention (e.g., laxatives, 
loperamide, metoclopramide) during 1 week before the randomization visit. 

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14. 
Use of drugs within 1 week prior to the randomization visit which are substrates for 
Breast Cancer Resistance Protein (BCRP) (e.g., atorvastatin, daunorubicin, fluvastatin, 
gefitinib, hymecromone, imatinib, irinotecan, lapatinib, methotrexate, mitoxantrone, 
nitrofurantoin, pibrentasvir, pitavastatin, prazosin, rifampicin, rosuvastatin, 
simvastatin, sulfasalazine, sunitinib, topotecan, vincristine, zidovudine) (see also 
Appendix 10.6). 
15. 
Use of drugs within 1 week prior to the randomization visit which are substrates for 
Organic Anion Transporting Polypeptide (OATP) 1B1 and 1B3 (e.g., ambrisentan, 
asunaprevir, atorvastatin, bosentan, cerivastatin, docetaxel, donoprevir, ezetimibe, 
fexofenadine, fluvastatin, gadoxetic acid, glibenclamide, nateglinide, paclitaxel, 
pitavastatin, pravastatin, repaglinide, revefenacin, rosuvastatin, simeprevir, 
simvastatin) (see also Appendix 10.6). 
Prior/Concurrent Clinical Study Experience 
16. 
Current or previous (within 30 days of randomization visit) participation in a clinical 
trial involving an investigational product or non-approved use of a drug or are 
concurrently enrolled in any other type of medical research judged not to be scientifi-
cally or medically compatible with this study. 
17. 
Previous randomization in this study.  
Diagnostic Assessments 
18. 
Pregnancy (positive pregnancy test) or nursing at screening or randomization visit or 
considering becoming pregnant during the study. 
19. 
Positive hepatitis B or C serology (unless curative treatment and HCV-RNA-
negative). Subjects with positive HBsAb may be randomized provided they are 
hepatitis B-vaccinated and have negative HBsAg and HBcAb.  
20. 
Positive HIV serology test. 
21. 
Positive Quantiferon test for tuberculosis (i.e., QuantiFERON-TB Gold Plus test) at 
screening or participants with risk factors for TB and/or signs and symptoms 
suggestive for TB.  
22. 
Chronic liver disease with evidence for liver fibrosis/cirrhosis (i.e., Class A, B and C 
based on Child-Pugh criterion) as documented in medical history or at least one of the 
following will be excluded: 
- 
Total bilirubin > 1.0 x ULN in the absence of Gilbert's Syndrome or hemolysis 
- 
ALT > 1.5 x ULN 
- 
AST > 1.5 x ULN. 
23. 
eGFR < 60 mL/min/1.73 m2 using the modification-of-diet-in-renal-disease (MDRD)* 
formula at screening.  
*calculated by the following MDRD equation:  
eGFR = 175 × (serum creatinine in mg/dL)–1.154 × (age in years)–0.203 × 0.742 (if 
female) × 1.212 (if race is black). 
24. 
Any of the following laboratory abnormalities at screening visit: 

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- 
Absolute neutrophil count below < 2.0 x 109 /L (< 200/ mm3) 
- 
Hemoglobin < 11 g/dL at screening. 
Other Exclusion Criteria 
25. 
Any planned or scheduled vaccination (excluding passive immunization) including 
COVID-19 vaccination during the study. 
26. 
Receipt of live or attenuated vaccine 28 days prior to randomization visit. 
27. 
Patients who received COVID-19 vaccine or influenza vaccine < 28 days prior to 
randomization visit.  
28. 
History of chronic alcohol abuse, intravenous drug abuse, or other illicit drug abuse 
within the 2 years prior to the randomization visit. 
29. 
Close affiliation with the investigational site, e.g. a close relative of the investigator, 
dependent person (e.g., employee of the investigational site). 
30. 
Inability or unwillingness to make themselves available for the duration of the study 
and/or inability or unwillingness to follow study restrictions and procedures. 
31. 
Known hypersensitivity to the study drug (active substance or excipients - 
croscarmellose sodium, mannitol, magnesium stearate, microcrystalline cellulose, 
hypromellose, sodium lauryl sulfate, for details, see IB). 
Re-screening  
Re-screening of subjects is possible under certain circumstances. For details, see Section 5.4. 
5.3 
Lifestyle Considerations 
It is recommended that intake of fluids should be relatively stable throughout study 
participation. As a precautionary measure, excessive exposure to sunlight such as sunbathing 
or the use of solarium should be avoided during the study period.  
5.3.1 
Meals and Dietary Restrictions 
No specific food and drink restrictions apply.  
5.3.2 
Caffeine, Alcohol, and Tobacco 
There are no specific lifestyle restrictions for caffeine, alcohol and tobacco. 
5.3.3 
Activity 
It is recommended that participants should abstain from strenuous exercise for 48 hours 
before each blood collection for clinical laboratory tests. 
5.3.4 
Other Restrictions 
Participants are asked to refrain from donating blood for the duration of their study 
participation. Also, participants should not engage in phototherapy or tanning in a booth/bed 
during the duration if the study. 

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5.4 
Screen Failures 
A screen failure occurs when a participant consents to participate in the clinical study but is 
not subsequently randomly assigned to study intervention. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet 
the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes informed 
consent date, date of last visit, demography, screen failure details, and eligibility criteria. 
 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened once. Rescreened participants should be assigned a new participant identification 
(PID).  
Rescreening may occur for the following reasons (examples): 
• The participant had successfully passed the screening procedures but could not start 
subsequent treatment on schedule. 
• Initial screening occurred too early to complete the required washout period after prior 
therapy. 
• The in- / exclusion criteria preventing the participant’s initial attempt to participate 
have been changed (via protocol amendment). 
• The participant suffered from a temporary and not clinically relevant disease like a 
common cold. 
• In the case of any of the following laboratory abnormalities (not within the screening 
period), screening tests may be repeated once within 2 weeks of the initial values, and 
values resulting from repeat testing may be accepted for eligibility: 
- Total bilirubin > 1.0 x ULN in the absence of Gilbert's Syndrome or hemolysis 
- ALT > 1.5  x ULN  
- AST > 1.5. x ULN 
- Absolute neutrophil count < 2 x 109 cells/L (< 2000/ mm3) 
- eGFR < 60 mL/min/1.73m2 (MDRD) formula 
- Hemoglobin < 11.0 g/dL 
- CK > 5 x ULN 
In any case, the investigator has to ensure that the repeated screening procedures do not 
expose the participant to an unjustifiable health risk. Also, for re-screening, the participant has 
to re-sign the informed consent form, even if it was not changed after the participant’s 
previous screening. 
5.5 
Criteria for Temporarily Delaying Enrollment/Randomization/Study 
Intervention Administration 
No specific criteria apply. 
6 
Study intervention(s) and Concomitant Therapy 

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Study interventions are all pre-specified, investigational and non-investigational medicinal 
products, medical devices and other interventions (e.g., surgical and behavioral) intended to 
be administered to the study participant during the study conduct. 
6.1 
Study Intervention(s) Administered 
The study interventions administered for this trial are summarized in Table 6–1. 
Table 6–1: Study interventions 
Intervention Label 
Zabedosertib 
Placebo 
Intervention Name 
Zabedosertib; IRAK4 inhibitor 
Placebo (matching to zabedosertib) 
Intervention Description 
120 mg tablet orally twice daily (BID) for 
12 weeks 
1 placebo tablet orally twice daily (BID) 
for 12 weeks 
Type  
Drug 
Drug 
Dose Formulation 
Tablet 
Tablet 
Unit Dose Strength(s) 
120 mg 
not applicable 
Dosage Level(s) 
120 mg BID 
BID dosing 
Route of Administration 
Oral 
Oral 
Use 
Experimental drug 
Control 
Packaging and Labeling 
Study intervention will be provided in HDPE bottles closed with child-resistant 
screw cap. Each bottle will be labeled as required per country requirement. 
HDPE = high-density polyethylene; IRAK4 = interleukin1 receptor-associated kinase 4 
Tablets containing zabedosertib or corresponding placebo are identical in appearance (size, 
color, shape). In order to remain blinded, study interventions will be packaged in bottles 
labeled with a unique number which will be pre-printed on each bottle. 
All participants will take study intervention (zabedosertib or matching placebo) BID (morning 
and evening doses) approximately the same time each day 12 hours apart. 
Tablets are not to be broken, halved or crushed; they should be swallowed as a complete unit 
with water. Daily tablet intake should be done at home.  At visits with PK, study drug intake 
of the morning dose should occur at the study site. 
If a dose of study intervention has been missed: 
• If up to 6 hours have passed since the dose was due, it should be taken immediately 
• If more than 6 hours have passed since the dose was due, the dose should be 
skipped, and the next dose should be taken according to the regular schedule. 
Table 6–2: Study Arms 
Arm Title 
Zabedosertib 
Placebo 
Arm Type 
experimental 
placebo 
Arm Description 
Participants will receive 120 mg 
zabedosertib BID for 12 weeks.  
Participants will receive an 
equivalent number of tablets of 
matching placebo for 12 
weeks. 
Associated Intervention 
Labels 
zabedosertib 120 mg 
Placebo 
6.2 
Preparation, Handling, Storage, and Accountability 

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The investigator or designee must confirm study interventions have been received and, if a 
temperature data logger has been included, appropriate temperature conditions have been 
maintained during transit. Any discrepancies are reported and resolved before use of the study 
intervention.  
Only participants randomized in the study may receive study intervention and only authorized 
site staff may supply, prepare or administer study intervention. All study intervention must be 
stored in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff. 
The investigator or the head of the medical institution (where applicable) is responsible for 
study intervention accountability, reconciliation, and record maintenance (i.e., receipt, 
reconciliation, and final disposition records). Drug returns, reconciliation and destruction 
information will be captured in the IRT.  
A record of the number of tablets dispensed to and taken by each participant must be 
maintained and reconciled with study treatment and compliance records. An adequate record 
of receipt, distribution, and return/destruction of all study treatment must be captured on the 
dispensing log and/or in the IRT. 
Study drug tablets not returned will be considered to have been taken unless otherwise 
specified. At the end of the study, any remaining drugs will be collected and returned to the 
sponsor, destruction depot or destroyed at the site. Any discrepancies between the returned 
and expected returned study drugs should be explained. 
Study intervention will be dispensed at the study visits summarized in SoA (see Section 1.3). 
Returned study intervention should not be re-dispensed to the participants.  
6.3 
Assignment to Study Intervention 
Eligible participants who meet all the inclusion criteria and none of the exclusion criteria will 
be assigned a randomization number and randomly allocated in a 2:1 ratio to receive either 
zabedosertib or matching placebo.   
The randomization will be done in blocks.  
6.4 
Blinding 
As this is a double-blind study design, both investigators and participants will be blinded to 
study interventions. 
All participants will be centrally assigned to randomized study intervention using Interactive 
Response Technology (IRT); the use of central randomization via IRT will minimize potential 
bias. Before the study is initiated, the directions for the IRT will be provided to each site.  
The IRT will be programmed with blind-breaking instructions. In case of an emergency, the 
investigator has the responsibility for determining if unblinding of a participant’s intervention 
assignment is warranted. If the investigator is unavailable, and a treating physician not 
associated with the study requests emergency unblinding, the emergency unblinding requests 
are forwarded to the study specific emergency medical advice 24 hours / 7 days service. 
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the investigator decides that unblinding is warranted, the investigator should make every 
effort to contact the sponsor prior to unblinding a participant’s intervention assignment unless 
this could delay emergency treatment of the participant. If a participant’s intervention 
assignment is unblinded, the sponsor must be notified within 24 hours after breaking the 
blind. The date and reason that the blind was broken must be recorded in the source documen-
tation and case report form, as applicable. In order to maintain the blind, study interventions 
will be packaged in bottles labeled with a unique number which will be pre-printed on each 
bottle. 
Bioanalytical staff will be unblinded according to the corresponding Bayer standard operating 
procedure (SOP). Pharmacometrics and pharmacokinetics staff may also be unblinded 
according to Bayer SOPs. PK and exposure-response analysis might be performed using 
population approaches (popPK and popPK/PD, e.g. by non-linear mixed effect modeling). 
Analysis and report will be done under a separate cover if applicable. This evaluation might 
be started prior to database lock. If this is applicable, appropriate measures will be taken to 
maintain blinding of the study team, e.g. data will be stored separately, and members of the 
study team will neither have access to the randomization list nor to individual data. 
6.5 
Study Intervention Compliance 
Participants will be requested to bring along all used and unused study intervention including 
packaging material to selected visit (see SoA, Section 1.3). Any discrepancies between actual 
and expected amount of returned study intervention or any discrepancies with the patient drug 
intake diary must be discussed with the participant at the time of the visit and should be 
resolved, if possible.  
The data of participant’s daily intake of study intervention will be collected as daily question 
on an electronic patient handheld device and reminders to take the study drug are planned to 
be sent via the device. 
Further information about the participant’s treatment compliance can be derived from drug 
concentration measurements. 
6.6 
Dose Modification 
Dose modifications (dose and frequency of intake) of zabedosertib or placebo are not allowed 
during the intervention period of the study. 
6.7 
Continued Access to Study Intervention after the End of the Study 
Participants who complete the treatment period or who are prematurely withdrawn from the 
study will not have further access to study intervention, and it will be up to the investigators 
discretion to provide follow-up medical care for all participants who complete the study or 
who are prematurely withdrawn from the study or refer them for appropriate ongoing care as 
required. 
6.8 
Treatment of Overdose 
In this study, an overdose is defined as an intentional or accidental administration of 
zabedosertib, to or by a study participant, at a dose which is higher than the dose assigned to 
that individual participant according to the study protocol. 

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In the event of an overdose, no antidote or specific treatment is recommended. The 
investigator should: 
• Contact the Medical Monitor immediately.  
• Evaluate the participant to determine, in consultation with the Medical Monitor, if 
possible, whether study intervention should be interrupted or whether the dose should 
be reduced. 
• Closely monitor the participant for any AE/SAE and laboratory abnormalities. 
• Overdose per se will not be reported as an AE and/or SAE unless it is associated with 
clinically relevant signs and/or symptoms, or an intentional overdose taken with 
possible suicidal and/or self-harming intent (Section 10.3). In these cases, if feasible, a 
plasma sample for PK analysis may be obtained, ideally as soon as possible after the 
overdose, with recording of date and time of sampling.  
• An overdose should be treated as clinically indicated based on signs and symptoms.  
• Document the quantity of the excess dose as well as the duration of the overdose in the 
electronic case report form (eCRF/eDiary). 
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the participant. 
6.9 
Prior and Concomitant Therapy 
Any medication or vaccine (including over-the-counter or prescription medicines, recreational 
drugs, vitamins, and/or herbal supplements) or other specific categories of interest that the 
participant has received within the last 30 days before randomization visit, is receiving at the 
time of enrollment or receives during the study must be recorded along with: 
• Reason for use 
• Dates of administration including start and end dates 
• Dosage information including dose and frequency. 
AD relevant medication (including emollients) will be recorded for 6 months before 
randomization visit. 
Any SARS-CoV-2 vaccination prior to study entry should be recorded independent of the 
timeframe under prior/concomitant medication. 
The sponsor should be contacted if there are any questions regarding concomitant or prior 
therapy. 
See Section 8, Screening, Medical history and AD history for information relating to 
previously used medications. 
 
6.9.1 
Background Therapy with Emollients / Moisturizers 
All participants must use a stable amount (i.e., approximately the same amount for each 
application to the whole body at least twice daily) of emollient as background therapy during 
the course of the study, starting at least 7 days before the randomization visit. Any type of 

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emollient is permitted, but participants may not initiate treatment with prescription emollients 
/ moisturizers or emollients / moisturizers containing additives such as urea, ceramides, 
hyaluronic acid, heparinoid, probiotics or any other active substances during the screening 
period or during the study. Participants may continue using stable amounts of such emollients 
/ moisturizers, if initiated before the screening visit. Emollients used by the participant before 
entering the study should be continued with the same frequency/intensity. Participants will be 
reminded once a week about emollient usage by the electronic hand held device. 
The emollient is considered an auxiliary medicinal product in this study (not an investiga-
tional product). The maximum daily amount and frequency of application should be agreed 
with the investigator and be in line with the user information.  
The emollient will be locally supplied/reimbursed by the sponsor during the study, including 
follow-up, according to the locally agreed process. 
Before the use of the defined topical rescue medication, investigators should attempt to 
manage participant’s AD symptoms with emollients / moisturizers, e.g. with an increased 
frequency of use. If this is not successful or advisable, topical rescue treatment can be given 
to participants who are experiencing unacceptable or worsening symptoms of AD at any time 
after randomization visit. 
For further information on the use of rescue medication, see also Section 6.9.2. 
6.9.2 
Rescue Medication 
In the event of a disease flare or AD symptoms defined as any worsening of AD to an vIGA 
≥ 3 requiring escalation of treatment confirmed by an investigator, which cannot be tolerated 
by the study participant, topical rescue medication as defined below may be used for a 
timeframe of several days at the discretion of the investigator. Before topical treatment for 
AD (= rescue medication) is initiated, the frequency of emollient use should be increased to 
try to control AD symptoms and efficacy assessments should be performed (see below and 
Section 8.1 [Unscheduled visit]).  
Defined rescue medication for this study is the methylprednisolone aceponate (Advantan® 
cream). Only if Advantan cream is not available in the respective country, an alternative TCS 
with similar potency may be used (see WHO definition for potent corticosteroids group III, 
such as betamethasone, fluclorolone, desoximetasone, fluocinolone acetonide, budesonide, 
mometasone, beclomethasone, hydrocortisone aceponate). If TCSs are not tolerated or their 
use is not advisable, the topical TCIs pimecrolimus 1% (Elidel® cream) or tacrolimus 
(Protopic® 0.1% or 0.03% ointment) may be used.  
The rescue medication is considered an auxiliary medicinal product (not an investigational 
product). The daily amount and frequency of application should be once daily for 1 week. If 
necessary, the duration of application may be extended to a maximum of 2 weeks. The use of 
rescue medication has to be documented in the CRF, providing information on product, dose, 
frequency and duration of therapy. 
Topical rescue medication will be locally supplied/reimbursed by the sponsor during the 
study, including follow-up, according to the locally agreed process. Whenever possible, the 
efficacy assessments using the EASI, vIGA-AD and BSA affected by AD should be 
performed immediately before start of topical rescue therapy and at its end. Site visits 

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(scheduled or unscheduled) are therefore strongly recommended before start of rescue 
treatment. 
If topical rescue medication is used, study intervention (zabedosertib or placebo) will be 
continued and study visits performed according to the SoA (see Section 1.3).  
6.9.3 
Prohibited Medication and Therapies 
Prior and concomitant therapies not permitted in this study are listed in Section 5.2, exclusion 
criteria. Therapies listed in the exclusion criteria are also prohibited during the study (excep-
tion: TCSs and TCIs may only be used as rescue medication).  
In addition, the use of antihistamines and live vaccination are not allowed during the study. 
If the participant took a prohibited medication or used a prohibited non-drug therapy for any 
reason, the investigator should consult with the sponsor to determine if the participant should 
be withdrawn from study intervention and/or the study. 
For the purpose of efficacy analysis, participants receiving any pharmacologically active non-
study medication or phototherapy for AD will be considered as treatment failures after the 
start of such medication, except for the use of defined topical rescue medication up 
to/including Week 8. Whenever possible, efficacy and safety assessments according to Visit 7 
(EOT) should be conducted immediately before administering any systemic medications for 
AD or initiation of phototherapy (= SoC). For zabedosertib, a wash-out period of 7 days 
(approximately 5 half-lives) is recommended, because there is no experience or data with a 
combination of zabedosertib and systemic AD treatment. 
SoC should be reserved for participants who do not respond adequately to topical treatment 
(at least 7 days of use). If a participant receives SoC treatment with systemic corticosteroids 
or non-steroidal systemic immunosuppressive drugs (cyclosporine, methotrexate, MMF, 
azathioprine, baricitinib etc.) dupilumab, tralokinumab or initiation of phototherapy, study 
intervention has to be discontinued and EOT assessments including FU visits performed.  
7 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal  
Discontinuation of specific sites or of the study as a whole are detailed in Appendix 1 
(Section 10.1.11). 
 
7.1 
Discontinuation of Study Intervention  
In rare instances, it may be necessary for a participant to permanently discontinue study 
intervention. If study intervention is permanently discontinued, the participant should, if at all 
possible, remain in the study to be evaluated for EOT and FU assessments, as described at the 
end of this section. See the SoA (see Section 1.3) for data to be collected at the time of 
discontinuation of study intervention and FU and for any further evaluations that need to be 
completed. 
If an exclusion criterion is met during the study, the investigator should consider discon-
tinuation of the participant’s study intervention, if medically indicated. 
The participant’s study intervention must be permanently discontinued, if anything of the 
following occurs: 

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• Pregnancy (see also Section 8.4.5). 
• Participant receives SoC treatment with systemic corticosteroids or non-steroidal 
systemic immunosuppressive drugs or phototherapy (see also Section 6.9.3). 
• Participant interrupts study intervention for more than 10 consecutive days (see also 
Section 7.1.4). 
• Participant experiences an AE which is considered to be related to study treatment or 
study procedure and, in the investigator’s judgment, is severe enough in nature to 
warrant treatment discontinuation. Common Terminology Criteria for AEs (CTCAE) 
current version, Grade 3 or higher (may be used as guidance). 
• Any malignancy. 
• Febrile illness for more than 48 hours and clinical or biochemical signs of infection 
(e.g., clinically relevant abnormality of hsCRP level). 
• Participants who received COVID-19 vaccine during the study treatment phase, must 
be withdrawn from the study. An interval of at least 14 days between the last study 
drug and the vaccine dose is recommended. 
• Positive SARS-CoV-2 viral RNA test or clinical evidence for COVID-19 during the 
study despite a negative test result (study intervention should be interrupted until test 
results are available). Testing during the study should be done on an individual basis 
as medically indicated according to local practice, triggered by signs and symptoms of 
a potential SARS-CoV-2 infection or contact history. If current COVID-19 infection is 
confirmed, the participant must be permanently discontinued from study intervention. 
• The participant’s randomized treatment assignment is unblinded by the investigator or 
treating physician. 
• Sponsor request (after discussion with the investigator), for reasons such as a 
significant protocol deviation or participant non-compliance. 
• Study as whole is terminated by the sponsor. 
• Liver safety-related discontinuation criteria are met as described in Section 7.1.1. 
• Confirmed creatine kinase (CK) > 10 x ULN or clinical signs of rhabdomyolysis 
(Section 10.2.1). 
• Herpes zoster 
A participant should also be permanently discontinued from study intervention for the 
following laboratory abnormalities:  
• WBC count < 1000 cells/μL; < 1.0 x 109 /L 
• Absolute neutrophil count < 500 cells/μL; < 0.5 x 109 /L 
• Lymphocyte count < 200 cells/μL; < 0.2 x 109 /L 
• Hemoglobin < 8 g/dL. 
 
Handling of discontinuation of study intervention  
For participants who permanently discontinue the study intervention, an EOT visit with all 
assessments as specified in the SoA (see Section 1.3) should be performed as soon as the 
study intervention has been discontinued. If the decision to stop the study intervention early is 

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taken during a site visit, this visit becomes the EOT visit. The FU visit should be performed 
as planned after the last dose. 
After the early EOT visit, treatment with SoC may be started at the discretion of the 
investigator and entered into the eCRF. For zabedosertib, a wash-out period of 7 days 
(approximately 5 half-lives) is recommended, because there is no experience or data with a 
combination of zabedosertib and systemic AD treatment. 
See the SoA (Section 1.3) for data to be collected at the EOT and FU and for any further 
evaluations that need to be completed.  
7.1.1 
Liver Chemistry Stopping Criteria 
Permanent discontinuation of study intervention for abnormal liver tests is required by the 
investigator when a participant meets one of the conditions outlined below or in the presence 
of abnormal liver chemistry not meeting protocol-specified stopping rules if the investigator 
believes that it is in best interest of the participant: 
• ALT or AST > 3 x ULN and total bilirubin (TBL) > 2 x ULN 
• ALT or AST > 3 x ULN and INR > 1.5 x ULN a 
• ALT or AST > 3 x ULN with appearance of fatigue, nausea, vomiting, right upper 
abdominal quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%) 
• ALT or AST > 5 x ULN for more than 2 weeks 
• ALT or AST > 8 x ULN 
a  Relevant only if the participant is not on Vitamin K antagonist, new oral anticoagulants (NOACs) or heparin. 
• Study intervention restart or rechallenge after liver chemistry stopping criteria are met 
by any participant in this study is not allowed. 
 
7.1.2 
QTc Stopping Criteria 
If a clinically significant finding is identified (including, but not limited to changes from 
baseline in QT interval corrected using Bazett’s formula [QTcB] after enrollment), the 
investigator or qualified designee will determine if the participant can continue in the study 
and if any change in participant management is needed. A review of the ECG at the time of 
collection must be documented. Any new clinically relevant finding should be reported as an 
AE. 
7.1.3 
Temporary Discontinuation  
In some circumstances, it may be necessary to temporarily interrupt treatment as a result of 
AEs or abnormal laboratory values that may have an unclear relationship to investigational 
study drug. 
Reasons for temporary discontinuation may include the following: 
• Skin infection such as impetigo 

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• Participant experiences an AE that does not resolve promptly with supportive care and 
which is consistent with specific Common Terminology Criteria for AEs (CTCAE) 
current version, Grade 2 (may be used as guidance) 
• If a SARS-CoV-2 viral RNA test is indicated during this study, it should be done 
according to local standards and regulations. If initiated by the investigator the study 
central lab or local lab may be used for the SARS-CoV-2 viral RNA test. The study 
intervention should be discontinued until test results exclude an infection. The 
participant may resume study intervention at the discretion of the investigator. 
• Abnormal laboratory findings: (to monitor closely and if the abnormal results persist 
after a second assessment, participant must be temporarily discontinued from the study 
drug. (For permanent discontinuation criteria, see Section 7.1.) 
− WBC count < 2000 cells/µL; < 2.0 x 109/L 
− Absolute neutrophil count < 1000 cells/µL; < 1.0 x 109/L 
− Lymphocyte count < 500 cells/µL; < 0.5 x 109/L 
− Hemoglobin < 10.0 g/dL  
− ALT or AST > 3 x ULN after start of study intervention  
− ALT or AST value 2-fold increases above the lowest baseline value for 
participants with elevated liver enzymes before drug exposure. 
7.1.4 
Temporary Discontinuation and Restart of Study Medication  
Regarding potential resuming of interrupted study intervention, the following rules apply: 
• Discontinuation of up to 10 consecutive days: 
→ Resume study intervention intake as planned  
• Discontinuation for more than 10 consecutive days: 
→ Participant must permanently discontinue study intervention. 
7.2 
Participant Discontinuation/Withdrawal from the Study 
• A participant may withdraw from the study at any time at the participant’s own 
request, for any reason (or without providing any reason) 
• A participant may be withdrawn at any time at the discretion of the investigator for 
safety, behavioral, compliance, or administrative reasons.  
• At the time of discontinuing from the study, if possible, the EOT and FU visits should 
be conducted, as shown in the SoA (Section 1.3). See SoA for data to be collected at 
the time of study discontinuation (EOT) and FU and for any further evaluations that 
need to be completed. 
• The participant will be permanently discontinued both from the study intervention and 
from the study at that time. 
• If the participant withdraws consent for disclosure of future information, the sponsor 
may retain and continue to use any data collected before such a withdrawal of consent. 

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7.3 
Lost to Follow Up 
A participant will be considered lost to follow-up if the participant repeatedly fails to return 
for scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
• The site must attempt to contact the participant and reschedule the missed visit as soon 
as possible and counsel the participant on the importance of maintaining the assigned 
visit schedule and ascertain whether or not the participant wishes to and/or should 
continue in the study. 
• Before a participant is deemed lost to follow up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing address 
or local equivalent methods). These contact attempts should be documented in the 
participant’s medical record. 
• Should the participant continue to be unreachable, the participant will be considered to 
have withdrawn from the study. 
 
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 1 
(Section 10.1.1). 

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8 
Study Assessments and Procedures 
8.1 
Administrative and General Procedures  
• Study procedures and their timing are summarized in the SoA (Section 1.3). Protocol 
waivers or exemptions are not allowed. 
• Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study intervention. 
• Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
• All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log 
to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable.  
• Procedures conducted as part of the participant’s routine clinical management (e.g., 
blood count) and obtained before signing of the ICF may be utilized for screening or 
baseline purposes provided the procedures met the protocol-specified criteria and were 
performed within the time frame defined in the SoA. 
• Laboratory/analyte results that could unblind the study will not be reported to 
investigative sites or other blinded personnel until the study has been unblinded. 
• Patient-reported outcomes as listed in Section 8.2.2 will be provided in local language, 
and in the case of completion at the study site they should always be completed by the 
study participants prior to any activities at site. 
• In the event of a significant trial-continuity issue (e.g., caused by a pandemic), 
alternate strategies for participant visits, assessments, medication distribution and 
monitoring may be implemented by the sponsor or the investigator, as per local health 
authority / ethics requirements. 
The maximum amount of blood collected from each participant over the duration of the study, 
including any extra assessments that may be required, is not expected to exceed 180 mL. Repeat 
or unscheduled samples may be taken for safety reasons or for technical issues with the samples.  
Unscheduled visit(s)  
Participants who experience a suspected AD flare/relapse between scheduled study visits will 
return to the clinic for an unscheduled visit to determine if AD flare/relapse is confirmed  
Investigators should make every attempt to conduct efficacy and safety assessments 
immediately before administering any AD treatment prohibited in the study (see Section 
6.9.3) or rescue medication (see Section 6.9.2). An unscheduled visit may be used for this 
purpose, if necessary. 
 

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Screening (population characteristics) 
Demography 
Subject to local legislation, the following information will be collected for demography in the 
eCRF: Year of birth, age, sex, ethnicity and race. 
 
Medical history and AD history 
All relevant information on medical history including history of COVID infection(s), history 
of AD and associated comorbidities will be collected in the eCRF at screening. 
History of AD will include: Date of AD diagnosis, number of AD flares and episodes of skin 
infections requiring pharmacological treatment within the last year prior to screening, history 
of asthma, allergic rhinitis and allergic conjunctivitis.  
Any SARS-CoV-2 vaccination prior to study entry should be recorded independent of the 
timeframe under prior/concomitant medication. 
8.2 
Efficacy Assessments  
Efficacy will be assessed using clinical outcome assessments (COAs) including ClinROs and 
PROs, as well as objective methods. Planned time points for all efficacy assessments are 
provided in the SoA. 
A ClinRO is a measurement based on a report that comes from a trained health care 
professional after observation of a patient’s health condition. In this trial, ClinROs will be 
used for the assessment of primary, secondary and exploratory efficacy endpoints. It is 
recommended to have skin-related assessments performed by the same trained dermatologist 
or under his/her supervision. All investigators will be trained prior to the start of the study 
(see Section 8.2.1). 
 
ClinRO assessments include: 
• EASI 
• vIGA-AD 
• BSA affected by AD. 
A patient-reported outcome (PRO) is a measurement based on a report that comes directly 
from the patient about the status of the patient’s health condition without interpretation of the 
patient’s response by a clinician or anyone else. In this trial, language/country versions of the 
PROs will be used for the assessment of secondary and exploratory endpoints collected using 
an electronic patient handheld device during the entire study duration (including days of the 
study visits) without interaction with the investigator. 
  The PRO instrument used for assessments of efficacy is: 
• Peak Pruritus 0-10 NRS. 
An overview on the different measurements and the planned time points for all efficacy 
assessments is provided in the SoA (Section 1.3). 

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8.2.1 
Clinician-Reported Outcomes (ClinROs) 
Before the start of the study at the individual site, all investigators are or will be trained for 
the use of all clinician reported outcomes (ClinROs). During the study and in accordance with 
the SoA, the investigator will enter the results into an electronic device provided to the study 
site. 
All ClinROs can be considered “fit for purpose”. The responder definitions used for the 
efficacy endpoints in this study are robust. 
 
8.2.1.1 Eczema Area and Severity Index (EASI) 
The EASI is a ClinRO assessing the extent of AD at four body regions (head and neck, trunk 
and upper and lower extremities) by measuring the average severity of four clinical signs at 
each body region: (1) erythema, (2) induration/papulation, (3) excoriation, and (4) 
lichenification, each on a scale of 0 to 3 (Hanifin et al, 2001).  
For scoring, the sum of these severity scores for each region is multiplied by a region score, a 
value of between 0 and 6 representing the percentage of skin affected by eczema, and finally 
weighted by a body region dependent multiplier (0.1 for head/neck; 0.3 for trunk, 0.2 for 
upper extremities and 0.4 for lower extremities). This provides an EASI score per body 
region, with the final EASI score being the sum of the 4 region scores. The minimum EASI 
score is 0 and the maximum EASI score is 72, with a higher score indicating worse severity of 
AD. A scoring table can be found in Figure 10–1.  
The EASI 75 will be assessed as the primary efficacy endpoint.  
8.2.1.2 Validated Investigator’s Global Assessment for Atopic Dermatitis (vIGA-
AD) 
The vIGA-AD is a 1-item static ClinRO using a 5-point scale from 0 (clear) to 4 (severe) 
based on 4 clinical features of AD lesions: erythema, induration/papulation, lichenification, 
and oozing/crusting, and takes extent of disease into account (Simpson et al, 2020). A scoring 
table can be found in Figure 10–2.  
In this study, the vIGA-AD will be a secondary endpoint. 
8.2.1.3 Assessment of Body Surface Area (BSA) Affected by Atopic Dermatitis 
BSA affected by AD will be assessed for each section of the body, e.g. using the rule of nines. 
The possible highest score for each region is:  
Head and neck: 9%  
Anterior trunk: 18%  
Back: 
18%  
Upper limbs: 
18%  
Lower limbs: 36% 
Genitals: 
1%. 
Affected BSA will be reported as a percentage of all major body sections combined.  

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Overall, the BSA has shown appropriate measurement properties and is widely used in 
clinical practice and research. The BSA may provide important information about the AD 
severity and is considered appropriate for use to assess secondary efficacy endpoints in this 
study. 
8.2.2 
Patient-Reported Outcomes (PROs) – General Information 
In this clinical trial, efficacy on the most important symptom, itch will be assessed by the 
study participants themselves and is therefore considered a PRO.  
The Peak Pruritus 0-10 NRS will be collected daily in the morning if possible (collection is 
possible later in the day as well) on the electronic handheld device (ePRO) at home. 
The Peak Pruritus 0-10 NRS was developed by Yosipovitch et al, 2019 and is a single patient-
reported item designed to measure peak pruritus (itch), or ‘worst’ itch, over the previous 24 h 
based on the following question: ‘On a scale of 0 to 10, with 0 being “no itch” and 10 being 
“worst itch imaginable”, how would you rate your itch at the worst moment during the 
previous 24 hours?’(see Figure 10–3.) 
≥ 4 points reduction of the Peak Pruritus 0-10 NRS is considered a clinically relevant within-
person response. 
In this study, the Peak Pruritus 0-10 NRS will be assessed electronically every day during the 
entire study period in accordance with the SoA. 
This tool can be considered “fit for purpose”. The responder definitions used for the efficacy 
endpoints in this study are robust. 
Time for completion 
Time for completion of each item of the PRO is conservatively estimated with approximately 
30 seconds per individual item. The daily completion time at home, therefore, is 
approximately 30 seconds.  
Dispense of the patient handheld device, data entry and transmission 
During screening Visit 2, study participants will be provided with a training on the use of the 
patient handheld device. The participants will be asked to confirm their understanding on the 
use of the device and completion of the ePRO before the handheld device is activated and 
dispensed to the study participants at the screening Visit 2. 
The specific time window for data entry into the patient handheld device is ePRO-specifically 
technically regulated and alarms will be set as appropriate to remind the study participant to 
complete the ePRO respectively.  
Participants’ data entries from the patient handheld device will be transmitted by wireless 
connection to the electronic diary provider’s database and on systematic basis to Bayer AG. 
Automatic continuous checking of the data transfer will be performed, and completeness of 
diary entries will be monitored, so that a failure to make entries is detected by the data-
logging system and a warning will be sent to the study site. The ePRO device will be returned 
to the site as soon as a participant leaves the study. 

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Training of study participants 
Study participants will be educated during all study visits regarding the importance of their in-
time correct completion of the ePRO especially the daily completion. Standardized technical 
training for the use of the patient handheld device at screening Visit 2 and randomization visit 
and ongoing technical support during the entire study duration will be provided by the study 
site staff to prevent missing data entry to the extent possible. Beyond this technical support, 
no other help should be given to study participants regarding the completion of the 0-10 peak 
pruritus NRS  and the study participant will be instructed to complete the ePRO on their own.  
Training of and by study site staff, 24-hour help desk 
The study site staff will be instructed to explain to the study participants the importance of 
completing the ePRO on the patient handheld device. 
The study site staff will be trained regarding the use of the patient handheld device, and in 
resolving technical issues with the patient handheld device during the Investigator Meeting 
and site initiation process. Educational material will be available in the Investigator Site File. 
The study site staff will provide a standardized technical training on the handling of the 
patient handheld device to the study participants during screening visit 2 and will assist the 
study participants in case of any technical queries during the entire study duration. 
In addition to the technical support by the study site staff, a 24-hour help desk by the ePRO 
provider will be available during the entire study duration to respond urgent technical 
questions. 
Measures to further prevent missing patient handheld device entries 
When the study site becomes aware of missing patient handheld device entries, the study site 
staff will contact the study participant who has missed 2 consecutive daily entries as soon as 
possible and ask for reasons for failure in data entry and transfer. The study site staff will 
remind the study participants the importance of daily diary entry. 
Further to the automatic continuous checking of completeness of the patient handheld device 
entries, at all the study visits following screening Visit 2, the patient handheld device entries 
will be checked by the study site personnel for completeness. 
 
Assessment of efficacy 
In this study participants achieving a 4-point improvement in the Peak Pruritus 0-10 NRS for 
participants with Peak Pruritus 0-10 NRS ≥ 4 at baseline will be assessing a secondary 
efficacy endpoint. 
Further secondary and other pre-specified endpoints will be assessed using the Peak Pruritus 
0-10 NRS. 
Eligibility 
For decision on participants’ eligibility, the average of the Peak Pruritus assessed during the 7 
days immediately preceding randomization will be calculated. A minimum of 4 daily scores 
out of the 7 days is required to calculate this baseline score for the peak pruritus. For 
participants who do not have at least 4 daily scores reported during the 7 days immediately 

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preceding the planned randomization date, randomization should be postponed until this 
requirement is met, but without exceeding the 28-day maximum duration for screening. 
8.3 
Safety Assessments  
Planned time points for all safety assessments are provided in the SoA (Section 1.3).  
8.3.1 
Physical Examinations 
Physical examinations will be conducted according to the schedule provided in the SoA. 
• A complete physical examination will include, at a minimum, assessments of the 
cardiovascular, respiratory, gastrointestinal and neurological systems.  
• A symptom-directed physical examination will be performed according to the signs 
and/or symptoms reported by the participant; therefore, it may vary with each visit.   
Height will be documented at screening. Weight will be measured at the time points given in 
the SoA.  
Investigators should pay special attention to clinical signs related to previous serious illnesses. 
8.3.2 
Vital Signs 
Vital signs will be assessed according to the schedule provided in the SoA (see Section 1.3). 
Vital signs will be measured in a sitting position after 10 minutes rest and will include body 
temperature, systolic and diastolic blood pressure, and pulse rate.   
8.3.3 
Electrocardiograms 
Single 12-lead ECG will be obtained as outlined in the SoA (see Section 1.3) or as clinically 
indicated using an ECG machine that automatically measures the ECG mean ventricular rate, 
PR, QRS, QT, and QTc intervals. Refer to Section 7.1.2 for QTcB withdrawal criteria and any 
additional QTcB readings that may be necessary. 
ECG for each participant should be obtained using the same electrocardiograph machine 
whenever possible. To minimize variability, participants should remain in a resting position 
for at least 5-10 minutes prior to each ECG recording. 
Quality of ECGs should be assessed immediately and in case of improper quality of an ECG 
another ECG(s) should be recorded to replace the improper ECGs, which would be 
documented as invalid by the investigator.  
For each ECG, the investigator has to perform a thorough review that may result in ECG 
findings and an overall assessment (including clinical relevance) deviating from the 
automated device output.  
Each ECG will be evaluated for the overall normality as follows: 
• Normal 
• Abnormal, clinically insignificant 
• Abnormal, clinically significant.  
Only the results of this local review will be entered as findings into the electronic CRF and 
any clinically relevant abnormality should be documented as an AE or SAE. ECG findings 
observed before first study intervention intake that reflects any previous cardiovascular 

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disease (e.g., atrial fibrillation, previous myocardial infarction or any abnormality in the 
electrical conduction system) should be documented as medical history.  
ECG recordings will be kept as part of subjects file at the site as per site practice. 
8.3.4 
Clinical Safety Laboratory Tests 
• See Section 10.2 for the list of clinical laboratory tests to be performed and the SoA 
(Section 1.3) for the timing and frequency.  
Note: If screening laboratory assessments were done at Visit 1, only CRP, blood 
count, and urinalysis must be re-assessed at Visit 2.  
• The investigator must review the laboratory report, document this review, and record 
any clinically significant changes occurring during the study as an AE. The laboratory 
reports must be filed with the source documents.   
• Abnormal laboratory findings associated with the underlying disease are not 
considered clinically significant unless judged by the investigator to be more severe 
than expected for the participant's condition. 
• All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 28 days after the last dose of study intervention 
should be repeated until the values return to normal or baseline or are no longer 
considered clinically significant by the investigator or the medical monitor. 
− 
If clinically significant values do not return to normal/baseline within a period of 
time judged reasonable by the investigator, the etiology should be identified, and 
the sponsor notified. 
− 
All protocol-required laboratory tests, as defined in Section 10.2, must be 
conducted in accordance with the laboratory manual and the SoA.   
− 
If laboratory values from non-protocol-specified laboratory tests performed at the 
institution’s local laboratory require a change in participant management or are 
considered clinically significant by the investigator (e.g., SAE or AE or dose 
modification), then the results must be recorded. 
• Laboratory abnormalities leading to discontinuation of study intervention are listed in 
Section 7. 
8.3.5 
Pregnancy Testing 
The defined time points for pregnancy testing are displayed in the SoA (see Section 1.3). 
Zabedosertib was non-genotoxic. In addition, it did not show a phototoxic potential.  
In the developmental toxicity studies in mice, effects on fetuses were seen starting at the low 
dose with a higher incidence of cleft palates at the high dose. No effects were seen in the pilot 
and pivotal embryofetal development studies in rabbits up to the maximum feasible dose 
tested.  
A central laboratory (serum test) will be used for the pregnancy testing during screening 
(Visits 1 and 2) and at EOS for all WOCBP (Section 10.4). Further pregnancy tests (urine 
test) will be performed locally for all WOCBP at the time points in the SoA. 

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8.3.6 
Suicidal Ideation and Behavior Risk Monitoring 
Severe AD is associated with increased suicidality and suicidal ideations (Sandhu et al, 2019). 
Therefore, assessment of suicidal ideation and behavior will be monitored during the study by 
the investigators as part of the clinical routine in managing adult patients with moderate-to-
severe AD. 
8.4 
Adverse Events (AEs), Serious Adverse Events (SAEs) and Other Safety 
Reporting  
The definitions of adverse events (AEs) and serious adverse events (SAEs) can be found in 
Section 10.3. 
The definition of unsolicited and solicited AEs can be found in Section 10.3.1.  
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study intervention or study 
procedures, or that caused the participant to discontinue the study intervention (see Section 7). 
This includes events reported by the participant. 
AEs are considered to be treatment-emergent if they have started or worsened after first 
administration of study intervention until 7 days after the last intake of the study intervention. 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Section 10.3. 
8.4.1 
Time Period and Frequency for Collecting AE and SAE Information 
(S)AEs will be collected from the start of study intervention until the last FU visit (28 days 
after EOT) at the time points specified in the SoA (Section 1.3). (S)AEs which are related to 
protocol-required study procedures (e.g., (S)AE related to invasive study procedures) will be 
recorded as (S)AEs from the signing of the ICF. 
Any medical occurrences/conditions that begin in the period between signing ICF and the 
start of study intervention, and which are not related to a protocol-required study procedure, 
will be recorded as medical history/current medical conditions, not as AEs.  
All SAEs will be recorded and reported to the sponsor or designee immediately and under no 
circumstance should this exceed 24 hours, as indicated in Section 10.3. The investigator will 
submit any updated SAE data to the sponsor within 24 hours of it being available. 
Investigators are not obligated to actively seek AE or SAE after conclusion of the study 
participation. However, if the investigator learns of any SAE, including a death, at any time 
after a participant has been discharged from the study, and the investigator considers the event 
to be reasonably related to the study intervention or study participation, the investigator must 
promptly notify the sponsor.   
8.4.2 
Method of Detecting AEs and SAEs 
The method of recording, evaluating, and assessing causality of AE and SAE and the 
procedures for completing and transmitting SAE reports are provided in Section 10.3. 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
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8.4.3 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each partici-
pant at subsequent visits/contacts. All SAEs and AESIs (as defined in Section 8.4.8), will be 
followed until resolution, stabilization, the event is otherwise explained, or the participant is 
lost to follow-up (as defined in Section 7.3). Further information on follow-up procedures is 
provided in Section 10.3.   
8.4.4 
Regulatory Reporting Requirements for SAEs 
• Prompt notification by the investigator to the sponsor of an SAE is essential so that 
legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met.   
• The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB) / Independent Ethics Committees (IEC), and investigators. 
• An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (e.g., summary or listing of SAEs) from the sponsor will 
review and then file it along with the Investigator’s Brochure and will notify the 
IRB/IEC, if appropriate according to local requirements. 
• For all studies except those utilizing medical devices investigator safety reports must 
be prepared for suspected unexpected serious adverse reactions (SUSAR) according to 
local regulatory requirements and sponsor policy and forwarded to investigators as 
necessary. 
8.4.5 
Pregnancy 
• Details of all pregnancies in female participants and in female partners of male 
participants will be collected after the start of study intervention and until last safety 
FU visit, but at least until 2 weeks after the last dose of study intervention in case of 
early termination.   
• If a pregnancy is reported, the investigator will record pregnancy information on the 
appropriate form and submit it to the sponsor within 24 hours of learning of the 
pregnancy and should follow the procedures outlined in Section 10.4. 
• While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be 
reported as an AE or SAE. 
• Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs, and will be reported as 
such. 
• The participant/pregnant female partner will be followed to determine the outcome of 
the pregnancy. The investigator will collect follow-up information on the participant / 
pregnant female partner and the neonate and the information will be forwarded to the 
sponsor. 
• Any post-study pregnancy-related SAE considered reasonably related to the study 
intervention by the investigator will be reported to the sponsor as described in 

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Section 8.4.4. While the investigator is not obligated to actively seek this information 
in former study participants/pregnant female partner, the investigator may learn of an 
SAE through spontaneous reporting. 
• Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention. 
8.4.6 
Cardiovascular and Death Events 
BAY 1834845 and its metabolite M-5 (BAY 2822815) did not show activity at potential off-
targets and did not interact with cardiac ion channels (human ether-à-go-go-related gene 
[hERG], human sodium channel/current isoform 1.5 [hNav1.5], and human calcium 
channel/current isoform 1.2 [hCav1.2]). 
In-vivo, BAY 1834845 was devoid of acute adverse effects on vital organ functions in rats 
(central nervous and respiratory system), and in both Beagle dogs and Cynomolgus monkeys 
(hemodynamic and electrocardiogram parameters).  
In the FiM study (18384), no TEAEs were reported relating to changes in vital sign values nor 
to cardiac-related symptoms following treatment with zabedosertib.  
In the drug interaction study (18387, Part B), one subject had documented palpitations; there 
were no subjects with clinically significant ECG findings, and no further TEAEs were 
reported relating to changes in ECG values following treatment with zabedosertib. 
In the multiple dose study (18385), one subject had documented palpitations; there were no 
subjects with clinically significant ECG findings, and no further TEAEs were reported 
relating to changes in ECG values following treatment with zabedosertib. No new safety 
findings related to cardiovascular and death events were identified from Study 21329. 
8.4.7 
Disease-related Events and/or Disease-related Outcomes Not 
Qualifying as AEs or SAEs 
Not applicable. 
8.4.8 
Adverse Events of Special Interest  
Adverse events of special interest (AESIs) will include: 
• Confirmed or suspected severe invasive bacterial infections  
• Systemic hypersensitivity reactions 
• Non-invasive infections (skin)  
• Unexplained cases of rhabdomyolysis 
 
AESIs must be reported in an expedited fashion as described for SAEs in Section 10.3.4. 

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8.5 
Pharmacokinetics 
8.5.1 
PK measurements of zabedosertib and its metabolite M-5 
Sparse blood samples for PK analyses of zabedosertib and its metabolite BAY 2822815 (M-5) 
in plasma will be collected at the time points given in the study SoA (Section 1.3). Details 
about the collection, processing, storage and shipment of samples for PK analyses will be 
provided separately (e.g., sample handling sheets or laboratory manual) and available at the 
Investigator Site File. 
The PK analyses will be performed using validated analytical methods. Quality Control (QC) 
and calibration samples will be analyzed concurrently with study samples. The results of 
calibration samples and QC samples will be reported in the Bioanalytical Report, which will 
be included in the Clinical Study Report for this study. Concentrations are calculated from the 
chromatographic raw data in accordance with current Bayer guidelines. 
The PK evaluation, if applicable, will be based on the actual sampling and dosing times.  
Blood samples will be considered valid for the population PK analysis (see below) under the 
following conditions: 
1. The dose amount and time of drug intake prior to the blood sample is known 
2. The time of the blood sample collection is known 
Therefore, it is important to have these data thoroughly documented in the CRF. Deviations 
from the specified time points are possible and should not be considered as protocol viola-
tions. Exact collection dates and times of the PK samples and the times of the evening and 
morning doses of the previous day as well as the time of the morning dose on the visit day 
must be documented. In addition, to reassure PK results drug measurements may be 
performed from samples taken for other laboratory investigations (e.g., safety lab). The results 
of those measurements will be reported internally in the PK study file. 
No non-compartmental analysis assessment will be performed. Measured concentrations will 
be listed and presented by descriptive statistics. 
Drug concentration information that would unblind the study will not be reported to 
investigative sites or blinded personnel. The bioanalyst will remain unblinded for analysis of 
study samples. 
8.5.2 
Population pharmacokinetic (popPK) evaluation  
The variability in the pharmacokinetics of zabedosertib (and optionally its metabolite 
BAY 2822815), drug-related pharmacodynamic (PD) biomarker and/or safety and efficacy 
measurements collected during the trial might be analyzed using nonlinear mixed effects 
modeling. 
Mixed effects models, e.g. population pharmacokinetic (popPK) models, describe the 
relationship between dose and time and variables such as drug plasma concentrations or 
clinical response. Both structural and random effects are involved in this relationship. A 
previously developed population PK model based on phase-1 data will be further developed 
to evaluate the variability in PK based on intrinsic factors (e.g., body weight, race) and 
extrinsic factors (e.g., concomitant medication) (covariates) that are of clinical relevance. If 
applicable, a separate Modeling and Simulation (M&S) analysis plan, providing details of the 

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model development and evaluation will be provided prior to the beginning of the population 
PK analysis and results will be presented in a separate M&S Report. 
The population PK analysis might start prior to database lock. If this is applicable, appropriate 
measures will be taken to maintain blinding of the study team, e.g. data will be stored 
separately, and members of the study team will neither have access to the randomization list 
nor to individual data. 
PK/PD and/or exposure-response evaluations might be conducted to evaluate the relationship 
between zabedosertib pharmacokinetics and or exposure and specific PD and/or safety and/or 
efficacy measures. If applicable, a separate M&S analysis plan, providing details of the 
methodology and evaluation will be provided prior to the beginning of the PK/PD and/or 
exposure-response analysis/ analyses and the results will be presented in a separate M&S 
Report(s). 
The PK/PD and/or exposure-response evaluations might start prior to database lock. If this is 
applicable, appropriate measures will be taken to maintain blinding of the study team, e.g. 
data will be stored separately, and members of the study team will neither have access to the 
randomization list nor to individual data. 
8.6 
Pharmacodynamics 
None. 
8.7 
Genetics 
In this study, no genetic sampling will be performed. 
8.8 
Biomarkers 
In this study, genetic as well as non-genetic biomarkers will be investigated. 
Table 8–1: Sample types for biomarkers 
Skin biopsy substudy (formalin fixation) 
Skin sample 1 
IHC (protein expression) 
Skin biopsy substudy (RNA fixation) 
Skin sample 2 
mRNA expression 
BM plasma 
Blood sample 1 
Inflammatory markers / other 
exploratory BMs 
BM whole blood 
Blood sample 2 
e.g. Kinase activity 
BM = biomarker; (m)RNA = (messenger) ribonucleic acid; IHC = immunohistochemistry 
 
• Timing – see SoA (Section 1.3) for planned time points of sample collection. 
• Sample handling and storage – details on the collection, processing, shipment and 
storage of samples will be provided in separate documents (e.g., lab manual). Samples 
may be stored for a maximum of 15 years (or according to local regulations) following 
the end of the study at a facility selected by the sponsor to enable further analyses. 
• Medical history information – if any additional information about the status of disease 
was collected in the course of treatment prior to entry of the participant in the study, 
the results may be collected in order to include this data in biomarker analyses. 

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• Reporting – the results of biomarker investigations may be reported separately (e.g, 
gene expression analysis of skin biopsies in a biomarker evaluation report). 
 
An exploratory biomarker (BM) analysis will be conducted in this study. The sample types 
are summarized in Table 8–1. 
 
Skin biopsy samples will be collected from a subgroup of participants willing to participate in 
this substudy, independent of the study intervention (n = approximately 40) at time points 
defined in the SoA. See Section 10.5.  
8.8.1 
Biomarkers Monitoring Disease Activity 
AD is the most common, complex chronic inflammatory skin disease. PD biomarkers will be 
evaluated in samples collected before and during treatment in order to determine the impact of 
the study intervention on these biomarkers. 
Candidate PD biomarkers may give hints to drug efficacy and may include (but are not 
limited to) for example: 
− Skin biopsies:  Molecular analysis (gene expression (customized host response panel 
[NanoString] with addtl. AD-specific probes);  immunohistochemistry (eg K16, Ki 
67), optional analysis) of the lesional skin biopsies will be performed. in a substudy (n 
= approximately 40 planned). See Section 10.5. 
− Blood: Plasma levels of inflammatory markers and kinase activity (optional analysis).  
In addition, a blood sample may be subjected to a further inflammatory BM analysis in order 
to identify biomarkers which respond to treatment or biomarkers which may indicate disease 
progression (optional analysis). 
8.8.2 
Other Biomarkers 
BMs related to the mode of action or the safety of zabedosertib may be examined in addition 
to the BMs described above. 
Further BMs deemed relevant to atopic dermatitis or other inflammatory diseases of the skin 
and associated health problems may be examined in addition to the BMs described above. 
Those investigations may include, e.g. diagnostic, safety, PD, monitoring, or potentially 
predictive BMs. 
8.9 
Immunogenicity Assessments 
See Section 8.4.8.  
8.10 
Health Economics 
Health economics parameters are not evaluated in this study. 

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8.11 
Other Procedures 
Photographs of a representative area of AD involvement (e.g., the lesioned area used for EASI 
assessments) may be taken on an individual basis at selected sites (optional procedure) to 
exemplary document the course of disease during the study. The photographs taken in this 
study are primarily planned to be used for publication purposes. The sponsor will check the 
quality of the received image data. Instructions for taking the photographs (for timepoints, see 
SoA in Section 1.3) will be provided and available in a specific manual.  
9 
Statistical Considerations  
The analysis and reporting will be done on all data from all participants at the time the study 
ends. 
The statistical analysis plan will be finalized prior to unblinding and it will include a more 
technical and detailed description of the statistical analyses described in this section. This 
section is a summary of the planned statistical analyses of the most important endpoints 
including primary and key secondary endpoints. 
9.1 
Statistical Hypothesis 
The primary efficacy endpoint is achievement of 75% reduction from baseline in the EASI 
(EASI 75 response) at Week 12 (Day 84, EOT).  
Let πBAY and πPlac be the responder rate with respect to EASI 75 after zabedosertib and 
placebo, respectively. 
The statistical hypothesis of the study is defined as follows: 
πBAY > πPlac      (‘clinical activity’ criterion), 
      
i.e. that the EASI 75 responder rate after treatment with zabedosertib is higher than 
after placebo. 
The study will be evaluated using Bayesian statistics, which allows to determine the posterior 
probability in favor of a hypothesis. Therefore it is not needed to specify a pair of hypotheses. 
The statistical hypothesis will be considered accepted if the posterior probability for the 
hypothesis of interest is higher than 90%. 

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9.2 
Analysis Sets 
The analysis sets are defined in Table 9–1. 
 
Table 9–1: Analysis sets 
Analysis set 
Description 
Enrolled 
All participants who signed the ICF. 
All Randomized  
(RAND) 
All participants randomly assigned to study intervention  
Participants will be analyzed according to the intervention they were randomized to. 
Safety analysis set 
(SAF) 
All participants who took at least 1 dose of study intervention.  
Participants will be analyzed according to the intervention they actually received. 
Per protocol set (PPS) All randomized participants who meet the following criteria: 
− have an EASI score at baseline 
− have an EASI score at Day 56 (Visit 6) or later  
or took rescue medication between Day 56 (Visit 6) and Day 84 (Visit 7) or took 
SoC 
or discontinued study intervention due to lack of efficacy (at any time) 
− showed compliance of at least 80% with study intervention between start of 
treatment and end of treatment or start of rescue medication at or after Day 56 
(Visit 6), whatever comes first 
− showed compliance of at least 80% with study intervention during the last 4 weeks 
before end of treatment or start of rescue medication at or after Day 56 (Visit 6), 
whatever comes first. 
−  are without validity findings with respect to the efficacy related entry criteria 
Participants will be analyzed according to the treatment they actually received. 
Pharmacokinetic set  
(PKS) 
All participants who 
− were treated with zabedosertib, 
− have at least 1 valid zabedosertib plasma concentration sample, 
− are without protocol deviations, which would interfere with the evaluation of the 
PK data. 
See Section 8.5.1 for PK details 
 
 
Details on additional analysis sets which may be of interest will be provided in the SAP.  
The assignment of participants to the analysis sets will be decided before unblinding. 
9.3 
Statistical Analyses 
The SAP will be finalized prior to unblinding (the final SAP is prerequisite for Blind Review 
Meeting), and it will include a more technical and detailed description of the statistical 
analyses described in this section. This section is a summary of the planned statistical 
analyses of the most important endpoints including primary and specific secondary endpoints. 
If not otherwise indicated, the statistical analyses will be performed using the Statistical 
Analysis System (SAS); the version used will be specified in the SAP. 
9.3.1 
General Considerations 
Continuous variables assumed to be normally distributed will be summarized using number of 
participants, mean, standard deviation, minimum, median, and maximum. Continuous 
variables assumed to be log-normally distributed will be summarized using number of 
participants, geometric mean, geometric standard deviation, geometric coefficient of 
variation, arithmetic mean, arithmetic standard deviation, arithmetic coefficient of variation, 
minimum, median, and maximum. 

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For categorical data frequency tables will be provided. 
In general, summary statistics and frequency tables will be presented by treatment group, visit 
and time point (if applicable). Plots over time (if applicable) will also be presented by 
treatment group. 
9.3.2 
Efficacy Analyses 
The primary efficacy analysis will be performed on the PPS. 
9.3.2.1 Primary Efficacy Endpoint 
The primary efficacy endpoint is achievement of 75% reduction from baseline in the Eczema 
Area and Severity Index (EASI 75 response) at Week 12 (Day 84). The EASI score ranges 
from 0 to 72. The lower the EASI score the better the state of the participant with respect to 
severity and extent of AD symptoms.  
The analysis of the primary efficacy endpoint on the PPS will be performed as follows: 
The impact of a potential use of rescue medication (TCSs or TCIs) or SoC for treatment of 
AD on the efficacy effect will be accounted for as follows: 
If rescue medication is used between Day 56 (Visit 6) and Day 84 (Visit 7) or if SoC is used 
(at any time), the participant will be specified as a non-responder with respect to the EASI 75 
response from the time the rescue medication or SoC medication is used. 
If a participant discontinues study intervention due to lack of efficacy at any time (e.g., due to 
an adverse event related to AD such as disease flare), the participant will also be specified as 
a non-responder with respect to EASI 75 response from the time of the discontinuation.  
Otherwise, missing data - e.g. due to study intervention discontinuation due to other reasons 
such as reasons related to Covid-19 pandemic (individual reasons or prevention/logistic 
measures), withdrawal of consent not due to lack of efficacy or adverse events not related to 
AD - will be imputed using a multiple imputation approach based on logistic regression 
model. Details will be specified in the SAP. Furthermore, alternative imputation methods 
might also be specified in SAP. 
The following supplementary analyses will be performed to further assess rescue medication 
use. The study participant is considered a non-responder in case of rescue medication use 
between the EOT visit and 
− baseline 
− 1 week after baseline, 
− 2 weeks after baseline, 
− 4 weeks after baseline, 
− 6 weeks after baseline. 
One additional analysis will be performed where rescue medication does not trigger the 
classification as non-responder at all to assess the effect of combined treatment of 
zabedosertib with topical AD medication. 
Participants who take SoC medication or who discontinue study intervention due to lack of 
efficacy will still be counted as a non-responder for the time points after SoC use or 
discontinuation of study intervention due to lack of efficacy as described above.   

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Bayesian inference will be used to quantify the EASI 75 responder rates on Day 84 in the 
zabedosertib and placebo treatment group. For each treatment group a non-informative 
Beta(1,1) prior will be used. The Beta(1,1) prior produces a posterior distribution in the same 
distribution family, namely Beta(k+1,n-k+1) with k being the number of EASI 75 responders 
in the respective treatment group and n being the number of all participants in the respective 
treatment group. Simulations based on the posterior distributions of the EASI 75 response rate 
in both treatment groups will then be used to calculate the posterior probability P(πBAY > πPlac 
| data). In addition, median and 90% and 95% credible intervals will be calculated based on 
the posterior distributions for the response rates in both treatment groups as well as for the 
difference between both treatment groups. 
9.3.2.2 Secondary Efficacy Endpoints 
For binary endpoints, the secondary efficacy analysis will use the same approach as for the 
primary analysis. 
In detail, the proportion of participants reaching EASI 50 response at Week 12 (Day 84) will 
be analyzed. An EASI 50 response is defined as achievement of 50% reduction from baseline 
in the Eczema Area and Severity Index.  
Likewise, the proportion of participants reaching EASI 90 response at Week 12 (Day 84) will 
be analyzed. An EASI 90 response is defined as achievement of 90% reduction from baseline 
in the Eczema Area and Severity Index.   
Furthermore, the proportion of participants with a response with respect to vIGA-AD at Week 
12 (Day 84) will be analyzed. A vIGA-AD response refers to achievement of a vIGA-AD of 0 
or 1 with at least a 2-grade reduction from baseline (vIGA-AD scale ranges from 0-4). 
In addition, the proportion of participants with a response with respect to the average of the 
Peak Pruritus 0-10 NRS at Week 12 (Day 84) will be analyzed. A response with respect to 
peak pruritus will be defined as achievement of a ≥4 point improvement (reduction) in the 
weekly average of the Peak Pruritus 0-10 NRS score from baseline (for participants with Peak 
Pruritus 0-10 NRS score ≥ 4 at baseline) (Phan et al, 2012).  
For continuous endpoints, i.e. percent change from baseline in EASI score, absolute change 
from baseline in BSA as well as percent change from baseline in the weekly average of the 
Peak Pruritus 0-10 NRS score , the impact of a potential use of rescue treatment or SoC for 
treatment of AD on the efficacy will be accounted for as follows: 
If rescue medication is used between Day 56 (Visit 6) and Day 84 (Visit 7) or if SoC is used 
(at any time) or study drug is discontinued due to lack of efficacy (at any time), data collected 
afterwards will be handled as missing.   
Missing data will be imputed using a multiple imputation approach followed by an analysis of 
covariance model. Further approaches for imputation might be defined in the SAP. 
A mixed-effect repeated measurement model will be applied. This model will include the 
respective continuous efficacy endpoint as dependent variable. All post-dose data will be 
included in the model. The model will include the respective baseline value as covariate, 
treatment group, visit and the interaction of visit and treatment group (visit*treatment group) 
as fixed effects. The covariance structure will be assumed to be unstructured, but the same for 
both treatment groups. The structure of the covariance matrix might be adapted, e.g. in case of 
convergence problems. The treatment difference (including 95% confidence intervals) at the 

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planned end of treatment at Day 84 (Visit 7), as well as at the other time points, will be 
calculated by appropriate contrasts from the mixed-effect repeated measurement model. 
9.3.3 
Safety Analyses 
All safety analyses will be performed on the SAF. 
9.3.3.1 Secondary Endpoint - Safety 
The secondary safety endpoint is the frequency and severity of TEAEs.  
TEAEs are events that start after the first treatment with the study intervention and until 7 
days after the last intake of study intervention. All TEAEs will be listed. 
An overview table will be given presenting the frequencies and percentage of all participants 
with at least one TEAE by intensity, relationship to study intervention and seriousness, at 
least one TEAE leading to discontinuation of study intervention, and at least one TEAE of 
special interest. 
The frequencies of participants with TEAEs will be summarized using MedDRA terms 
grouped by SOC and PT. Furthermore, the frequencies of participants with TEAEs will be 
summarized by intensity and by relationship to study intervention. In addition, the frequencies 
of participants with related TEAEs will be summarized by intensity.   
Death, TESAEs, TEAESIs or TEAEs leading to discontinuation of study intervention will be 
listed separately and frequencies will be summarized, if applicable. 
9.3.3.2 Other Safety Endpoints 
Laboratory values, ECG parameters and vital signs will be summarized descriptively by 
parameter including changes from baseline. Arithmetic mean plots including standard 
deviation over time will be presented. 
For laboratory values shift tables will be provided (by time point including any time point) 
focusing on the frequency and percentage of participants with shifts from within normal range 
(or below normal range) at baseline to above normal range post-baseline and from within 
normal range (or above normal range) at baseline to below normal range post-baseline. 
Courses of laboratory values out of normal range at least at one time point will be listed by 
parameter and treatment group (abnormal values will be flagged with ‘H’ for high and ‘L’ for 
low). 
A frequency table will be provided for ECG findings (by time point including any time point). 
9.3.4 
Pharmacokinetic Analyses 
Analysis of PK data will be reported in a separate M&S report, if applicable. However, the 
following statistics will be reported for plasma concentrations of zabedosertib at each visit 
(and time point if applicable): geometric mean, geometric standard deviation (re-transformed 
standard deviation of the logarithms) and geometric coefficient of variation (CV), arithmetic 
mean, standard deviation and CV, minimum, median, maximum value and the number of 
measurements as well as the number of measurements ≥ limit of quantification (LLOQ). 
Means at any visit will only be calculated if at least 2/3 of the individual data were measured 
and were above LLOQ. For the calculation of the mean value a data point below LLOQ will 
be substituted by one half of this limit. In tables showing mean values, where values below 
LLOQ are included in the calculation of mean values, these means will be marked. 

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9.3.5 
Exploratory/Other Endpoint(s) 
Exploratory endpoints will be analyzed using descriptive statistics and frequency tables. 
Details will be provided in the SAP. 
9.3.6 
Other Analyses 
Other exploratory analyses may include the analyses of  
• Correlation of efficacy data with weather and environmental data derived from 
outside this study setting. 
o It is considered to correlate disease activity parameters as assessed using 
the EASI, vIGA-AD, BSA affected by AD and Peak Pruitus 0-10 NRS 
with weather and environmental data derived from local weather stations 
(e.g., high pollen counts or specific weather situations such as dry/hot 
weather) on an exploratory basis. Results of this exploratory analysis, 
which will be stored and assessed in an external database, will be reported 
under a separate cover. 
9.4 
Interim Analysis 
An interim analysis may be performed using the data of all study participants having either 
regularly completed or prematurely discontinued study intervention at a certain cutoff date, 
when a minimum of 80% of patients are evaluable. The eligibility of the respective study 
participants for the analysis sets will be checked and documented before unblinding for the 
interim analysis. Study intervention of participants not having completed the intervention 
period by the time of the interim analysis will not be unblinded. Access to the treatment codes 
of the participants included in the interim analysis prior to final database release will be 
restricted to an unblinded team, whereas the rest of the team remains blinded. No individual 
data of the interim analysis will be disclosed to the blinded study team responsible for further 
study conduct. Details of the measures to restrict access to unblinding data will be described 
in detail in a dedicated study blinding plan. The further study conduct or study design will not 
be affected by the results of the interim analysis. The final evaluation of study results will be 
performed as described in Section 9.4 and SAP.  
Additionally, a blinded monitoring of sample size assumptions using methodology described 
in Friede et al, 2004 may be applied. 
9.5 
Sample Size Determination  
A Bayesian concept will be used for inference, which is based on the posterior probability that 
the research hypothesis is true. Therefore, it is the goal of this study to demonstrate that 
zabedosertib is superior to placebo with posterior probability > 90%, i.e. P(πBAY > πPlac | data) 
> 90% (=’clinical activity’ criterion).   
 
The EASI 75 responder rate of 0.49 for assumed systemic standard of care (SoC) dupilumab 
was derived as the mean responder rate from a meta-analysis on the active treatment arms in 
two Phase 3 AD studies (Simpson et al, 2017), comprising 919 participants. 
Non-informative Beta(1,1) priors will be used for the Bayesian inference.  
For Placebo, a response rate of 16% was assumed. The statistical power was determined with 
SAS 9.4. 

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Assuming that the EASI 75 responder rate in zabedosertib-treated participants is 0.49, 
evaluable data from 57 participants (38 on zabedosertib, 19 on placebo) will provide at least 
90% power to establish superiority of zabedosertib. Approximately 72 participants will be 
randomly assigned to the study to obtain 57 evaluable participants overall (2:1 randomization 
zabedosertib versus placebo). 
 
 

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10 Supporting documentation and operational considerations 
10.1.1 
Appendix 1: Regulatory, ethical, and study oversight considerations  
10.1.2 
Regulatory and ethical considerations 
• This study will be conducted in accordance with the protocol and with the following: 
− Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
− Applicable ICH Good Clinical Practice (GCP) Guidelines 
− Applicable laws and regulations. 
• The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (e.g., advertisements) must be submitted,  reviewed and approved in 
accordance with national legislation and undergo scientific and ethical assessment 
before the study is initiated.   
• Any substantial amendments to the protocol will require IRB/IEC approval before 
implementation of changes made to the study design, except for changes necessary to 
eliminate an immediate hazard to study participants. Any substantial modification of the 
protocol will be submitted to the competent authorities as substantial amendments for 
approval, in accordance with ICH Good Clinical Practice and national and international 
regulations. 
• Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation except for changes necessary to eliminate an immediate 
hazard to study participants. 
• The investigator will be responsible for the following, as applicable: 
− Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
− Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
− Providing oversight of the conduct of the study at the site and adherence to 
requirements of ICH guidelines, the IRB/IEC, European regulation 536/2014 for 
clinical studies (if applicable), and all other applicable local regulations. 
10.1.3 
Financial disclosure 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study. 

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10.1.4 
Informed consent process 
Detailed description of the recruitment strategy will be provided in country-specific 
documentation as required. 
 
• The investigator or his/her representative will explain the nature of the study to the 
participant and answer all questions regarding the study.   
• Potential Participants must be informed that their participation is voluntary. They will 
be required to sign a statement of informed consent that meets the requirements of 21 
CFR 50, local regulations, ICH guidelines, Health Insurance Portability and 
Accountability Act (HIPAA) requirements, where applicable, and the IRB/IEC or study 
center.   
• The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written consent 
was obtained. The authorized person obtaining the informed consent must also sign the 
ICF. 
• Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study. 
• Participants of skin biopsy sub-study will need to separately consent to participation. 
• Participants providing photographs will need to separately consent to procedure. 
• A copy of the ICF(s) must be provided to the participant. 
• Participants who are rescreened are required to sign a new ICF(s). 
The ICF will contain a separate section that addresses the use of remaining mandatory 
samples for optional exploratory research. The investigator or authorized designee will 
explain to each participant the objectives of the exploratory research. Participants will be told 
that they are free to refuse to participate and may withdraw their consent at any time and for 
any reason during the storage period. A separate signature will be required to document a 
participant's agreement to allow any remaining specimens to be used for exploratory research. 
Participants who decline to participate in this optional research will not provide this separate 
signature. 
10.1.5 
Recruitment strategy 
Not applicable. 
10.1.6 
Data protection 
• Participants will be assigned a unique identifier by the sponsor. Any participant records, 
datasets or biological samples that are transferred to the sponsor will contain the identifier 
only; participant names or any information which would make the participant identifiable 
will not be transferred to the sponsor.   
• The participants must be informed that they personal study-related data will be used by 
the sponsor in accordance with local data protection law. The level of disclosure must 

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also be explained to the participant who will be required to give consent for their data to 
be used as described in the informed consent  
• The participants must be informed that they medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
10.1.7 
Committees structure  
Not applicable. 
10.1.8 
Dissemination of clinical study data 
Bayer fulfills its commitment to publicly disclose study results through posting the result of 
the studies on public registries in accordance with applicable law and regulations. 
Result Summaries of Bayer's sponsored clinical trials in drug development phases II, III and 
IV and Phase I studies in patients are provided in the Bayer Trial Finder application after 
marketing authorization approval in line with the position of the global pharmaceutical 
industry associations laid down in the "Joint Position on the Disclosure of Clinical Trial 
Information via Clinical Trial Registries and Databases". In addition results of clinical drug 
trials will be provided on the publicly funded website www.ClinicalTrials.gov and EU 
Clinical Trials Register in line with the applicable regulations. 
In accordance with the current EU regulation, result summaries will be submitted within one 
year from the end of the studies in adult populations or within 6 months for studies in 
pediatric population, in all participating countries. No preliminary data analysis (eg, on EU 
data only) will be performed, as this might compromise data integrity and the scientific 
validity of the study. Bayer commits to sharing upon request from qualified scientific and 
medical researchers patient-level clinical trial data, study-level clinical trial data, and 
protocols from clinical trials in patients for medicines and indications approved in the United 
States (US) and European Union (EU) on or after January 01, 2014 as necessary for 
conducting legitimate research. 
All Bayer-sponsored clinical trials are considered for publication in the scientific literature 
irrespective of whether the results of the clinical trials are positive or negative. 

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10.1.9 
Data quality assurance 
• All participant data relating to the study will be recorded on printed or electronic CRF 
and eCOA provider database unless transmitted to the sponsor or designee 
electronically (e.g., laboratory data). The investigator is responsible for verifying that 
data entries are accurate and correct by physically or electronically signing the CRF.   
• Guidance on completion of CRFs will be provided in the CRF Completion Guidelines.  
• The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.   
• Monitoring details describing strategy (e.g., risk-based initiatives in operations and 
quality such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site 
monitoring) are provided in the Monitoring Plan. 
• The sponsor or designee is responsible for the data management of this study including 
quality checking of the data.   
• The sponsor assumes accountability for actions delegated to other individuals 
(e.g., Contract Research Organizations). 
• Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator for 15 years after study completion unless local 
regulations or institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the sponsor. No 
records may be transferred to another location or party without written notification to 
the sponsor.   
10.1.10 
Source documents 
• Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the investigator’s site. 
• Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available. 
• Definition of what constitutes source data can be found in Investigator Site File. 
• The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.   
• The following data will be the source and no additional source documentation will be 
available. These data are not needed for the participant’s routine medical care. 
− Race (will be entered directly into the eCRF) 
− ECG data 
− ePRO data (study drug exposure data excluded) 
− ClinRO data 
− IRT (site-specific source identification list is maintained at the Investigator Site File) 
− Central laboratory data 

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10.1.11 
Study and site start and closure 
Study Start 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. The first act of recruitment is the first site open and will be the study start date. 
Study/Site Termination 
The sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to: 
For study termination: 
• Discontinuation of further study intervention development 
 
For site termination: 
• Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the sponsor's procedures, or GCP guidelines 
• Inadequate or no recruitment (evaluated after a reasonable amount of time) of 
participants by the investigator 
• Total number of participants included earlier than expected. 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified by 
the applicable regulatory requirements. The Investigator shall promptly inform the participant 
and should assure appropriate therapy and/or follow-up. 
10.1.12 
Publication policy 
• The results of this study may be published or presented at scientific meetings by the 
sponsor. If this is foreseen by the investigator, the investigator agrees to submit all 
manuscripts or abstracts to the sponsor before submission. This allows the sponsor to 
protect proprietary information and to provide comments.  
• The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally 
support publication of multicenter studies only in their entirety and not as individual site 
data. In this case, a coordinating investigator will be designated by mutual agreement. 
• Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 

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10.2 
Appendix 2: Clinical laboratory tests 
• The tests detailed in Table 10–1 will be performed by the central laboratory (exception: 
dipstick urinalysis and  pregnancy tests in urine ). Detailed information about the 
collection, processing, storage and shipment of the samples will be provided separately 
in a laboratory manual. 
• Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol. 
• Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations. 
• Pregnancy testing will be performed as detailed in Table 10–1. 
 
Investigators must document their review of each laboratory safety report. 

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Table 10–1: Protocol-required safety laboratory assessments at visits V1 (screening), V3 
(randomization), V 4 (Day 14), V5 (Day 28), V6 (Day 56), V7 (Day 84) and EOS (Day 112) 
Hematology 
White blood cell (WBC) count with 
differential 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
 
Platelet count 
 
 
Red blood cell (RBC) count 
 
 
RBC indices: Mean corpuscular volume (MCV) 
Mean corpuscular hemoglobin (MCH) 
%Reticulocytes 
 
Hemoglobin 
 
 
Hematocrit 
 
 
Coagulation 
Prothrombin time (Quick) 
Activated partial thromboplastin time (aPTT) 
Fibrinogen 
International normalized ratio (INR) 
Clinical chemistry1 
 
Blood urea nitrogen (BUN) 
Glucose (non-fasting or fasting) - only at screening and end of treatment 
Creatinine  
Urea  
Uric acid  
Total protein  
Albumin  
Alpha-acid glycoprotein (AGP) 
High sensitivity C reactive protein (hsCRP) 
Creatine kinase (CK)2 
 
Electrolytes 
• 
Sodium  
• 
Potassium  
• 
Calcium  
• 
Chloride  
 
Liver tests 
• 
Total bilirubin  
• 
Direct bilirubin  
• 
Aspartate aminotransferase (AST/SGOT)  
• 
Alanine aminotransferase (ALT/SGPT)  
• 
Gamma-glutamyl transferase (GGT)  
• 
Alkaline phosphatase (AP)  
• 
Lactate dehydrogenase (LDH) 
 
Lipid profile (fasting4) - only 
at randomization and end 
of treatment 
• 
Low-density lipoprotein (LDL)  
• 
High-density lipoprotein (HDL)  
• 
Total Cholesterol  
• 
Triglycerides (TGL) 
Routine urinalysis  Dipstick test (local) 
Urinalysis) 
pH, glucose, protein, blood, ketones, leukocytes, nitrite 
Urinalysis including myoglobin and sediment, only if CK elevation > 
5 x ULN was confirmed and other causes such as physical 
exercise are excluded (central lab preferred) 
 
Microscopic examination at central laboratory (only if blood or protein is abnormal in dipstick test) 
Pregnancy test 
Urine and serum hCG pregnancy test (as needed for women of childbearing potential) 3 
Other tests 
At screening or 
randomization (if screening 
is not available) and EOT: 
 
Total immunoglobulin E (IgE) 
At screening and EOT:  
Estimated glomerular filtration rate (eGFR; MDRD formula) 
Only at screening: 
Hepatitis B: Hepatitis B surface antigen (HBsAg), Anti-Hepatitis 
B core antibody (HBcAb), Hepatitis B surface antibody 
(HBsAb) 
Hepatitis C: (Hep C antibody)  
Human immunodeficiency virus (HIV) 1 and 2 
Tuberculosis test (QuantiFERON GOLD Plus test) 
At visit 2 and if clinically 
indicated: 
SARS-CoV-2 RNA test (real time-PCR, test specimen 
according to test recommendation)  
For footnotes, see next page. 

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Footnotes to Table 10–1 
1  Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping or monitoring 
event are given in Section 7. All events of ALT  3 × upper limit of normal (ULN) and bilirubin  2 × ULN (> 35% direct 
bilirubin) or ALT  3 × ULN and international normalized ratio (INR) > 1.5, if INR measured which may indicate severe liver 
injury (possible Hy’s Law), must be reported as an SAE (excluding studies of hepatic impairment or cirrhosis). 
2 Lab follow up includes: 
− 
Serum: CK (incl. isoforms), creatinine, urea nitrogen, uric acid and calcium, potassium, phosphate, 
Prothrombin time (PT) 
− 
Urine: urinalysis incl. myoglobin and sediment. 
3  Local urine testing (pregnancy test and dipstick urinalysis) will be standard for the protocol unless serum testing is indicated 
by the SoA or required by local regulation or IRB/IEC. 
4 If the participant arrives in a non-fasting state, the blood sample should be obtained and indicated in the CRF as non-fasting. 
 
10.2.1 Guidance for management of muscle symptoms and CK elevations 
If confirmed CK elevation > 5 fold ULN and other causes such as exercise are excluded, lab 
follow up and management according to the guidance for management of muscle symptoms 
and CK elevations as described in this section should be followed. 
• Lab follow up (central lab analysis preferred) includes: 
− Serum: CK (incl. isoforms), creatinine,  urea nitrogen, uric acid and 
calcium, potassium, phosphate, Prothrombin time (PT), thyroid 
stimulating hormone (TSH) 
− Urine: urinalysis incl. myoglobin and sediment. 
 
• Throughout the study, subjects should be instructed to promptly report unexplained 
muscle pain or weakness, particularly if associated with malaise or fever. If this occurs, 
CK should be measured as soon as possible. 
• If CK is found to be elevated ≥ 5 x ULN on routine testing, the subject should be 
questioned about muscle symptoms and re-tested within 3 days. 
• A suitably-experienced physician should be involved in deciding appropriate 
management for the subject. The physician should be alerted to the occurrence of 
unexplained muscle symptoms, and any CK values ≥ 5 x ULN and must take immediate 
action if CK > 10 x ULN. 
• For CK > 10 x ULN (confirmed, 2nd sample required) with or without muscle 
symptoms, discontinue study drug. 
• For CK > 5 - 10 x ULN (confirmed, 2nd sample required) 
− If symptomatic and no alternative explanation exists, withhold therapy. 
− If symptomatic, or if symptomatic but alternative explanation exists, 
follow symptoms and CK level weekly until there is no longer medical 
concern or symptoms worsen and meet criteria above 
• The following questioning and follow-up investigations should be performed: 
− Clarify the nature, duration and intensity of relevant symptoms 
− Clarify and document whether the patient was taking study treatment at 
the time of the event, or when the last done of study treatment was taken. 
Document dosing information in source and report if appropriate (e.g., if 
considered an SAE). 

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− Review possible predisposing factor, such as: unaccustomed exercise 
(including decorating, gardening, etc.), heavy alcohol intake, viral illness 
or severe bacterial infections (consider performing serology), 
concomitant medications (e.g., anesthetics, cholesterol-lowering agents – 
niacin, clofibrate, statins, ezetimibe, glucocorticoids, narcotic, 
chloroquine etc.) and consider diagnosis of other conditions which can 
cause myopathy (e.g. trauma). 
→ Physical examination for muscle tenderness, weakness and rash 
→ Measure lab parameters (as described above) within a few days  
→ Arrange to review the participant again in 4 to 10 days, or if 
symptoms of myopathy appear or worsen, or if the urine becomes 
very dark 
• Myopathy is defined as muscle aches or weakness in association with CK increased to 
> 10 x ULN. If myopathy occurs or if on clinical grounds, statin-induced myopathy is 
diagnosed or suspected, statin therapy should be discontinued. Myopathy should always 
be recorded as an adverse event, and the Bayer representative must be informed. 
• If the study treatment is temporarily disrupted, it is suggested that the Bayer 
representative be consulted before restarting study treatment. 
• The Bayer representative should be consulted prior to permanently withdrawing a 
participant. 
10.3 
Appendix 3: Adverse events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting 
10.3.1 
Definition of AE 
AE Definition 
• An AE is any untoward medical occurrence in a clinical study participant, associated 
with the use of study intervention, whether or not considered related to the study 
intervention. 
• NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) associated 
with the use of study intervention. 
Definition of Unsolicited and Solicited AE 
• An unsolicited adverse event is an adverse event that was not solicited using a 
participant diary and that is communicated by a participant who has signed the 
informed consent. Unsolicited AEs include serious and nonserious AEs. 
• Potential unsolicited AEs may be medically attended (i.e., symptoms or illnesses 
requiring a hospitalization, emergency room visit, or visit to/by a healthcare provider). 
The participant will be instructed to contact the site as soon as possible to report 
medically attended event(s), as well as any events that, though not medically attended, 

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are of participant concern. Detailed information about reported unsolicited AEs will be 
collected by qualified site personnel and documented in the participant’s records. 
• Unsolicited AEs that are not medically attended nor perceived as a concern by the 
participant will be collected during an interview with the participant and by review of 
available medical records at the next visit. 
Solicited AEs are predefined local and systemic events for which the participant is 
specifically questioned, and which are noted by the participant in their diary. 
Events Meeting the AE Definition 
• Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (e.g., ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator (i.e., not related to progression of 
underlying disease). 
• Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected intervention-intervention 
interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-harming 
intent. Such overdoses should be reported regardless of sequelae. 
• Sign, symptoms, or the clinical sequelae of suspected medication errors, misuse and 
abuse of either study intervention or a concomitant medication. Medication errors, 
misuse and abuse per se will not be reported as an AE/SAE, unless it is resulting in 
AE/SAE. Such medication errors, misuse and abuse should be reported regardless of 
sequelae. 
• Lack of efficacy or failure of expected pharmacological action per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy 
assessments. However, the signs, symptoms, and/or clinical sequelae resulting from 
lack of efficacy will be reported as AE or SAE if they fulfill the definition of an AE or 
SAE. 
Events NOT Meeting the AE Definition 
• Any abnormal laboratory findings or other abnormal safety assessments that are 
associated with the underlying disease, unless judged by the investigator to be more 
severe than expected for the participant’s condition 
• The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition 
• Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE 
• Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital) 

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• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen 
10.3.2 
Definition of SAE 
An SAE is defined as any untoward medical occurrence that, at any dose, meets the one or 
more of the criteria listed: 
a. Results in death 
b. Is life threatening 
• The term life threatening in the definition of serious refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe. 
c. Requires inpatient hospitalization or prolongation of existing hospitalization 
• In general, hospitalization signifies that the participant has been admitted (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether hospitalization occurred or was necessary, the 
AE should be considered serious. 
• Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE. 
d. Results in persistent or significant disability/incapacity 
• The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
• This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g., sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption. 
e. Is a congenital anomaly/birth defect 
f. Other situations: 
• Medical or scientific judgment should be exercised by the investigator in deciding 
whether SAE reporting is appropriate in other situations such as significant medical 
events that that may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the participant or may require medical or surgical 
intervention to prevent one of the other outcomes listed in the above definition. These 
events should usually be considered serious. 
o Examples of such events include invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias, convulsions, or development of intervention dependency or 
intervention abuse. 
 

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10.3.3 
Recording and follow-up of AE and/or SAE 
AE and SAE Recording 
• When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event. 
• The investigator will then record all relevant AE/SAE information in the CRF. 
• It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the sponsor in lieu of completion of the AE/SAE CRF page. 
• There may be instances when copies of medical records for certain cases are requested 
by the sponsor. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to the sponsor. 
The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. Whenever possible, the diagnosis (not the individual 
signs/symptoms) will be documented as the AE/SAE. 
Assessment of Intensity  
• The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to one of the following categories:  
• Mild: A type of adverse event that is usually transient and may require only 
minimal treatment or therapeutic intervention. The event does not generally 
interfere with usual activities of daily living. 
• Moderate: A type of adverse event that is usually alleviated with additional 
specific therapeutic intervention. The event interferes with usual activities of daily 
living, causing discomfort but poses no significant or permanent risk of harm to 
the research participant.   
• Severe: A type of adverse event that interrupts usual activities of daily living, or 
significantly affects clinical status, or may require intensive therapeutic 
intervention.   
Assessment of Causality 
• The investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE. The investigator will use clinical judgment to 
determine the relationship. 
• A reasonable possibility of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled 
out. 
• Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
• For causality assessment, the investigator will also consult the IB and/or product 
information, for marketed products. 
• The investigator must review and provide an assessment of causality for each AE/SAE 
and document this in the medical notes There may be situations in which an SAE has 
occurred and the investigator has minimal information to include in the initial report to 

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the sponsor. However, it is very important that the investigator always make an 
assessment of causality for every event before the initial transmission of the SAE 
data to the sponsor. 
• The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment. 
• The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
Follow-up of AEs and SAEs 
• The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the 
sponsor to elucidate the nature and/or causality of the AE or SAE as fully as possible. 
This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals. 
• If a participant dies during participation in the study or during a recognized follow-up 
period, the investigator will provide the sponsor with a copy of any postmortem 
findings including histopathology. 
• New or updated information will be recorded in the originally submitted documents. 
• The investigator will submit any updated SAE data to the sponsor within 24 hours of 
receipt of the information. 
10.3.4 
Reporting of SAEs 
SAE Reporting to the Sponsor via an Electronic Data Collection Tool 
• The primary mechanism for reporting an SAE to the sponsor will be the electronic data 
collection tool. 
• If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) in order to report the event within 24 hours. 
• The site will enter the SAE data into the electronic system as soon as it becomes 
available. 
• After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data. 
• If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see next 
section). 
• Contacts for SAE reporting can be found in the Investigator Site File. 
 

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SAE Reporting to the Sponsor via Paper Data Collection Tool 
• Email transmission of the SAE paper data collection tool is the preferred method to 
transmit this information to the sponsor’s pharmacovigilance department. 
• In rare circumstances and if email transmission is not feasible, notification by telephone 
is acceptable with a copy of the SAE data collection tool sent by overnight mail or 
courier service.  
• Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE data collection tool pages within the designated reporting 
time frames. 
• Contacts for SAE reporting can be found in the Investigator Site File. 
10.4 
Appendix 4: Contraceptive guidance and collection of pregnancy 
information 
Definitions: 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below). 
Women in the following categories are considered WOCBP (fertile) 
1. Following menarche 
2. From the time of menarche until becoming premenopausal unless permanently sterile (see 
below): 
• A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
• A high follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not using 
hormonal contraception or hormonal replacement therapy (HRT). 
However, in the absence of 12 months of amenorrhea, confirmation with 
more than one FSH measurement >40 IU/L is required.  
• Females on HRT and whose menopausal status is in doubt will be required 
to use one of the non-estrogen hormonal highly effective contraception 
methods if they wish to continue their HRT during the study. Otherwise, 
they must discontinue HRT to allow confirmation of postmenopausal status 
before study enrollment. 
• Permanent sterilization methods (for the purpose of this study) include: 
• Documented hysterectomy 
• Documented bilateral salpingectomy 
• Documented bilateral oophorectomy 
• For individuals with permanent infertility due to an alternate medical cause 
other than the above, (e.g., Mullerian agenesis, androgen insensitivity, 
gonadal dysgenesis), investigator discretion should be applied to 
determining study entry. 

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Note: Documentation can come from the site personnel’s: review of the participant’s medical 
records, medical examination, or medical history interview. 
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered. 
 
Woman of Nonchildbearing Potential (WONCBP) 
Women in the following categories are considered WONCBP: 
1. Premenopausal female with permanent infertility due to one of the following: 
a) 
Documented hysterectomy 
b) 
Documented bilateral salpingectomy 
c) 
Documented bilateral oophorectomy 
d) 
For individuals with permanent infertility due to an alternate medical cause other 
than the above, (e.g., Mullerian agenesis, androgen insensitivity, gonadal 
dysgenesis), investigator discretion should be applied to determining study entry. 
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview 
2. 
Postmenopausal female 
• A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
• A high follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not using 
hormonal contraception or hormonal replacement therapy (HRT). 
However, in the absence of 12 months of amenorrhea, confirmation with 
more than one FSH measurement >40 IU/L is required.  
• Females on HRT and whose menopausal status is in doubt must 
discontinue HRT to allow confirmation of postmenopausal status before 
study enrollment. 
 

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Contraception guidance: 
CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE: 
Highly Effective Methodsb That Have Low User Dependency  
• 
Implantable progestogen-only hormone contraception associated with inhibition of ovulationc 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS)c 
• 
Bilateral tubal occlusion 
• 
Azoospermic partner (vasectomized or due to a medical cause) 
Azoospermia is a highly effective contraceptive method provided that the partner is the sole sexual 
partner of the woman of childbearing potential and the absence of sperm has been confirmed. If not, an 
additional highly effective method of contraception should be used. Spermatogenesis cycle is 
approximately 90 days. 
Note: documentation of azoospermia for a male participant can come from the site personnel’s review of 
the participant’s medical records, medical examination, or medical history interview. 
Highly Effective Methodsb That Are User Dependent  
• 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of 
ovulationc 
o 
oral 
o 
intravaginal 
o 
transdermal 
o 
injectable 
• 
Progestogen-only hormone contraception associated with inhibition of ovulationc 
o 
oral 
o 
injectable 
• 
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle 
of the participant. 
a) Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for those participating in clinical studies. 
b) Failure rate of < 1% per year when used consistently and correctly. Typical use failure rates differ from 
those when used consistently and correctly. 
c) Male condoms must be used in addition to hormonal contraception. If locally required, in accordance with 
Clinical Trial Facilitation Group (CTFG) guidelines, acceptable contraceptive methods are limited to those 
which inhibit ovulation as the primary mode of action.  
Note: Periodic abstinence (calendar, symptothermal, postovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhea method (LAM) are not acceptable methods of contraception for 
this study.  Male condom and female condom should not be used together (due to risk of failure from 
friction). 
 

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Collection of pregnancy information: 
Male participants with partners who become pregnant  
• The investigator will attempt to collect pregnancy information on any male 
participant’s female partner who becomes pregnant while the male participant is in this 
study. This applies only to male participants who receive study intervention. 
• After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the investigator will record pregnancy information on the appropriate 
form and submit it to the sponsor within 24 hours of learning of the partner’s 
pregnancy. The female partner will also be followed to determine the outcome of the 
pregnancy. Information on the status of the mother and child will be forwarded to the 
sponsor. Generally, the follow-up will be no longer than 6 to 8 weeks following the 
estimated delivery date. Any termination of the pregnancy will be reported regardless 
of fetal status (presence or absence of anomalies) or indication for the procedure. 
Female participants who become pregnant  
• The investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. The initial information will be 
recorded on the appropriate form and submitted to the sponsor within 24 hours of 
learning of a participant's pregnancy.   
• The participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on the participant and the neonate and 
the information will be forwarded to the sponsor. Generally, follow-up will not be 
required for longer than 6 to 8 weeks beyond the estimated delivery date. Any 
termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for the procedure. 
• While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be 
reported as an AE or SAE.   
• A spontaneous abortion (occurring at < 22 weeks gestational age) or still birth 
(occurring at > 22 weeks gestational age) is always considered to be an SAE and will 
be reported as such.   
• Any post-study-pregnancy-related SAE considered reasonably related to the study 
intervention by the investigator will be reported to the sponsor as described in 
Section 8.4.4. While the investigator is not obligated to actively seek this information 
in former study participants, the investigator may learn of an SAE through 
spontaneous reporting.   
Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention. 

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10.5 
Appendix 5: Skin biopsy assessment (substudy) 
Skin barrier dysfunction is the initial step in the development of AD. Pharmacodynamic 
biomarkers will be evaluated in samples collected before and during treatment in order to 
determine the impact of the study intervention on these biomarkers. 
• Participants will be offered a possibility to participate in an optional skin biopsy. In 
this study a molecular analysis of BMs will be performed.  
• The participation in the substudy is voluntary and has no influence on the participation 
in the main study 
• Skin biopsies will be taken at defined time points during the study as specified in the 
SoA  
• Skin biopsies should be taken from the same lesion, if possible. Otherwise, a similar 
location should be selected. 
• Candidate pharmacodynamic biomarkers in the skin biopsies may give hints to drug 
efficacy and may include (but are not limited to) for example: 
• Biomarkers which may be related to the mode-of-action or are likely correlated with 
treatment effects - such as markers of inflammation (e.g., cytokines: IL-1β, IL-4, IL-
33, TSLP, chemokines such as CCL17), epidermal hyperplasia (e.g., Ki67, keratin 16) 
and epidermal barrier markers (e.g., filaggrin).  
• Skin epithelial height, markers of keratinocyte proliferation K16 (keratin 16) and Ki6-
7 (optional analysis) 
The results of the gene expression analysis of the skin biopsies may be reported separately 
(e.g., in a Biomarker Evaluation Report). 
 

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10.6 
Appendix 6: Prohibited medications 
Medications listed in Table 10–2 should be omitted 1 week before randomization visit and 
throughout the study. Please note that this is not an exhaustive list. See also in-/exclusion 
criteria in Sections 5.1 and 5.2. 
Table 10–2: Substrates (X) for breast cancer resistance proteins (BCRP) and organic-
anion-transporting polypeptides (OATP) 1B1 and 1B3 
Drug 
BCRP 
OATP 1B1 
OATP 1B3 
Ambrisentan 
- 
X 
X 
Asunaprevir 
- 
X 
X 
Atorvastatin 
X 
X 
X 
Bosentan 
- 
X 
X 
Cerivastatin 
- 
X 
X 
Cimetidine 
- 
- 
- 
Daunorubicin 
X 
- 
- 
Docetaxel 
- 
- 
X 
Donoprevir 
- 
X 
X 
Ezetimibe 
- 
X 
- 
Fexofenadine 
- 
X 
- 
Fluvastatin 
X 
X 
X 
Gadoxetic acid 
- 
X 
X 
Gefitinib 
X 
- 
- 
Glibenclamide 
- 
X 
X 
Hymecromone 
X 
- 
- 
Imatinib 
X 
- 
- 
Irinotecan 
X 
- 
- 
Lapatinib 
X 
- 
- 
Mitoxantrone 
X 
- 
- 
Nateglinide 
- 
X 
X 
Nitrofurantoin 
X 
- 
- 
Paclitaxel 
- 
- 
X 
Pibrentasvir 
X 
- 
- 
Pitavastatin 
X 
X 
X 
Prazosin 
X 
- 
- 
Pravastatin 
- 
X 
X 
Repaglinide 
- 
X 
- 
Revefenacin 
- 
X 
X 
Rifampicin 
X 
- 
- 
Rosuvastatin 
X 
X 
X 
Simeprevir 
- 
X 
X 
Simvastatin 
X 
X 
- 
Sulfasalazine 
X 
- 
- 
Sunitinib 
X 
- 
- 
Topotecan 
X 
- 
- 
Vincristine 
X 
- 
- 
Zidovudine 
X 
- 
- 
 
 

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10.7 
Appendix 7: Questionnaires 
10.7.1 ClinROs scoring 
10.7.1.1 Eczema Area and Severity Index (EASI) 
 
 
easi-user-guide-dec-2016-v2.pdf (homeforeczema.org) 
 
The assessed parameters are inserted into Figure 10–1. The final EASI score ranges from 0-
72. 
 

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Figure 10–1: EASI scoring table  
 
 
10.7.1.2 Validated Investigator Global Assessment for Atopic Dermatitis (vIGA-
AD) 
The clinicians are asked to select that vIGA-AD score that best describes the overall 
appearance of the lesions at a given point in time. The scale’s morphology descriptors are 
nonoverlapping, noncomparative categories with “clear” skin representing the absence of 
disease and focus given to having clearly distinct categories for ratings of “mild” versus 
“almost clear”. A decrease in the vIGA-AD score relates to an improvement in signs and 
symptoms. 
Instructions: 
The IGA score is selected using the descriptors below that best describe the overall 
appearance of the lesions at a given time point. It is not necessary that all characteristics under 
Morphological Description be present. 

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Figure 10–2: COA instrument: vIGA-AD 
 
Notes: 
1. In indeterminate cases, please use extent to differentiate between scores.  
For example:  
• Patient with marked erythema (deep or bright red), marked papulation and/or marked 
lichenification that is limited in extent, will be considered “3 – Moderate”.  
2. Excoriations should not be considered when assessing disease severity.  
 
Validated-Investigator-Global-Assessment-Scale_vIGA-AD_2017.pdf (eczemacouncil.org) 
10.7.1.3 Assessment of body surface area (BSA) affected by atopic dermatitis 
Body surface area affected by AD will be assessed for each section of the body, using the 
“rule of nines”.  The possible highest score for each region is:  
Head and neck: 9%  
Anterior trunk: 18%  
Back: 
18%  
Upper limbs: 
18%  
Lower limbs: 36% 
Genitals: 
1%. 
It will be reported as a percentage of all major body sections combined.   
Before the start of the study at the individual site, all investigators will be trained on the 
correct assessment of BSA.  

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10.7.2 PROs scales and questionnaires 
 
Figure 10–3: Peak Pruritus 0-10 NRS 
On a scale of 0 to 10, with 0 being ‘no itch’ and 10 being ‘worst itch imaginable’, how would 
you rate your itch at the worst moment during the previous 24 hours? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No itch 
 
 
 
 
 
 
 
 
 
Worst itch 
imaginable 
 
 
10.8 
Appendix 8: Country-specific Requirements  
10.8.1 France (FRA) 
10.8.1.1 FRA-1: Country-specific requirements for France only 
Amendment France - FRA-1 (15 FEB 2023) 
This local amendment was prepared for France to address the country-specific changes 
requested by the local ethics committee (EC) in France Comité de Protection des personnes 
Ouest IV. The requested change only affects one inclusion criterion which was specified 
according to the French Public Health Code to further clarify exclusion of vulnerable persons 
in France. 
This amendment is considered to be non-substantial based on the criteria set forth in Article 
10(a) of Directive 2001/20/EC of the European Parliament and the Council of the European 
Union because it neither significantly impacts the safety or physical/mental integrity of 
participants nor the scientific value of the study. 
 
This section implements country-specific modifications to the original protocol version 1.0, 
dated 08 JUL 2022, to meet local requirements in France. 

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Overview of changes 
A description of changes and a brief rationale is provided in the table below: 
Section # and Name 
Description of Change 
Brief Rationale 
Section 5.1 Inclusion 
criteria 
Text added to inclusion criterion 8 to exclude 
vulnerable persons according to the French Public 
Health Code (persons referred in Articles L1121-5 
to L 1121-8-1 and L1122-1-2, viewed on 10 FEB 
2023).  
As per French 
local EC 
(Comité de 
Protection des 
personnes 
Ouest IV) 
request 
Changes to the protocol 
Section 5.1 Inclusion criteria 
[…] 
8. Capable of giving signed informed consent as described in Section 10.1.4, which includes 
compliance with the requirements and restrictions listed in the informed consent form (ICF) 
and in this protocol and are not falling under the definition for vulnerable persons according 
to the French Public Health Code (persons referred in Articles L1121-5 to L 1121-8-1 and 
L1122-1-2, viewed on 10 FEB 2023) as follows: 
• pregnant women, parturient and breastfeeding women 
• deprived of their liberty by a judicial or administrative decision  
• undergoing psychiatric care and people admitted to a health or social institution for 
purposes other than research 
• adults subject to a legal protection measure or unable to express their consent. 
• minors  
• persons who are not affiliated to a social security scheme or beneficiary of such a scheme 
• persons deceased or brain-dead (listed for completeness) 

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