A Phase 2b, Randomized, Double-blind, Placebo-controlled, Multi-site, Parallel-group, Dose-finding Trial to Evaluate the Efficacy and Safety of Different Doses of Subcutaneously Administered LEO 138559 in Adult Subjects With Moderate-to-severe Atopic Dermatitis
Phase: PHASE2
Conditions: Atopic Dermatitis
Sponsor: LEO Pharma

 
 
1 
Cover Page 
Study title: 
A phase 2b, randomized, double-blind,  
placebo-controlled, multi-site, parallel-group, 
dose-finding trial to evaluate the efficacy and 
safety of different doses of subcutaneously 
administered LEO 138559 in adult subjects 
with moderate-to-severe atopic dermatitis 
LEO Pharma number: LP0145-2240 
NCT number: 
NCT05923099 
Date: 
28-Jun-2024 
 
 
 
 
 
 

CONFIDENTIAL
THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION AND MUST NOT BE COPIED OR MADE AVAILABLE TO ANY THIRD PARTY WITHOUT 
THE PRIOR WRITTEN CONSENT OF THE LEO PHARMA GROUP 
Updated clinical trial protocol
Trial ID: LP0145-2240
A phase 2b, randomized, double-blind, placebo-controlled, multi-site, parallel-group, 
dose-finding trial to evaluate the efficacy and safety of different doses of subcutaneously 
administered LEO 138559 in adult subjects with moderate-to-severe atopic dermatitis.
Phase 2b dose-finding trial
Approval statement, LEO Pharma A/S
The following persons have approved this CTP.
Name, academic degree
Role
Department
 MD
Vice president
Global Clinical 
Development
 MSc Stat
Biostatistics lead
Biostatistics
 MD, PhD
Medical lead
Medical Department
 MSc pharm
Clinical operations lead
Global Clinical 
Operations
Stephan Weidinger, MD
Signatory investigator
External
TMF-000757181 - Version 5.0

Trial ID: LP0145-2240
Version: 8.0
Date: 28-Jun-2024
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Title page
Trial ID
LP0145-2240
Protocol title:
A phase 2b, randomized, double-blind, placebo-controlled, multi-
site, parallel-group, dose-finding trial to evaluate the efficacy and 
safety of different doses of subcutaneously administered 
LEO 138559 in adult subjects with moderate-to-severe atopic 
dermatitis.
Brief title: 
A trial to evaluate the efficacy and safety of different doses of 
LEO 138559 in adults with moderate-to-severe atopic dermatitis.
Trial phase:
Phase 2b
Compound:
LEO 138559
Indication:
Moderate-to-severe AD
Trial sponsor:
LEO Pharma A/S
Industriparken 55, DK 2750 Ballerup, Denmark 
Regulatory 
agency identifier 
numbers:
Universal trial number: U1111-1286-0955
ClinicalTrials.gov ID: NCT05923099
IND number: 146054
EU CT number: 2022-500777-14
Japanese trial registration number: 2023-1450
Version:
8.0
Approval date:
28-Jun-2024
This clinical trial will be conducted in compliance with the clinical trial protocol, ICH GCP (1), and the applicable regulatory 
requirement(s). 
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Trial ID: LP0145-2240 
Version: 8.0 
Date: 28-Jun-2024 
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Protocol amendment summary of changes 
Document history 
Document 
Date 
Type of protocol amendment 
Amendment 2 (substantial) 
28-Jun-2024 
Global 
Amendment 1 (non-substantial)/GBR-1 
05-Feb-2024 
Country-specific 
Amendment 1 (non-substantial) 
13-Nov-2023 
Global 
Amendment 3 (non-substantial)/CZE-2/DEU-2/ESP-2/ 
FRA-3/HUN-2/POL-2/ROU-2 
05-Oct-2023 
Country-specific 
Amendment 2 (non-substantial)/FRA-2 
28-Sep-2023 
Country-specific 
Amendment 1 (non-substantial)/CZE-1/DEU-1/ESP-1/ 
FRA-1/HUN-1/POL-1/ROU-1 
16-Sep-2023 
Country-specific 
Amendment 1 (non-substantial)/JPN-1 
12-Jul-2023 
Country-specific 
Original protocol 
04-May-2023 
NA 
Abbreviations: CZE = Czech Republic; DEU = Germany; ESP = Spain; FRA = France; GBR = United 
Kingdom; HUN = Hungary; JPN = Japan; NA = not applicable; POL = Poland; ROU = Romania. 
Amendment 2 (28-Jun-2024) 
This amendment is considered to be substantial based on the criteria set forth in Article 2 (13) 
of Regulation 536/2014 of the European Parliament and the Council of the European Union or 
subsequent regulation. 
Overall rationale for the amendment 
The main purpose of this protocol amendment is to improve the hypothetical estimand to 
better reflect the underlying trial objective of estimating an effect in a scenario where the 
subjects do not discontinue IMP or take rescue treatment. Changes to the protocol are 
summarized in the table below (text added to the protocol is written in bold). 
Section no. and title 
Description of change 
Brief rationale 
Section 3 
Trial objectives, estimands, 
and endpoints 
Panel 3 and Panel 4 
Section 11.3.7 
Estimand strategy 
Panel 17 
Changed description of POEM-related 
exploratory endpoint: 
• Change in POEM score (and individual 
item scores related to itch and sleep) 
from baseline to Week 16. 
To evaluate the effect of 
LEO 138559 on itch and 
sleep. 
Section 3 
Trial objectives, estimands, 
and endpoints 
Panel 4 
Added hypothetical supplementary analysis 
for continuous endpoints. 
Changed descriptions of: 
- Strategy/Intercurrent events for primary 
estimand for binary endpoints. 
For consistency with 
other changes 
implemented in 
Sections 11.3.7 and 
11.3.8. 
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Section no. and title 
Description of change 
Brief rationale 
- Population level summary for primary 
estimand for time-to-event endpoints. 
Section 11.3.7 
Estimand strategy 
Panel 16 
Added hypothetical supplementary analysis 
for continuous endpoints. Changed description 
of handling of missing data. 
To improve handling of 
missing data to better 
reflect the trial objective. 
Section 11.3.7 
Estimand strategy 
Panel 17 
Added estimands to be analyzed for 
continuous endpoints. 
To ensure extra quality 
and robustness of the 
results. 
Section 11.3.7.1 
Estimands for continuous 
endpoints 
Added hypothetical supplementary analysis 
for continuous endpoints. 
To ensure extra quality 
and robustness of the 
results. 
Section 11.3.7.2 
Estimands for binary endpoints 
Section 11.3.7.4 
Baseline subgroup estimands 
Estimands changed so that permanent 
discontinuation of IMP due to an AE is 
considered non-response only if the AE is 
related to worsening of AD. 
To achieve more 
meaningful definitions of 
binary endpoints. 
Section 11.3.8.1 
Analysis of primary estimand 
for continuous endpoints 
Changed handling of the missing data. 
To improve handling of 
missing data to better 
reflect the trial objective. 
Section 11.3.8.2 
Analysis of primary estimand 
for binary endpoints 
Changed definition of non-responder. 
To make the term 
‘responder’ more 
meaningful. 
Section 11.3.9.1 
Analysis of hypothetical 
supplementary estimand for 
continuous endpoints 
Added section describing analysis of a new 
supplementary estimand. 
To ensure extra quality 
and robustness of results. 
Section 11.3.9.3 
Analysis of supplementary 
estimand for binary endpoints 
Changed estimand for the primary analysis. 
To introduce a treatment 
policy estimand for 
binary endpoints. 
Section 12.5.5 
Specific requirements for the 
United Kingdom 
Section added to implement changes from 
Amendment 1 (05-Feb-2024, non-substantial, 
country-specific for the UK). 
Administrative change. 
Section 12.8 
Appendix 8: Protocol 
amendment history 
Section updated. Added Amendment 1 
(05-Feb-2024, non-substantial, 
country-specific for the UK). 
Administrative change. 
Throughout document 
Minor editorial revisions. 
Minor, have therefore 
not been summarized. 
Abbreviations: please refer to the list of abbreviations.
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Table of contents 
Title page ................................................................................................................................... 2 
Protocol amendment summary of changes ............................................................................ 3 
Table of contents ....................................................................................................................... 5 
List of panels ........................................................................................................................... 10 
List of abbreviations ............................................................................................................... 11 
1 
Protocol summary ......................................................................................................... 16 
1.1 
Protocol synopsis ................................................................................................... 16 
1.2 
Schematic of trial design........................................................................................ 20 
1.3 
Schedule of activities ............................................................................................. 21 
2 
Introduction and trial rationale .................................................................................. 29 
2.1 
Atopic dermatitis.................................................................................................... 29 
2.2 
Experience with IMP ............................................................................................. 30 
2.2.1 
Non-clinical data .......................................................................................... 30 
2.2.2 
Clinical data ................................................................................................. 32 
2.2.3 
PK ................................................................................................................ 33 
2.3 
Trial rationale ......................................................................................................... 34 
2.4 
Ethical considerations ............................................................................................ 35 
2.5 
Benefit/risk assessment .......................................................................................... 36 
3 
Trial objectives, estimands, and endpoints ................................................................. 39 
4 
Trial design .................................................................................................................... 49 
4.1 
Overall trial design................................................................................................. 49 
4.2 
Number of subjects needed .................................................................................... 50 
4.3 
End-of-trial definition ............................................................................................ 51 
5 
Trial population ............................................................................................................ 52 
5.1 
Subject eligibility ................................................................................................... 52 
5.2 
Inclusion criteria .................................................................................................... 52 
5.3 
Exclusion criteria ................................................................................................... 53 
5.4 
Screening and subjects excluded prior to randomization ...................................... 56 
6 
Treatments ..................................................................................................................... 59 
6.1 
Trial product description ........................................................................................ 59 
6.2 
Administration of IMP ........................................................................................... 59 
6.3 
Treatment assignment and blinding ....................................................................... 62 
6.3.1 
Treatment assignment .................................................................................. 62 
6.3.2 
Blinding ....................................................................................................... 62 
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6.3.3 
Emergency unblinding of individual subject treatment ............................... 63 
6.4 
Background treatment ............................................................................................ 64 
6.5 
Rescue treatment .................................................................................................... 64 
6.6 
Prior and concomitant medication and concurrent procedures .............................. 65 
6.7 
Prohibited medications and procedures ................................................................. 65 
6.8 
Treatment logistics and accountability .................................................................. 66 
6.8.1 
Labelling and packaging of trial products ................................................... 66 
6.8.2 
Storage and accountability of trial products ................................................ 67 
6.8.3 
Treatment compliance .................................................................................. 67 
6.8.4 
Trial product destruction .............................................................................. 68 
6.9 
Provision for subject care following trial completion ........................................... 68 
6.10 
Reporting product complaints ................................................................................ 68 
7 
Discontinuation and withdrawal ................................................................................. 70 
7.1 
General principles .................................................................................................. 70 
7.2 
Reasons for discontinuation of IMP ...................................................................... 70 
7.2.1 
Reasons for permanent discontinuation of IMP .......................................... 70 
7.2.2 
Reasons for temporary discontinuation of IMP ........................................... 71 
7.3 
Subject withdrawal from the trial .......................................................................... 71 
7.4 
Early termination assessments ............................................................................... 71 
7.5 
Lost to follow-up ................................................................................................... 72 
8 
Trial assessments and procedures ............................................................................... 74 
8.1 
Overview ................................................................................................................ 74 
8.2 
Administrative and baseline procedures ................................................................ 75 
8.2.1 
Demographics .............................................................................................. 75 
8.2.2 
Medical history ............................................................................................ 75 
8.2.3 
Body measurement (height) ......................................................................... 76 
8.2.4 
C-SSRS ........................................................................................................ 76 
8.2.5 
Laboratory assessments ............................................................................... 76 
8.3 
Efficacy assessments .............................................................................................. 76 
8.3.1 
EASI ............................................................................................................. 76 
8.3.2 
SCORAD ..................................................................................................... 78 
8.3.3 
vIGA-AD ..................................................................................................... 79 
8.3.4 
BSA involvement ......................................................................................... 80 
8.3.5 
PROs ............................................................................................................ 80 
8.4 
Safety assessments ................................................................................................. 85 
8.4.1 
Vital signs .................................................................................................... 85 
8.4.2 
Physical examination ................................................................................... 86 
8.4.3 
Body measurement (weight) ........................................................................ 86 
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8.4.4 
Electrocardiography ..................................................................................... 87 
8.4.5 
Laboratory testing ........................................................................................ 88 
8.4.6 
ADA measurements ..................................................................................... 91 
8.5 
PK assessments ...................................................................................................... 92 
8.6 
PD assessments ...................................................................................................... 92 
8.7 
Other assessments .................................................................................................. 95 
8.7.1 
Photography (selected sites) ........................................................................ 95 
8.7.2 
Qualitative interviews (selected sites) ......................................................... 96 
8.8 
End of trial ............................................................................................................. 97 
8.9 
Storage of biological samples ................................................................................ 98 
9 
Scientific rationale for trial design and appropriateness of assessments ................ 99 
9.1 
Scientific rationale for trial design......................................................................... 99 
9.2 
Appropriateness of assessments........................................................................... 102 
10 
AE, SAE, and other safety reporting ........................................................................ 104 
10.1 
Time period and frequency of collecting AE information ................................... 104 
10.2 
Method of detection AEs ..................................................................................... 104 
10.3 
Follow-up of AEs and SAEs ................................................................................ 104 
10.4 
Regulatory reporting requirements for SAE ........................................................ 105 
10.5 
Pregnancy............................................................................................................. 105 
10.6 
Other events that require expedited reporting ...................................................... 106 
10.7 
Reporting of other events ..................................................................................... 106 
10.7.1 
AEs of special interest ............................................................................... 106 
10.7.2 
Medication error ........................................................................................ 106 
11 
Statistical considerations ............................................................................................ 108 
11.1 
Sample size .......................................................................................................... 108 
11.2 
Trial analysis sets ................................................................................................. 110 
11.3 
Statistical analysis ................................................................................................ 110 
11.3.1 
General principles ...................................................................................... 110 
11.3.2 
Handling of missing values ........................................................................ 111 
11.3.3 
Disposition of subjects ............................................................................... 111 
11.3.4 
Demographics and other baseline characteristics ...................................... 111 
11.3.5 
Exposure and treatment compliance .......................................................... 112 
11.3.6 
Testing strategy .......................................................................................... 112 
11.3.7 
Estimand strategy ....................................................................................... 112 
11.3.8 
Primary estimand analysis ......................................................................... 123 
11.3.9 
Supplementary estimand analysis .............................................................. 126 
11.3.10 
Analysis of baseline subgroup estimands .................................................. 128 
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11.3.11 
PRO analysis .............................................................................................. 129 
11.3.12 
PD .............................................................................................................. 129 
11.3.13 
Safety analysis ........................................................................................... 129 
11.3.14 
PK analysis ................................................................................................ 131 
11.3.15 
Interim analysis .......................................................................................... 131 
11.3.16 
Timing of reporting trial results ................................................................. 131 
12 
Supporting documentation and operational considerations ................................... 133 
12.1 
Appendix 1: Regulatory, ethical, and trial governance considerations ................ 133 
12.1.1 
Regulatory and ethical considerations ....................................................... 133 
12.1.2 
Financial disclosure ................................................................................... 134 
12.1.3 
Informed consent process .......................................................................... 134 
12.1.4 
Recruitment strategy .................................................................................. 135 
12.1.5 
Data protection ........................................................................................... 135 
12.1.6 
Committee structure ................................................................................... 136 
12.1.7 
Dissemination of clinical trial data ............................................................ 136 
12.1.8 
Data quality assurance ............................................................................... 137 
12.1.9 
Source documents ...................................................................................... 138 
12.1.10 
Trial and trial site start and closure ............................................................ 138 
12.1.11 
Publication policy ...................................................................................... 139 
12.1.12 
Insurance .................................................................................................... 140 
12.2 
Appendix 2: AEs and SAEs: Definitions and procedures for recording, 
evaluating, follow-up, and reporting.................................................................... 141 
12.2.1 
AE definition .............................................................................................. 141 
12.2.2 
SAE definition ........................................................................................... 141 
12.2.3 
Definition of AESIs ................................................................................... 142 
12.2.4 
Recording and follow-up of AEs ............................................................... 142 
12.2.5 
Reporting of SAEs ..................................................................................... 147 
12.2.6 
Narratives ................................................................................................... 148 
12.3 
Appendix 3: Hanifin and Rajka (1980) diagnostic criteria for AD...................... 149 
12.4 
Appendix 4: Guidance for anaphylaxis diagnosis ............................................... 150 
12.5 
Appendix 5: Country-specific requirements ........................................................ 151 
12.5.1 
Specific requirements for all EU countries ................................................ 151 
12.5.2 
Specific requirements for Czech Republic ................................................ 168 
12.5.3 
Specific requirements for France ............................................................... 169 
12.5.4 
Specific requirements for Japan ................................................................. 170 
12.5.5 
Specific requirements for the United Kingdom ......................................... 174 
12.6 
Appendix 6: Contact list ...................................................................................... 175 
12.7 
Appendix 7: Pandemic contingency plan (e.g. COVID-19) ................................ 176 
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12.8 
Appendix 8: Protocol amendment history ........................................................... 177 
13 
References .................................................................................................................... 190 
 
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List of panels 
Panel 1: Trial design ................................................................................................................. 20 
Panel 2: Schedule of trial activities .......................................................................................... 21 
Panel 3: Objectives and endpoints ........................................................................................... 39 
Panel 4: Objectives, estimands, and endpoints ........................................................................ 42 
Panel 5: Identification of IMPs ................................................................................................ 59 
Panel 6: Combinations of IMP administration per dose regimen ............................................ 60 
Panel 7: Calculation of the EASI score .................................................................................... 77 
Panel 8: EASI severity score scale and area score scale .......................................................... 78 
Panel 9: vIGA-AD .................................................................................................................... 80 
Panel 10: Overview of PROs to be completed ......................................................................... 81 
Panel 11: PGI-S ........................................................................................................................ 84 
Panel 12: Clinical laboratory tests ............................................................................................ 88 
Panel 13: Simulated serum concentrations of LEO 138559 in the phase 2b trial 
(LP0145-2240) at a body weight of 75.0 kg ..................................................... 101 
Panel 14: Assumed values for the mean change from baseline in EASI score from Week 
1 to Week 16 ...................................................................................................... 108 
Panel 15: Approximate nominal and prioritized power for rejecting the null hypotheses 
including in the testing hierarchy, based on the results of the simulation ......... 110 
Panel 16: Handling of observed and missing data according to intercurrent events in the 
primary analysis of the estimands defined in Sections 11.3.7.1, 11.3.7.2, 
and 11.3.7.3 ....................................................................................................... 114 
Panel 17: Statistical analysis of endpoints ............................................................................. 116 
Panel 18: Schedule of trial activities for EU countries .......................................................... 155 
 
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List of abbreviations 
Ab 
antibody 
AD 
atopic dermatitis 
ADA 
anti-drug antibodies 
ADSD 
Atopic Dermatitis Symptom Diary 
AE 
adverse event 
AESI 
adverse events of special interest 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
anti-HBc 
hepatitis B core antibody 
anti-HBs 
hepatitis B surface antibody 
anti-HCV 
hepatitis C virus antibody 
APC 
antigen-presenting cell 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
BP 
blood pressure 
BSA 
body surface area 
CA 
Canada 
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
confidence interval 
CMO 
contract manufacturing organization 
CONSORT 
Consolidated Standards of Reporting Trials 
COVID-19 
corona virus disease 2019 
CPM 
clinical project manager 
CRA 
clinical research associate 
CRO 
contract research organization 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CTIS 
Clinical Trials Information System 
CTR 
clinical trial report 
CZ 
Czech Republic 
DE 
Germany 
DLQI 
Dermatology Life Quality Index 
DNA 
deoxyribonucleic acid 
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EASI 
Eczema Area and Severity Index 
EASI-50 
at least 50% reduction in EASI score 
EASI-75 
at least 75% reduction in EASI score 
EASI-90 
at least 90% reduction in EASI score 
EASI-100 
100% reduction in EASI score 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
eDiary 
electronic diary 
EMA 
European Medicines Agency 
ePRO 
electronic patient-reported outcome 
EQ-5D-5L 
EuroQol 5-Dimension Health Questionnaire 5 Level 
ES 
Spain 
EU 
European Union 
FAS 
full analysis set 
FDA 
United States Food and Drug Administration 
FiH 
first in human 
FR 
France 
GCP 
Good Clinical Practice 
GCTM 
global clinical trial manager 
HADS 
Hospital Anxiety and Depression Scale 
HbA1c 
glycated haemoglobin 
HBsAg 
hepatitis B surface antigen 
HCP 
healthcare professional 
HIV 
human immunodeficiency virus 
HRQoL 
health-related quality of life 
HU 
Hungary 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
ICHS6 (R1) 
Preclinical Safety Evaluation of Biotechnology-derived Pharmaceuticals 
ICS-LABA 
inhaled corticosteroid-long-acting beta-2-agonist 
ID 
identification number 
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IEC 
independent ethics committee 
IGA 
Investigator’s Global Assessment 
IgE 
immunoglobulin E 
IgG 
immunoglobulin G 
IgM 
immunoglobulin M 
IL-4 
interleukin 4 
IL-4Rα 
interleukin 4 receptor α 
IL-5 
interleukin 5 
IL-10R2 
interleukin 10 receptor 2 
IL-13 
interleukin 13 
IL-17 
interleukin 17 
IL-22 
interleukin 22  
IL-22BP 
interleukin 22 binding protein 
IL-22R 
interleukin 22 receptor 
IL-22RA1 
interleukin 22 receptor subunit alpha 1 
IMP 
investigational medicinal product 
IND 
Investigational New Drug 
IRB 
institutional review board 
IRT 
interactive response technology 
IT 
information technology 
IUD  
intrauterine device 
IUS 
intrauterine hormone-releasing system 
IV 
intravenous 
JAK 
janus kinase 
JAK1 
janus kinase 1 
JP 
Japan 
KLH 
keyhole limpet hemocyanin 
LEO Pharma 
LEO Pharma A/S 
LLQ 
lower level of quantification 
LSmean 
least squares mean 
mAb 
monoclonal antibody 
MAD 
multiple ascending dose 
MAR 
missing at random 
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MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
multiple imputation 
MMRM 
mixed model repeated measures 
MNAR 
missing not at random 
mRNA 
messenger ribonucleic acid 
NBUVB 
narrow band ultraviolet B 
NOAEL 
no observed adverse effect level 
PCR 
polymerase chain reaction 
PD 
pharmacodynamics 
PDE-4 
phosphodiesterase-4 
PEF 
peak expiratory flow 
PGI-C 
Patient Global Impression of Change 
PGI-S 
Patient Global Impression of Severity   
PK 
pharmacokinetics 
PL 
Poland 
POEM 
Patient-Oriented Eczema Measure 
PRO 
patient-reported outcome 
PT 
preferred term 
PUVA 
psoralen + ultraviolet A 
qPCR 
quantitative polymerase chain reaction 
QW 
every week 
Q2W 
every 2 weeks 
RNA 
ribonucleic acid 
RO 
Romania 
SAD 
single ascending dose 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
subcutaneous(ly) 
SCORAD 
SCORing Atopic Dermatitis 
SD 
standard deviation 
SOC 
system organ class 
STAT3 
signal transducer and activator of transcription 3 
SUSAR 
suspected, unexpected serious adverse reaction 
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TCI 
topical calcineurin inhibitor(s) 
TCS 
topical corticosteroid(s) 
TEAE 
treatment-emergent adverse event 
TMDD 
target-mediated drug disposition 
UK 
United Kingdom 
ULN 
upper limit of normal 
US 
United States 
UVA1 
ultraviolet A1 
UVB 
ultraviolet B 
VAS 
Visual Analogue Scale 
vIGA-AD 
validated Investigator Global Assessment Scale for Atopic Dermatitis 
WPAI-SHP 
Work Productivity and Activity Impairment: Specific Health Problem 
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1 
Protocol summary 
1.1 
Protocol synopsis 
Trial ID 
LP0145-2240 
Protocol title 
A phase 2b, randomized, double-blind, placebo-controlled, multi-site, 
parallel-group, dose-finding trial to evaluate the efficacy and safety of 
different doses of subcutaneously (SC) administered LEO 138559 in adult 
subjects with moderate-to-severe atopic dermatitis. 
Brief title 
A trial to evaluate the efficacy and safety of different doses of LEO 138559 in 
adults with moderate-to-severe atopic dermatitis. 
Regulatory 
agency identifier 
numbers 
Universal trial number: U1111-1286-0955 
ClinicalTrials.gov ID: NCT05923099 
IND number: 146054 
EU CT number: 2022-500777-14 
Japanese trial registration number: 2023-1450 
Trial rationale 
Despite the recent improvements in treatment, there still remains an unmet 
need for more safe and efficacious treatments to be used long-term for 
moderate-to-severe atopic dermatitis patients. Management of moderate-to-
severe AD is challenging because of the chronicity of the disease and the 
limited therapeutic options that are both efficacious and have an acceptable 
long-term safety profile. A ‘control-based’ and ‘risk-based’ model of disease 
management in which an initial diagnosis is followed by treatment according 
to categorization of severity is usually recommended. The pharmacological 
treatment algorithm for AD progresses from mild topical anti-inflammatory 
therapy to high-potency topical anti-inflammatory therapy, and in more severe 
cases leads to systemic immunomodulating therapy. In general, the national 
treatment guidelines recommend the use of systemic treatment in patients who 
are refractory to optimized topical therapies. 
Despite promising efficacy, the dupilumab pivotal trials showed that more 
than 60% of the trial participants with AD did not meet the primary endpoint 
of Investigator’s Global Assessment 0/1 (IGA 0/1) or clear/almost clear skin. 
Further, tralokinumab and janus kinase (JAK) inhibitors have been recently 
approved, but even with those advances, there remains an unmet need to 
develop new therapies with improved efficacy and/or safety. Further, it is 
increasingly recognized that AD is a phenotypically and molecularly 
heterogenous disease that may require differentiated and/or combined 
therapeutic approaches in order to adequately address the needs of moderate-
to-severe AD patients.  
LEO 138559 is a mAb that binds to the interleukin 22 receptor subunit 
alpha 1 (IL-22RA1) subunit of the IL-22 receptor, thereby blocking the 
binding of the ligand (IL-22).  
The results from the LP0145-1315, phase 1, first in human (FiH) trial 
indicated a clinical effect of both 
 mg and 
 mg every week (QW) for 
up to 5 weeks in moderate-to-severe AD subjects followed for 17 weeks. In 
addition, the results from the LP0145-1376, phase 2a, proof-of-concept trial 
showed evidence of a clinical effect seen in the LEO 138559 450 mg Q2W 
group versus placebo in adult subjects with moderate-to severe AD, meeting 
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the primary endpoint (improvement in Eczema Area and Severity Index 
[EASI] score) and with no major safety concerns identified.  
In summary, based on the mode of action of LEO 138559, and the findings in 
the phase 1 and phase 2a trials, it is expected that LEO 138559 is a safe and 
efficacious treatment for patients with moderate-to-severe AD. 
All doses studied so far have had an acceptable benefit/risk profile and no 
major safety concerns have been identified. 
Ethical 
considerations 
This trial will be conducted in accordance with the ethical principles 
originating from the Declaration of Helsinki and ICH GCP and in compliance 
with the approved protocol and applicable regulatory requirements. 
The trial design is considered scientifically justified and considered to adhere 
to ethical standards ensuring the rights, safety, and well-being of the subject. 
The efficacy and safety of LEO 138559 will be evaluated in adults with 
moderate-to-severe AD who may benefit from treatment with LEO 138559.  
There is a clear unmet need for safe, long-term treatment options for subjects 
with moderate-to-severe AD, and the novel IL-22RA1 antagonist, 
LEO 138559, is expected to be efficacious in AD treatment. A benefit for all 
subjects participating in this trial, regardless of whether they receive active 
drug or placebo, is that they receive close monitoring of their disease and easy 
access to specialist care. Risks to subjects in the trial will be minimized by 
inclusion of subjects fulfilling all eligibility criteria.  
Main objectives, 
endpoints, and 
estimands 
 
Objectives 
Endpoints 
Primary objective 
Primary endpoint 
To compare the efficacy of 
4 different dose regimens 
of LEO 138559 with 
placebo in subjects with 
moderate-to-severe AD. 
Primary endpoint 
• 
Percent change in EASI1 score from 
baseline to Week 16. 
 
Secondary objective 
Secondary endpoint 
To compare the safety of 
4 different dose regimens of 
LEO 138559 with placebo in 
subjects with moderate-to-
severe AD. 
• 
Number of treatment-emergent adverse 
events (TEAEs) recorded for each 
subject from baseline to Week 16. 
 
1 The EASI is a validated measure used in clinical practice and clinical trials 
to assess the severity and extent of AD. The EASI is a composite index 
with scores ranging from 0 to 72, with higher values indicating more 
severe and/or more extensive condition. 
 
The primary estimand for the primary endpoint attempts to quantify the effect 
of treatment, in the hypothetical scenario, where subjects do not permanently 
discontinue IMP for any reason and where rescue treatment is not made 
available. 
Trial design 
The trial design is illustrated in the figure below: 
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In addition to placebo administrations to subjects in the placebo group (at Weeks 0, 1, 
2, 3, 4, 6, 8, 10, 12, 14), placebo administrations will also be used to mask the 
weekly loading doses and the different dose levels of active IMP. 
Abbreviations: AD = atopic dermatitis; N = number of subjects; 
SC = subcutaneously; Q2W = every 2 weeks; W = Week. 
 
This is a phase 2b, randomized, double-blind, placebo-controlled, multi-site, 
parallel-group, dose-finding trial to evaluate the efficacy and safety of 
different doses of SC administered LEO 138559 in adult subjects with 
moderate-to-severe atopic dermatitis. 
The trial will consist of a screening period of up to 4 weeks (including an 
applicable washout period of 1 week for topical AD treatment), a treatment 
period of 16 weeks, and a 16-week follow-up period. Assessments will 
include efficacy, safety, pharmacokinetics (PK), and anti-drug antibodies 
(ADAs) assessments.  
At the start of the washout period, subjects will stop any treatment with 
topical corticosteroids (TCS), topical calcineurin inhibitors (TCI), topical 
phosphodiesterase 4 (PDE-4) inhibitors, topical JAK inhibitors, or other 
medicated topical treatments. Subjects should continue using their current 
daily skin care moisturizing routine from screening throughout the trial (until 
Week 32), if approved by the investigator, who will otherwise make an 
alternative suggestion. 
At Day 1 (baseline), eligible subjects will be randomized 1:1:1:1:1 to 1 of 
5 dose regimens: LEO 138559 (4 different dose regimens) or placebo. 
Brief summary 
The purpose of this trial is to compare the efficacy, health-related quality of 
life, and safety of LEO 138559 with placebo administered as subcutaneous 
injections in adult subjects with moderate-to-severe atopic dermatitis. The 
treatment will be initiated with loading doses within the first 4 weeks and 
followed by dosing every 2 weeks for the rest of the treatment period. The 
treatment duration will be 16 weeks, and the trial duration will be up to 36 
weeks. The visit frequency will be weekly, every 2 weeks, or every 4 weeks 
depending on the trial period (screening, treatment period, or follow-up). 
Number of 
subjects 
A total of approximately 250 subjects (at least 25 Japanese subjects) will be 
randomized 1:1:1:1:1 to 1 of 5 treatment groups: LEO 138559 (4 different 
dose regimens) or placebo. 
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Treatment groups 
and duration 
For each subject the trial will last at least 33 weeks and up to 36 weeks, 
including: 
• 
A screening period of up to 4 weeks (from Week -4 up to Week 0) 
including an applicable washout period of 1 week for topical AD 
treatment (from Week -1 up to Week 0). 
• 
A treatment period of 16 weeks (from Week 0 up to Week 16) with 
subjects randomized into 1 of 4 active treatment groups or a placebo 
treatment group. 
• 
A follow-up period of 16 weeks (from Week 16 up to Week 32) for the 
assessment of efficacy, safety, PK, and ADAs. 
 
4 different LEO 138559 dose regimens and 1 placebo regimen of bi-weekly 
SC injections, each with a preceding loading dose regimen, will be tested: 
• 
Dose regimen 1: LEO 138559 
 mg SC Weeks 0, 1, 2, 3 and then 
 mg SC Q2W from Week 4 (50 subjects). 
• 
Dose regimen 2: LEO 138559 
 mg SC Weeks 0, 1, 2 and then 
 mg 
SC Q2W from Week 4 (50 subjects). 
• 
Dose regimen 3: LEO 138559 
 mg SC Weeks 0 and 2 and then 
 mg SC Q2W from Week 4 (50 subjects). 
• 
Dose regimen 4: LEO 138559 
 mg SC Weeks 0 and 2 and then 
 mg SC Q2W from Week 4 (50 subjects). 
• 
Placebo regimen: Placebo SC Weeks 0, 1, 2, 3 and then placebo SC Q2W 
from Week 4 (50 subjects). 
DMC / Other 
Committee 
No 
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1.2 
Schematic of trial design 
The trial design is illustrated in Panel 1 and described in Section 4.1. 
Panel 1: Trial design 
 
In addition to placebo administrations to subjects in the placebo group (at Weeks 0, 1, 2, 3, 4, 6, 8, 10, 12, 14), 
placebo administrations will also be used to mask the weekly loading doses, and the different dose levels of 
active IMP. 
Abbreviations: AD = atopic dermatitis; N = number of subjects; SC = subcutaneously; Q2W = every 2 weeks; 
W = Week. 
 
 
 
TMF-000757181 - Version 5.0

 
 
 
 
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1.3 
Schedule of activities 
Panel 2 presents schedule of trial activities specific for CA, JP, UK and US. For schedule of trial activities specific for EU 
countries i.e. CZ, DE, ES, FR, HU, PL and RO, see Section 12.5.1.1 (Panel 18). 
Panel 2: Schedule of trial activities 
 
 
 
 
Early 
term, 
if 
app.b),
c),d) 
 
Protocol 
section 
 
Screeninga) 
Treatment period 
Follow-up 
Uns. 
visit
e) 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13/ 
EoTb) 
14 
15 
16 
17b),c) 
 
 
 
Week 
-4 
-1 
0 
1 
2 
3 
4 
6 
8 
10 
12 
14 
16b) 
20 
24 
28 
32 
 
 
 
Day 
-28 
-7 
1 
8 
15 
22 
29 
43 
57 
71 
85 
99 
113 
14
1 
16
9 
197 
225 
 
 
 
Visit window 
(days)f)  
NA 
-3 
NA 
±1 
±1 
±1 
±1 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
 
 
 
Administrative and baseline procedures 
Informed consentg) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
App 1 
(12.1.3) 
Subject eligibility 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.2 and 
5.3 
Demographics  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.2.1 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.2.2 
Body measurement 
(height)  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.2.3 
Serum pregnancy 
testh) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.2.5 
C-SSRS 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.2.4 
TMF-000757181 - Version 5.0

 
 
 
 
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Early 
term, 
if 
app.b),
c),d) 
 
Protocol 
section 
 
Screeninga) 
Treatment period 
Follow-up 
Uns. 
visit
e) 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13/ 
EoTb) 
14 
15 
16 
17b),c) 
 
 
 
Week 
-4 
-1 
0 
1 
2 
3 
4 
6 
8 
10 
12 
14 
16b) 
20 
24 
28 
32 
 
 
 
Day 
-28 
-7 
1 
8 
15 
22 
29 
43 
57 
71 
85 
99 
113 
14
1 
16
9 
197 
225 
 
 
 
Visit window 
(days)f)  
NA 
-3 
NA 
±1 
±1 
±1 
±1 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
 
 
 
Treatments and randomization 
Randomization 
 
 
Xk) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.3 
IMP 
administrationo) and 
compliance 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
(X) 
6.2 and 
6.8.3 
Background 
treatment 
(moisturizer)i) 
<================================================================================> 
 
 
6.4 
Concomitant 
medicationj) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(X) 
6.6 
Concurrent 
proceduresj) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(X) 
6.6 
Assessments of efficacy: Investigator assessments 
EASI 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(X) 
8.3.1 
SCORAD 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(X) 
8.3.2 
vIGA-AD 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(X) 
8.3.3 
Assessments of efficacy: Subject assessments 
eDiary hand-
out/training 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Early 
term, 
if 
app.b),
c),d) 
 
Protocol 
section 
 
Screeninga) 
Treatment period 
Follow-up 
Uns. 
visit
e) 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13/ 
EoTb) 
14 
15 
16 
17b),c) 
 
 
 
Week 
-4 
-1 
0 
1 
2 
3 
4 
6 
8 
10 
12 
14 
16b) 
20 
24 
28 
32 
 
 
 
Day 
-28 
-7 
1 
8 
15 
22 
29 
43 
57 
71 
85 
99 
113 
14
1 
16
9 
197 
225 
 
 
 
Visit window 
(days)f)  
NA 
-3 
NA 
±1 
±1 
±1 
±1 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
 
 
 
Return of eDiary 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
eDiary completionl) 
 
<================================================================================> 
===> 
 
8.3.5.1 
DLQI 
 
 
X 
X 
 
 
X 
 
X 
 
X 
X 
X 
 
 
 
 
(X) 
(X) 
8.3.5.6 
POEM 
 
 
X 
X 
 
 
X 
 
X 
 
X 
X 
X 
 
 
 
 
(X) 
(X) 
8.3.5.7 
EQ-5D-5L  
 
 
X 
 
 
 
X 
 
X 
 
X 
X 
X 
 
 
 
 
(X) 
(X) 
8.3.5.8 
WPAI-SHP 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
(X) 
(X) 
8.3.5.9 
HADS 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
(X) 
(X) 
8.3.5.10 
PGI-Sm) 
 
 
X 
 
 
 
X 
 
X 
 
X 
X 
X 
 
 
 
 
(X) 
(X) 
8.3.5.11 
PGI-Cn) 
 
 
 
 
 
 
X 
 
X 
 
X 
X 
X 
 
 
 
 
(X) 
(X) 
8.3.5.12 
Assessments of safety 
Vital signso) 
X 
 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
 
 
X 
(X) 
(X) 
8.4.1 
Physical 
examination 
X 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
(X) 
(X) 
8.4.2 
Body measurement 
(weight) 
X 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
(X) 
(X) 
8.4.3 
ECG 
X 
 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
(X) 
(X) 
8.4.4 
AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
10 
TMF-000757181 - Version 5.0

 
 
 
 
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Version: 8.0 
Date: 28-Jun-2024 
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Early 
term, 
if 
app.b),
c),d) 
 
Protocol 
section 
 
Screeninga) 
Treatment period 
Follow-up 
Uns. 
visit
e) 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13/ 
EoTb) 
14 
15 
16 
17b),c) 
 
 
 
Week 
-4 
-1 
0 
1 
2 
3 
4 
6 
8 
10 
12 
14 
16b) 
20 
24 
28 
32 
 
 
 
Day 
-28 
-7 
1 
8 
15 
22 
29 
43 
57 
71 
85 
99 
113 
14
1 
16
9 
197 
225 
 
 
 
Visit window 
(days)f)  
NA 
-3 
NA 
±1 
±1 
±1 
±1 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
 
 
 
Laboratory tests 
Hepatitis B and C, 
HIV 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.2.5 
Tuberculosis test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.2.5 
Chemistry and 
hematology (central 
laboratory)   
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
X 
 
 
X 
(X) 
(X) 
8.4.5 
IgE 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
X 
 
 
X 
(X) 
(X) 
8.4.5 
Urinalysis (urine 
dipstick) 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
X 
 
 
X 
(X) 
(X) 
8.4.5 
Urine pregnancy 
test 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
(X) 
(X) 
8.4.5 
ADA 
 
 
X 
 
X 
 
 
 
 
 
 
 
X 
X 
 
 
X 
(X) 
(X) 
8.4.6 
Other assessments: Pharmacokinetics 
Blood sample 
(LEO 138559 serum 
concentration)p) 
 
 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
 
X 
(X) 
(X) 
8.5 
TMF-000757181 - Version 5.0

 
 
 
 
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Early 
term, 
if 
app.b),
c),d) 
 
Protocol 
section 
 
Screeninga) 
Treatment period 
Follow-up 
Uns. 
visit
e) 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13/ 
EoTb) 
14 
15 
16 
17b),c) 
 
 
 
Week 
-4 
-1 
0 
1 
2 
3 
4 
6 
8 
10 
12 
14 
16b) 
20 
24 
28 
32 
 
 
 
Day 
-28 
-7 
1 
8 
15 
22 
29 
43 
57 
71 
85 
99 
113 
14
1 
16
9 
197 
225 
 
 
 
Visit window 
(days)f)  
NA 
-3 
NA 
±1 
±1 
±1 
±1 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
 
 
 
Other assessments: Pharmacodynamics 
Blood sample  
(biomarkers) 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
 
(X) 
(X) 
8.6 
Skin swabs 
(Staphylococcus 
aureus abundance) 
and microbiome 
profiling 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
(X) 
(X) 
8.6 
Skin tape strips 
(molecular profile)q)  
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
(X) 
(X) 
8.6 
Skin biopsies 
(biomarker 
expression)r) 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
8.6 
TMF-000757181 - Version 5.0

 
 
 
 
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Early 
term, 
if 
app.b),
c),d) 
 
Protocol 
section 
 
Screeninga) 
Treatment period 
Follow-up 
Uns. 
visit
e) 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13/ 
EoTb) 
14 
15 
16 
17b),c) 
 
 
 
Week 
-4 
-1 
0 
1 
2 
3 
4 
6 
8 
10 
12 
14 
16b) 
20 
24 
28 
32 
 
 
 
Day 
-28 
-7 
1 
8 
15 
22 
29 
43 
57 
71 
85 
99 
113 
14
1 
16
9 
197 
225 
 
 
 
Visit window 
(days)f)  
NA 
-3 
NA 
±1 
±1 
±1 
±1 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
 
 
 
Other assessments: Photography 
Photographys) 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
(X) 
(X) 
8.7.1 
Qualitative interviews in CA, UK and USt) 
Scheduling 
interview 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
8.7.2 
Clinigma to conduct 
trial interviews 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
8.7.2 
End of treatment/trial 
End of treatmentu) 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
(X) 
8.8 
End of trialv) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Xw) 
(X) 
8.8 
a) The screening period has a maximum duration of 4 weeks, with 2 planned visits. Visit 2 can be conducted by phone or on site. 
b) Subjects who permanently discontinue IMP for any reason will be asked to attend an early termination visit as soon as possible after discontinuation of 
IMP. Subjects should be encouraged to attend all trial visits and be assessed for safety and efficacy according to the schedule of assessments. For subjects 
who no longer wish to attend all trial visits, the following visits should be prioritized: The primary endpoint visit (i.e. the Week 16 visit) and a final follow-
up visit 18 weeks after last administration of IMP (with assessments identical to those to be done at the regular Week 32 visit).  
c) Subjects who withdraw from the trial prior to Week 16 will be asked to attend an early termination visit as soon as possible after withdrawal (with 
assessments identical to those to be done at the regular Week 32 visit). 
d) Some assessments to be performed at early termination visits will be at the discretion of the investigator. These are marked with an (X) in the table.     
e) Assessments to be performed at unscheduled visits will be at the discretion of the investigator (marked with an (X) in the table). 
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f) 
If the date of a trial visit does not conform to the clinical trial protocol, subsequent visits should be planned to maintain the visit schedule relative to 
randomization/baseline. 
g) The ICF must be signed prior to performing any protocol-related procedures, including, but not limited to, screening evaluations and washout of prohibited 
medications. 
h) Only for women of childbearing potential (as defined in inclusion criterion no. 10). 
i) 
Subjects should continue using their current daily skin care moisturizing routine from screening throughout the trial (until Week 32), if approved by the 
investigator, who will otherwise make an alternative suggestion. 
j) 
Any medication, vaccine, or procedure received/performed from 3 months (12 months for medications related to AD) prior to screening through end of 
trial must be recorded. 
k) In order to ensure a sufficient number of subjects naive for biologics and systemic JAK inhibitors used for their AD, there will be a capping at 50% of 
subjects who received prior treatment with such therapies. These capping criteria will also apply for Japanese subjects. 
l) 
Nocturnal 
, Difficulty 
, and Frequency of 
 During the Night (to be completed in the morning), and ADSD (to be 
completed in the evening) will be initiated at least 7 days prior to baseline (Day 1) and will be completed in the eDiary daily. After Week 16, only ADSD 
will be completed. Subjects who discontinue IMP, but remain in the trial, will continue completing the eDiary until the Week 16 visit. 
m) PGI-S includes: 
, ADSD, Nocturnal 
, Difficulty 
, and Frequency of 
 During the Night. 
n) PGI-C includes: 
, ADSD, Nocturnal 
, Difficulty 
, and Frequency of 
 During the Night. 
o) Vital signs must be assessed prior to IMP administration. In addition, at Weeks 0, 1, 2, 3, and 4, subjects will be monitored after IMP administration for 
potential immediate drug reactions for a minimum of 2 hours with vital signs taken immediately (within 5 minutes) after last IMP administration as well as 
after 30 minutes (± 5 minutes), after 1 hour (± 5 minutes), and after 2 hours (± 5 minutes), or until stable, whichever is later. 
p) Samples to be collected pre-dose. 
q) Skin tape strips will be collected at selected trial sites. 
r) 
Skin biopsies will be collected at selected trial sites. It is voluntary for subjects at these sites to have skin biopsies collected, and if done, they will need to 
have provided informed consent to this component. Paired lesional and non-lesional biopsies will be collected at baseline. At the post-baseline visit, 
1 biopsy will be collected from the original lesion; no skin biopsy will be collected from non-lesional skin at the post-baseline visit. 
s) 
Photography will be performed at selected trial sites. It is voluntary for subjects at these sites to have photographs taken, and if done, they will need to 
have provided informed consent to this component. 
t) 
Interviews will be conducted at selected trial sites. The interview will be scheduled to occur as soon as possible and within 14 days after Week 14 
(Visit 12). 
u) An end-of-treatment form must be completed once in the eCRF for all subjects exposed to IMP either at Week 16 or early termination.  
v) An end-of-trial form must be completed in the eCRF for all subjects randomized and/or exposed to IMP. 
w) Only applicable to subjects who withdraw from the trial prior to Week 16. 
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Abbreviations: AD = atopic dermatitis; ADA = anti-drug antibodies; ADSD = Atopic Dermatitis Symptom Diary; AE = adverse event; app = applicable; 
CA = Canada; C-SSRS = Columbia-Suicide Severity Rating Scale; DLQI = Dermatology Life Quality Index; EASI = Eczema Area and Severity Index; 
ECG = electrocardiogram; eCRF = electronic case report form; eDiary = electronic diary; EoT = end-of-treatment; EQ-5D-5L = EuroQoL 5-Dimension Health 
Questionnaire 5 Level; HADS = Hospital Anxiety and Depression Scale; HIV = human immunodeficiency virus; ICF = informed consent form; 
IgE = immunoglobulin E; IMP = investigational medicinal product; JAK = janus kinase; NA = not applicable; PGI-C = Patient Global Impression of Change; 
PGI-S =  Patient Global Impression of Severity; POEM = Patient-Oriented Eczema Measure; SCORAD = SCORing Atopic Dermatitis; term = termination; 
Uns = unscheduled; UK = United Kingdom; US = United States; vIGA-AD = validated Investigator’s Global Assessment for atopic dermatitis; WPAI-SHP = 
Work Productivity and Activity Impairment: Specific Health Problem.
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2 
Introduction and trial rationale 
2.1 
Atopic dermatitis 
AD is a chronic inflammatory skin disease characterized by recurrent widespread inflamed 
and dry skin lesions, intractable itch, and increased susceptibility to bacterial, viral, and 
fungal skin infections (2-5). The clinical course of AD typically follows a chronic, relapsing-
remitting pattern with periods of worsening (‘flares’). AD lesions are accompanied by intense 
pruritus and sometimes skin pain leading to poor quality of life, sleep deprivation, mood 
changes, and lost productivity (6-8). AD is the most common inflammatory skin disorder with 
a lifetime prevalence of 15–20% (9). While AD was initially thought to be a disease of early 
childhood, more recent evidence demonstrates adult annual prevalence rates up to 10%, and 
1 in 4 adults with AD report adult-onset disease (2, 10).  
AD is a heterogenous disease mediated by varying degrees of epidermal barrier disruption, 
immune cell activation, and microbiome dysbiosis. Epidermal barrier disruption leads 
keratinocytes to express chemokines and cytokines that activate APCs and recruit Th2 cells 
and innate lymphoid cells (11, 12). These cells amplify the type 2 immune response by 
secreting IL-4, IL-5, and IL-13 (13-15). As AD progresses from acute to chronic, a mixed 
T cell infiltrate including Th17 and Th22 cells develops (16). These cells secrete IL-17 and 
IL-22, which have been reported to play a role in AD pathogenesis (17, 18). Whether IL-22 is 
a key driver of AD pathogenesis remains unknown. 
Topical therapies are the mainstay of treatment for AD and include moisturizers, TCS, TCI, 
and PDE-4 inhibitors (19). The topical JAK inhibitor ruxolitinib (cream) has received 
marketing approval in the US (20, 21), and the topical JAK inhibitor delgocitinib (ointment) 
has received marketing approval in Japan (22, 23). If disease control cannot be achieved with 
topical treatments, phototherapy can be considered (24).  
For patients with moderate-to-severe AD, topical therapy and phototherapy are often 
insufficient or impractical, and therefore systemic therapy is indicated. Conventional systemic 
therapies that patients are generally started on include cyclosporine, azathioprine, 
methotrexate, and mycophenolate mofetil. Cyclosporine is approved for the treatment of 
severe AD in multiple European countries and Japan. However, its use is limited by the risk of 
nephrotoxicity and therefore long-term therapy (>1-2 years) is not recommended. 
Azathioprine, methotrexate, and mycophenolate mofetil have demonstrated varying levels of 
efficacy (25, 26) and are used off-label. For patients who do not respond to these conventional 
systemic therapies or for whom these therapies are contraindicated, biologics are usually 
considered first line, both in Europe and the US. In 2017, the first biologic was approved for 
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the treatment of moderate-to-severe AD (dupilumab, anti-IL-4Rα mAb) (27-29). 
Tralokinumab (anti-IL-13 mAb) was approved in Europe and the US (30-32) in 2021, and 
was approved in Japan in 2022 (33). Also in 2022, nemolizumab was approved in Japan for 
the treatment of itching associated with AD (34). In addition, several targeted biologic 
therapies are in development for AD, including lebrikizumab and nemolizumab (35, 36). 
Second line therapies for patients not responding to conventional systemics or biologics, or 
for whom those therapies are contraindicated, are the JAK inhibitors. Several JAK inhibitors 
have been approved in Europe, the US, and Japan (34, 37-46). However, use of systemic JAK 
inhibitors has been associated with safety concerns and limited knowledge is currently 
available on safety with long-term use (47, 48). 
2.2 
Experience with IMP 
2.2.1 
Non-clinical data 
2.2.1.1 
Pharmacology 
LEO 138559 binds to the IL-22RA1 with a dissociation constant of  pM (assessed by surface 
plasmon resonance). LEO 138559 inhibits the binding of IL-22 to its receptor with a 
half-maximal inhibitory concentration value of 
 pM measured by blockade of induction of 
 release, and thereby leads to full inhibition of the 
signaling induced by IL-22 in human primary dermal keratinocytes. An approximate 1:1 ratio 
between binding and inhibition is demonstrated. Importantly, LEO 138559 inhibits IL-22 
induced signals in intact human skin in a reconstructed 3D skin equivalent skin model. In this 
skin model, LEO 138559 reverses both inflammatory markers, and normalizes skin barrier 
markers. Furthermore, LEO 138559 inhibits 
 signaling in cells harboring the 
IL-22RA1:IL-20R2 dimer. LEO 138559 is devoid of any agonistic potential. 
Species cross reactivity was shown by similar binding of LEO 138559 to cynomolgus, rhesus 
monkey, and human IL-22RA1, whereas no binding to rodent, dog, or rabbit IL-22RA1, and 
only very weak binding to pig IL-22RA1, was observed. Furthermore, functional inhibition of 
cynomolgus IL-22RA1 was demonstrated in both transfected cells and intact cynomolgus skin 
ex vivo stimulated by IL-22. Lastly, LEO 138559 also lowered the imiquimod-induced skin 
inflammatory phenotype in cynomolgus monkeys. 
The risk of adverse Fc effector function of LEO 138559, such as Ab-dependent cellular 
cytotoxicity or complement-dependent cytotoxicity, is low as it has been demonstrated that 
there is no or very weak binding to FcγRs and low complement fixation potential. 
A detailed overview of non-clinical data on LEO 138559 is available in the current 
investigator’s brochure (49). 
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2.2.1.2 
PK 
The non-clinical PK of LEO 138559 was assessed in cynomolgus monkeys following single 
and multiple IV and SC administrations. 
LEO 138559 displayed typical IgG kinetics with a half-life of approximately 
 days and 
linear kinetics at higher doses but with a more than dose-proportional decrease in exposure 
(AUC) at lower doses due to TMDD. The absolute SC bioavailability of LEO 138559 at the 
100 mg/kg/week dose level was 
 for males and 
 for females. 
In all toxicology studies, except for 1 monkey in the 26-week study with high ADA titres, 
sufficient and sustained exposure to LEO 138559 was demonstrated at all dose levels 
throughout the entire dosing period with no indication of ADA formation affecting exposure 
or causing adverse effects. 
A detailed overview of non-clinical data on LEO 138559 is available in the current 
investigator’s brochure (49). 
2.2.1.3 
Toxicology 
The cynomolgus monkey was chosen as the most relevant non-clinical species for evaluation 
of local and systemic toxicities of LEO 138559, which was shown to bind to the cynomolgus 
monkey IL-22R with near-equivalent potency as compared with the human IL-22R. 
LEO 138559 is also pharmacodynamically active in cynomolgus monkeys, as shown by its 
ability to reduce imiquimod-induced skin thickness and reverse IL-22-mediated filaggrin-2 
mRNA reduction. 
Following multiple SC or IV doses of LEO 138559 in cynomolgus monkeys, there were no 
local or systemic toxicities, resulting in a NOAEL of 100 mg/kg/week, the highest dose tested 
(based on studies of 4- and 26-weeks of dosing duration). 
The 26-week cynomolgus study used sexually mature animals and included a fertility 
assessment. In males, there were no effects on sperm motility, sperm morphology, or testicular 
spermatogenesis. In females, menstrual cycle data were not affected by administration of 
LEO 138559.  
There were no LEO 138559-related effects on safety pharmacology endpoints evaluating the 
respiratory, cardiovascular, and central nervous systems in repeated-dose toxicity studies in 
cynomolgus monkeys at doses up to 100 mg/kg (SC and IV).   
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No evidence of immunotoxicity or generalized immune suppression was found in cynomolgus 
monkeys, with assessments including standard hematology, immunophenotyping, immune 
organ histopathology, and functional assessment. Due to the absence of IL-22RA1 on immune 
cells and lack of Ab effector function, no immunosuppression is expected upon IL-22RA1 
blocking.  
In a cytokine release assay, LEO 138559, either immobilized or soluble, did not stimulate the 
release of pro-inflammatory cytokines or chemokines at any test concentration (up to 
100 µg/mL). 
In conclusion, the LEO 138559 non-clinical data indicated a toxicity profile that is amenable 
to clinical monitoring, is of low concern for human risk, and provides an approximate 
-fold 
margin of exposure between the NOAEL and the expected human exposure at steady state 
following 
 mg Q2W dosing. 
A detailed overview of non-clinical data on LEO 138559 is available in the current 
investigator’s brochure (49). 
2.2.2 
Clinical data 
To date, clinical data are available from 3 completed trials (defined as trials with a final 
clinical trial report); a phase 1 FiH trial (LP0145-1315), a phase 1 PK and safety trial 
(LP0145-1486) in Japanese subjects living in the US, and a phase 2a trial (LP0145-1376). 
LP0145-1315 was a phase 1, randomized, double-blind, placebo-controlled, multi-center, 
SAD, and MAD trial that evaluated the safety, tolerability, PK, and PD of LEO 138559 in 
healthy volunteers and subjects with moderate-to-severe AD. The trial consisted of 2 parts: 
SAD and MAD.  
In the LP0145-1315 trial, single IV doses up to 
 mg LEO 138559 or placebo and single SC 
doses up to 
 mg LEO 138559 or placebo were administered to healthy subjects. 
LEO 138559 or placebo were administered SC as once weekly doses in healthy subjects 
(
 mg) and in AD subjects (
 and 
 mg) for 5 weeks. In total, 35 subjects were dosed 
with LEO 138559 in this trial. In AD subjects, a reduction in disease severity based on 
individual EASI scores was observed for LEO 138559 (both the 
 mg and 
 mg QW 
dose regimens) compared with placebo. No SAEs and no AE patterns giving rise to any 
concerns were reported. No risks for humans were identified at the dose levels tested.  
Prior to LP0145-1315, there was no clinical experience of administering LEO 138559 to 
humans. However, the anti-IL-22 mAb fezakinumab (ILV-094, Pfizer) was well tolerated 
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when administered IV to AD subjects and improved disease scores in subjects with severe AD 
after 12 weeks in a phase 2a trial (50). Fezakinumab was also well tolerated in a safety and 
efficacy trial where it was administered SC in rheumatoid arthritis patients on a stable 
background of methotrexate (51). 
The LP0145-1486 trial was a phase 1 clinical trial conducted in 24 Japanese healthy 
volunteers with the aim of evaluating the PK and safety of single SC administration of 
LEO 138559 (
 mg, 
 mg, or 
 mg) or placebo. In this trial, the PK was as expected 
for the population. TMDD was observed at the lowest dose level (
 mg). As a result of 
 dependency of the PK of LEO 138559, higher serum concentration was observed 
in Japanese subjects as compared to non-Japanese subjects due to a lower 
 of 
Japanese subjects. However, Japanese subjects are expected to have the same exposure as 
non-Japanese subjects if the 
 is the same, and the benefit/risk profile is thus not 
changed for Japanese subjects. 
In a phase 2a trial (LP0145-1376), adults with moderate-to-severe AD were treated with LEO 
138559 or placebo. A total of 58 subjects were randomized 1:1 into the 2 treatment groups, 
either LEO 138559 450 mg Q2W (with an additional LEO 138559 450 mg administration at 
Week 1) or placebo Q2W (with an additional placebo administration at Week 1), to evaluate 
the safety and efficacy over a treatment period of 16 weeks, followed by a 16-week follow-up 
period. The primary endpoint was change from baseline in EASI score at Week 16. The 
secondary endpoint was the number of TEAEs from baseline to Week 16. In this phase 2a 
trial, the primary endpoint was met, with a statistically significant improvement in EASI score 
at Week 16 in the LEO 138559 450 mg Q2W group versus placebo. Fewer subjects in the 
LEO 138559 group (7 subjects) than in the placebo group (11 subjects) discontinued IMP 
and/or withdrew from the trial. The most frequent reasons for IMP discontinuation were: AEs 
in the LEO 138559 group (6 subjects, of which 4 had AEs related to COVID-19 infection) 
and withdrawal by subject in the placebo group (7 subjects). Note that as per protocol, 
subjects that were positive for SARS-CoV-2 (COVID-19) had to permanently discontinue 
IMP. No SAEs and no AE patterns giving rise to any concerns were reported.  
2.2.3 
PK 
Based on the human PK data from the LP0145-1315, LP0145-1486 and LP0145-1376 trials, 
the PK of LEO 138559 is as expected for a mAb directed towards a membrane-bound target, 
and the TMDD characteristics are also visible in the observed human data as it was in the 
cynomolgus data. 
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After SC administration, LEO 138559 is slowly absorbed with a mean time to maximum 
concentration of approximately 
 days. After multiple dosing, the elimination half-life was 
observed to be between 
 days. At and above the exposure level relevant for clinical 
testing (dose ≥
 mg Q2W), the elimination is dominated by linear clearance and close to 
dose proportionality is expected at steady state. Following administration of 
 mg Q2W, 
average Ctrough at steady state was approximately 
 µg/mL with a maximum observed value 
of 
 µg/mL. 
A detailed overview of clinical data on LEO 138559 is available in the current investigator’s 
brochure (49). 
2.3 
Trial rationale 
Despite the recent improvements in treatment, there still remains an unmet need for more 
safe, long-term treatment options for patients with moderate to-severe AD. Management of 
moderate-to-severe AD is challenging because of the chronicity of the disease and the limited 
therapeutic options that are both efficacious and have an acceptable long-term safety profile. 
A ‘control-based’ and ‘risk-based’ model of disease management in which an initial diagnosis 
is followed by treatment according to categorization of severity is usually recommended. The 
pharmacological treatment algorithm for AD progresses from mild topical anti-inflammatory 
therapy to high-potency topical anti-inflammatory therapy, and in more severe cases leads to 
systemic immunomodulating therapy. In general, the national treatment guidelines 
recommend the use of systemic treatment in patients who are refractory to optimized topical 
therapies (24, 52-55). 
Despite promising efficacy, the dupilumab pivotal trials showed that more than 60% of the 
trial participants with AD did not meet the primary endpoint of IGA 0/1 or clear/almost clear 
skin (56). Further, tralokinumab and JAK inhibitors have been recently approved, but even 
with those advances, there remains an unmet need for new therapies with improved efficacy 
and/or safety. Further, it is increasingly recognized that AD is a phenotypically and 
molecularly heterogenous disease that may require differentiated and/or combined therapeutic 
approaches in order to adequately address the needs of moderate-to-severe AD patients (57, 
58). 
LEO 138559 is a mAb that binds to the IL-22RA1 chain of the IL-22 receptor, thereby 
blocking the binding of the ligand (IL-22), dimerization of IL-22RA1 with IL-10R2, and 
downstream signaling via JAK1-STAT3 (59). LEO 138559 does not bind to the IL-22BP 
(IL-22RA2) thereby leaving its IL-22 inhibitory capacity intact (60). 
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The results from the LP0145-1315, phase 1, FiH trial indicated a clinical effect of both 
 mg and 
 mg QW for up to 5 weeks in moderate-to-severe AD subjects followed for 
17 weeks. In addition, the results from the LP0145-1376, phase 2a, proof-of-concept trial 
showed evidence of a clinical effect seen in the LEO 138559 450 mg Q2W group versus 
placebo in adult subjects with moderate-to severe-AD, meeting the primary endpoint 
(improvement in EASI score) and with no major safety concerns identified.  
In summary, based on the mode of action of LEO 138559, and the findings in the phase 1 and 
phase 2a trials, it is expected that LEO 138559 is a safe and efficacious treatment for patients 
with moderate-to-severe AD. 
All doses studied so far have had an acceptable benefit/risk profile and no major safety 
concerns have been identified. 
2.4 
Ethical considerations 
This trial will be conducted in accordance with the ethical principles originating from the 
Declaration of Helsinki (61) and ICH GCP (1) and in compliance with the approved protocol 
and applicable regulatory requirements. 
The trial design is considered scientifically justified and considered to adhere to ethical 
standards ensuring the rights, safety, and well-being of the subject. The efficacy and safety of 
LEO 138559 will be evaluated in adults with moderate-to-severe AD who may benefit from 
treatment with LEO 138559. Appropriate measures will be taken to protect the subject from 
potential risks related to treatment with LEO 138559 and to closely monitor the subject, with 
weekly visits for the first 4 weeks, followed by visits Q2W, and with regular laboratory tests, 
ECG, and vital signs. In addition, at Weeks 0, 1, 2, 3, and 4, subjects will be monitored for a 
period of 2 hours to detect potential immediate drug reactions (for requirements specific for 
EU countries i.e. CZ, DE, ES, FR, HU, PL and RO, see Section 12.5.1). 
Participation in the trial is voluntary and the subject can discontinue IMP and/or withdraw 
from the trial at any time. If a subject is withdrawn from the trial, they will be treated at the 
discretion of the investigator or referred to (an)other physician(s) according to standard 
practice. 
Women who are pregnant (or trying to become pregnant) and women who are breastfeeding 
will not be included in the trial. Women of childbearing potential must agree to use a highly 
effective form of contraception to prevent pregnancy during the trial. In addition, pregnancy 
tests for all women of childbearing potential will frequently be conducted during the trial to 
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detect any pregnancies. Subjects will permanently discontinue IMP in the event of evidence 
of pregnancy. 
Subjects not able to provide informed consent will not be included in the trial. 
In accordance with the current version of ICH and GCP guidelines, qualified medical 
personnel employed by LEO Pharma will be readily available to advise on trial-related 
medical questions. Medical monitoring will be conducted throughout the trial. Safety data will 
be reviewed by qualified personnel to ensure that prompt action is taken, if needed, to protect 
the subjects. 
2.5 
Benefit/risk assessment 
There is a clear unmet need for safe, long-term treatment options for subjects with moderate-
to-severe AD, and the novel IL-22RA1 antagonist, LEO 138559, is expected to be efficacious 
in AD treatment. Based on the phase 2a trial meeting the primary endpoint (i.e. LEO 138559 
demonstrating a statistically significant difference compared to placebo in change in EASI 
score from baseline to Week 16), a significant proportion of the subjects are anticipated to 
benefit from participation in the LP0145-2240 trial as 4 in 5 subjects will receive active IMP.  
IL-22R is expressed on epithelial cells and not on immune cells. IL-22 has been shown to be 
involved in the production of antimicrobial peptides in the skin, lungs, and intestines. 
Therefore, when blocking the IL-22 receptor, there is a potential for reduced antimicrobial 
peptide production and consequently a theoretically increased risk of infection. However, 
based on non-clinical studies, LEO 138559 is considered immunomodulatory, but not 
immunosuppressive. Regarding the ability to mount effective Ab immune responses, an 
assessment of the effect of LEO 138559 on the immune response was performed in an 
immunotoxicological study in monkeys. The study concluded that KLH-specific Ab responses 
(IgG and IgM) to the first and second immunizations with KLH occurred in all animals. 
Importantly, no adverse effect on the ability to mount a humoral primary or memory response 
was noted in animals administered up to 100 mg/kg LEO 138559. Further, no indicators of 
immunosuppression (e.g. hematological changes, organ weights, infections, and histology) 
were observed in 4- and 26-week non-clinical toxicology studies.  
The LEO 138559 non-clinical data provides an approximately 
-fold margin of exposure 
between the NOAEL and the expected human exposure at steady state for a dose of 
 mg 
Q2W (the highest dose regimen for LP0145-2240). The safety margin suggests that dosing 
with 
 mg Q2W in patients is safe with negligible risk of systemic toxicity. Considering 
that no adverse findings were observed in the 26-week cynomolgus studies, a safety margin of 
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 is justified and in line with ICHS6 (R1) which recommends a dose which provides an 
approximately 10-fold exposure multiple over the maximum exposure to be achieved in the 
clinic. 
Across the 3 completed trials (LP0145-1315, LP0145-1486, and LP0145-1376), treatment 
with LEO 138559 was safe and well tolerated. No fatal events, no SAEs, no severe AEs, and 
no patterns of AEs considered related to LEO 138559 were observed. There was no apparent 
correlation between AEs and exposure.  
The available aggregate non-clinical and clinical data from LEO 138559 have demonstrated 
that it is well tolerated, and no safety concerns have been identified.  
Risks to subjects in the trial will be minimized by inclusion of subjects fulfilling all eligibility 
criteria (Sections 5.1 to 5.3) and by close clinical monitoring. Discontinuation and withdrawal 
criteria have also been defined.  
The subjects will be informed that changes to their ongoing AD treatment may be required 
during the screening period and that their condition may worsen as a result. To minimize the 
negative consequences of this for the subject and ensure subject safety, investigators will be 
asked only to include subjects who are considered able to discontinue prohibited medications 
during the screening period without experiencing intolerable worsening of AD. 
The subjects will also be informed of the possibility and probability of receiving active or 
placebo treatment. In this trial, approximately 80% of the subjects will receive active 
treatment with LEO 138559. A benefit for all subjects participating in this trial, regardless of 
whether they receive active drug or placebo, is that they receive close monitoring of their 
disease and easy access to specialist care. 
If medically necessary (i.e. due to intolerable AD signs and/or symptoms), rescue treatment of 
AD may be provided to the subject at the discretion of the investigator. The subject will be 
instructed to inform the investigator if their AD significantly worsens at any time during the 
trial. 
Blood sampling presents the same low risk as normally associated with this procedure (i.e. 
bleeding into the surrounding tissue, infection at the site of injection, and, very rarely, 
inflammation of the vein, or formation of blood clots). Blood sampling will only be conducted 
by qualified medical personnel.  
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More detailed information about the known and expected benefits and risks, and reasonably 
expected AEs of LEO 138559 may be found in the investigator’s brochure (49) and informed 
consent form. 
In the event of a significant trial-continuity issue (e.g. caused by a pandemic), alternate 
strategies for subject visits, assessments, and monitoring may be implemented by 
LEO Pharma or the investigator, as per local health authority/ethics requirements 
(Appendix 7 [Section 12.7]). 
The risks associated with participating in the trial are considered low and outweighed by the 
benefit of a potential future SC treatment option for AD. The current benefit-risk profile is 
therefore deemed in favor of conducting this trial. 
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3 
Trial objectives, estimands, and endpoints 
Trial objectives and endpoints are presented in Panel 3. 
An estimand framework is used to ensure that occurrence of intercurrent events is taken into 
account. Further details about the estimands and statistical analyses of the endpoints are 
presented in Panel 4 and in Section 11.  
Panel 3: Objectives and endpoints 
Objectives 
Endpoints 
Primary objective 
 
To compare the efficacy of 4 different 
dose regimens of LEO 138559 with 
placebo in subjects with moderate-to-
severe AD. 
Primary endpoint 
• 
Percent change in EASI score from baseline to 
Week 16. 
Exploratory endpoints (efficacy) 
• 
Achievement of EASI-50 at Week 16. 
• 
Achievement of EASI-75 at Week 16. 
• 
Achievement of EASI-90 at Week 16. 
• 
Achievement of EASI-100 at Week 16. 
• 
Change in EASI score from baseline to Week 16. 
• 
Change in SCORAD score from baseline to 
Week 16. 
• 
Percent change in SCORAD score from baseline to 
Week 16. 
• 
Achievement of vIGA-AD score of 0 (clear) or 1 
(almost clear) at Week 16. 
• 
Change in BSA from baseline to Week 16. 
• 
Percent change in BSA from baseline to Week 16. 
Exploratory endpoints (PROs) 
• 
Reduction of ADSD Worst 
 score (weekly 
average) ≥4 from baseline to Week 16. 
• 
Change in DLQI (and individual domain scores) 
from baseline to Week 16. 
• 
Percent change in DLQI (and individual domain 
scores) from baseline to Week 16. 
• 
Change in POEM score (and individual item scores 
related to itch and sleep) from baseline to Week 16. 
• 
Percent change in POEM score from baseline to 
Week 16. 
• 
Change in EQ-5D-5L index score from baseline to 
Week 16. 
• 
Percent change in EQ-5D-5L index score from 
baseline to Week 16. 
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Objectives 
Endpoints 
• 
Change in EQ-5D-5L VAS score from baseline to 
Week 16. 
• 
Percent change in EQ-5D-5L VAS score from 
baseline to Week 16. 
• 
Change in HADS score from baseline to Week 16. 
• 
Percent change in HADS score from baseline to 
Week 16. 
• 
Change in Difficulty 
 (weekly 
average) from baseline to Week 16. 
• 
Percent change in Difficulty 
 
(weekly average) from baseline to Week 16. 
• 
Change in Nocturnal 
 (weekly average) 
from baseline to Week 16. 
• 
Percent change in Nocturnal 
 (weekly 
average) from baseline to Week 16. 
• 
Change in Frequency of 
 During the 
Night (weekly average) from baseline to Week 16. 
• 
Percent change in Frequency of 
 During 
the Night (weekly average) from baseline to 
Week 16. 
• 
Change in WPAI-SHP domain scores from baseline 
to Week 16. 
• 
Percent change in WPAI-SHP domain scores from 
baseline to Week 16. 
• 
Change in SCORAD Part C (Pruritus VAS) score 
from baseline to Week 16. 
• 
Percent change in SCORAD Part C (Pruritus VAS) 
score from baseline to Week 16. 
Secondary objective 
 
To compare the safety of 4 different 
dose regimens of LEO 138559 with 
placebo in subjects with moderate-to-
severe AD. 
Secondary endpoint 
• 
Number of TEAEs recorded for each subject from 
baseline to Week 16. 
Exploratory endpoint (safety) 
• 
Time from baseline to use of any rescue treatment. 
• 
Number of TEAEs recorded for each subject from 
baseline to Week 32. 
• 
Number of TEAEs recorded for each subject from 
Week 16 to Week 32. 
• 
Having a positive ADA response from baseline to 
Week 32. 
Exploratory objectives 
 
To compare the efficacy of 4 different 
dose regimens of LEO 138559 with 
Exploratory endpoint (PRO) 
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Objectives 
Endpoints 
placebo in subjects with moderate-to-
severe AD, having a weekly average 
ADSD Worst 
 score of ≥4 at 
baseline. 
• 
Reduction of ADSD Worst 
 score (weekly 
average) ≥4 from baseline to Week 16. 
To compare the efficacy of 4 different 
dose regimens of LEO 138559 with 
placebo in subjects with moderate-to-
severe AD, having a DLQI score of 
≥4 at baseline. 
Exploratory endpoint (PRO) 
• 
Reduction of DLQI ≥4 from baseline to Week 16. 
To compare the efficacy of 4 different 
dose regimens of LEO 138559 with 
placebo in subjects with moderate-to-
severe AD, having a POEM score of 
≥4 at baseline. 
Exploratory endpoint (PRO) 
• 
Reduction of POEM ≥4 from baseline to Week 16. 
To evaluate the PK of LEO 138559 in 
subjects with moderate-to-severe AD. 
Exploratory endpoint (PK) 
• 
Serum concentration of LEO 138559 at Weeks 1, 2, 
4, 8, 12, 16, 20, and 32. 
To evaluate the effect of treatment 
with LEO 138559 compared with 
placebo for 16 weeks on biomarkers in 
subjects with moderate-to-severe AD. 
Exploratory endpoints (PD) 
• 
Change in expression of biomarkers in serum from 
baseline to Week 2, Week 4, and to Week 16, 
respectively. 
• 
Change in skin Staphylococcus aureus abundance 
and microbiome profile from baseline to Week 16. 
• 
Change in skin lipid and molecular profile from 
baseline to Week 4, and to Week 16, respectively. 
• 
Change in biomarker expression from baseline to 
Week 16 in lesional skin biopsies. 
Abbreviations: AD = atopic dermatitis; ADA = anti-drug antibodies; ADSD = Atopic Dermatitis Symptom 
Diary; BSA = body surface area; DLQI = Dermatology Life Quality Index; EASI = Eczema Area and 
Severity Index; EASI-50 = at least 50% reduction in EASI score; EASI-75 = at least 75% reduction in EASI 
score; EASI-90 = at least 90% reduction in EASI score; EASI-100 = 100% reduction in EASI score; 
EQ-5D-5L = EuroQoL 5 Dimension Health Questionnaire 5 Level; HADS = Hospital Anxiety and 
Depression Scale; PK = pharmacokinetics, PD = pharmacodynamics; POEM = Patient-Oriented Eczema 
Measure; PRO = patient reported outcome; SCORAD = SCORing Atopic Dermatitis; 
TEAEs = treatment-emergent adverse events; VAS = Visual Analogue Scale; vIGA-AD = validated 
Investigator Global Assessment Scale for Atopic Dermatitis; WPAI-SHP = Work Productivity and Activity 
Impairment: Specific Health Problem. 
 
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Panel 4: Objectives, estimands, and endpoints 
Objectives 
Estimands 
Endpoints 
 
Estimand 
type 
Strategy/ 
Intercurrent 
events 
Target 
population 
Population level 
summary 
 
To compare the 
efficacy of 
4 different dose 
regimens of 
LEO 138559 with 
placebo in 
subjects with 
moderate-to-
severe AD. 
Primary 
estimand for 
continuous 
endpoints 
Hypothetical: 
- Permanent 
discontinuation of 
IMP. 
- Initiation of 
rescue treatment. 
Subjects with 
moderate-to-
severe AD. 
Difference in means 
of the response 
variable between 
the treatment 
conditions. 
Primary endpoint: 
• 
Percent change in EASI score from baseline to 
Week 16. 
Exploratory endpoints: 
• 
Change in EASI score from baseline to Week 16. 
• 
Change in SCORAD score from baseline to 
Week 16. 
• 
Percent change in SCORAD score from baseline to 
Week 16. 
• 
Change in BSA from baseline to Week 16. 
• 
Percent change in BSA from baseline to Week 16. 
• 
Change in DLQI (and individual domain scores) 
from baseline to Week 16. 
• 
Percent change in DLQI (and individual domain 
scores) from baseline to Week 16. 
• 
Change in POEM score (and individual item scores 
related to itch and sleep) from baseline to Week 16. 
• 
Percent change in POEM score from baseline to 
Week 16. 
• 
Change in EQ-5D-5L index score from baseline to 
Week 16. 
• 
Percent change in EQ-5D-5L index score from 
baseline to Week 16. 
• 
Change in EQ-5D-5L VAS score from baseline to 
Week 16. 
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Objectives 
Estimands 
Endpoints 
 
Estimand 
type 
Strategy/ 
Intercurrent 
events 
Target 
population 
Population level 
summary 
 
• 
Percent change in EQ-5D-5L VAS score from 
baseline to Week 16. 
• 
Change in HADS score from baseline to Week 16. 
• 
Percent change in HADS score from baseline to 
Week 16. 
• 
Change in Difficulty 
 (weekly 
average) from baseline to Week 16. 
• 
Percent change in Difficulty 
 (weekly 
average) from baseline to Week 16. 
• 
Change in Nocturnal 
(weekly average) 
from baseline to Week 16.  
• 
Percent change in Nocturnal 
 (weekly 
average) from baseline to Week 16.  
• 
Change in Frequency of 
 During the 
Night (weekly average) from baseline to Week 16. 
• 
Percent change in Frequency of 
 During 
the Night (weekly average) from baseline to 
Week 16. 
• 
Change in WPAI-SHP domain from baseline to 
Week 16. 
• 
Percent change in WPAI-SHP domain from baseline 
to Week 16. 
• 
Change in SCORAD Part C (Pruritus VAS) score 
from baseline to Week 16. 
• 
Percent change in SCORAD Part C (Pruritus VAS) 
score from baseline to Week 16. 
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Objectives 
Estimands 
Endpoints 
 
Estimand 
type 
Strategy/ 
Intercurrent 
events 
Target 
population 
Population level 
summary 
 
Suppl. 
estimands 
for 
continuous 
endpoints 
Hypothetical 
supplementary: 
- Permanent 
discontinuation of 
IMP. 
- Initiation of 
rescue treatment. 
Primary endpoint: 
• 
Percent change in EASI score from baseline to 
Week 16. 
Exploratory endpoints: 
• 
Change in EASI score from baseline to Week 16. 
• 
Change in SCORAD score from baseline to 
Week 16. 
• 
Percent change in SCORAD score from baseline to 
Week 16. 
• 
Change in BSA from baseline to Week 16. 
• 
Percent change in BSA from baseline to Week 16. 
• 
Change in DLQI (and individual domain scores) 
from baseline to Week 16. 
• 
Percent change in DLQI (and individual domain 
scores) from baseline to Week 16. 
• 
Change in POEM score (and individual item scores 
related to itch and sleep) from baseline to Week 16. 
• 
Percent change in POEM score from baseline to 
Week 16. 
• 
Change in EQ-5D-5L index score from baseline to 
Week 16. 
• 
Percent change in EQ-5D-5L index score from 
baseline to Week 16. 
• 
Change in EQ-5D-5L VAS score from baseline to 
Week 16. 
• 
Percent change in EQ-5D-5L VAS score from 
baseline to Week 16. 
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Objectives 
Estimands 
Endpoints 
 
Estimand 
type 
Strategy/ 
Intercurrent 
events 
Target 
population 
Population level 
summary 
 
• 
Change in HADS score from baseline to Week 16. 
• 
Percent change in HADS score from baseline to 
Week 16. 
• 
Change in Difficulty 
 (weekly 
average) from baseline to Week 16. 
• 
Percent change in Difficulty 
 (weekly 
average) from baseline to Week 16. 
• 
Change in Nocturnal 
 (weekly average) 
from baseline to Week 16.  
• 
Percent change in Nocturnal 
 (weekly 
average) from baseline to Week 16.  
• 
Change in Frequency of 
 During the 
Night (weekly average) from baseline to Week 16. 
• 
Percent change in Frequency of 
 During 
the Night (weekly average) from baseline to 
Week 16. 
• 
Change in WPAI-SHP domain from baseline to 
Week 16. 
• 
Percent change in WPAI-SHP domain from baseline 
to Week 16. 
• 
Change in SCORAD Part C (Pruritus VAS) score 
from baseline to Week 16. 
• 
Percent change in SCORAD Part C (Pruritus VAS) 
score from baseline to Week 16. 
Treatment policy: 
- Permanent 
discontinuation of 
IMP. 
Primary endpoint: 
Percent change in EASI score from baseline to Week 16. 
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Objectives 
Estimands 
Endpoints 
 
Estimand 
type 
Strategy/ 
Intercurrent 
events 
Target 
population 
Population level 
summary 
 
- Initiation of rescue 
treatment. 
Primary 
estimand for 
binary 
endpoints 
Composite: 
- Permanent 
discontinuation of 
IMP due to lack 
of efficacy or an 
AE related to 
worsening of AD. 
- Initiation of 
rescue treatment. 
Hypothetical: 
- Permanent 
discontinuation of 
IMP due to 
reasons other than 
lack of efficacy or 
an AE related to 
worsening of AD. 
Subjects with 
moderate-to-
severe AD. 
Difference in 
response rates of 
the response 
variable between 
the treatment 
conditions. 
Exploratory endpoints: 
• 
Achievement of EASI-50 at Week 16. 
• 
Achievement of EASI-75 at Week 16. 
• 
Achievement of EASI-90 at Week 16. 
• 
Achievement of EASI-100 at Week 16. 
• 
Achievement vIGA-AD score of 0 (clear) or 1 
(almost clear) at Week 16. 
• 
Reduction of ADSD Worst 
 score (weekly 
average) ≥4 from baseline to Week 16. 
Subjects with 
moderate-to-
severe AD, 
having an average 
ADSD Worst 
 score of ≥4 
at baseline. 
Exploratory endpoint: 
• 
Reduction of ADSD Worst 
 score (weekly 
average) ≥4 from baseline to Week 16. 
Subjects with 
moderate-to-
severe AD, 
having a DLQI 
score of ≥4 at 
baseline. 
Exploratory endpoint: 
• 
Reduction of DLQI ≥4 from baseline to Week 16.  
Subjects with 
moderate-to-
severe AD, 
having a POEM 
Exploratory endpoint: 
• 
Reduction of POEM ≥4 from baseline to Week 16. 
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Objectives 
Estimands 
Endpoints 
 
Estimand 
type 
Strategy/ 
Intercurrent 
events 
Target 
population 
Population level 
summary 
 
score of ≥4 at 
baseline. 
Suppl. 
estimand for 
binary 
endpoints 
Treatment-policy: 
- Permanent 
discontinuation of 
IMP. 
- Initiation of 
rescue treatment. 
Subjects with 
moderate-to-
severe AD. 
Exploratory endpoints: 
• 
Achievement of EASI-50 at Week 16. 
• 
Achievement of EASI-75 at to Week 16. 
• 
Achievement of EASI-90 at Week 16. 
• 
Achievement of EASI-100 at Week 16. 
• 
Achievement vIGA-AD score of 0 (clear) or 1 
(almost clear) at Week 16. 
• 
Reduction of ADSD Worst 
 score (weekly 
average) ≥4 from baseline to Week 16. 
To compare the 
safety of  
4 different dose 
regimens of 
LEO 138559 with 
placebo in 
subjects with 
moderate-to-
severe AD. 
Primary 
estimand for 
time-to-
event 
endpoints 
While on 
treatment: 
- Permanent 
discontinuation of 
IMP. 
Subjects with 
moderate-to-
severe AD. 
Difference in the 
cumulative 
incidence at 
Week 16. 
Exploratory endpoint: 
• 
Time from baseline to use of any rescue treatment. 
Suppl. 
estimand for 
time-to-
event 
endpoints 
Composite: 
- Permanent 
discontinuation of 
IMP. 
 
Subjects with 
moderate-to-
severe AD. 
Difference in the 
cumulative 
incidence at 
Week 16. 
Exploratory endpoint: 
• 
Time from baseline to use of any rescue treatment. 
 
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Abbreviations: AD = atopic dermatitis; AE = adverse events; ADSD = Atopic Dermatitis Symptom Diary; DLQI = Dermatology Life Quality Index; 
EASI = Eczema Area and Severity Index; EASI-50 = at least 50% decrease in EASI score; EASI-75 = at least 75% decrease in EASI score; EASI-90 = at least 
90% decrease in EASI score; EASI-100 = at least 100% decrease in EASI score; EQ-5D-5L = EuroQoL 5 Dimension Health Questionnaire 5 Level; 
HADS = Hospital Anxiety and Depression Scale; IMP = investigational medicinal product; POEM = Patient-Oriented Eczema Measure; 
Suppl. = supplementary; VAS = Visual Analogue Scale; vIGA-AD = Validated Investigator Global Assessment Scale for Atopic Dermatitis; WPAI-SHP = Work 
Productivity and Activity Impairment: Specific Health Problem. 
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4 
Trial design 
4.1 
Overall trial design 
Overview 
This is a phase 2b, randomized, double-blind, placebo-controlled, multi-site, parallel-group, 
dose-finding trial to evaluate the efficacy and safety of SC administered LEO 138559 in adult 
subjects with moderate-to-severe AD. A schematic overview of the trial design is presented in 
Panel 1. 
For each subject the trial will last at least 33 weeks and up to 36 weeks, including: 
• A screening period of up to 4 weeks (from Week -4 up to Week 0) including an applicable 
washout period of 1 week for topical AD treatment (from Week -1 up to Week 0). 
• A treatment period of 16 weeks (from Week 0 up to Week 16) with subjects randomized 
into 1 of 4 active treatment groups or a placebo treatment group.  
• A follow-up period of 16 weeks (from Week 16 up to Week 32) for the assessment of 
efficacy, safety, PK, and ADAs.  
Randomization will take place at Week 0 (Day 1, baseline). The primary endpoint will be 
assessed at Week 16. The final safety assessments will be conducted at Week 32 (end of trial). 
The subject’s visit schedule and the procedures and assessments to be conducted at each visit 
are presented in Section 1.3. The trial rationale is presented in Section 2.3 and the scientific 
rationale for trial design is presented in Section 9.1. 
Screening period (between 0 and 4 weeks prior to the baseline visit [Day 1]) 
Eligibility of the subject (Sections 5.1 to 5.3) to participate in the trial will be evaluated at a 
screening visit (Visit 1) and at the baseline visit (Visit 3). The screening visit will be 
performed up to 4 weeks before the baseline visit (Visit 3). 
Moreover, at the screening visit (Visit 1), the subjects will receive training in completion of an 
eDiary and will be given an electronic device to record the ADSD, Nocturnal 
, 
Difficulty 
, and Frequency of 
 During the Night. Completion of the 
eDiary twice daily will be initiated at the latest 1 week prior to the baseline visit (Visit 3, 
Week 0). 
At the start of the washout period (from Visit 2, Week -1), subjects should stop any treatment 
with TCS, TCI, topical PDE-4 inhibitors, topical JAK inhibitors, or other medicated topical 
treatments. 
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Subjects should continue using their current daily skin care moisturizing routine from 
screening throughout the trial (until Week 32), if approved by the investigator, who will 
otherwise make an alternative suggestion.  
Randomization (Week 0) 
At baseline (Visit 3, Week 0), eligibility of the subjects (Sections 5.1 to 5.3) to participate in 
the trial must be confirmed. Eligible subjects will be randomized 1:1:1:1:1 to 1 of 5 treatment 
groups: LEO 138559 (4 different dose regimens) or placebo. Randomization will be based on 
a permuted block design, stratified by baseline disease severity (baseline vIGA-AD score), 
region (Japan, Other countries), prior use of biologics or systemic JAK inhibitors for AD 
(Yes/No), and baseline biopsy status (willingness to provide biopsies: Yes/No). IRT will be 
used to control randomization and stratification factors. 
Treatment period (from Week 0 up to Week 16) 
In the treatment period, LEO 138559 and/or placebo injections will be administered at the site 
by unblinded site staff for 16 weeks, according to the treatment regimens outlined in 
Section 6.2.  
During the treatment period, the subjects will be asked to continue applying their moisturizer, 
and to complete their eDiary twice daily. The subjects will also be asked to visit the clinic for 
assessments and procedures. Final dosing will be administered at Week 14. If medically 
necessary (i.e. due to intolerable AD signs and/or symptoms), rescue treatment for AD may be 
used from Week 4 at the discretion of the investigator (any rescue treatment, regardless of 
type or class, used before Week 4 will lead to permanent discontinuation of IMP) (for details, 
see Sections 6.5 and 7.2). 
Follow-up period (from Week 16 up to Week 32) 
The subject will have 4 follow-up visits at Weeks 20, 24, 28, and 32 for assessment of 
efficacy, safety, PK, and ADAs. Rescue treatment may be prescribed during the follow-up 
period at the discretion of the investigator, if medically necessary (i.e. due to intolerable AD 
signs and/or symptoms) (for details, see Section 6.7). In such case, subjects will continue the 
schedule of trial visits and assessments. 
4.2 
Number of subjects needed 
Based on an anticipated screening failure rate of 35%, 385 subjects need to be screened for 
this trial to randomize approximately 250 subjects to treatment. 
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In order to ensure a sufficient number of subjects naive for biologics and systemic JAK 
inhibitors used for their AD, there will be a capping at 50% of subjects who received prior 
treatment with such therapies. These capping criteria will also apply for Japanese subjects. 
At Week 0 (baseline), a total of approximately 250 subjects (at least 25 Japanese subjects) will 
be randomized to 1 of the 5 treatment regimens outlined in Section 6.2. 
The statistical power considerations for this sample size are described in Section 11.1.  
The trial will be conducted at approximately 90 sites in Europe, North America, and Japan. 
4.3 
End-of-trial definition 
A subject is considered to have completed the trial if they have completed all periods of the 
trial including the final safety follow-up visit, regardless of early IMP discontinuation (see 
Section 8.8 for data to be recorded on the end-of-trial form).  
The end of the trial is defined as the date of the last follow-up visit (Week 32) for the last 
subject in the trial globally. 
Final data collection for evaluation of the primary endpoint will occur at Week 16. Therefore, 
the primary completion date is defined as the date of last Week 16 visit for the last subject in 
the trial globally. 
 
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5 
Trial population 
5.1 
Subject eligibility 
The investigator should only include subjects who meet all eligibility criteria, are not put at 
undue risk by participating in the trial and can be expected to comply with the protocol. 
The subject’s eligibility for the clinical trial must be verified according to the inclusion and 
exclusion criteria at visits specified in Section 1.3. It will be recorded in the eCRF if the 
subject has met all the inclusion criteria and none of the exclusion criteria. 
Any implementation of national requirements/law for the subject’s participation in the clinical 
trial will be ensured and described in submission documentation to regulatory authorities and 
IRBs/IECs, as applicable. 
5.2 
Inclusion criteria 
For the list of eligibility criteria specific for EU countries i.e. CZ, DE, ES, FR, HU, PL 
and RO, see Section 12.5.1.2. For requirements specific for JP, see Section 12.5.4. 
Subjects are eligible to be included in the trial only if all of the following criteria apply: 
Informed consent 
1. Signed and dated informed consent as described in Appendix 1 (Section 12.1.3) has been 
obtained prior to any protocol-related procedures. 
Age 
2. 18–75 years old (both included) at screening (Visit 1). For requirements specific for JP, 
see Section 12.5.4. 
Compliance 
3. Willingness to comply with the clinical trial protocol.  
Type of subject and disease characteristics 
4. At screening, diagnosis of AD as defined by the Hanifin and Rajka (1980) criteria for AD 
((62) and Appendix 3 [Section 12.3]). 
- 
History of AD for ≥1 year. 
5. Subjects who have a recent history (within 12 months before screening) with documented 
inadequate response to treatment with TCS (±TCI as appropriate) or for whom these 
topical AD treatments are medically inadvisable (e.g. due to important side effects or 
safety risks*). 
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- 
Inadequate response is defined as failure to achieve and maintain remission or a low 
disease activity state (comparable to IGA 0=clear to 2=mild) despite treatment with a 
daily regimen of TCS of medium to higher potency (EU class II-IV, JP ≥ Medium, US 
class I-V) (±TCI as appropriate), applied for at least 28 days or for the maximum 
duration recommended by the product prescribing information (e.g. 14 days for super 
potent TCS), whichever is shorter. 
- 
Subjects with documented systemic treatment or phototherapy for AD in the past 
1 year are considered as inadequate responders to TCS treatment and are potentially 
eligible for trial inclusion after appropriate washout. 
*Important side effects or safety risks are those that outweigh the potential treatment 
benefits and include intolerance to treatment, hypersensitivity reactions, significant skin 
atrophy, and systemic effects, as assessed by the investigator, or by the subject’s treating 
physician. 
6. EASI score ≥12 at screening and ≥16 at baseline. 
7. vIGA-AD score ≥3 at screening and baseline. 
8. BSA of AD involvement ≥10% at screening and baseline. 
9. ADSD Worst 
 score (weekly average) ≥4 at baseline. The baseline weekly average 
will be calculated from daily assessments of 
 severity during the 7 days immediately 
preceding the baseline visit (Day -7 to Day -1). A minimum of 4 
 scores out of the 
7 days is required to calculate the baseline average score. 
Contraceptive/barrier requirements 
10. A woman of childbearing potential* must use a highly effective** form of birth control 
throughout the trial and for at least 18 weeks after last administration of IMP. 
* A woman of childbearing potential is defined as a female subject aged ≥12 years or a 
younger girl who, at the discretion of the investigator, is deemed to be of reproductive 
potential. A woman is defined as not being of childbearing potential if she is 
postmenopausal (at least 12 months with no menses prior to screening without an 
alternative medical cause), or surgically sterile (hysterectomy, bilateral salpingectomy, 
or bilateral oophorectomy). 
**A highly effective method of birth control is defined as one which results in a low 
failure rate (less than 1% per year) such as bilateral tubal occlusion, IUD, IUS, 
combined (oestrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation (oral, intravaginal, transdermal), progestogen-only 
hormonal contraception associated with inhibition of ovulation (oral, injectable, 
implantable), sexual abstinence (when this is in line with the preferred and usual life 
style of the subject and not just being without a current partner), same-sex partner, or 
vasectomized partner (given that the subject is monogamous). 
For requirements specific for JP, see Section 12.5.4. 
5.3 
Exclusion criteria 
For the list of eligibility criteria specific for EU countries i.e. CZ, DE, ES, FR, HU, PL 
and RO, see Section 12.5.1.2. For requirements specific for JP, see Section 12.5.4. 
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Subjects are excluded from the trial if any of the following criteria apply:  
Medical conditions 
1. Major* surgery within 8 weeks prior to screening, or planned inpatient surgery or 
hospitalization during the trial period (*at the discretion of the investigator). 
2. Active dermatologic condition that could confound the diagnosis of AD or interfere with 
assessment of the treatment (e.g. scabies, contact dermatitis, rosacea, urticaria, or 
psoriasis). 
3. History of cancer, with the following exceptions: 
- 
Subjects who have had basal cell carcinoma, localized squamous cell carcinoma of the 
skin or in situ carcinoma of the cervix are eligible provided that the subject is in 
remission and curative therapy was completed at least 12 months prior to screening. 
- 
Subjects who have had other malignancies are eligible provided that the subject is in 
remission and curative therapy was completed at least 5 years prior to screening. 
4. History of or current immunodeficiency syndrome. 
5. History of anaphylaxis following any biologic therapy. 
6. History of clinically significant infection within 4 weeks prior to baseline which, in the 
opinion of the investigator, may compromise the safety of the subject in the trial, interfere 
with evaluation of the IMP, or reduce the subject’s ability to participate in the trial. 
Clinically significant infections are defined as: 
- 
a systemic infection. 
- 
a serious skin infection requiring parenteral (IV or intramuscular) antibiotics, antiviral, 
or antifungal medication. 
NOTE: Subject may be rescreened (once) after infection resolves. However, rescreening 
will require approval by the sponsor’s medical expert (see Section 5.4). 
7. Non-serious skin infection within 7 days prior to baseline. NOTE: Subject may be 
rescreened (once) after infection resolves. However, rescreening will require approval by 
the sponsor’s medical expert (see Section 5.4). 
8. Positive HBsAg or positive anti-HCV AND positive HCV-RNA at screening. 
- 
Subjects with a negative HBsAg and a positive anti-HBc or anti-HBs at screening will 
have reflex testing for HBV-DNA. Subjects who have HBV-DNA above LLQ will be 
excluded. For requirements specific for EU countries i.e. CZ, DE, ES, FR, HU, PL 
and RO, see Section 12.5.1.2. For requirements specific for JP, see Section 12.5.4. 
9. History of HIV infection or positive HIV serology at screening. 
10. Evidence of active or latent tuberculosis according to local standard of care for patients 
requiring initiation of a biologic treatment. 
- 
A tuberculosis test can be performed at the central or local laboratory. Subjects with a 
positive or indeterminate test at screening will be excluded. NOTE: Subject may be 
retested (once) if the initial test was indeterminate. 
11. ALT or AST level ≥2.0 times the ULN at screening. 
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12. Uncontrolled/untreated clinically significant depression or history of attempted suicide or 
is at significant risk of suicide (either in the opinion of the investigator or defined as a 
“yes” to suicidal ideation questions no. 4 or 5 or answering “yes” to suicidal behavior on 
the C-SSRS Screening version). 
13. Known or suspected hypersensitivity to any component(s) of the IMP. 
14. Any disorder* at screening and/or baseline, which is not stable in the opinion of the 
investigator, and could: 
- 
Affect the safety of the subject throughout the trial. 
- 
Influence the results of the trial. 
- 
Impede the subject’s ability to complete the trial. 
 
 
. For 
requirements specific for EU countries i.e. CZ, DE, ES, FR, HU, PL and RO, see 
Section 12.5.1.2. 
15. Any significant abnormal finding* at screening and/or baseline which may in the opinion 
of the investigator:  
- 
Put the subject at risk because of their participation in the trial. 
- 
Influence the results of the trial. 
- 
Influence the subject’s ability to complete the trial. 
*The abnormal finding must be clinically significant and observed during the screening 
period. Examples include abnormal findings in physical examination, vital signs, ECG, 
hematology, biochemistry, or urinalysis. For requirements specific for EU countries i.e. 
CZ, DE, ES, FR, HU, PL and RO, see Section 12.5.1.2. 
16. Current or recent chronic alcohol or drug abuse, or any other condition associated with 
poor compliance as judged by the investigator. 
17. Women who are pregnant or breastfeeding. 
Prior/concomitant therapy 
18. Previous treatment with LEO 138559. 
19. Previous exposure to fezakinumab (anti-IL-22 Ab). 
20. Systemic treatment with immunosuppressive drugs (e.g. methotrexate, cyclosporine, 
azathioprine), immunomodulating drugs, retinoids (e.g. alitretinoin), corticosteroids 
(steroid eyedrops and inhaled or intranasal steroids are allowed), or JAK inhibitors within 
28 days or 5 half-lives prior to baseline, whichever is longer. 
21. Use of tanning beds or phototherapy (NBUVB, UVB, UVA1, PUVA), within 4 weeks 
prior to baseline. 
22. Receipt of blood products within 28 days prior to screening. 
23. Treatment with: 
- 
 Any marketed or investigational biologic agents within 3 months or 5 half-lives, 
whichever is longer, prior to baseline. 
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- 
Any cell-depleting agents including but not limited to rituximab: within 6 months 
prior to baseline, or until lymphocyte count returns to normal, whichever is longer. 
24. Treatment with TCS, TCI, topical PDE-4 inhibitors, topical JAK inhibitors, or other 
medicated topical treatments within 7 days prior to baseline. NOTE: Subject may be 
rescreened (once) if failed for this criterion. However, rescreening will require approval 
by the sponsor’s medical expert (see Section 5.4). 
25. Receipt of live attenuated vaccines 30 days prior to baseline or longer if recommended so 
by local guidelines. 
26. Treatment with any non-marketed drug substance (that is, an agent which has not yet been 
made available for clinical use following registration) within the last 4 weeks or 
5 half-lives prior to randomization, whichever is longer. 
Prior/concurrent clinical trial experience 
27. Current participation in any other interventional clinical trial. 
28. Previously randomized in this clinical trial. 
Other exclusion criteria 
29. Employees of the trial site, or any other individuals directly involved with the planning or 
conduct of the trial, or immediate family members of such individuals. 
30. Subjects who are legally institutionalized. For requirements specific for EU countries 
i.e. CZ, DE, ES, FR, HU, PL and RO, see Section 12.5.1.2. 
5.4 
Screening and subjects excluded prior to randomization  
Subject ID 
Trial participation begins once written informed consent is obtained. Refer to Appendix 1 
(Section 12.1.3) for details on the informed consent process. Once informed consent is 
obtained, a subject ID will be assigned by a central IRT system, and hereafter the assessment 
of subject eligibility may begin. The date of first screening activity could be on the same day 
the informed consent has been obtained, or at a later date. The subject ID will be used to 
identify the subject during the screening process and throughout trial participation, if 
applicable. Subjects who have given written informed consent to participate in the trial and 
who have been assigned a subject ID are considered ‘screened’ subjects. 
Investigator logs 
The investigator will maintain a log of all subjects considered for screening, whether they 
have provided written informed consent or not (screening log). This log will be anonymous 
and will include the reason(s) for not entering the trial, if applicable, or the allocated 
subject ID. In addition, the investigator will maintain a log of all consented subjects at the 
trial site (subject identification list). This log will include each subject’s identity, date of 
consent, and corresponding subject ID, so that any subject may be identified if required for 
any reason. The log must not be copied or retained by LEO Pharma. 
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Subjects excluded prior to randomization 
Subjects excluded prior to randomization include screen failures and other subjects not 
subsequently assigned to trial treatment for other reasons. Screening failures are defined as 
subjects who consent to participate in the trial but do not meet 1 or more eligibility criteria 
required for participation in the trial. Other subjects not assigned to trial treatment are defined 
as subjects who meet the eligibility criteria but do not participate in the trial for other reasons 
such as lost to follow-up, withdrawal by subject, and other reasons. 
To meet the CONSORT publishing requirements (63) and to respond to queries from 
regulatory authorities, a minimal set of information is required to ensure transparent reporting 
of screen failures and other subjects not assigned to trial treatment. For these subjects, the 
following data will be collected in the eCRF: 
• Date of informed consent. 
• A specification of which eligibility criteria were not met, if any. 
• Date of birth (day, month, and year; only month and year; or only year, as per local 
legislation), age, sex, ethnicity, race (for requirements specific for FR, see Section 
12.5.3). 
• Date of exclusion. 
• Reason for exclusion. 
- 
Screen failure. 
- 
Lost to follow-up. 
- 
Withdrawal by subject. 
- 
Other (if other, a specification should be provided).  
• Any AEs and SAEs. 
 
In case of any SAEs, these must be followed up as described in Section 10. 
Rescreening of screening failures (subjects who did not meet the eligibility criteria for 
participation in the trial) is not allowed except in specific situations as described below. 
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If for administrative or logistical reasons (e.g. delayed results or temporary site closure due to 
force majeure) eligibility cannot be assessed, rescreening may be permitted once. In addition, 
rescreening may be permitted (once) after initially having violated the exclusion criteria 6, 7, 
and 24. Rescreening will require approval by the sponsor’s medical expert after thorough 
review of eCRF data from the first screening visit. Subjects to be rescreened must sign a new 
ICF, and all screening assessments will be re-performed. Rescreened subjects will get a new 
subject ID. In addition, the subject ID from the previous screening will be recorded in the 
eCRF. 
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6 
Treatments 
6.1 
Trial product description 
The IMPs included in this trial are listed in Panel 5. 
Panel 5: Identification of IMPs 
Investigational 
medicinal product 
Dosage form 
 
Active ingredient 
and concentration 
Pack size 
Manufacturer 
responsible for batch 
release 
LEO 138559 
Solution for 
injection.  
LEO 138559, 
 mg/mL. 
Vial containing 
1.0 mL solution. 
LEO Pharma 
Placebo  
Solution for 
injection. 
Not applicable. 
Vial containing 
1.0 mL solution. 
LEO Pharma 
Note: To ensure that 1.0 mL can be withdrawn by a syringe, there will be a small overfill in the vials. 
Abbreviations: IMP = investigational medicinal product. 
6.2 
Administration of IMP 
General 
Dosing visits are shown in the schedule of trial activities (Section 1.3). Dispensing of the IMP 
will be handled by an IRT system. The IRT system will assign the required kit numbers for 
each subject at each dispensing visit. 
From randomization, LEO 138559 and placebo will be administered SC for a period of 
14 weeks (Visits 3-12, with the last IMP administration at Week 14 [Visit 12]) according to 
1 of the following treatment regimens: 
• Dose regimen 1: LEO 138559 
 mg SC Weeks 0, 1, 2, 3 and then 
 mg SC Q2W 
from Week 4 (50 subjects). 
• Dose regimen 2: LEO 138559 
 mg SC Weeks 0, 1, 2 and then 
 mg SC Q2W from 
Week 4 * (50 subjects). 
• Dose regimen 3: LEO 138559 
 mg SC Weeks 0 and 2 and then 
 mg SC Q2W from 
Week 4 * (50 subjects). 
• Dose regimen 4: LEO 138559 
 mg SC Weeks 0 and 2 and then 
 mg SC Q2W from 
Week 4 * (50 subjects). 
• Placebo regimen: Placebo SC Weeks 0, 1, 2, 3 and then placebo SC Q2W from Week 4 * 
(50 subjects). 
* In addition to placebo administrations to subjects in the placebo group (at Weeks 0, 1, 2, 3, 
4, 6, 8, 10, 12, 14), placebo administrations will also be used to mask the weekly loading 
doses, and the different dose levels of active IMP. 
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The first day of dosing is considered Day 1 (Week 0). Each subject will receive a total of 3 SC 
injections (2 mL + 2 mL + 1 mL) per dose with either LEO 138559 or placebo, or a 
combination, to maintain the blinding, and to achieve a total volume of 5 mL per dose as 
shown in Panel 6. 
Panel 6: Combinations of IMP administration per dose regimen 
 
LEO 138559, 
 mg/mL 
Placebo 
Dose regimen 1 
 
 
LEO 138559 
 mg 
2 x 2 mL 
1 x 1 mL 
Dose regimen 2 
 
 
LEO 138559 
 mg 
1 x 2 mL 
1 x 1 mL 
1 x 2 mL 
Dose regimen 3 
 
 
LEO 138559 
 mg (loading dose) 
2 x 2 mL 
1 x 1 mL 
LEO 138559 
 mg 
1 x 2 mL 
1 x 2 mL 
1 x 1 mL 
Dose regimen 4 
 
 
LEO 138559 
 mg (loading dose) 
1 x 2 mL 
1 x 2 mL 
1 x 1 mL 
LEO 138559 
 mg 
1 x 1 mL 
2 x 2 mL 
Placebo regimen 
 
 
Placebo 
- 
2 x 2 mL 
1 x 1 mL 
Note: Placebo administrations to mask the weekly loading doses will be identical to the administrations in the 
placebo regimen. 
During the treatment period, final dosing will be administered at Week 14 and only clinical 
assessment will occur at Week 16. IMP administration will continue until Week 14. 
IMP will be administered by qualified, unblinded site staff as the active drug is visually 
distinct from placebo (see Section 6.3.2 for blinding details). The IMP must be injected SC in 
the upper legs (thighs), stomach area (abdomen) or in the upper, outer arm but should not be 
given into areas where the skin is tender, bruised, red, hard, thick, scaly, or affected by AD. It 
is advised that the site of injection of IMP is rotated such that the subject receives IMP at a 
different anatomical part (i.e. anterior thigh, abdomen or upper arm) at each treatment visit. 
The anatomical location of the injection (left/right anterior thigh, left/right abdominal region, 
left/right upper arm) must be recorded in the source documents at each treatment visit and 
recorded in the eCRF.  
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At each treatment visit, the 3 injections of IMP must be administered within a maximum of 
10 minutes. The 3 injections of IMP should be administered in the same injection site area 
(e.g. left upper arm) separated by at least 3 cm.  
If any issues with the IMP (e.g. damaged kit or vial/syringe) or a malfunction during 
administration should arise, the unblinded CRA should be contacted, and the issue should be 
documented. 
Further details on IMP preparation and administration will be provided in an instruction for 
use and in the trial product handling manual. IMP administration must be carried out 
according to these instructions. 
After IMP administration 
At Weeks 0, 1, 2, 3, and 4, subjects will be monitored for potential immediate drug reactions 
for a minimum of 2 hours after IMP administration. Vital signs will be taken immediately 
(within 5 minutes) after last IMP administration, as well as after 30 minutes (± 5 minutes), 
after 1 hour (± 5 minutes), and after 2 hours (± 5 minutes), or until stable, whichever is later 
(for requirements specific for EU countries i.e. CZ, DE, ES, FR, HU, PL and RO, see 
Section 12.5.1). Vital signs will be documented in the eCRF. 
As with any Ab, allergic reactions to dose administration are possible. The World Allergy 
Organization has categorized anaphylaxis into 2 subgroups: allergic anaphylaxis (mediated by 
an immunologic mechanism) and nonallergic anaphylaxis (which has a nonimmunologic 
cause) (64). The clinical criteria for defining anaphylaxis for this trial are listed in Appendix 4 
(Section 12.4) and (65). Appropriate drugs, such as epinephrine, antihistamines, 
corticosteroids, etc., and medical equipment to treat acute anaphylactic reactions must be 
immediately available at trial sites, and trial personnel should be trained to recognize and 
respond to anaphylaxis according to local guidelines. 
If an anaphylactic reaction occurs, a blood sample will be drawn from the subject 1) as soon 
as possible after the event, 2) at 60 minutes (± 30 minutes) after the event, and 3) at discharge 
for analysis of serum tryptase at the central laboratory. 
Conditions requiring IMP administration rescheduling 
If any of the following should occur, the investigator should reschedule the visit and IMP 
should not be administered until the rescheduled visit: 
• The subject has an intercurrent illness that in the opinion of the investigator may 
compromise the safety of the subject in the trial. 
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• The subject is febrile (defined as ≥38°C; ≥100.4°F) within 72 hours prior to IMP 
administration. 
From baseline to Week 4, if the trial visit cannot be rescheduled in order to maintain a 
minimum of 5 days to subsequent dose, the sponsor’s medical expert should be contacted. 
From Week 4 and onwards, if the trial visit cannot be rescheduled in order to maintain a 
minimum of 7 days to subsequent dose, the sponsor’s medical expert should be contacted. 
Overdose is specified in Section 10.7.2. LEO Pharma does not have any specific treatment 
recommendations in relation to overdose. The investigator will use clinical judgement to treat 
any overdose if necessary. 
6.3 
Treatment assignment and blinding 
6.3.1 
Treatment assignment 
Subjects who meet all the eligibility criteria (Sections 5.1 to 5.3) will be randomized at 
baseline (Day 1) to receive treatment according to 1 of the treatment regimens outlined in 
Section 6.2. 
Treatment assignment will be pre-planned according to a computer-generated randomization 
schedule in a 1:1:1:1:1 ratio (4 LEO 138559 dose regimens and 1 placebo regimen), based on 
a permuted block design and stratified by baseline disease severity (baseline vIGA-AD score), 
region (Japan, Other countries), prior use of biologics or systemic JAK inhibitors for AD 
(Yes/No), and baseline biopsy status (willingness to provide biopsies: Yes/No).  
IRT will be used to control randomization and stratification factors, along with IMP supply 
chain, and expiry tracking. 
6.3.2 
Blinding 
This is a double-blinded trial in which LEO 138559 and placebo are visually distinct from 
each other and not matched for viscosity. Neither the subject nor any of the investigators or 
LEO Pharma staff (except unblinded LEO team members, such as the unblinded CRA, 
unblinded GCTM, or unblinded CPM, etc.) who are involved in the clinical evaluation and 
monitoring of the subjects will be aware of the treatment received.  
IMP will be prepared, handled, and administered by qualified, unblinded site staff who will 
not be involved in the management of trial subjects and who will not perform any of the 
assessments. 
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In the event that the treatment allocation for a subject becomes known to the investigator, 
other trial staff involved in the management of trial subjects, or a trial subject, LEO Pharma 
must be notified immediately.  
Should an issue arise with the IMP (e.g. damaged kit or syringe that has been assigned to a 
subject prior to administration, or any other unexpected event with the kit or syringe [e.g. a 
malfunction during IMP administration]), the unblinded site staff will contact the unblinded 
CRA to determine whether any specific actions are required. 
The trial site will maintain a written plan (site blinding plan) detailing which staff members 
are blinded/unblinded and the process of IMP administration used to maintain the blind. 
6.3.3 
Emergency unblinding of individual subject treatment 
While the safety of a subject always comes first, it is still important to carefully consider if 
unblinding is necessary to ensure a subject’s safety. An emergency unblinding request can be 
made by the investigators, HCPs who are not members of the trial staff, or authorized LEO 
Pharma personnel. 
Provisions are in place for 24-hour emergency unblinding of individual subject treatment. If 
emergency unblinding is required, the investigator can unblind a subject’s treatment via the 
IRT system, or unblinding CRO. Only the investigator should be unblinded and keep 
treatment allocation confidential. LEO Pharma must remain blinded until the end of the trial.  
For a requester who is not a member of the trial staff and who does not have access to the IRT 
system (e.g. a physician at an emergency room), a local contact number for the emergency 
unblinding CRO is provided on the subject card (see Appendix 1 [Section 12.1.3]) to be used 
if the investigator or delegated site staff cannot be reached. The requester will provide the 
trial ID and subject ID to the emergency unblinding CRO who will immediately reveal the 
individual treatment allocation. 
The emergency unblinding CRO will clarify that the requester requires immediate unblinding 
without further medical consultation. Should the requester wish to discuss whether unblinding 
is necessary, the emergency unblinding CRO will provide the requester with the 
LEO Pharma 24/7 medical cover. 
LEO Pharma Global Safety may unblind subject(s) if it is deemed necessary, including for 
regulatory purposes in relation to reporting of SUSARs. 
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6.4 
Background treatment 
All subjects should continue using their current daily skin care moisturizing routine from 
screening throughout the trial (until Week 32), if approved by the investigator, who will 
otherwise make an alternative suggestion. 
6.5 
Rescue treatment 
Rescue treatment is defined as the use of any of the prohibited medications or procedures 
listed in no. 1-6 of Section 6.7 initiated to treat intolerable AD signs and/or symptoms during 
the treatment and follow-up period. Rescue treatment for AD may be prescribed to trial 
subjects at the discretion of the investigator.  
• In case rescue treatment is initiated before Week 4; 
- 
IMP will be permanently discontinued (see Section 7.2.1). 
• In case rescue treatment is initiated at or after Week 4: 
- 
Subjects should preferably be started on topical treatment (TCS and/or TCI), and these 
subjects will continue IMP and the schedule of trial visits and assessments. Rescue 
treatment should only be used in situations where the subject is at risk of 
discontinuation, and should be continued for as short a period as possible.  
Note: It is recommended that the investigator starts with a TCI or least potent TCS for 
the face (e.g. hydrocortisone 1%, 2.5% cream/ointment) and moderately potent TCS 
for the body (e.g. triamcinolone acetonide 0.1% cream/ointment). 
- 
If the subject experiences intolerable AD signs and/or symptoms and the TCS and/or 
TCI rescue treatment is insufficient, the subject might need to progress to other rescue 
treatment or procedures listed in Section 6.7. In that case, IMP will be permanently 
discontinued (see Section 7.2.1). 
• In case rescue treatment is initiated at or after Week 16: 
- 
If the subject experiences intolerable AD signs and/or symptoms during the follow-up 
period (Week 16 to 32), topical and systemic rescue treatment or procedures listed in 
Section 6.7 may be prescribed at the discretion of the investigator. In such case, 
subjects will continue the schedule of trial visits and assessments.  
Investigators should make every attempt to conduct efficacy and safety assessments (for 
example disease severity scores, safety laboratory assessments) immediately before 
administering rescue treatment. An unscheduled visit may be used for this purpose, if 
necessary. 
Reporting in eCRF 
It will be recorded in the eCRF if a medication or procedure is given as rescue treatment. 
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6.6 
Prior and concomitant medication and concurrent procedures 
Any medication or vaccine that the subject receives from 3 months (12 months for 
medications related to AD) prior to screening through the follow-up period must be recorded 
in the subject’s medical record and the eCRF along with details such as: 
• Medication name or therapy (generic or brand name). 
• Whether the medication or therapy is a rescue treatment for AD. 
• Indication. 
• Start and stop date of administration (it will also be recorded if the medication is 
ongoing). 
• Dose information, including dose per administration, unit, and frequency. 
• Route of administration.  
Similarly, any concurrent procedure conducted within 3 months prior to screening through the 
follow-up period must also be recorded in the subject’s medical record and the eCRF with 
details such as: 
• Procedure name (include anatomical area if relevant).  
• Indication.  
• Start and stop date (it will also be recorded if the procedure is ongoing).  
Investigators may prescribe concomitant medications or procedures to provide adequate 
supportive care as deemed necessary, except for treatments listed in Section 6.7. The 
sponsor’s medical expert should be contacted if there are any questions regarding concomitant 
or prior medications and procedures. 
The following concomitant medications are permitted during the trial: 
• Paracetamol use (maximum 2 g/day).  
• Concomitant therapies taken for the long-term treatment of pre-existing conditions can 
continue during the trial provided they are not violating the exclusion criteria (see 
Section 5.3) and the list of prohibited medications (Section 6.7). 
• Systemic antihistamines and/or anti-infectives. 
• Ophthalmic, inhaled, and nasal corticosteroids. 
6.7 
Prohibited medications and procedures 
The medications and procedures listed below are prohibited during the trial from 
randomization (Week 0). Medications and procedures disallowed prior to randomization are 
covered by the exclusion criteria (see Section 5.3). In case any prohibited treatments are used 
during the trial, they must be recorded in the eCRF as concomitant medication. 
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From randomization through the last follow-up visit (Week 32), the below treatments are 
prohibited: 
1. TCS and TCI. 
2. Topical PDE-4 inhibitors. 
3. Topical JAK inhibitors. 
4. Use of UVA or UVB, PUVA, other phototherapy, tanning beds, or prolonged sun 
exposure. 
5. Systemic corticosteroids (nasal, ophthalmic, and inhaled corticosteroids are allowed). 
6. Systemic treatment with immunosuppressive drugs (e.g. methotrexate, cyclosporine, 
azathioprine), immunomodulating drugs, JAK inhibitors, and retinoids (e.g. alitretinoin). 
7. Biological products. 
8. Investigational agents other than LEO 138559. 
9. Allergen immunotherapy. 
10. Live (attenuated) vaccine. 
11. Immunoglobulins. 
12. Blood products. 
Prescription of prohibited medications and procedures in no. 1-6 do not constitute a protocol 
deviation if given as rescue treatment for AD (Section 6.5). If prohibited medications and 
procedures are used for reasons other than rescue treatment for AD, they must be recorded as 
protocol deviations and IMP will be permanently discontinued (see Section 7.2.1).  
Please note that receipt of inactive/killed vaccines (e.g. inactive influenza) is allowed, 
provided that they are not administered within 5 days before/after any trial visit. 
6.8 
Treatment logistics and accountability 
6.8.1 
Labelling and packaging of trial products 
The IMP will be packaged open-label in individually numbered kits. 
Primary and secondary packaging materials (vial and outer carton, respectively) will be 
individually labelled by a CMO. 
The labelling of IMPs will be in accordance with the EU Clinical Trial Regulation No 
536/2014 Annex VI (66), local regulations, and trial requirements. Label text will be 
translated into local languages as required. 
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6.8.2 
Storage and accountability of trial products 
The investigator or designee must confirm appropriate conditions (e.g. temperature) have 
been maintained during transit for all IMPs received, and any discrepancies are reported and 
resolved before use of the IMP. 
Only eligible subjects may receive the IMP, and only authorized site staff may supply, 
prepare, or administer the IMP.  
All IMPs must be stored in a secure and restricted area in accordance with the labeled storage 
conditions with access limited to the investigator and authorized site staff and remain in the 
original container until dispensed. 
The IMP must be stored at 2 to 8°C at the trial site. The temperature during storage should be 
monitored by a calibrated, stationary, and continuously monitoring system. Minimum 
requirement is a calibrated min/max thermometer.  
A temperature log must be kept to document the storage within the right temperature interval. 
Storage facilities should be checked at least every working day. 
Storage of IMP may be delegated, e.g. to a hospital pharmacy, as locally applicable, and must 
be documented in the site signature and designation of responsibility log. 
The investigator or authorized site staff is responsible for IMP accountability, and record 
maintenance (e.g. receipt, and final disposition records). 
Further details regarding storage (including handling of temperature excursions upon receipt 
or during storage at the trial site) and handling of damaged IMPs (including kits damaged 
upon receipt) are provided in the trial product handling manual. 
6.8.3 
Treatment compliance 
IMP injections will be performed by unblinded site staff who will also keep the accountability 
records up to date. Any non-compliance and the reason for it must be recorded in the eCRF. 
Reporting in eCRF 
The following data will be recorded in the eCRF: 
• Did the subject comply with the IMP dosing schedule (yes, no); If no, a reason will be 
given. It will also be recorded how much IMP the subject received (full dose, partial dose, 
or no dose). 
• Primary reason for non-compliance: AE, or other (if other, a specification should be 
provided). 
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• Date and time of IMP administration (stated for all 3 injections). 
• Site of IMP injection: Left/right anterior thigh, left/right abdominal region, left/right upper 
arm.  
• Other: If other, a specification should be provided. 
6.8.4 
Trial product destruction 
All IMP (i.e. used, partly used, and unused vials) must be returned to the CMO, where it will 
be destroyed according to approved procedures and/or local requirements (for requirements 
specific for the UK, see Section 12.5.5). Used IMP and unused IMP that is no longer 
available for dispensation (e.g. expired or damaged IMP) can be returned on an ongoing basis 
throughout the trial. Unused IMP (i.e. IMP that is still available for dispensation) can be 
returned for destruction after the last dosing visit of the last subject at the site.  
Syringes used for administration of IMP can be destroyed at site according to local procedures 
in compliance with local regulations. 
6.9 
Provision for subject care following trial completion 
In order to ensure appropriate treatment of the subjects after they have completed the trial, the 
subjects will be treated at the investigator’s discretion or referred to other physician(s) 
according to standard practice. 
6.10 Reporting product complaints 
Any defects or issues with the IMP as well as any device deficiency that has or potentially 
could have a serious impact on the subject must be reported to the unblinded CRA within 
24 hours of knowledge.  
(S)AEs which occur due to a defect or issue with the IMP or due to a device deficiency must 
be reported by the investigator as described in Sections 12.2.4 and 12.2.5. 
Examples of product complaints are: 
• Device malfunctions and use errors 
• Problems with the physical or chemical appearance of the IMP (e.g. particles in the 
syringe) 
• Problems with the packaging material including labelling. 
The unblinded CRA will report the product complaint to the Quality department via Global 
Safety at LEO Pharma within 3 days of first knowledge. 
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The reporting of the product complaint should contain a detailed description of the defect, 
issue, or device deficiency, including whether it led to an AE.  
During the investigation of the product complaint, the IMP or device must be stored separate 
from other trial medication at labelled conditions unless otherwise instructed; the trial site will 
be notified whether the IMP or device needs to be returned for further investigation or may be 
destroyed.  
Global Safety, LEO Pharma contact information for reporting product complaints: 
Fax number: +45 6910 2468 
E-mail address: drug.safety@leo-pharma.com 
Additional reporting information can be found on the SAE form.  
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7 
Discontinuation and withdrawal 
7.1 
General principles 
A subject may withdraw from the trial (prior to first dose or during the treatment period) or 
permanently discontinue trial treatment at any time if the subject, the investigator, or LEO 
Pharma considers that it is not in the subject’s best interest to continue. 
A subject who withdraws from the trial is a subject who stops treatment with the IMP and all 
further protocol-defined trial activities. A subject who permanently discontinues IMP is a 
subject who, although they stop treatment with the IMP, agree to their follow-up as described 
in Section 7.3. Early termination assessments to be conducted for both events are described in 
Section 7.3. 
Subjects who withdraw from the trial and subjects who permanently discontinue IMP will not 
be replaced. 
If a subject withdraws from the trial and verbally, or in writing, withdraw their consent to 
further analysis of samples already taken but not yet tested, the investigator should document 
this in the subject’s medical record and inform LEO Pharma. 
Discontinuation of specific sites or of the trial are detailed in Appendix 1 (Section 12.1.10). 
7.2 
Reasons for discontinuation of IMP 
7.2.1 
Reasons for permanent discontinuation of IMP 
Subjects will permanently discontinue IMP in the event of: 
• Evidence of pregnancy, or if the subject is non-compliant with the contraception 
requirements (see inclusion criterion no. 10). 
• An AE that, in the opinion of the investigator or sponsor’s medical expert, contraindicates 
further dosing. 
• Withdrawal by subject. 
• Protocol-specified withdrawal criterion met, defined as initiation of: 
- 
Any rescue treatment before Week 4. 
- 
Prohibited medication (except use of rescue treatment with TCS and/or TCI at or after 
Week 4, see Section 6.5). 
• Other reasons, at the discretion of the investigator. If other, a specification should be 
provided. 
For requirements specific for EU countries i.e. CZ, DE, ES, FR, HU, PL and RO, see 
Section 12.5.1) 
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Data to be recorded in the eCRF 
The date and time of last dose for IMP will be recorded in the eCRF. The primary reason for 
permanent discontinuation of IMP must be recorded in the medical records and on the 
end-of-treatment form in the eCRF, e.g.: 
• Death. 
• Pregnancy. 
• AE (if AE, a specification must be provided). 
• Lost to follow-up. 
• Lack of efficacy. 
• Randomized by mistake. 
• Withdrawal by subject. 
• Protocol-specified withdrawal criterion met. 
• Other (if other, a specification should be provided). 
 
In case the primary reason is AE, the AE in question will be linked to the permanent 
discontinuation of IMP.  
7.2.2 
Reasons for temporary discontinuation of IMP 
In case an urgent situation requires immediate action, IMP dosing may be temporary 
discontinued if, at the investigator’s discretion, this is determined to be in the subject’s best 
interest. In such cases, sponsor’s medical expert should be informed as soon as possible.  
A decision to re-initiate IMP must always be discussed with and approved by the sponsor’s 
medical expert. 
7.3 
Subject withdrawal from the trial 
• A subject may withdraw from the trial at any time at their own request or may be 
withdrawn at any time at the discretion of the investigator for safety or compliance 
reasons. The subject will be permanently discontinued from the IMP and the trial at that 
time. 
• If the subject withdraws consent for disclosure of future information, LEO Pharma may 
retain and continue to use any data collected before such a withdrawal of consent. 
• If a subject withdraws from the trial, he/she may request destruction of any samples taken 
and not tested, and the investigator must document this in the site trial records. 
7.4 
Early termination assessments 
Permanent discontinuation of IMP 
Subjects who permanently discontinue IMP for any reason will be asked to attend an early 
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termination visit as soon as possible after discontinuation of IMP. Subjects should be 
encouraged to attend all trial visits and be assessed for safety and efficacy according to the 
schedule of assessments.  
For subjects who no longer wish to attend all trial visits, the following visits should be 
prioritized: 
• An early termination visit. 
• The primary endpoint visit (16 weeks after randomization). 
• A final follow-up visit (18 weeks after last administration of IMP). 
Subjects who discontinue IMP but remain in the trial will continue completing the eDiary 
until the Week 16 visit. The investigator will review any AEs which will be followed up 
according to Appendix 2 (Section 12.2.4) if the subject agrees. 
Withdrawal from trial 
Subjects who withdraw/are withdrawn from the trial for any reason should attend an early 
termination visit as soon as possible after withdrawal. Assessments/procedures to be 
conducted at this visit are listed in the schedule of trial activities (Section 1.3). If the subject 
agrees, the investigator will review any AEs which will be followed up according to 
Section 12.2.4. 
Treatment regimen following withdrawal from the trial will be at the investigator’s discretion. 
Details on data to be recorded in the eCRF for subjects who withdraw from the trial can be 
found in Section 8.8. 
7.5 
Lost to follow-up 
A subject will be considered lost to follow-up if they repeatedly fail to return for scheduled 
visits and if the trial site is not able to get in contact with the subject. 
The following actions must be taken if a subject fails to return to the trial site for a required 
visit: 
• The trial site must attempt to contact the subject and reschedule the missed visit as soon as 
possible and counsel the subject on the importance of maintaining the assigned visit 
schedule and ascertain whether the subject wishes to continue in the trial. 
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• Before a subject is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the subject (where possible, 3 telephone calls and, if 
necessary, a certified letter to the subject’s last known mailing address or local equivalent 
methods). These contact attempts should be documented in the subject’s medical record. 
Should the subject continue to be unreachable, they will be considered to have withdrawn 
from the trial with a primary reason of lost to follow-up. 
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8 
Trial assessments and procedures 
8.1 
Overview 
Trial procedures and their timing are summarized in the schedule of activities in Section 1.3. 
Protocol waivers or exemptions are not allowed. 
At visits including PRO assessments, the PROs should be completed before any other 
assessments or procedures. IMP administrations should always occur after all other 
assessments and procedures planned for the same visit have been performed. 
Adherence to the trial design requirements, including those specified in the schedule of 
activities, is essential and required for trial conduct.  
All screening evaluations must be completed and reviewed to confirm that potential subjects 
meet all eligibility criteria. 
Subjects participating in the trial will be under careful supervision of a qualified principal 
investigator who must be a dermatologist or an allergist. Investigators must be experienced in 
treating AD and have documented experience and/or training in use of the assessments 
required by the protocol and must be either a physician, a certified physician’s assistant, or an 
advanced registered nurse practitioner (for requirements specific for CZ, see 
Section 12.5.2). All dermatologic assessments must be performed by a dermatologist or an 
adequately qualified medical doctor. 
AEs must be assessed by a physician (see details in Section 10.2). 
Immediate safety concerns should be discussed with LEO Pharma immediately upon 
occurrence or awareness to determine if the subject should continue or discontinue the IMP. 
The investigators performing the assessments must not be involved in the administration of 
IMP (Section 6.3.2). 
Data to be collected should follow CDISC controlled terminology whenever it exists (e.g 
laboratory parameters, questionnaires, ADA, biomarker parameters, anatomical locations, 
withdrawal reasons, etc.). 
 
 
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8.2 
Administrative and baseline procedures 
8.2.1 
Demographics 
The following demographic data will be recorded: 
• Date of birth; in general, day, month, and year of birth should be collected. Where it is not 
allowed to collect the subject’s full date of birth, only month and year of birth, or year of 
birth should be collected as per local legislation. 
• Age (years); age (as on the day ICF was signed) must be collected if full date of birth 
cannot be collected due to local legislations. (If the full date of birth is not collected on the 
demographics form, age and age unit must be collected on the randomization form.) 
• Sex (as determined by the investigator): female, male. 
• Ethnic origin (self-reported by the subject): ‘Hispanic or Latino’, ‘not Hispanic or Latino’, 
not reported (not provided or available). For requirements specific for FR, see 
Section 12.5.3. 
• Race (self-reported by the subject, more than 1 race may be reported): American Indian or 
Alaska native, Asian Japanese, Asian Chinese, Asian other, Black or African American, 
native Hawaiian or other Pacific Islander, White, not reported (not provided or available). 
For requirements specific for FR, see Section 12.5.3. 
8.2.2 
Medical history 
Medical history will be recorded according to the schedule of trial activities (Section 1.3). 
In case medical history is incomplete at the screening visit, missing data will be retrieved at 
Week 0 (baseline). 
Relevant past and concurrent medical history must be recorded in the eCRF including all past 
and current skin disease history: 
• Atopy history:  
- 
Date of AD diagnosis. 
- 
Previous AD treatments (e.g. dupilumab, tralokinumab, lebrikizumab, nemolizumab, 
JAK inhibitor, methotrexate, cyclosporine, azathioprine), with the following details: 
- 
Treatment duration. 
- 
If treatment terminated: reason for termination (e.g. due to insufficient effect or 
AE). 
- 
In case of treatment with dupilumab, tralokinumab, lebrikizumab, nemolizumab, 
or a JAK inhibitor: 
- 
Received in a trial or as prescription. 
- 
Asthma. 
- 
Food allergy. 
- 
Hay fever. 
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- 
Allergic conjunctivitis 
- 
Atopic keratoconjunctivitis 
- 
Eczema herpeticum 
• Medical and surgical history including concurrent diagnoses within the previous 
12 months. For each condition, surgical procedure, or diagnosis, the start and stop dates 
will be recorded. It will also be recorded if the condition or diagnosis is ongoing. 
Relevant medical history also includes diseases which are specifically listed as exclusion 
criteria and diseases for which treatments are listed as exclusion criteria or prohibited 
medications. 
8.2.3 
Body measurement (height) 
Height will be recorded according to the schedule of trial activities (Section 1.3). 
The subject’s height (without shoes) will be measured (in cm/in). 
8.2.4 
C-SSRS 
C-SSRS will be assessed according to the schedule of trial activities (Section 1.3). 
The C-SSRS Screening version is a rater-administered instrument used to assess severity of 
suicidal ideation and suicidal behaviour through a series of simple, plain-language 
questions (67). The C-SSRS must be completed at the screening visit to check that exclusion 
criterion no. 12 is not met. 
8.2.5 
Laboratory assessments 
The laboratory assessments conducted at screening are listed in Section 8.4.5. 
8.3 
Efficacy assessments 
8.3.1 
EASI 
EASI will be assessed by the investigator according to the schedule of trial activities 
(Section 1.3). At an unscheduled visit, it will be at the discretion of the investigator if EASI 
should be assessed. 
The EASI is a validated measure used in clinical practice and clinical trials to assess the 
severity and extent of AD (68). The assessment will be based on the condition of the disease 
at the time of evaluation and not in relation to the condition at a previous visit. The scoring is 
based on the Harmonising Outcome Measures for Eczema (http://www.homeforeczema.org/) 
EASI guidance version 3. 
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The EASI is a composite index with scores ranging from 0 to 72, with higher values 
indicating more severe or more extensive condition. The index will be calculated as shown in 
Panel 7. Briefly, the investigator will assess the severity of 4 AD disease characteristics 
(erythema, edema/papulation, excoriation, and lichenification) on the 4 body regions 
(head/neck, trunk, upper extremities, lower extremities); severity will be assessed according 
to the scale shown in Panel 8. For each body region, a severity sum score will be calculated 
which will be multiplied by an area score (Panel 8) and by a weighting factor. The EASI score 
equals the sum of the scores obtained for each body region (Panel 7).  
Reporting in eCRF 
The body region, severity of the disease characteristics (erythema, edema/papulation, 
excoriation, and lichenification), and the area score will be recorded in the eCRF. Refer to 
Appendix 1 (Section 12.1.8) for principles for data entry in the eCRF. 
Panel 7: Calculation of the EASI score 
Body region 
Erythema 
Edema/  
papulation 
Excoriation 
Lichenification 
Area score 
Weighting factor 
Score 
Head/neck 
(SS   + 
   SS   + 
   SS   + 
   SS) 
×  AS 
× 0.1 
 
Trunk 
(SS   + 
   SS   + 
   SS   + 
   SS) 
×  AS 
× 0.3 
 
Upper extremities 
(SS   + 
   SS   + 
   SS   + 
   SS) 
×  AS 
× 0.2 
 
Lower extremities 
(SS   + 
   SS   + 
   SS   + 
   SS) 
×  AS 
× 0.4 
 
The EASI score is the sum of the 4 body region scores 
 
(range 0-72) 
Abbreviations: AS = area score; EASI = Eczema Area and Severity Index; SS = severity score. 
Modified from (69). 
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Panel 8: EASI severity score scale and area score scale 
Severity score scale 
 
Area score scale 
0 
None/absent 
 
0 
0% affected area 
1 
Mild 
 
1 
1% to 9% affected area 
2 
Moderate 
 
2 
10% to 29% affected area 
3 
Severe 
 
3 
30% to 49% affected area 
Note: half-points (1.5 and 2.5) are 
allowed. 0.5 is not permitted. 
 
4 
50% to 69% affected area 
 
5 
70% to 89% affected area 
 
6 
90% to 100% affected area 
Abbreviations: EASI = Eczema Area and Severity Index. 
8.3.2 
SCORAD 
The SCORAD is a validated tool to evaluate the extent and severity of AD lesions, along with 
subjective symptoms (70). The maximum total score is 103, with higher values indicating 
more severe disease. SCORAD will be assessed according to the schedule of trial activities 
(Section 1.3). 
The assessment will be based on the condition of the disease at the time of evaluation and not 
in relation to the condition at a previous visit.  
The assessment consists of 3 components: A = extent, B = intensity, and C = subjective 
symptoms. 
Extent (A) 
The extent of AD is assessed as a percentage of each defined body area and reported as the 
sum of all areas (maximum score = 100%). 
Intensity (B) 
The intensity of 6 specific symptoms of AD (erythema, edema/papulation, oozing/crusting, 
excoriation, lichenification, and dryness) is assessed by the investigator on an average 
representative area using the following scale: 
0 
= 
None/absent 
1 
= 
Mild 
2 
= 
Moderate 
3 
= 
Severe 
Note: dryness is evaluated on uninvolved areas. 
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The sum of intensity score of the 6 symptoms will be reported (maximum score = 18). 
Subjective symptoms (C) 
A subjective assessment of the average pruritus and sleep loss over the last 3 days/nights is 
recorded for each symptom by the subject on a VAS, where 0 is no itching (or no trouble 
sleeping) and 10 is unbearable itching (or lot of trouble sleeping), with a maximum possible 
score of 20. 
The SCORAD is calculated as: A/5+7B/2+C. 
Reporting in eCRF 
The extent and intensity of disease, as well as the subjective assessment of pruritus and sleep 
loss, will be reported in the eCRF. Refer to Appendix 1 (Section 12.1.6) for principles for data 
entry in the eCRF. 
8.3.3 
vIGA-AD 
vIGA-AD will be assessed by the investigator according to the schedule of trial activities 
(Section 1.3). At an unscheduled visit, it will be at the discretion of the investigator if the 
vIGA-AD should be assessed. 
The vIGA-AD is an instrument used in clinical trials to assess the subject’s global disease 
severity and is based on a 5-point scale ranging from 0 (clear) to 4 (severe) (Panel 9) (71). 
The vIGA-AD score will be assessed according to the schedule of trial activities (Section 1.3). 
The assessment will be based on the condition of the disease at the time of evaluation and not 
in relation to the condition at a previous visit.  
Reporting in eCRF  
The disease severity assessment score will be recorded in the eCRF. Refer to Appendix 1 
(Section 12.1.8) for principles for data entry in the eCRF. 
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Panel 9: vIGA-AD 
Score 
Morphological description 
0 - Clear 
No inflammatory signs of AD (no erythema, no induration/papulation, no 
lichenification, no oozing/crusting). Post-inflammatory hyperpigmentation and/or 
hypopigmentation may be present. 
1 - Almost clear 
Barely perceptible erythema, and barely perceptible induration/papulation, and/or 
minimal lichenification. No oozing or crusting. 
2 - Mild 
Slight but definite erythema (pink), slight but definite induration/papulation, and/or 
slight but definite lichenification. No oozing or crusting. 
3 - Moderate 
Clearly perceptible erythema (dull red), clearly perceptible induration/papulation, 
and/or clearly perceptible lichenification. Oozing and crusting may be present. 
4 - Severe 
Marked erythema (deep or bright red), marked induration/papulation, and/or marked 
lichenification. Disease is widespread in extent. Oozing or crusting may be present. 
Abbreviations: AD = atopic dermatitis; vIGA-AD = validated Investigator Global Assessment Scale for Atopic 
Dermatitis. 
8.3.4 
BSA involvement 
The total BSA affected by AD will be assessed by the investigator for each section of the body 
as component A of SCORAD (Section 8.3.2) and will be reported as a percentage of all major 
body sections combined. The following body regions will be assessed (brackets show the 
highest possible score for each region): head and neck (9%), anterior trunk (18%), back 
(18%), upper limbs (18%), lower limbs (36%), and genitals (1%). The total BSA score will be 
assessed according to the schedule of activities (Section 1.3). 
The investigator will assess the total AD involvement for the whole body, i.e. head/neck, 
upper limbs, trunk, genitalia, and lower limbs, as a percentage of the total BSA. As a guidance 
for this estimate, the surface of a full, flat palm (including the 5 fingers) of an adult subject 
corresponds to approximately 1% of the total BSA. 
Reporting in eCRF 
BSA involvement will be recorded as part of the SCORAD assessment. Refer to Appendix 1 
(Section 12.1.8) for principles for data entry in the eCRF. 
8.3.5 
PROs 
8.3.5.1 
Overview 
During the trial, each subject should make individual assessments relating to their perception 
of their disease and quality of life. These should be performed independently of the 
investigator. At the screening visit (at the earliest Week -4), the subject’s eligibility to 
participate in the trial needs to be established before the PROs can be completed.  
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The subject will be asked to complete PROs according to the schedule of trial activities 
(Section 1.3). PROs will either be completed at home (eDiary) or at the trial site (electronic 
device) (Panel 10). 
Panel 10: Overview of PROs to be completed 
PROs to be completed at home (eDiary) 
PROs to be completed at the trial site  
(electronic device) 
To be completed in the morninga) 
DLQI (Section 8.3.5.6) 
Nocturnal 
 (Section 8.3.5.2) 
POEM (Section 8.3.5.7) 
Difficulty 
 (Section 8.3.5.3) 
EQ-5D-5L (Section 8.3.5.8) 
Frequency of 
 During the Night 
(Section 8.3.5.4) 
WPAI-SHP (Section 8.3.5.9) 
To be completed in the eveninga) 
HADS (Section 8.3.5.10) 
ADSD (all components) (Section 8.3.5.5) 
PGI-S (Section 8.3.5.11) 
 
 
 
 
 
ADSD 
 
Nocturnal 
 
 
Difficulty 
 
 
Frequency of 
 During the Night 
 
PGI-C (Section 8.3.5.12) 
 
 
 
 
 
ADSD 
 
Nocturnal 
 
 
Difficulty 
 
 
Frequency of 
 During the Night 
a) The morning assessments will only be completed until Week 16, the evening assessments will be 
completed until Week 32. 
Abbreviations: ADSD = Atopic Dermatitis Symptom Diary; DLQI = Dermatology Life Quality Index; 
eDiary = electronic diary; EQ-5D-5L = EuroQol 5-Dimension Health Questionnaire 5 Level; 
HADS = Hospital Anxiety and Depression Scale; PGI-C = Patient Global Impression of Change; 
PGI-S = Patient Global Impression of Severity; POEM = Patient-Oriented Eczema Measure; 
PRO = patient-reported outcome; WPAI-SHP = Work Productivity and Activity Impairment: Specific Health 
Problem. 
At the screening visit, the subjects will receive an eDiary device and training in using the 
device. The subjects must start completing the eDiary at least 1 week prior to baseline, but 
preferably from the date the subjects receive the eDiary. From Week -1 to Week 16, the 
subjects will be asked to complete the eDiary twice daily, once in the morning and once in the 
evening. After Week 16, up to Week 32, the subjects will be asked to complete the eDiary in 
the evening only (Panel 10). 
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Between Week -1 and Week 32, an e-mail notification alarm will inform the investigator/site 
staff about non-compliance with eDiary completion. In case of non-compliance, the 
investigator should remind the subject of the importance of completing the eDiary daily. 
Subjects will be asked to return the eDiary at Week 32 or at their last visit in the trial. 
8.3.5.2 
Nocturnal 
 (eDiary) 
Nocturnal 
 is a single item questionnaire designed developed by LEO Pharma to 
assess how much the subject 
 during the past night. It will be 
assessed on a 6-point categorical scale (‘none of the night’, ‘a little of the night’, ‘some of the 
night’, ‘a lot of the night’, ‘all of the night’, ‘I don't know’).  
8.3.5.3 
Difficulty 
 (eDiary) 
Difficulty 
 is a single item questionnaire designed developed by LEO Pharma 
to assess the subject’s difficulty to
 the past night. It will be 
assessed on a 5-point categorical scale (‘not difficult’, ‘a little difficult’, ‘moderately 
difficult’, ‘extremely difficult’, ‘I don’t know’).  
8.3.5.4 
Frequency of 
 During the Night (eDiary) 
Frequency of 
 During the Night is a single item questionnaire designed developed 
by LEO Pharma to assess how many times the subject 
 the past 
night. It will be assessed on a 5-point categorical scale (‘not at all’, ‘
 1 time’, ‘
 
 2 times’, ‘
 3 times or more’, ‘I don’t know’).  
8.3.5.5 
ADSD (eDiary) 
ADSD is considered a subject’s assessment of efficacy. ADSD is a 9-item sign and symptom 
diary developed by LEO Pharma. It assesses the severity of 
 
. The subject assesses 
the severity of each symptom ‘at its worst’ over the past 24 hours using an 11-point numeric 
rating scale, with anchors at 0=‘no [symptom]’ and 10=‘worst possible [symptom]’. 
From Week -1 to Week 32, ADSD will be completed by the subject on the eDiary daily. An 
overview of all PROs, including other PROs collected in the eDiary and PROs collected at the 
trial site, is presented in Section 8.3.5.1. 
8.3.5.6 
DLQI (at trial site) 
DLQI consists of 10 items addressing the subject’s perception of the impact of their skin 
disease on different aspects of their quality of life over the past week such as dermatology 
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related symptoms and feelings, daily activities, leisure, work or school, personal relationships, 
and the treatment. Each item will be scored on a 4 point Likert scale (0=‘not at all/not 
relevant’, 1=‘a little’, 2=‘a lot’, 3=‘very much’). The total score (0 to 30) is the sum of the 
10 items with higher scores indicating a poorer quality of life (72). The subject will be asked 
to complete DLQI on an electronic device at the trial site according to the schedule of trial 
activities (Section 1.3). 
8.3.5.7 
POEM (at trial site) 
POEM consists of 7 items, each addressing a specific symptom (itching, sleep, bleeding, 
weeping, cracking, flaking, and dryness). The subject will be asked to score how often they 
experienced each symptom over the past week on a 5 point categorical scale (0=‘no days’, 
1=‘1 to 2 days’, 2=‘3 to 4 days’, 3=‘5 to 6 days’, 4=‘every day’). The total score (0 to 28) is 
the sum of the 7 items and reflects disease related morbidity with higher scores indicating 
more severe symptoms (73). The subject will be asked to complete POEM on an electronic 
device at the trial site according to the schedule of trial activities (Section 1.3). 
8.3.5.8 
EQ-5D-5L (at trial site) 
 EQ-5D-5L is a self-administered questionnaire used to assess health status ‘today’ and is 
divided into 2 sections. The first section includes 5 dimensions (mobility, self-care, usual 
activity, pain/discomfort, and anxiety/depression). Each dimension is assessed using a 5-point 
categorical scale (‘no problems’, ‘slight problems’, ‘moderate problems’, ‘severe problems’, 
and ‘extreme problems’). The second section consists of a vertical VAS anchored at 0 (‘the 
worst health you can imagine’) and 100 (‘the best health you can imagine’) (74). The subject 
will be asked to complete EQ-5D-5L on an electronic device at the trial site according to the 
schedule of trial activities (Section 1.3). 
8.3.5.9 
WPAI-SHP (at trial site) 
WPAI-SHP (v2.0) consists of 6 items and scores can be calculated for 4 domains, each 
reflecting the percentage impairment due to AD during the past week, with higher scores 
indicating a greater impairment and lesser productivity (75): 
• Absenteeism: percentage work time missed due to AD for those who were employed the 
past week. 
• Presenteeism: percentage impairment while working due to AD for those who were 
employed and actually worked the past week. 
• Work productivity loss: percentage overall work impairment due to AD for those who 
were employed the past week. 
• Activity impairment: percentage activity impairment due to AD for all respondents. 
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The subject will be asked to complete WPAI-SHP on an electronic device at the trial site 
according to the schedule of trial activities (Section 1.3). 
8.3.5.10 
HADS (at trial site) 
HADS is a 14-item questionnaire with scores ranging from 0 to 21 for anxiety and 0 to 21 for 
depression. Each of the 14 items will be evaluated on a Likert scale. Scores are considered 
normal from 0 to 7 and abnormal from 11 to 21 and are categorized as: normal (0 to 7), mild 
(8 to 10), moderate (11 to 14), and severe (15 to 21) (76). The subject will be asked to 
complete HADS on an electronic device at the trial site according to the schedule of trial 
activities (Section 1.3). If the subject presents with symptoms of clinical depression and/or 
anxiety, the investigator should take appropriate action at their discretion. 
8.3.5.11 
PGI-S (at trial site) 
PGI-S is a questionnaire designed to assess the subject’s overall perception of severity. In this 
trial the severity of 
, ADSD, nocturnal 
, difficulty 
, and 
frequency of 
 during the night over the past week will be evaluated. The subject 
will be asked to choose 1 option from a 4-point categorical scale as described in Panel 11 
(77). The subject will be asked to complete the PGI-S questionnaire on an electronic device at 
the trial site according to the schedule of trial activities (Section 1.3). 
Panel 11: PGI-S 
PGI-S 
Scale 
 
 
ADSD 
Nocturnal 
 
Difficulty 
 
‘None’, ‘mild’, ‘moderate’, ‘severe’ 
Frequency of 
 During the Night PGI-S 
‘Never’, ‘sometimes’, ‘often’, ‘very often’ 
Abbreviations: ADSD = atopic dermatitis symptom diary; PGI-S = Patient’s Global Impression of Severity. 
8.3.5.12 
PGI-C (at trial site) 
PGI-C is a questionnaire designed to assess the subject’s overall impression of change. In this 
trial the change in 
, ADSD, nocturnal 
, difficulty 
, and 
frequency of 
 during the night since the subject started treatment will be evaluated. 
The subject will be asked to choose 1 option from a 5 point categorical scale (‘much better’, 
‘a little better’, ‘no change’, ‘a little worse’, ‘much worse’) (77). The subject will be asked to 
complete the PGI-C questionnaire on an electronic device at the trial site according to the 
schedule of trial activities (Section 1.3). 
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8.4 
Safety assessments 
Planned timepoints for all safety assessments are provided in the schedule of activities 
(Panel 2). 
8.4.1 
Vital signs 
Vital signs (resting BP, pulse, and body temperature) must be assessed prior to IMP 
administration according to the schedule of trial activities (Section 1.3). Vital signs will be 
measured in a supine or sitting position following at least 5 minutes of rest, and will include 
resting blood pressure, pulse, and body temperature. At an unscheduled visit, it will be at the 
discretion of the investigator if vital signs should be assessed. 
In addition, at Weeks 0, 1, 2, 3, and 4, subjects will be monitored after IMP administration for 
immediate drug reactions for a minimum of 2 hours with vital signs taken immediately 
(within 5 minutes) after last IMP administration, after 30 minutes (± 5 minutes), after 1 hour 
(± 5 minutes), and after 2 hours (± 5 minutes), or until stable, whichever is later (for 
requirements specific for EU countries i.e. CZ, DE, ES, FR, HU, PL and RO, see 
Section 12.5.1). 
If a subject presents with an abnormal vital sign, the measurement of the vital sign can be 
repeated approximately 15 minutes later to verify the first measurement. Should the repeated 
measurement result in a normal value, the measurement must be repeated once more. If the 
third measurement verifies the second normal value, the first measurement should be 
considered false and the second measurement should be recorded in the eCRF. If the third 
measurement confirms the first measurement abnormal, the second measurement should be 
considered false and the first measurement should be recorded in the eCRF. Only the 
measurement considered true should be recorded in the eCRF, but note that all measured 
values should be documented in source in these scenarios. 
In case of a clinically significant abnormal vital sign at screening and/or baseline, it will be at 
the discretion of the investigator if the subject should be included in the trial in accordance 
with exclusion criterion no. 15. During the trial, if a subject presents with a clinically 
significant abnormal vital sign, the investigator must take appropriate action, at their 
discretion. 
Reporting in eCRF 
It will be recorded in the eCRF if vital signs were measured. The investigator’s evaluation 
(‘normal’, ‘abnormal, not clinically significant’, ‘abnormal, clinically significant’) will also 
be recorded in the eCRF. If vital signs are not measured, a reason should be provided. 
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Clinically significant abnormal vital signs at screening will be documented as medical history 
in the eCRF. Any clinically significant worsening of a pre-existing condition or any new 
clinically significant abnormality occurring after screening will be reported as an AE in 
accordance with Section 12.2.4. 
Refer to Appendix 1 (Section 12.1.8) for principles for data entry in the eCRF. 
8.4.2 
Physical examination 
A physical examination of the subject including general appearance, regional lymph nodes, 
and dermatologic examination of the skin, must be performed according to the schedule of 
trial activities (Section 1.3). At an unscheduled visit, it will be at the discretion of the 
investigator if a physical examination should be performed. 
In case of a clinically significant abnormal finding during physical examination at screening 
and/or baseline, it will be at the discretion of the investigator if the subject should be included 
in the trial in accordance with exclusion criterion no. 15. During the trial, if a subject presents 
with a clinically significant abnormal finding during physical examination, the investigator 
must take appropriate action, at their discretion. 
Reporting in eCRF 
It will be recorded in the eCRF if a physical examination was conducted. If not, a reason 
should be provided. The investigator’s evaluation of the physical examination (‘normal’, 
‘abnormal, not clinically significant’, ‘abnormal, clinically significant’) will also be recorded. 
Clinically significant abnormal findings during physical examination at screening will be 
documented as medical history in the eCRF. Any clinically significant worsening of a 
pre-existing condition or any new clinically significant abnormality after screening will be 
reported as an AE as described in Section 12.2.4. 
Refer to Appendix 1 (Section12.1.8) for principles for data entry in the eCRF. 
8.4.3 
Body measurement (weight) 
Weight will be recorded according to the schedule of trial activities (Section 1.3). The 
subject’s weight (in indoor clothing and without shoes) will be measured (in kg/lb). At an 
unscheduled visit, it will be at the discretion of the investigator if weight should be measured. 
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8.4.4 
Electrocardiography 
ECGs must be measured according to the schedule of trial activities in (Section 1.3). At an 
unscheduled visit, it will be at the discretion of the investigator if an ECG should be 
measured. 
At each visit, the individual measurement will be recorded after the subject has been in supine 
position for at least 5 minutes. 
A pre-evaluation of the ECGs will be performed by the investigator to evaluate immediate 
subject safety. At a minimum, the date of ECG pre-evaluation will be recorded in the source 
documents. In case of a suspected abnormal ECG, the investigator must take appropriate 
action, at their discretion. 
The ECG data will be transferred to a central ECG service company for central evaluation. A 
cardiologist at the ECG service company will analyze and interpret the ECG data. The ECG 
service company will provide ECG evaluation reports to the trial sites. The collection and 
transmission of ECG data will be described in a separate ECG manual. 
The investigator must evaluate all abnormal ECG results (‘clinically significant’ or ‘not 
clinically significant’) and sign and date the evaluation. It will be at the discretion of the 
investigator to take appropriate actions and provide a justification in the medical record. 
If a result is abnormal at the screening or baseline visit and considered by the investigator to 
be clinically significant, it will be up to the investigator’s discretion to decide if the subject 
should be randomized into the trial (respecting exclusion criterion no. 15). If a subject with an 
abnormal and clinically significant ECG result is randomized, the investigator should provide 
a justification in the medical record. 
Reporting in eCRF 
It must be recorded in the eCRF if an ECG was measured. If not, a reason must be provided. 
In case of a suspected abnormal ECG, the action taken with the subject, if any, must be 
recorded. The investigator’s assessment of ECG result (‘normal’, ‘abnormal, not clinically 
significant’, ‘abnormal, clinically significant’) must also be recorded in the eCRF. 
Clinically significant abnormal findings at the screening visit (or originating from the ECG 
taken at the screening visit) will be documented as medical history in the eCRF. Any 
clinically significant worsening of a pre-existing condition or any new clinically significant 
abnormality occurring after the screening visit will be reported as an AE as described in 
Section 12.2.4. 
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Refer to Appendix 1 (Section 12.1.8) for principles for data entry in the eCRF. 
8.4.5 
Laboratory testing 
8.4.5.1 
Overview 
Blood and urine samples will be collected according to the schedule of trial activities 
(Section 1.3).  
The evaluations shown in Panel 12 will be performed by the central laboratory. 
Protocol-specific requirements for inclusion or exclusion of subjects are detailed in Section 5 
of the protocol. 
Additional tests may be performed at any time during the trial as determined necessary by the 
investigator or required by local regulations. 
Panel 12: Clinical laboratory tests 
Clinical chemistry 
Hematology 
Sodium 
Potassium 
Creatinine 
Urea nitrogen 
Calcium  
Alkaline phosphatase  
AST 
ALT 
Gamma glutamyl transferase 
Lipase 
Bilirubin1 
(Direct bilirubin)1 
(Indirect bilirubin)1 
Cholesterol 
LDL cholesterol and HDL cholesterol 
Triglycerides 
Tryptase2 
Hemoglobin 
Leukocytes  
Neutrophils   
Neutrophils/leukocytes4 
Lymphocytes  
Lymphocytes/leukocytes4 
Monocytes  
Monocytes/leukocytes4 
Eosinophils  
Eosinophils/leukocytes4 
Basophils  
Basophils/leukocytes4 
Thrombocytes  
Serology 
Tuberculosis test3 
Hepatitis B virus surface antigen3 
Hepatitis B virus surface Ab3 
Hepatitis B virus core Ab3 
Hepatitis C virus Ab3 
HIV-1 Ab3 and HIV-2 Ab3 
IgE 
A tuberculosis test will be performed according to local 
standard of care for patients requiring initiation of biologic 
treatment. A tuberculosis test can be performed at the 
central or local laboratory. 
Serum pregnancy test3,5  
Choriogonadotropin Beta 
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Urinalysis6 
Urine pregnancy test5) 
Protein 
Glucose 
Ketones 
Occult blood 
Leukocytes 
Nitrite 
Choriogonadotropin Beta 
1) 
If bilirubin is above upper limit of normal, direct and indirect bilirubin will also be measured.  
2) 
In case of an anaphylactic reaction, analysis of serum tryptase must be performed (please refer to Section 6.2). 
3) 
Conducted at screening. In case additional analyses are needed to support the interpretation of the initial test results for 
hepatitis B, hepatitis C, or HIV, these will be conducted by the central laboratory, as applicable (e.g. HBV-DNA, 
HCV-RNA). 
4) 
The symbol ‘/’included in the table represents ‘a ratio’. 
5) 
Only women of childbearing potential. 
6) 
The analytes listed will only be measured if the urine dipstick is abnormal. 
Abbreviations: Ab = antibody; ALT = alanine aminotransferase; AST = aspartate aminotransferase; HDL = high density 
lipoprotein; HIV = human immunodeficiency virus; IgE = immunoglobulin E; LDL = low density lipoprotein. 
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8.4.5.2 
Investigator evaluation of laboratory samples 
Laboratory samples sent to the central laboratory 
Clinical chemistry, hematology, serology, and serum pregnancy tests will be analyzed by a 
central laboratory which will provide results to the trial sites. Laboratory parameters will be 
classified as low, normal, or high, depending on whether the value is below, within, or above 
the reference range. The investigator must evaluate all results outside the reference range 
(‘clinically significant’ or ‘not clinically significant’) and sign and date their evaluation which 
will be archived in the investigator’s trial file.  
In case of an abnormal clinically significant laboratory result at screening and/or baseline, it 
will be at the discretion of the investigator if the subject should be randomized in the trial in 
accordance with exclusion criterion no. 15. During the trial, if a subject presents with an 
abnormal clinically significant laboratory result, the investigator must take appropriate action, 
at their discretion.  
In case additional analyses are needed to support the interpretation of the initial test results for 
hepatitis B, hepatitis C, or HIV, these will be conducted by the central laboratory, as 
applicable (e.g. HBV-DNA, HCV-RNA). Subjects with a positive serology, or tuberculosis 
test at screening should be referred to a competent health care structure for treatment and 
follow-up. 
Serum pregnancy tests for women of childbearing potential will be analyzed by a central 
laboratory which will provide results to the trial sites. A woman with a positive serum 
pregnancy test at screening must not be included in the trial (exclusion criterion no. 17). 
Instructions for collection, processing, storage, and shipment of laboratory samples, as well as 
laboratory contact information specific to this trial will be provided in a separate laboratory 
manual. 
Tests performed at the trial site 
Urine samples will be tested with a dipstick according to the schedule of trial activities 
(Section 1.3). In case of abnormal clinically significant findings, investigator must take 
appropriate action, at their discretion. 
If a dipstick shows any abnormal reading, a urine sample must always be collected and sent to 
the central laboratory for further analysis, regardless of causality or investigator’s assessment 
of significance. 
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Urine pregnancy tests for women of childbearing potential will be conducted at the trial sites. 
The test will be repeated every 4 weeks until Week 20, as well as at Week 32 as shown in the 
schedule of trial activities (Section 1.3). A woman with a positive urine pregnancy test at 
Week 0 (baseline) must not be randomized in the trial (exclusion criterion no. 17). A positive 
urine pregnancy test must be verified with a serum pregnancy test. If the urine pregnancy test 
is positive but not confirmed by the serum pregnancy test, the subject may continue IMP 
treatment, but the LEO medical expert should be consulted (for requirements specific for 
EU countries i.e. CZ, DE, ES, FR, HU, PL and RO, see Section 12.5.1).  
Reporting in eCRF 
It will be recorded in the eCRF if a blood sample was taken. If not, a reason should be 
provided. The investigator’s assessment of the results (‘normal’, ‘abnormal, not clinically 
significant’, ‘abnormal, clinically significant’) will also be recorded. 
Site staff will record in the eCRF if a urine dipstick was performed and whether urinalysis is 
required for further assessment, as judged by the investigator. If so, a urine sample should be 
sent to the central laboratory. If the urine sample was not tested with a dipstick, a reason will 
be provided. In case urinalysis is performed, the investigator’s assessment of the results 
(‘normal’, ‘abnormal, not clinically significant’, ‘abnormal, clinically significant’) will be 
recorded in the eCRF. 
It will be recorded in the eCRF if the subject is a woman of childbearing potential and if a 
urine pregnancy test was conducted. If not, a reason should be provided. The date and 
outcome (‘positive’, ‘negative’) of the urine pregnancy test will also be recorded. 
Clinically significant abnormal laboratory results at screening (or originating from laboratory 
tests taken at the screening visit) will be documented as medical history in the eCRF. Any 
clinically significant worsening of a pre-existing condition or any new clinically significant 
abnormality occurring after screening will be reported as an AE as described in 
Section 12.2.4. 
Refer to Appendix 1 (Section 12.1.8) for principles for data entry in the eCRF. 
8.4.6 
ADA measurements 
Blood samples will be collected to determine ADA levels at pre-determined time points 
according to the schedule of trial activities (Section 1.3). At an unscheduled visit, it will be at 
the discretion of the investigator if a blood sample to determine ADA levels should be 
collected.  
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Serum samples for determination of presence or absence of ADA will be analyzed by a 
laboratory using a validated bioanalytical method. A tiered testing scheme will be employed, 
with the first step being screening. Samples found positive in the screening step will be tested 
in the confirmatory step. Samples confirmed positive for ADA in the confirmatory step will 
undergo endpoint titer determination. Details of the analytical method used will be described 
in a bioanalytical report. 
Collection, handling, and shipment instructions for ADA blood samples are provided in a 
laboratory manual. 
The ADA results will not be made available to the trial sites during the trial, but will be made 
available to the investigator upon request after completion of the CTR. 
Reporting in eCRF 
It will be recorded in the eCRF if an ADA blood sample was taken. If not, a reason should be 
provided. Refer to Appendix 1 (Section 12.1.8) for principles for data entry in the eCRF. 
8.5 
PK assessments 
Blood samples for PK assessments will be collected at the time points specified in the 
schedule of trial activities (Section 1.3). At an unscheduled visit, it will be at the discretion of 
the investigator if a blood sample to determine PK should be collected.  
Serum samples for determination of LEO 138559 concentrations will be analyzed by a 
laboratory using a validated bioanalytical method. 
Instructions for collection, handling, and shipment of PK samples will be provided in a 
separate laboratory manual. 
LEO Pharma will not provide IMP concentration results to the trial sites during the trial. The 
results will be available to the investigator upon request after completion of the CTR. 
Reporting in eCRF 
It will be recorded in the eCRF if the PK sample was taken; if not, a reason will be provided. 
Refer to Appendix 1 (Section 12.1.8) for principles for data entry in the eCRF. 
8.6 
PD assessments 
The PD assessments will include: 
• Analysis of biomarker expression in serum. 
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• Analysis of skin swabs to assess Staphylococcus aureus abundance and microbiome 
profile.  
• Analysis of skin tape strip samples to assess the molecular profile of the skin (only at 
selected sites). 
• Analysis of skin biopsies to assess biomarker expression. (Skin biopsies will only be 
collected at a selected number of sites; for subjects who provide informed consent to this 
component.)  
The PD assessments are considered exploratory. A summary of the results will be included in 
the CTR if the results are available in time for this. The full PD/biomarker results will be 
reported in an addendum to the CTR. 
LEO Pharma will not provide biomarker, skin swab, skin tape strip, and skin biopsy results to 
the trial sites during the trial. The results will be available to the investigator upon request 
after completion of the CTR. 
Biomarker expression in serum 
Biomarker expression in serum will be measured to evaluate treatment effect of LEO 138559 
on disease biomarkers and biomarkers related to the mechanism of action of LEO 138559. 
Blood samples for biomarker analyses will be collected according to the schedule of trial 
activities (Section 1.3). At an unscheduled visit, it will be at the discretion of the investigator 
if a blood sample should be collected to determine blood biomarkers.  
The serum biomarkers to be analyzed include, but are not limited to, IL-13, IL-22, and IL-31.  
Collection, handling, and shipment instructions for serum samples will be provided in a 
separate laboratory manual. 
S. aureus abundance and microbiome profiling in skin swabs 
Skin swab samples will be collected according to the schedule of trial activities (Section 1.3) 
to determine S. aureus abundance by means of qPCR and additional analysis of microbiome 
diversity investigated by use of next generation sequencing methods. At an unscheduled visit, 
it will be at the discretion of the investigator if a skin swab should be collected to determine S. 
aureus abundance and microbiome profiling. 
At baseline, standardized swabs will be collected from 3x5 cm skin areas at one lesional area 
(defined as “swab/strip target lesion”) as well as from an adjacent non-lesional area (the 
non-lesional area needs to be located between 5 to 20 cm from the lesional area). At baseline 
visit (Week 0) skin swabs should be taken from both lesional and non-lesional sites. At the 
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post-baseline visit (Week 16), 1 skin swab will be collected from the original lesion; no skin 
swab will be collected from non-lesional skin. Skin swabs will be collected from lower limbs, 
upper limbs, or trunk. 
Collection, handling, and shipment instructions for skin swabs will be provided in a separate 
laboratory manual. 
Molecular profile of skin tape strip samples 
Skin tape strip samples will be collected according to the schedule of trial activities 
(Section 1.3). Skin tape strips will only be collected at the trial sites selected to collect skin 
biopsies (see below). At these sites, skin tape strips will be mandatory for all subjects, up to a 
global cap of 75 subjects.  
A maximum of 8 consecutive skin tape strips from paired lesional areas (defined as 
“swab/strip target lesion”) as well as from an adjacent non-lesional area will be collected (the 
non-lesional area needs to be located between 5 to 20 cm from the lesional area). Tape strips 
will be collected from lower limbs, upper limbs, or trunk. 
At an unscheduled visit, it will be at the discretion of the investigator if a skin tape strip 
sample should be collected to determine the molecular profile of the skin. 
Collection, handling, and shipment instructions for skin tape strip samples will be provided in 
a separate laboratory manual. 
Biomarker expression and histology in skin biopsies 
Skin biopsies for biomarker expression analysis (RNA analysis) in the skin and for histology 
will be collected according to the schedule of trial activities (Section 1.3) at selected trial sites 
only and for subjects who provide informed consent to this component up to a global cap of 
75 subjects.  
For patients who have consented to participate in the provision of skin biopsies, 5 mm paired 
lesional and non-lesional biopsies will be collected at baseline (the non-lesional biopsy needs 
to be located between 5 to 20 cm from the lesional biopsy). At the post-baseline visit, 
1 biopsy will be collected from the original lesion; no skin biopsy will be collected from 
non-lesional skin at the post-baseline visit. Biopsies will be collected from lower limbs, upper 
limbs, or trunk. Each 5-mm biopsy will be split in 2; 1 part will be used for analysis of RNA, 
and 1 part will be used for histology/immunohistochemistry/in-situ hybridization. At an 
unscheduled visit, it will be at the discretion of the investigator if a skin biopsy should be 
collected. 
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The biopsy area needs to be separate from the skin swab and tape strip area (unless samples 
can be taken from a large area). 
The biomarkers to be analyzed by histology/immunohistochemistry/in-situ/hybridization 
include, but are not limited to, the following: markers for inflammation (e.g. S100A9), 
epidermal markers (e.g. epidermal thickness, keratin type I cytoskeletal 16), and barrier 
markers (e.g. loricrin). 
Collection, handling, and shipment instructions for skin biopsies will be provided in separate 
laboratory manuals. 
Reporting in eCRF 
It will be recorded in the eCRF if blood samples, skin swabs, skin tape strips, and skin 
biopsies were collected. If not collected, a reason should be provided. For skin swabs, skin 
tape strips, and skin biopsies, it will be recorded if they were collected from lesional or 
non-lesional skin, and from which body area they were collected.  
Refer to Appendix 1 (Section 12.1.8) for principles for data entry in the eCRF. 
8.7 
Other assessments 
8.7.1 
Photography (selected sites) 
Subjects at selected trial sites will be asked to participate in a voluntary photography 
component of the trial which involves digital photography assessments to show disease 
progression over time. Participation in this photography component requires that the subject 
provides informed consent to this component. 
Digital color photographs will be taken of the legs including feet (dorsal and ventral image), 
torso including arms (dorsal and ventral image), and head and neck (anterior image) 
according to the schedule of trial activities (Section 1.3). The photographs must always be 
taken with underwear (modesty garments, provided by the central photography vendor) and 
female subjects should have their breasts hidden. All faces (eyes and mouth) will be 
anonymized upon receipt of the images by the central photography vendor. It will be recorded 
in the eCRF if the photograph(s) was (were) taken; if not, a reason should be provided.  
The trial sites will use their own equipment or equipment provided by the photography vendor 
to take the photographs. Instructions for photography will be provided to the sites in a 
photography manual. Photography standards and procedures will be provided to the trial sites 
by the central photography vendor. 
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The photographs will have no other subject identifier than the subject ID and will be 
transmitted electronically to the photography vendor using a secure file transfer protocol. 
LEO Pharma may at its discretion use the photographs in scientific presentations to other 
researchers, or in scientific books or journals. The photographs may also be part of material 
used for training and educational purposes. Steps will be taken to ensure that the identity of 
the subject is protected by blinding or covering any potential identifying features in the 
photographs. 
8.7.2 
Qualitative interviews (selected sites) 
Approximately 75 subjects at selected trial sites in CA, DE, PL, UK and US will be asked to 
participate in a qualitative interview. 
Participation in the interview will be part of the local ICF in the relevant countries. 
The site personnel will enter the participants’ contact details and schedule the interviews at 
the participants’ convenience on a secure IT portal at Week 10 (Visit 10). The site personnel 
can also request the participants to schedule the interview themselves. In that case a secure 
link will be sent to the participants’ phone via text message and to their email.  
Interviews will be conducted by a CRO within 14 days after Week 14 (Visit 12). Subjects who 
discontinue IMP or withdraw from the trial prior to Week 14 will not be invited to participate 
in the interviews. Interviews will be conducted in English, German or Polish, depending on 
the subject’s country of residence. Interviews will be conducted via a phone call. Each 
interview is expected to last approximately 45-60 minutes. A semi-structured interview guide 
will be used to explore the subjects’ experience of participating in the trial, including their 
experience on therapy and impact on symptoms. 
The interview results will be reported separately from the CTR. The coding, analysis and 
reporting of the interview data will be performed by a CRO based on a separate analysis plan. 
The interviewers will be trained in capturing potential AEs. If during the interviews the 
participant communicates an unreported potential AE, serious or non-serious, it will be 
reported to the investigator by the interviewer within 24 hours for the investigator to make an 
assessment and further reporting to the sponsor if needed according to Section 10. 
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8.8 
End of trial 
Reporting in eCRF: 
End-of-treatment form 
An end-of-treatment form will be completed in the eCRF for all subjects who had been 
exposed to IMP, at the time when they have had their last administration of IMP. This form 
will also be completed for subjects who permanently discontinue IMP and subjects who 
withdraw from trial after having been exposed to IMP (see schedule of trial activities, 
Section 1.3 and Section 7.3 for early termination assessments). 
The date and time of last administration of IMP will be recorded on the end-of-treatment 
form. It will also be recorded if the subject completed the treatment (i.e. did not permanently 
discontinue IMP prior to Week 16). If not, the primary reason for permanent discontinuation 
of IMP must be recorded (see Section 7.2.1).  
End-of-trial form 
An end-of-trial form must be completed in the eCRF for all subjects that have been 
randomized and/or exposed to treatment. The following data will be collected:  
• Did the subject complete the trial (see Section 4.3)? If not, primary reason for not 
completing the trial will be recorded.  
• Date of last contact. 
• Primary reason for not completing the trial based on the following categories: Death, 
pregnancy, AE, lost to follow-up, lack of efficacy, randomized by mistake, withdrawal by 
subject, or other (if other, please specify). 
• Did the subject attend the primary endpoint visit?  
• Primary reason for not attending the primary endpoint visit based on the above categories. 
• Did the subject attend the follow-up visit? 
• Primary reason for not attending follow-up visit based on the above categories.  
The end-of-trial form will be completed when the subject has had their last visit (that is, the 
final follow-up visit [either at Week 32 for subjects who complete the trial or earlier for 
subjects who permanently discontinue IMP before Week 16 or subjects who withdraw after 
Week 16] or the early termination visit [for subjects who withdraw from the trial before 
Week 16]). 
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8.9 
Storage of biological samples 
Primary samples (set A samples) for PK will be discarded by the bioanalytical lab upon 
finalization of the CTR whereas backup samples (set B samples) stored at the central 
laboratory will be retained no longer than 6 months after completion of the CTR. 
Primary samples (set A samples) for ADA evaluation will be discarded by the bioanalytical 
lab upon finalization of the CTR whereas backup samples (set B samples) stored at the central 
laboratory will be retained for up to 10 years after final CTR, and then they will be destroyed. 
Any B samples that have been sent to the bioanalytical lab and used for analysis will also be 
discarded upon finalization of the CTR. The B samples stored at the central laboratory will be 
transferred to a central archive facility for long-term storage upon finalization of the CTR. 
Any residual PD sample (serum and biopsy) will be stored in a biobank as described below. 
Biobank 
This protocol includes the collection and analysis of biological samples. If consent is given by 
the subject, LEO Pharma will store residual serum and biopsy samples collected in a biobank. 
The biobanked biological samples will be used for future research by LEO Pharma. Donation 
of the samples for future research is voluntary and subjects must give their written consent to 
this component to confirm donation and storage and the terms associated herewith. Consent to 
this component will be recorded in the eCRF.  
The samples will be transferred from the relevant laboratory to the biobank. The samples will 
be labelled with the trial ID, subject ID, and the sample date to protect the privacy of the 
subjects and to allow continued blinding for future analyses. The samples in this trial will be 
stored in the biobank for a maximum of 10 years after CTR finalization and will then be 
destroyed. Results of future research will be reported separately, and individual subject data 
will not be provided to trial sites unless requested. 
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9 
Scientific rationale for trial design and appropriateness of 
assessments 
9.1 
Scientific rationale for trial design 
This is a randomized, double-blind, placebo-controlled, multi-site, parallel-group, 
dose-finding trial, which will be conducted in accordance with the protocol, ICH GCP, and 
applicable regulatory requirements. 
The trial will be conducted at multiple trial sites located in Europe, North America, and Japan.  
Patients with AD represent a heterogeneous patient population with disease severity ranging 
from mild to severe. To mitigate any potential difference in trial outcome based on baseline 
characteristics, eligibility criteria for inclusion have been carefully selected and trial subjects 
will be randomized according to a stratified, permuted block design. The randomization will 
minimize selection bias and ensure that the effect of treatment is not confounded by baseline 
factors. The stratified permuted block design and the inclusion of prognostic baseline factors 
in the analysis will improve the precision of the estimated treatment effect. 
The most important inclusion criteria for entry into the trial is a diagnosis of AD (as defined at 
screening by the Hanifin and Rajka 1980 criteria (62)) and history of AD for at least 1 year, to 
ensure correct diagnosis and rule out differential diagnoses. 
Patients with moderate-to-severe AD with inadequate response to treatment with TCS (±TCI 
as appropriate), or for whom these topical AD treatments are medically inadvisable, are the 
target population for treatment with LEO 138559. Only adults (aged 18–75 years) are 
included. In order to evaluate any efficacy of LEO 138559, subjects in the trial cannot be on 
concomitant medication for AD or have diseases that may influence the evaluation of AD 
signs and symptoms. 
LEO Pharma plans to evaluate LEO 138559 administered SC in 4 different dose regimens. 
The following LEO 138559 dose regimens will be included: 
• Dose regimen 1: LEO 138559 
 mg SC Weeks 0, 1, 2, 3 and then 
 mg SC Q2W 
from Week 4. 
• Dose regimen 2: LEO 138559 
 mg SC Weeks 0, 1, 2 and then 
 mg SC Q2W from 
Week 4. 
• Dose regimen 3: LEO 138559 
 mg SC Weeks 0 and 2 and then 
 mg SC Q2W from 
Week 4. 
• Dose regimen 4: LEO 138559 
 mg SC Weeks 0 and 2 and then 
 mg SC Q2W from 
Week 4. 
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The dose regimens selected for the trial are based on the PK data from the FiH phase 1 
(LP0145-1315) trial, a phase 1 (LP0145-1486) trial, and a phase 2a trial (LP0145-1376) 
pooled in a population PK model. The efficacy data from these trials have also been used to 
guide the dose selection, and the preliminary PK/PD model suggests correlation between 
, exposure, and response. Due to the limited data from the phase 2a trial, a 
subgroup analysis based on 
 is associated with high uncertainty, but the data suggest 
that 
 subjects 
 would benefit from a higher dose than in the phase 2a 
trial (LP0145-1376, 450 mg Q2W). No safety concern is thought to be associated with higher 
exposure in 
 subjects, as only mild and moderate AEs have been observed in the 
completed clinical trials and there was no apparent correlation between exposure and AEs. 
The rationale for the dose selection is also described and summarized in a separate document 
that also includes details of the population PK model (78). 
Based on the available efficacy and safety data from completed clinical trials and in order to 
identify a dose which can provide maximum efficacy in this patient population, a dose 
regimen of 
 mg loading dose at Week 0, 1, 2, 3 (to reach steady-state concentrations 
faster), followed by 
 mg Q2W dosing from Week 4 onwards (dose regimen 1) is included 
in the planned phase 2b trial. With this dose regimen, it is predicted that maximum serum 
concentration (Cmax) will be reached by Week 4 
 µg/mL in a 75-kg subject) (Panel 13). 
The predicted average Cmax is below the maximum observed serum concentrations in the 
phase 2a trial (LP0145-1376). 
 
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Panel 13: Simulated serum concentrations of LEO 138559 in the phase 2b trial 
(LP0145-2240) at a body weight of 75.0 kg 
 
Simulated serum concentrations for the 4 dose regimens in the phase 2b trial for a subject with a body weight of 
75.0 kg. The red dashed line indicates the maximum observed concentration in the phase 2a trial (
 µg/mL).  
Abbreviations: Q2W = every 2 weeks; W = Week. 
The dosing of 
 mg Q2W in dose regimen 
 dose regimen used in the phase 
 
. In the phase 
 demonstrated a statistically 
significant difference in favor of LEO 138559 compared to placebo with regards to change in 
EASI score from baseline to Week 16, and it was shown to be well tolerated. With this dose 
regimen, steady-state concentration is predicted to be reached by Week 14 (
 µg/mL in a 
75-kg subject) (Panel 13).  
Dose regimens 3 and 4 have been included to provide a 2- and 4-fold lower exposure 
compared to the dose regimen 1, respectively. This is to provide a sufficient difference in 
exposure between the dose regimens to allow for a meaningful comparison of efficacy, and to 
secure that the dose regimens cover a sufficient exposure range to investigate a dose exposure 
response relationship. It will also allow for testing the impact of possible covariates, such as 
body weight, on the response. 
A treatment duration of 16 weeks was chosen to ensure capturing a maximal effect of the 
active compound, LEO 138559, after exposure steady state is reached. Based on phase 2a 
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data, the clinical efficacy steady state for EASI-75 is anticipated to have been reached by 
Week 
. The 18 weeks of follow-up after the last active IMP administration at Week 14 
(corresponding to 16 weeks after the end of the treatment period at Week 16), is based on 
 half-lives for LEO 138559 (t1/2 between 
 days). 
The trial endpoints have been selected to evaluate the efficacy of LEO 138559 in improving 
the severity and extent of AD. EASI and vIGA-AD will be used in this clinical trial as 
investigator-rated assessments of disease severity. EASI is a validated measure used in 
clinical practice and clinical trials to assess the severity and extent of AD (68, 79). vIGA-AD 
is a validated instrument used in clinical trials to assess the subject’s global AD. The primary 
endpoint of the trial is to evaluate the percent change in EASI score from baseline to Week 16. 
The trial endpoints will also address subject’s perception of disease severity and the impact on 
sleep, daily activity, and HRQoL, and safety. 
9.2 
Appropriateness of assessments 
Efficacy assessments 
EASI, SCORAD, and vIGA-AD are validated measures used in clinical trials by investigators 
to assess the severity and/or extent of AD (see Sections 8.3.1, 8.3.2, and 8.3.3) (68-71). 
PROs 
A range of validated PROs will be used to assess subject perception of AD independently of 
the investigator or trial staff. The PROs have been selected to assess the key signs and 
symptoms of AD (including itch) and HRQoL (Section 8.3.5). 
Safety assessments 
Standard clinical methods of subject evaluations, such as AE monitoring (Section 10), vital 
signs, physical examination, ECG, laboratory testing including pregnancy testing, and ADA 
will be used to assess subject safety (Section 8.4). Given some large proteins may cause 
indirect adverse cardiac effects upon long-term exposure, data on ECG will be collected and 
evaluated (Section 8.4.4). Data on ADA will be collected in order to evaluate the potential 
immunogenicity of LEO 138559 (Section 8.4.6). 
PK assessments 
Serum concentration of LEO 138559 will be measured to further characterize the PK of 
LEO 138559 in subjects with moderate-to-severe AD (Section 8.5). The serum concentrations 
will be summarized and reported in the CTR as well as subjected to population PK analysis 
and reported separately and may be used in an exploratory exposure-response analysis to 
support dose selection in future clinical trials. 
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PD assessments 
Biomarkers in serum will be evaluated to assess the molecular response of LEO 138559 on 
inflammatory processes in AD in general, and more specifically on the IL-22 pathway. The 
collection of skin tape strips (mandatory for subjects at selected sites) and biopsies (volunteer 
subjects at selected sites) permits the exploratory analysis of the effect of LEO 138559 
treatment on cutaneous features of AD and in particular the IL-22 pathway. The collection of 
skin swabs will allow to capture the impact of LEO 138559 treatment on S. aureus abundance 
and the microbiome profile. All PD assessments aim at exploring the mechanism of 
LEO 138559 and to potentially identify sub-populations of AD subjects with increased 
response to treatment. 
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10 AE, SAE, and other safety reporting 
AEs and SAEs are defined in Appendix 2 (Section 12.2). 
10.1 Time period and frequency of collecting AE information 
All AEs will be collected from the signing of the ICF until end-of-trial (defined as the last 
visit in the trial), at the timepoints specified in the schedule of activities (Section 1.3). 
Pre-existing conditions (including those found as a result of screening procedures) will be 
recorded as medical history. 
The timing of AE start (i.e. whether prior to or after IMP administration) will be recorded in 
the eCRF as described in Appendix 2 (Section 12.2.4). 
All SAEs will be recorded and reported to LEO Pharma immediately without undue delay but 
no later than within 24 hours of awareness, as indicated in Appendix 2 (Section 12.2.5). The 
investigator will submit any updated SAE data to LEO Pharma within 24 hours of it being 
available. 
10.2 Method of detection AEs 
AEs must be assessed by a physician.  
Care will be taken not to introduce bias when detecting AEs. Open-ended and non-leading 
verbal questioning of the subject is the preferred method to inquire about AE occurrence. 
At all visits, the subject will be asked a non-leading question by the investigator about AEs, 
e.g.: “How have you felt since I saw you last?” It is important that the investigator also 
observes the subject for any changes not reported by the subject and records these changes. 
Principles for data entry in the eCRF are described in Sections 8.4.1 to 8.4.5.  
10.3 Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow-up with the 
subject at subsequent visits/contacts. All SAEs will be followed until resolution, stabilization, 
until the event is otherwise explained, or the subject is lost to follow-up (as defined in 
Section 7.5). Further information on follow-up procedures is given in Appendix 2 
(Section 12.2.4). 
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10.4 Regulatory reporting requirements for SAE 
Prompt notification (within 24 hours, see Appendix 2 [Section 12.2.5]) by the investigator to 
LEO Pharma of an SAE is essential so that legal obligations and ethical responsibilities 
towards the safety of subjects and the safety of a trial treatment under clinical investigation 
are met. 
LEO Pharma has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a trial treatment under clinical investigation. 
LEO Pharma will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRB/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 LEO Pharma will review and then 
file it along with the investigator’s brochure and will notify the IRB/IEC, if appropriate 
according to local requirements. 
All SAEs that occur during the trial until the last safety follow-up visit, whether considered to 
be associated with the IMP or not, must be reported to LEO Pharma on the (paper) SAE form 
immediately, without undue delay and no later than within 24 hours of obtaining knowledge.  
The completed SAE forms must be faxed or scanned and e-mailed to Global Safety at LEO 
Pharma. Contact details are given as described in Appendix 2 (Section 12.2.5). 
Investigators will be notified of the evolving safety profile of the IMP on an ongoing basis. 
10.5 Pregnancy 
Details of all pregnancies will be collected after first exposure to IMP and until the subject has 
completed the trial. The pregnancy must be reported to LEO Pharma within 24 hours of first 
knowledge using the (paper) pregnancy form (part I). All pregnancies must be followed up 
until delivery or termination, and outcome must be reported on the (paper) pregnancy form 
(part II) within 24 hours of first knowledge.  
The completed pregnancy forms must be faxed or scanned and e-mailed to Global Safety at 
LEO Pharma. Contact details are given in Appendix 2 (Section 12.2.5). 
Pregnant subjects must immediately discontinue IMP permanently (Section 7.2.1). 
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. 
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Abnormal pregnancy outcomes (e.g. spontaneous abortion, foetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered to be SAEs and will be reported as such. For 
SAE definitions, see Appendix 2 (Section 12.2.2). 
The subject will be followed to determine the outcome of the pregnancy. The investigator will 
collect follow-up information on the subject and the neonate and the information will be 
forwarded to LEO Pharma. 
Any post-trial pregnancy-related SAE considered reasonably related to the IMP by the 
investigator will be reported to LEO Pharma as described in Section 10.4. While the 
investigator is not obligated to actively seek this information about former trial subjects, he or 
she may learn of an SAE through spontaneous reporting. 
10.6 Other events that require expedited reporting 
Not applicable. 
10.7 Reporting of other events 
10.7.1 
AEs of special interest 
Eczema herpeticum is considered an AESI. If available (e.g. as part of the standard clinical 
practice), the below additional skin findings are to be recorded in the eCRF: 
• Lesion type (papules, vesicles, crusts, eroded pits, other). 
• Disseminated/localized. 
• Location (face, scalp, back, chest, upper limb, lower limb, genitals). 
• Present in an area with visible eczema / no visible eczema / present in areas with and 
without eczema. 
• Monomorphic/polymorphic. 
• Confirmation of herpes simplex virus (not confirmed, PCR, viral culture, Tzanck, other). 
10.7.2 
Medication error 
Medication error refers to any unintentional error in the dispensing or administration of an 
IMP.  
Medication errors include accidental overdose or underdose, inappropriate schedule of 
product administration, incorrect route of product administration, wrong product 
administered, and expired product administered.  
Accidental overdose or underdose where a clinical consequence occurred or could have 
occurred should be recorded based on investigator judgement.  
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Inappropriate schedule of product administration where a clinical consequence occurred or 
could have occurred should be recorded based on investigator judgement. See also 
Section 6.8.3 for recording of treatment non-compliance. 
Medication error must be recorded on the Other Events Involving IMP form in the eCRF. In 
addition, any clinical consequences of the medication error must be recorded as separate AEs 
on the AE form. If the AE originating from the medication error qualifies as an SAE, 
expedited reporting is required (Appendix 2, [Section 12.2.5]). 
If the medication error is due to a device deficiency, the device deficiency must be reported as 
a product complaint as described in Section 6.10. 
 
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11 Statistical considerations 
11.1 Sample size 
A total of 250 subjects, including at least 25 Japanese subjects will be randomized in a 
1:1:1:1:1 ratio to 1 of the 5 treatment regimens outlined in Section 6.2.  
The sample size is chosen, based on the results of a simulation. The simulation assessed the 
power to reject the null hypotheses included in the testing hierarchy specified in 
Section 11.3.6. Additionally, the simulation was used to discern, for which effect sizes, the 
trial would have approximately 50% power to detect a significant difference, in the mean 
percent change from baseline in EASI score at Week 16 between dose regimens 1 and 2, at the 
5% significance level. 
The percent change from baseline was simulated in a 4-step process. First, baseline EASI 
scores were obtained by resampling from a large phase 3 development program in 
moderate-to-severe AD. Next, the change from baseline was simulated for each subject under 
a multivariate normal assumption. The assumed mean change from baseline in EASI score 
from Week 1 to 16 was based on a component related to the effect of treatment, provided in 
Panel 14 for all 5 dose regimens and an effect related to the baseline EASI score for each 
assessment. 
Panel 14: Assumed values for the mean change from baseline in EASI score from Week 1 
to Week 16 
 
Wk 1 
Wk 2 
Wk 3 
Wk 4 
Wk 6 
Wk 8 
Wk 10 
Wk 12 
Wk 14 
Wk 16 
Dose 
regimen 1 
-6.8 
-10.3 
-13.8 
-17.3 
-19.6 
-18.8 
-18.2 
-17.8 
-19.3 
-20.7 
Dose 
regimen 2 
-5.0 
-7.6 
-10.2 
-12.8 
-14.5 
-13.9 
-13.5 
-13.2 
-14.3 
-15.3 
Dose 
regimen 3 
-5.0 
-6.8 
-9.2 
-11.5 
-13.1 
-12.5 
-12.2 
-11.9 
-12.9 
-13.8 
Dose 
regimen 4 
-3.3 
-5.0 
-6.6 
-8.3 
-9.4 
-9.0 
-8.8 
-8.6 
-9.3 
-10.0 
Placebo 
-1.9 
-3.8 
-4.2 
-4.6 
-5.4 
-3.8 
-4.6 
-5.4 
-4.5 
-3.5 
Abbreviations: Wk = Week. 
The assumptions for the placebo and dose regimen 2 groups are based on the observed data 
from the phase 2a proof-of-concept trial. Based on PK/PD modeling, it is anticipated that dose 
regimens 3 and 4 will retain approximately 90% and 65% of the mean change from baseline 
in EASI score observed for dose regimen  in the phase 
 trial. For dose regimen 1, the mean 
change from baseline in EASI score from Week 1 to Week 16 is assumed to have an 
additional reduction of 35% compared to dose regimen 2. 
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The covariance matrices for the 5 dose regimens in the simulation were assumed to be equal 
and have a compound symmetry structure with variances equal to 111.0 and covariances equal 
to 32.5.  
The third step was to ensure that the underlying EASI scores from Week 1 to 16 were within 
the range of the EASI score scale, which runs from [0,72]. This implies natural bounds for the 
individual simulated changes from baseline in EASI score, as they must lie within the 
interval, [-baseline score, 72-baseline score].   
The final step was to derive the percent change from baseline in EASI score from Week 1 to 
Week 16, by dividing the simulated changes in baseline in EASI score from Week 1 to 16 by 
the subject’s baseline EASI score. 
The simulation further assumed that percentage of subjects withdrawing or experiencing an 
intercurrent event by Week 16 in dose regimens 1-4 and placebo arms are 20%, 20%, 30%, 
40%, and 40%, respectively, the timing of which was assumed to be exponentially distributed. 
To approximate the power, 1,000 data sets with 250 subjects were generated based on the 
randomization scheme. For each data set, 100 complete versions were generated by imputing 
missing data separately for each treatment arm. The baseline and all post-baseline EASI 
assessments were included in the imputation model. The imputed data sets were analyzed 
based on an ANCOVA model. The pooled estimate of the difference in the LSmean change 
from baseline, along with the associated 95% Cis and nominal p-values, were derived for each 
simulated data set by applying Rubin’s rules to the estimates and standard errors from the 
ANCOVA analysis of the imputed datasets.  
Panel 15 provides the nominal power as well as the prioritized power based on the 
hierarchical testing procedure, to reject the null hypotheses testing the LEO 138559 dose 
regimens 1-4 versus placebo, with respect to the differences in the mean percent change in 
EASI score from baseline to Week 16. 
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Panel 15: Approximate nominal and prioritized power for rejecting the null hypotheses 
including in the testing hierarchy, based on the results of the simulation 
Hypothesis 
Nominal power 
Prioritized power 
Dose regimen 1 vs Placebo 
~100% 
~100% 
Dose regimen 2 vs Placebo 
99.1% 
~99.1% 
Dose regimen 3 vs Placebo 
97.2% 
~96.4% 
Dose regimen 4 vs Placebo 
67.4% 
~65.0% 
Dose regimen 1 vs 2 
49.7% 
NA 
Note: ~100% power refers to scenarios in which the associated null hypothesis was rejected in each of the 
1,000 simulated trials. 
Abbreviations: NA = not applicable. 
11.2 Trial analysis sets 
All screened subjects will be accounted for in the CTR. 
All subjects randomized will be included in the FAS and will be analyzed for efficacy based 
on the planned (randomized) treatment allocation. Exclusions from the FAS can be considered 
in special cases as described in ICH E9, Section 5.2.1., Full Analysis Set. If it is decided to 
exclude a randomized subject from the FAS, a justification addressing ICH E9 will be given. 
A safety analysis set will be defined as all subjects who received IMP and will be analyzed 
according to the actual treatment received.  
A PK analysis set will be defined as all subjects who received at least 1 dose of LEO 138559 
and have at least 1 quantifiable PK sample. 
The decisions regarding inclusion/exclusion of subjects or subject data from the trial analysis 
sets will be documented in the analysis set definition document before breaking the 
randomization code. 
11.3 Statistical analysis 
11.3.1 
General principles 
Baseline measurements are defined as the latest available observation at or prior to the date of 
the first IMP administration, unless otherwise specified. 
All significance tests will be two-sided using the 5% significance level. All CIs will be 
presented with 95% degree of confidence, unless otherwise specified. LSmeans will be 
estimated using the observed margins for the FAS. 
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An observed-cases approach will be used for tabulations of data by visit (that is, involving 
only those subjects who attended each specific visit). 
Categorical data will be summarized using the number and percentage of subjects in each 
category and treatment group. Continuous data will be summarized using the mean, SD, 
median, 1st quartile and 3rd quartile, minimum, and maximum values. 
All the analyses specified in the protocol will be reviewed in relation to the blinded data 
actually obtained, and the SAP will be finalized before breaking the randomization code. 
Any changes from the statistical analyses planned in this clinical trial protocol will be 
described and justified in a protocol amendment, the SAP and/or in the CTR, dependent on 
the type of change. 
Unless otherwise stated, efficacy analyses will be performed based on the FAS, safety 
analyses will be based on the safety analysis set, and PK analyses will be based on the PK 
analysis set. 
11.3.2 
Handling of missing values 
The methods for handling of missing values for the efficacy endpoints are described in 
Sections 11.3.7, 11.3.8, and 11.3.9.   
11.3.3 
Disposition of subjects 
The reasons for permanent discontinuation of IMP or withdrawal from trial will be presented 
for all randomized subjects by last visit attended and by treatment group. 
11.3.4 
Demographics and other baseline characteristics 
Descriptive statistics of demographics and other baseline characteristics will be presented for 
all randomized subjects and by treatment group. Presentations of age, sex, ethnicity, race, and 
baseline EASI score by treatment group will also be given by baseline disease severity 
(baseline vIGA-AD score), region (Japan, Other countries), prior use of biologics or systemic 
JAK inhibitors for AD (Yes/No), and baseline biopsy status (willingness to provide biopsies: 
Yes/No). 
Other baseline characteristics include height, weight, body mass index, duration of AD, 
concurrent diagnoses (from medical history and indications for concomitant medication), 
concomitant medication, and previous AD treatments. 
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11.3.5 
Exposure and treatment compliance 
Exposure to treatment will be presented for the safety analysis set as days of exposure per 
treatment group.  
The cumulated dose administered to each subject will be determined and summarized 
descriptively. For subjects who withdraw from the trial, are lost to follow-up, or permanently 
discontinue IMP, their cumulated dose will be calculated up until the time of 
withdrawal/permanent discontinuation of IMP/loss to follow-up. 
Treatment compliance will be presented for the safety analysis set per treatment group as the 
percentages of missed IMP doses. 
11.3.6 
Testing strategy 
The following hierarchical procedure will be used to ensure strong control of the familywise 
error rate at the 5% significance level (two-sided significance tests), when testing the null 
hypotheses associated with the primary endpoint, percent change in EASI score from baseline 
to Week 16: 
1. LEO 138559 
 mg SC Weeks 0, 1, 2, 3 and then 
 mg Q2W from Week 4 (dose 
regimen 1) versus placebo. 
2. LEO 138559 
 mg SC Weeks 0, 1, 2 and then 
 mg Q2W from Week 4 (dose 
regimen 2) versus placebo. 
3. LEO 138559 
 mg SC Weeks 0 and 2 and then 
 mg Q2W from Week 4 (dose 
regimen 3) versus placebo. 
4. LEO 138559 
 mg SC Weeks 0 and 2 and then 
 mg Q2W from Week 4 (dose 
regimen 4) versus placebo. 
Under the hierarchical procedure, the first null hypothesis (the difference in the mean percent 
change in EASI score from baseline to Week 16 between dose regimen 1 and placebo is equal 
to 0), is tested at the 5% significance level. If that null hypothesis is rejected, the procedure 
will proceed to test null hypothesis 2 at the 5% significance level. However, if the first null 
hypothesis cannot be rejected, the procedure stops and null hypotheses 2-4 will not be 
formally tested. The procedure continues in this fashion, until it either encounters a null 
hypothesis that cannot be rejected, or all null hypotheses have been rejected. For the purposes 
of the hierarchical testing procedure, the hypothesis tests will be based on the analysis of the 
primary estimand for the primary endpoint. 
11.3.7 
Estimand strategy 
The estimand strategy is specified in terms of the variable type, e.g. continuous, 
binary/categorical, and time-to-event. A primary analysis will be pre-specified for each 
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estimand and pre-specified sensitivity analyses will be conducted to assess the robustness of 
the results with respect to departures from the statistical assumptions of the primary analysis. 
Description of intercurrent events 
An intercurrent event refers to a post-baseline event that affects either the interpretation or the 
existence of the measurements of an endpoint. For the purposes of this trial, we define the 
following 2 intercurrent events: 
• Initiation of rescue treatment: This event occurs when a subject initiates rescue treatment 
as listed in no. 1-6 of Section 6.7 for intolerable AD signs and/or symptoms. The timing of 
the event will be taken as the date of initiation of the rescue treatment recorded in the 
eCRF. 
• Permanent discontinuation of IMP: This event occurs when a subject permanently 
discontinues IMP. This event can occur either at the subject’s own initiative or at the 
investigator’s or sponsor’s discretion. The timing of the event will be taken as the date of 
permanent discontinuation of IMP as recorded in the eCRF. 
Panel 16 provides an overview of the estimand strategies defined in Sections 11.3.7.1, 
11.3.7.2, and 11.3.7.3 that will be used to address occurrences of the intercurrent events 
described above. 
An overview of statistical analysis of endpoints can be found in Panel 17. 
 
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Panel 16: Handling of observed and missing data according to intercurrent events in the primary analysis of the estimands 
defined in Sections 11.3.7.1, 11.3.7.2, and 11.3.7.3 
Events 
Observed 
data or 
missing 
Continuous endpoints 
Binary endpoints 
TTE 
endpoints 
 
 
Primary 
Estimand 
Hypothetical 
Suppl. Estimand 
Second Suppl. 
Estimand 
Primary Estimand  
Suppl. Estimand 
Primary 
Estimand 
Initiation of 
rescue 
treatment 
Observed 
Treated as 
missing,  
MI 
Treated as 
missing,  
MI 
Value will be used 
as observed 
NRI 
Value will be used 
as observed 
Not 
applicable 
Missing 
MI 
MI 
MI 
NRI 
MI 
Not 
applicable 
Permanent 
discontinuation 
of IMP, for 
reasons other 
than lack of 
efficacy or an 
AE related to 
worsening of 
AD 
Observed 
Treated as 
missing,  
MI 
Treated as 
missing,  
MI 
Value will be used 
as observed 
Treated as missing,  
MI  
Value will be used 
as observed 
Accounted 
for as a 
competing 
riska  
Missing 
MI 
MI 
MI 
MI 
MI 
Accounted 
for as a 
competing 
riska 
Permanent 
discontinuation 
of IMP, due to 
lack of 
efficacy or an 
AE related to 
worsening of 
AD 
Observed 
Treated as 
missing,  
LOCF 
Treated as 
missing,  
MI 
Value will be used 
as observed 
NRI 
Value will be used 
as observed 
Accounted 
for as a 
competing 
riska  
Missing 
LOCF 
MI 
MI 
NRI 
MI 
Accounted 
for as a 
competing 
riska  
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Events 
Observed 
data or 
missing 
Continuous endpoints 
Binary endpoints 
TTE 
endpoints 
 
 
Primary 
Estimand 
Hypothetical 
Suppl. Estimand 
Second Suppl. 
Estimand 
Primary Estimand  
Suppl. Estimand 
Primary 
Estimand 
No intercurrent 
events 
Observed 
Value will 
be used as 
observed 
Value will be 
used as observed 
Value will be used 
as observed 
Value will be used as observed 
Value will be used 
as observed 
Not 
applicable  
Missing 
MI 
MI 
MI 
MI 
MI 
Not 
applicable 
a) Withdrawal from trial will also be accounted for as a competing risk.  
Abbreviations: AD = atopic dermatitis; AE = adverse event; IMP = investigational medicinal product; LOCF = last observation carried forward; MI = multiple 
imputation; NRI = non-responder imputation; Suppl. = supplementary; TTE = time-to-event. 
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Panel 17: Statistical analysis of endpoints 
Endpoint 
Estimands to be analyzed 
Percent change in EASI score from baseline to Week 16. 
Primary estimand for continuous endpoints. 
Hypothetical supplementary estimand for continuous 
endpoints. 
Second supplementary estimand for continuous 
endpoints. 
Achievement of EASI-50 at Week 16. 
Primary estimand for binary endpoints. 
Supplementary estimand for binary endpoints. 
Achievement of EASI-75 at Week 16. 
Primary estimand for binary endpoints.  
Supplementary estimand for binary endpoints. 
Achievement of EASI-90 at Week 16. 
Primary estimand for binary endpoints.  
Supplementary estimand for binary endpoints. 
Achievement of EASI-100 at Week 16. 
Primary estimand for binary endpoints.  
Supplementary estimand for binary endpoints. 
Change in EASI score from baseline to Week 16. 
Primary estimand for continuous endpoints. 
Hypothetical supplementary estimand for continuous 
endpoints. 
Change in SCORAD score from baseline to Week 16. 
Primary estimand for continuous endpoints. 
Hypothetical supplementary estimand for continuous 
endpoints. 
Percent change in SCORAD score from baseline to Week 16. 
Primary estimand for continuous endpoints. 
Hypothetical supplementary estimand for continuous 
endpoints. 
Achievement of vIGA-AD score of 0 (clear) or 1 (almost clear) 
at Week 16. 
Primary estimand for binary endpoints.  
Supplementary estimand for binary endpoints. 
Change in BSA from baseline to Week 16. 
Primary estimand for continuous endpoints. 
Hypothetical supplementary estimand for continuous 
endpoints. 
Percent change in BSA from baseline to Week 16. 
Primary estimand for continuous endpoints. 
Hypothetical supplementary estimand for continuous 
endpoints. 
Reduction of ADSD Worst 
 score (weekly average) ≥4 from 
baseline to Week 16. 
Primary estimand for binary endpoints.  
Supplementary estimand for binary endpoints. 
Change in DLQI (and individual domain scores) from baseline 
to Week 16. 
Primary estimand for continuous endpoints. 
Hypothetical supplementary estimand for continuous 
endpoints. 
Percent change in DLQI (and individual domain scores) from 
baseline to Week 16. 
Primary estimand for continuous endpoints. 
Hypothetical supplementary estimand for continuous 
endpoints. 
Change in POEM score (and individual item scores related to 
itch and sleep) from baseline to Week 16. 
Primary estimand for continuous endpoints. 
Hypothetical supplementary estimand for continuous 
endpoints. 
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Endpoint 
Estimands to be analyzed 
Percent change in POEM score from baseline to Week 16. 
Primary estimand for continuous endpoints. 
Hypothetical supplementary estimand for continuous 
endpoints. 
Change in EQ-5D-5L index score from baseline to Week 16. 
Primary estimand for continuous endpoints. 
Hypothetical supplementary estimand for continuous 
endpoints. 
Percent change in EQ-5D-5L index score from baseline to 
Week 16. 
Primary estimand for continuous endpoints. 
Hypothetical supplementary estimand for continuous 
endpoints. 
Change in EQ-5D-5L VAS score from baseline to Week 16. 
Primary estimand for continuous endpoints. 
Hypothetical supplementary estimand for continuous 
endpoints. 
Percent change in EQ-5D-5L VAS score from baseline to 
Week 16. 
Primary estimand for continuous endpoints. 
Hypothetical supplementary estimand for continuous 
endpoints. 
Change in HADS score from baseline to Week 16. 
Primary estimand for continuous endpoints. 
Hypothetical supplementary estimand for continuous 
endpoints. 
Percent change in HADS score from baseline to Week 16. 
Primary estimand for continuous endpoints. 
Hypothetical supplementary estimand for continuous 
endpoints. 
Change in Difficulty 
 (weekly average) from 
baseline to Week 16. 
Primary estimand for continuous endpoints. 
Hypothetical supplementary estimand for continuous 
endpoints. 
Percent change in Difficulty 
 (weekly average) 
from baseline to Week 16. 
Primary estimand for continuous endpoints. 
Hypothetical supplementary estimand for continuous 
endpoints. 
Change in Nocturnal 
 (weekly average) from baseline 
to Week 16. 
Primary estimand for continuous endpoints. 
Hypothetical supplementary estimand for continuous 
endpoints. 
Percent change in Nocturnal 
 (weekly average) from 
baseline to Week 16. 
Primary estimand for continuous endpoints. 
Hypothetical supplementary estimand for continuous 
endpoints. 
Change in Frequency of 
 During the Night (weekly 
average) from baseline to Week 16. 
Primary estimand for continuous endpoints. 
Hypothetical supplementary estimand for continuous 
endpoints. 
Percent change in Frequency of 
 During the Night 
(weekly average) from baseline to Week 16. 
Primary estimand for continuous endpoints. 
Hypothetical supplementary estimand for continuous 
endpoints. 
Change in WPAI-SHP domain scores from baseline to  
Week 16. 
Primary estimand for continuous endpoints. 
Hypothetical supplementary estimand for continuous 
endpoints. 
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Endpoint 
Estimands to be analyzed 
Percent change in WPAI-SHP domain scores from baseline to 
Week 16. 
Primary estimand for continuous endpoints. 
Hypothetical supplementary estimand for continuous 
endpoints. 
Change in SCORAD Part C (Pruritus VAS) score from baseline 
to Week 16. 
Primary estimand for continuous endpoints. 
Hypothetical supplementary estimand for continuous 
endpoints. 
Percent change in SCORAD Part C (Pruritus VAS) score from 
baseline to Week 16. 
Primary estimand for continuous endpoints. 
Hypothetical supplementary estimand for continuous 
endpoints. 
Time from baseline to use of any rescue treatment. 
Primary estimand for time-to-event endpoints. 
Supplementary estimand for time-to-event endpoints 
Reduction of ADSD Worst 
 score (weekly average) ≥4 
from baseline to Week 16. 
Baseline subgroup estimand. 
Reduction of DLQI ≥4 from baseline to Week 16. 
Baseline subgroup estimand.  
Reduction of POEM ≥4 from baseline to Week 16. 
Baseline subgroup estimand. 
Abbreviations: ADSD = Atopic Dermatitis Symptom Diary; BSA = body surface area; DLQI = Dermatology 
Life Quality Index; EASI = Eczema Area and Severity Index; EASI-50 = at least 50% reduction in EASI 
score; EASI-75 = at least 75% reduction in EASI score; EASI-90 = at least 90% reduction in EASI score; 
EASI-100 = 100% reduction in EASI score; EQ-5D-5L = EuroQoL 5 Dimension Health Questionnaire 5 
Level; HADS = Hospital Anxiety and Depression Scale; POEM = Patient-Oriented Eczema Measure;  
SCORAD = SCORing Atopic Dermatitis; VAS = Visual Analogue Scale; vIGA-AD = validated Investigator 
Global Assessment Scale for Atopic Dermatitis; WPAI-SHP = Work Productivity and Activity Impairment: 
Specific Health Problem. 
11.3.7.1 
Estimands for continuous endpoints 
The primary and hypothetical supplementary estimands for continuous endpoints, which 
differ only in handling of the missing data, attempt to quantify the effect of treatment, in the 
hypothetical scenario, where subjects do not permanently discontinue IMP for any reason and 
where rescue treatment is not made available. 
The estimands are described by the following attributes: 
A. Target Population: Subjects with moderate-to-severe AD, as defined through the 
inclusion and exclusion criteria listed in Section 5. 
B. Variable: Applied to continuous endpoints. 
C. Treatment conditions: LEO 138559 dose regimens 1-4 versus placebo. 
D. Strategies for handling intercurrent events: 
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a. For subjects requiring the use of rescue treatment or permanently discontinuing 
IMP, the hypothetical strategy will be used to estimate the treatment effect in 
the hypothetical scenario where rescue treatment is not available, and where 
subjects do not permanently discontinue IMP for any reason.  
E. Population level summary: Difference in means between the treatment conditions. 
Second supplementary estimand 
The second supplementary estimand for continuous endpoints attempts to quantify the effect 
of the decision to treat subjects with the randomized treatment, ignoring the occurrence of 
intercurrent events.  
The estimand is described by the following attributes: 
A. Target Population: Subjects with moderate-to-severe AD, as defined through the 
inclusion and exclusion criteria listed in Section 5. 
B. Variable: Applied to percent EASI change from baseline endpoints. 
C. Treatment conditions: LEO 138559 dose regimens 1-4 versus placebo. 
D. Strategies for handling intercurrent events 
a. The treatment policy strategy will be used to handle the initiation of rescue 
treatment or permanent discontinuation of IMP.  Data observed after the 
occurrence of such events will be included in the analysis.  
E. Population level summary: Difference in means between the treatment conditions. 
11.3.7.2 
Estimands for binary endpoints 
The primary estimand for binary endpoints attempts to quantify the effect of treatment in the 
hypothetical scenario where: 
• All subjects remain on treatment except for those permanently discontinuing IMP due to 
lack of efficacy or the occurrence of an AE related to worsening of AD. AEs considered 
related to worsening of AD will be specified in the SAP. 
The occurrence of the following intercurrent events will be treated as indicating a failure of 
the randomized treatment: 
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• Permanent discontinuation of IMP due to lack of efficacy or the occurrence of an AE 
related to worsening of AD. 
• Initiation of rescue treatment. 
The estimand is described by the following attributes: 
A. Target Population: Subjects with moderate-to-severe AD, as defined through the 
inclusion and exclusion criteria listed in Section 5. 
B. Variable: Applied to binary endpoints. 
C. Treatment conditions: LEO 138559 dose regimens 1-4 versus placebo. 
D. Strategies for handling intercurrent events 
a. Subjects initiating rescue treatment or permanently discontinuing IMP due to 
lack of efficacy or the occurrence of an AE related to worsening of AD are 
defined as treatment failures according to the composite strategy. 
b. For subjects permanently discontinuing IMP due to reasons other than lack of 
efficacy or the occurrence of an AE related to worsening of AD, the 
hypothetical strategy will be used to estimate the effect of treatment in the 
hypothetical scenario where subjects do not permanently discontinue IMP for 
reasons other than lack of efficacy or the occurrence of an AE related to 
worsening of AD.  
E. Population level summary: Difference in response rates between the treatment 
conditions. 
Supplementary estimand 
The supplementary estimand for binary endpoints attempts to quantify the effect of the 
decision to treat subjects with the randomized treatment, ignoring the occurrence of 
intercurrent events. 
 The estimand is described by the following attributes: 
A. Target Population: Subjects with moderate-to-severe AD, as defined through the 
inclusion and exclusion criteria listed in Section 5. 
B. Variable: Applied to EASI, vIGA-AD and ADSD Worst 
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C. Treatment conditions: LEO 138559 dose regimens 1-4 versus placebo. 
D. Strategies for handling intercurrent events: 
a. The treatment policy strategy will be used to handle the initiation of rescue 
treatment or permanent discontinuation of IMP. Data observed after the 
occurrence of such events will be included in the analysis. 
E. Population level summary: Difference in response rates between the treatment 
conditions. 
11.3.7.3 
Estimands for time-to-event endpoints 
The primary estimand for the time-to-event endpoint, time from baseline to the initiation of 
rescue treatment, quantifies the effect of treatment while subjects are receiving treatment.  
The estimand is described by the following attributes: 
A. Target Population: Subjects with moderate-to-severe AD, as defined through the 
inclusion and exclusion criteria listed in Section 5. 
B. Variable: Time from baseline to the initiation of rescue treatment. 
C. Treatment conditions: LEO 138559 dose regimens 1-4 versus placebo. 
D. Strategies for handling intercurrent events: 
a. Subjects permanently discontinuing IMP are considered to have experienced a 
competing risk, i.e. no longer considered at risk for initiating rescue treatment, 
in line with the while on treatment strategy.  
E. Population level summary: Difference in the cumulative incidence of initiation of 
rescue treatment at Week 16 between the treatment conditions. 
Supplementary estimand 
The supplementary estimand assesses the effect of the treatment on the composite endpoint, 
time from baseline to the initiation of rescue treatment or permanent discontinuation of IMP, 
whichever occurs first.  
The estimand is described by the following attributes:  
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A. Target Population: Subjects with moderate-to-severe AD, as defined through the 
inclusion and exclusion criteria listed in Section 5. 
B. Variable: Time from baseline to the initiation of rescue treatment or permanent 
discontinuation of IMP, whichever occurs first. 
C. Treatment conditions: LEO 138559 dose regimens 1-4 versus placebo. 
D. Strategies for handling intercurrent events: 
a. For subjects who permanently discontinue IMP prior to the initiation of rescue 
treatment, the event-time is taken as the time of permanent discontinuation of 
IMP according to the composite time to event variable defined above. 
E. Population level summary: Difference in the cumulative incidence at Week 16 
between the treatment conditions. 
11.3.7.4 
Baseline subgroup estimands 
The baseline subgroup estimands are identical to the primary binary estimand but restricted to 
subgroups, and are described by the following attributes: 
A. Target Population: Subjects with moderate-to-severe AD, as defined through the 
inclusion and exclusion criteria listed in Section 5 with: 
a. Having a weekly average ADSD Worst 
 score of ≥ 4 at baseline. 
b. Having a DLQI score of ≥ 4 at baseline. 
c. Having a POEM score of ≥ 4 at baseline 
B. Variable: 
a. Reduction of ADSD Worst 
 score (weekly average) ≥ 4 from baseline 
to Week 16. 
b. Reduction of DLQI ≥ 4 from baseline to Week 16. 
c. Reduction of POEM score ≥ 4 from baseline to Week 16. 
C. Treatment conditions: LEO 138559 dose regimens 1-4 vs placebo. 
D. Strategies for handling intercurrent events: 
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a. Subjects initiating rescue treatment or permanently discontinuing IMP due to 
lack of efficacy or the occurrence of an AE related to worsening of AD are 
defined as treatment failures according to the composite strategy. 
b. For subjects permanently discontinuing IMP due to reasons other than lack of 
efficacy or the occurrence of an AE related to worsening of AD, the 
hypothetical strategy will be used to estimate the effect of treatment in the 
hypothetical scenario where subjects do not permanently discontinue IMP for 
any reason.  
E. Population level summary: Difference in response rates between the treatment 
conditions. 
11.3.8 
Primary estimand analysis 
11.3.8.1 
Analysis of primary estimand for continuous endpoints 
Primary analysis 
Data collected after permanent discontinuation of IMP or after initiation of rescue treatment 
will be excluded from the analysis and “treated as missing”. Missing data and data “treated as 
missing” will be split into two groups: 
1. Data “treated as missing” due to permanent discontinuation of IMP due to lack of 
efficacy, an AE related to worsening of AD, or rescue treatment.  
2. Missing data or data “treated as missing” for other reasons than permanent 
discontinuation of IMP due to lack of efficacy, an AE related to worsening of AD, or 
rescue treatment.  
The first group will have their missing values imputed using last observation carried forward. 
This reflects an assumption that subjects that need rescue treatment or permanently 
discontinue IMP due to lack of efficacy or an AE related to worsening of AD must be 
expected not to improve going forward even if they had continued IMP. 
The second group will be imputed using MI (100 iterations) under a MAR assumption within 
each treatment group. All subject-level data observed prior to the occurrence of an 
intercurrent event will be used to inform the imputation models. Further details regarding the 
specification of the imputation models, including choice of seed, will be specified in the SAP. 
The imputed datasets will be combined to create 100 complete datasets. For each of the 100 
complete datasets, the response will be analyzed using an ANCOVA model adjusted for 
treatment, baseline disease severity (baseline vIGA-AD score), region (Japan, Other 
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countries), and prior use of biologics or systemic JAK inhibitors for AD (Yes/No). The model 
will also be adjusted for the baseline value of the dependent variable.  
The pooled estimate of the difference in the LSmean change from baseline, along with the 
associated 95% CIs and nominal p-values will be presented. Inference will be based on 
applying Rubin’s rules to the estimates and standard errors from the ANCOVA analysis of the 
imputed datasets.  
Sensitivity analysis 
A sensitivity analysis will be performed for the change and percent change in EASI score 
from baseline to Week 16 endpoints. 
A tipping point analysis will be performed based on implementing a delta-adjusted MI 
approach. The delta-adjusted imputation approach allows for missing data to be imputed 
under a MNAR assumption. Heuristically, the imputation strategy, adjusts/shifts the 
parameters of the MAR distribution based on the value of a numeric offset term, denoted by 
delta. The tipping point analysis will adjust the values of the parameters in the MAR 
distribution representing the mean change in EASI score from baseline to Week 16. The 
analysis will assess how robust the results of the main analysis are to varying departures from 
the MAR assumption within each treatment group. The range of the shift parameter for the 
treatment arms will be specified in the SAP along with the seed, the MAR imputation 
strategy, and the number of imputations.  
Supplementary analysis 
For the continuous endpoints related to the EASI score, the primary analysis will be repeated 
for all protocol-defined visit weeks.  
11.3.8.2 
Analysis of primary estimand for binary endpoints  
Subjects receiving rescue treatment or who have permanently discontinued IMP due to lack of 
efficacy, or the occurrence of an AE related to worsening of AD, prior to the endpoint of 
interest, are defined as non-responders, reflecting an assumption that the occurrence of such 
intercurrent events indicates a failure of the randomized treatment. 
Data observed after the permanent discontinuation of IMP for reasons besides lack of efficacy 
or the occurrence of an AE related to worsening of AD will be excluded from the analysis and 
treated as missing. Missing data and data treated as missing will be imputed using MI 
(100 iterations) under a MAR assumption within each treatment group. All subject-level data 
observed prior to the occurrence of an intercurrent event will be used to inform the imputation 
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models. Further details regarding the specification of the imputation models will be specified 
in the SAP.  
The 100 complete datasets will be analyzed based on a logistic regression model, including 
treatment, baseline disease severity (vIGA-AD score at baseline), region (Japan, Other 
countries), prior use of biologics or systemic JAK inhibitors for AD (Yes/No) and the baseline 
value of the endpoint as a covariate. The logistic regression model will be used to estimate the 
risk, risk difference, and associated 95% CI based on the standardized estimator presented in 
Bartlett (80). For the analysis of the vIGA-AD responder endpoints, baseline disease severity 
will not be included as a covariate in the logistic regression model.  
The pooled estimate of the risk difference, along with the associated 95% CIs and nominal 
p-values will be presented. Inference will be based on applying Rubin’s rules to the estimates 
obtained from the analysis of the imputed data sets using the standardized estimator. 
Sensitivity analysis 
A 2-dimensional tipping point sensitivity analysis will be performed for the binary endpoints 
related to EASI, vIGA-AD, and ADSD Worst 
 score.  
For each treatment comparison versus placebo, responder statuses that are either missing or 
treated as missing will be imputed for both arms across a range of response probabilities. The 
exact range, along with the number of imputations, imputation models, and the seeds will be 
specified in the SAP. The multiple imputed complete data sets for each point in the 
2-dimensional tipping point analysis will be analyzed as specified for the primary analysis. 
For the cases where there is no variation in the imputed response statuses, the analysis will be 
conducted based on fitting the logistic regression model (as described earlier in this section) 
to a single complete data set. The p-values from the analysis of each point in the 
2-dimensional tipping point analysis will be presented in a figure, along with any potentially 
identified tipping point (in this case a tipping line). 
Supplementary analysis 
For the binary endpoints related to EASI, vIGA-AD and ADSD Worst 
 score, the primary 
estimand will be analyzed for all protocol-defined visit weeks. 
11.3.8.3 
Analysis of primary estimand for time-to-event endpoint 
Primary analysis 
Let T represent the time from baseline to initiation of rescue treatment and TIE represent the 
time from baseline to occurrence of permanent discontinuation of IMP or withdrawal from 
trial. The while on treatment estimand evaluates: 
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 Pr(T < TIE ∧ 𝐶௔ௗ௠௜௡) 
where TIE ∧ 𝐶௔ௗ௠௜௡ is the minimum of TIE and the end of the treatment period (administrative 
censoring time), corresponding to Week 16. Since interest lies in estimating the time to 
initiating rescue treatment, the occurrence of permanent discontinuation of IMP or withdrawal 
from trial can be accounted for through the formulation of a competing risks model.  
The null hypothesis, H0,i: λLEO 138559, regimen i(t) = λplacebo(t), ∀ t ∈ (0,16),  where λ(t) denotes 
the sub-distribution hazard rate associated with the time-to-event endpoint at time t (measured 
in weeks) and 𝑖∈(1,2,3,4) denotes the LEO 138559 dose regimen, will be tested against the 
alternative, HA,i: λLEO 138559, dosage regimen i(t) ≠ λplacebo(t) based on Gray’s test, stratified by 
baseline disease severity (baseline vIGA-AD score), region (Japan, Other countries), and prior 
use of biologics or systemic JAK inhibitors for AD (Yes/No). 
To quantify the magnitude of the potential treatment effect, the estimated cumulative 
incidence functions for the competing risks model will be presented for the treatment groups, 
based on the Aalen-Johansen estimator, along with 95% CIs.  
11.3.9 
Supplementary estimand analysis 
11.3.9.1 
Analysis of hypothetical supplementary estimand for continuous endpoints 
Primary analysis 
Data collected after permanent discontinuation of IMP or after initiation of rescue treatment 
will be excluded from the analysis and “treated as missing”. Missing data and data “treated as 
missing” will be split into two groups: 
1. Data “treated as missing” due to discontinuation due to lack of efficacy, an AE related 
to worsening of AD, or rescue treatment.  
2. Missing data or data “treated as missing” for other reasons than discontinuation due to 
lack of efficacy, an AE related to worsening of AD, or rescue treatment.  
The first group will have their missing values imputed using an ANCOVA model adjusting for 
treatment, region, and time as a continuous covariate. Noise will be added to the predicted 
values from the imputation model. The imputation will be repeated 100 times. Further details 
regarding the imputation model, including choice of seed, will be specified in the SAP.  
The second group will be imputed using MI (100 iterations) under a MAR assumption within 
each treatment group. All subject-level data observed prior to the occurrence of an 
intercurrent event will be used to inform the imputation models. Further details regarding the 
specification of the imputation models will be specified in the SAP. 
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The imputed datasets will be combined to create 100 complete datasets. For each of the 100 
complete datasets, the response will be analyzed using an ANCOVA model adjusted for 
treatment, baseline disease severity (baseline vIGA-AD score), region (Japan, Other 
countries), and prior use of biologics or systemic JAK inhibitors for AD (Yes/No). The model 
will also be adjusted for the baseline value of the dependent variable. 
The pooled estimate of the difference in the LSmean change from baseline, along with the 
associated 95% CIs and nominal p-values will be presented. Inference will be based on 
applying Rubin’s rules to the estimates and standard errors from the ANCOVA analysis of the 
imputed datasets. 
11.3.9.2 
Analysis of second supplementary estimand for continuous endpoints 
Primary analysis 
All observed data will be included in the analysis, including data observed after the 
occurrence of intercurrent events. 
Missing data will be imputed using MI (100 iterations) under a MAR assumption within each 
treatment group. All observed data will be used to inform the imputation model. Further 
details regarding the specification of the imputation models will be detailed in the SAP.  
For each of the 100 complete datasets, the response will be analyzed using an ANCOVA 
model adjusted for treatment, baseline disease severity (baseline vIGA-AD score), region 
(Japan, Other countries), and prior use of biologics or systemic JAK inhibitors for AD 
(Yes/No). The model will also be adjusted for the baseline value of the dependent variable.  
The pooled estimate of the difference in the LSmean change from baseline, along with the 
associated 95% Cis and nominal p-values will be presented. Inference will be based on 
applying Rubin’s rules to the estimates and standard errors from the ANCOVA analysis of the 
imputed datasets. 
11.3.9.3 
Analysis of supplementary estimand for binary endpoints 
Primary analysis 
All observed data will be included in the analysis, including data observed after the 
occurrence of intercurrent events. 
Missing data will be imputed using MI (100 iterations) under a MAR assumption within each 
treatment group. All observed data will be used to inform the imputation model. Further 
details regarding the specification of the imputation models will be detailed in the SAP.  
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For each of the 100 complete datasets, the response will be analyzed using a logistic 
regression model including treatment, baseline disease severity (vIGA-AD score at baseline), 
region (Japan, Other countries), prior use of biologics or systemic JAK inhibitors for AD 
(Yes/No) and the baseline value of the endpoint as a covariate. For the analysis of the 
vIGA-AD responder endpoints, baseline disease severity will not be included as a factor in 
the logistic regression model.  
The pooled estimate of the estimated risk differences and standard errors based on the 
standardized estimator presented in Bartlett (80), along with the associated 95% CIs and 
nominal p-values will be presented. Inference will be based on applying Rubin’s rules to the 
estimates and standard errors from the analyses of the imputed datasets. 
11.3.9.4 
Analysis of supplementary estimand for time to event endpoint 
Primary analysis 
Let T represent the time from baseline to the initiation of rescue treatment or permanent 
discontinuation of IMP, whichever occurs first. The composite estimand evaluates: 
 
 Pr(T < 𝐶௔ௗ௠௜௡) 
where 𝐶௔ௗ௠௜௡ is the end of the treatment period (administrative censoring time), 
corresponding to Week 16.  
The null hypothesis, H0,i: λLEO 138559, regimen i(t) = λplacebo(t), ∀ t ∈ (0,16), where λ(t) denotes 
the hazard rate associated with the time-to-event endpoint at time t (measured in weeks) and 
𝑖∈(1,2,3,4) denotes the LEO 138559 dose regimen, will be tested against the alternative, 
HA,i: λLEO 138559, dosage regimen i(t) ≠ λplacebo(t) based on the log-rank test, stratified by baseline 
disease severity (baseline vIGA-AD score), region (Japan, Other countries), and prior 
biologics or systemic JAK inhibitors for AD (Yes/No). 
To quantify the magnitude of the potential treatment effect, the estimated cumulative 
incidence functions will be presented for the treatment groups, based on the Kaplan-Meier 
estimator, along with 95% CIs. Additionally, the difference in the estimated cumulative 
incidence functions at Week 16 between the LEO 138559 dose regimens and placebo will be 
presented along with 95% CIs.  
11.3.10 
Analysis of baseline subgroup estimands 
The baseline subgroup estimands will be analyzed according to the primary analysis for the 
primary estimand for binary endpoints, specified in Section 11.3.8.2. 
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11.3.11 
PRO analysis 
Endpoints related to PROs will be analyzed as described in Section 11.3.7.  
11.3.12 
PD 
For the following endpoints, explorative analyses will be performed for the total population as 
well as by baseline disease severity: 
• Change in expression of biomarkers in serum from baseline to Week 2, Week 4, and to 
Week 16, respectively. 
• Change in skin Staphylococcus aureus abundance and microbiome profile from baseline 
to Week 16. 
• Change in skin lipid and molecular profile from baseline to Week 4, and to Week 16, 
respectively. 
• Change in biomarker expression from baseline to Week 16 in lesional skin biopsies. 
A summary of the results will be included in the CTR if the results are available in time for 
this. The full set of biomarker results will be reported in an addendum to the CTR. 
11.3.13 
Safety analysis 
The analysis of safety will be based on the safety analysis set. 
11.3.13.1 
AEs 
Coding of AEs 
AEs will be coded during the course of the trial according to MedDRA. AEs defined by 
MedDRA PTs within primary SOC will be presented. 
TEAEs 
An event will be considered treatment-emergent if started after the first dose of IMP or if 
started before the first dose of IMP and worsened in severity after first dose of IMP. An event 
will not be considered treatment-emergent if starting 18 weeks after the last dose of IMP. The 
tabulations described in the following will only include the TEAEs. All AEs recorded during 
the course of the trial will be included in subject data listings.  
AEs will be summarized in terms of the number of subjects with at least 1 event, the 
percentage of subjects with at least 1 event, the number of events, and the event rate per 
100 patient years of observation time. 
Related AEs are defined as AEs for which the investigator has not described the causal 
relationship to IMP as ‘not related’. The number of related AEs and the number of subjects 
with each type of related AE will be tabulated.  
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An overall summary of the number of events and the number (percentage) of subjects with 
any TEAEs, deaths, SAEs, AESIs, permanent discontinuations from IMP and/ or withdrawals 
from the trial due to AEs, treatment-related AEs, and severe AEs will be presented. 
Tabulations by SOC and PT will be presented for all AEs, SAEs, related AEs, AESIs, and AEs 
leading to withdrawal from trial and/or permanent discontinuation of IMP. In addition, all AEs 
will be presented by severity and causal relationship to IMP, respectively. 
SAEs will be evaluated separately, and a narrative will be given. 
AEs leading to withdrawal from trial or permanent discontinuation of IMP will be tabulated 
and listed. No narratives will be given.  
Other events (medication error) will be listed. No narratives will be given. 
11.3.13.2 
Vital signs 
The change in vital signs (resting BP, pulse, and body temperature) from baseline to each 
relevant visit will be summarized as mean, SD, median, minimum, and maximum values for 
each treatment group. Shift table for clinically significant abnormal vital signs will be 
presented. 
11.3.13.3 
ECG 
Subjects with abnormal, clinically significant ECG will be listed. Furthermore, a shift table 
for ECG showing the change from baseline to end-of-treatment in clinical assessment 
(normal; abnormal, not clinically significant; abnormal, clinically significant) will be 
provided. 
11.3.13.4 
Clinical laboratory evaluation 
The change in each of the laboratory parameters (except from hematology ratios) from 
baseline to each relevant visit will be summarized as mean, SD, median, minimum, and 
maximum values for each treatment group. 
For liver and kidney parameters (ALP, ALT, AST, BIL, and eGFR) and white blood cells 
(neutrophils, lymphocytes, and eosinophils), guideline or literature defined thresholds will be 
used for producing shift tables and categorical threshold tables. The remaining laboratory 
parameters will be classified as ‘low’, ‘normal’, or ‘high’, depending on whether the value is 
below, within, or above the reference range and these categories will be used for producing 
shift tables. 
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If any subjects have concurrent elevations of alkaline phosphatase, ALT, AST, and bilirubin, 
per the guideline or literature defined thresholds, an individual profile plot of the subjects’ 
alkaline phosphatase, ALT, AST, and bilirubin over the trial period will be provided. 
11.3.13.5 
ADA 
For the endpoint on having a positive ADA response from baseline to Week 32, the ADA 
status (positive vs. negative) at each assessment time point will be summarized by treatment 
group. If considered relevant, descriptive statistics including number of subjects, mean, SD, 
median, and range of the actual ADA titres by treatment group and visit will be provided. The 
ADA status across the trial for each subject (positive vs. negative) will also be classified and 
summarized by treatment group.  
The association of ADA status across the trial (positive vs. negative) with AEs /SAEs may be 
evaluated. In addition, the association of ADA titres (≥ median titre in positive subjects versus 
< median titre) with AEs /SAEs may be evaluated for ADA positive treated subjects only. The 
ADA positive subjects across the trial may also be divided into persistent positive versus 
transient positive. A subject will be considered as persistent positive if he/she has positive 
ADA for at least 2 consecutive visits with ADA assessment. Otherwise, the subject will be 
considered as transient ADA positive. The associations between ADA and AEs /SAEs may be 
summarized for both persistent positive subjects versus transient positives subjects.  
For subjects who develop ADA, the change in EASI at end-of-treatment will be listed.  
For ADA, all subjects with titre information will be listed. Graphical presentations may be 
performed. 
11.3.14 
PK analysis 
The following endpoint will be evaluated based on the PK analysis set: 
• Serum concentration of LEO 138559 at Weeks 1, 2, 4, 8, 12, 16, 20, and 32. 
LEO 138559 serum concentrations will be listed and summarized by treatment group and 
visit.  
11.3.15 
Interim analysis 
No interim analysis is planned. 
11.3.16 
Timing of reporting trial results 
The trial will be unblinded once all randomized subjects have completed the Week 16 visit. 
All pre-specified analyses will be based on the data lock point date of the last subject’s 
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Week 16 visit. The CTR will include all data from the trial including data from the follow-up 
period. 
A written plan (trial blinding plan) detailing the blinded/unblinded staff for the reporting of 
trial results based on the data lock point date of the last subject’s Week 16 visit will be 
prepared before FSFV.    
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12 Supporting documentation and operational considerations 
12.1 Appendix 1: Regulatory, ethical, and trial governance considerations 
12.1.1 
Regulatory and ethical considerations 
This trial will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines including the current 
version of the Declaration of Helsinki (61) and Council for International Organizations of 
Medical Sciences (CIOMS) International Ethical Guidelines (81). 
• Current version of applicable ICH GCP Guidelines (1). 
• EU General Data Protection Regulation 2016/679 of 27 April 2016. 
• Applicable laws and regulations. 
The appropriate regulatory authority(ies) must be notified of/approve the clinical trial as 
required. 
Any documents that the IRB/IEC may need to fulfill its responsibilities (such as the trial 
protocol, protocol amendments, investigator’s brochure, subject information sheet, and 
ICF(s), or advertisements) will be submitted to the IRB/IEC. These documents must be 
reviewed and approved by the IRB/IEC before the trial is initiated. 
Any amendments to the protocol must be approved by/receive favorable opinion from 
relevant regulatory authorities and IRBs/IECs, as required, prior to implementation. 
The principal investigator will be responsible for the following, if required by local 
legislation: 
• Providing written summaries of the status of the trial to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC. 
• Notifying the local IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures. 
• Informing LEO Pharma immediately of any urgent safety measures taken to protect the 
trial subjects against any immediate hazard. 
• Providing oversight of the conduct of the trial at the trial site and ensuring adherence to 
applicable national and international legislation. 
Handling of serious breach 
A serious breach is any deviation of the approved protocol version or the clinical trial 
regulation that is likely to affect the safety, rights of trial subjects and/or data reliability and 
robustness to a significant degree in a clinical trial. 
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The investigator and all site staff are responsible for reporting suspected serious breaches to 
LEO Pharma without undue delay and no later than 24 hours of obtaining knowledge. 
Suspected serious breaches must be reported to the CRA. 
If necessary for reporting the incident to the affected member state through the EU portal, 
LEO Pharma may request additional information from the reporter. 
12.1.2 
Financial disclosure 
Investigators will provide LEO Pharma with sufficient, accurate financial information as 
requested to allow LEO Pharma to submit complete and accurate financial certification or 
disclosure statements to the appropriate regulatory authorities. Investigators are responsible 
for providing information on financial interests and updating this information, should any 
relevant change occur, during the course of the clinical trial and for 1 year after completion of 
the clinical trial, or for a longer period of time if required by local legislation. 
12.1.3 
Informed consent process 
Subjects will receive written and verbal information concerning the clinical trial. This 
information will emphasize that participation in the clinical trial is voluntary and that the 
subject may withdraw from the clinical trial at any time and for any reason. All subjects will 
be given an opportunity to ask questions and will be given sufficient time to consider before 
consenting. 
The subject’s signed and dated informed consent to participate in the clinical trial will be 
obtained prior to any clinical trial-related procedure being carried out in accordance with 
ICH GCP and all applicable laws and regulations. The authorized person obtaining the 
informed consent must also sign the ICF. 
Subjects will be re-consented to the most current version of the ICF(s) during their 
participation in the trial, if required. 
A copy of the ICF(s) must be provided to the subject.  
Subject card 
At screening, subjects will be provided with a card stating that they are participating in a 
clinical trial and which contains contact address(es) and telephone number(s) of relevant trial 
site staff including the number for the investigator in case of emergency situations. The 
subject card also includes a local telephone number for the emergency unblinding CRO to be 
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used if the investigator or delegated site staff cannot be reached or if unblinding in the IRT 
system cannot be performed. 
12.1.4 
Recruitment strategy 
The recruitment strategy and tools will be the below including, but not limited to: 
Recruitment tools as approved by the regulatory authorities and IRB/IEC: 
• Advertisement – Poster, flier, brochure 
• HCP referral letter  
Local, site-initiated advertisement will be subject to the sponsor’s review and approval prior 
to submission to their local/central IRB/IEC. 
12.1.5 
Data protection 
This clinical trial protocol as well as all other information, data, and results relating to this 
clinical trial and/or to the IMP is confidential information of LEO Pharma and shall not be 
used by the investigator for purposes other than this clinical trial. 
The investigator agrees that LEO Pharma may use any and all information, data, and results 
from this clinical trial in connection with the development of the IMPs and, therefore, may 
disclose and/or transfer information, data, and/or results to other investigators, regulatory 
authorities, and/or commercial partners. 
Trial subjects will be assigned a unique identifier (subject ID) by LEO Pharma. Any subject’s 
records or datasets that are transferred to LEO Pharma will contain the identifier only; subject 
names or any information which would make the subject identifiable will not be transferred. 
Trial subjects must be informed that their personal trial-related data will be used by LEO 
Pharma in accordance with local data protection law. The level of disclosure must also be 
explained to the subject who will be required to give consent for their data to be used as 
described in the informed consent.  
Trial subjects must be informed that their medical records may be examined by clinical 
quality assurance auditors or other authorized personnel appointed by LEO Pharma, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
Trial subjects must be informed that LEO Pharma might keep their trial-related data for as 
long as they are useful for developing treatments for the disease or other diseases and future 
research. 
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Processing of personal data 
This protocol specifies the personal data on trial subjects (e.g. race, ethnicity, age, sex, health 
condition, medical history, test results, etc.) which shall be collected as part of the clinical trial 
and processed during and after trial completion. 
Personal data collected as part of the clinical trial will be transferred to/from the 
institution/investigator, LEO Pharma, and third parties acting on behalf of LEO Pharma. 
Processing of personal data on behalf of LEO Pharma requires a written agreement between 
LEO Pharma and the relevant party which covers collection, processing, and transfer of 
personal data in the clinical trial as well as reporting obligations in the event of any data 
breach. In certain cases, an agreement on transfer of personal data may also be required. 
Investigators and LEO Pharma must ensure that collection, processing, and transfer of 
personal data are in compliance with applicable legislation on data protection and privacy, 
including but not limited to the EU General Data Privacy Regulation. 
Subjects must be informed of the collection, processing, and transfer of their personal data to 
EU and non-EU countries for the purpose of conducting the clinical trial, research and 
development of new or existing products/services, improving existing products/services, 
applying for marketing authorizations for products/services, marketing of products/services, 
and other related activities. 
LEO Pharma has obtained the necessary authorizations for the processing of personal data 
collected in the trial. 
12.1.6 
Committee structure 
Not applicable. 
12.1.7 
Dissemination of clinical trial data 
LEO Pharma is committed to be transparent with respect to its clinical trials. 
Basic information of this clinical trial will be registered in the global data registry, 
www.ClinicalTrials.gov. before the first subject enters the trial. The trial may also become 
registered in other online data registries, according to applicable law and regulations. 
Results of this clinical trial will be posted in accordance with applicable laws and regulations 
as well as LEO Pharma’s commitment to transparency which can be found on LEO Pharma’s 
website. 
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12.1.8 
Data quality assurance 
Data will be collected by means of EDC unless transmitted electronically to LEO Pharma or 
designee (e.g. laboratory data). The investigator or staff authorized by the investigator will 
enter subject data into an eCRF. The investigator is responsible for verifying that data entries 
are accurate and correct by electronically signing the eCRF. 
Subject data should be entered into the eCRF no later than 5 working days after each visit, 
unless a different deadline is stated in the clinical trial agreement. Queries for discrepant data 
will be generated automatically by the system upon entry or manually by the CRA, sponsor’s 
medical expert, or the data manager. All queries will be raised electronically within the EDC 
system. This systematic validation will ensure that a clean and consistent database is provided 
for the statistical analysis. 
The investigator must permit trial-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source data documents. 
The monitoring will be performed in a systematic, prioritized, risk-based approach, and as a 
combination of on-site, remote, and centralized monitoring.  
LEO Pharma or designee is responsible for the data management of this trial including quality 
checking of the data. 
LEO Pharma assumes accountability for actions delegated to other individuals (e.g. CROs). 
Records and documents, including signed ICF, pertaining to the conduct of this trial must be 
retained by the investigator for 25 years after trial completion unless otherwise required by 
local regulations or institutional policies. No records may be destroyed during the retention 
period without the written approval of LEO Pharma. No records may be transferred to another 
location or party without the written approval of LEO Pharma. 
All data generated by the site personnel will be captured electronically at each trial site using 
eCRFs. Once the eCRF clinical data have been submitted to the central server, corrections to 
the data fields will be captured in an audit trail. The reason for change, the name of the person 
who performed the change, together with the time and date will be logged to provide an audit 
trail. 
If additional corrections are needed, the responsible CRA or data manager will raise a query 
in the electronic data capture application. The appropriate staff at the trial site will answer 
queries sent to the investigator. The name of the staff member responding to the query, and 
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time and date stamp will be captured to provide an audit trail. Once all source data 
verification is complete and all queries are closed, the data manager or CRA will freeze the 
eCRF page. 
Site personnel will receive training on the EDC system/eCRF. The specific procedures to be 
used for data entry and query resolution using the EDC system/eCRF will be described in the 
CRF completion guidelines. 
12.1.9 
Source documents 
For all data recorded, the source document must be defined in a source document agreement 
or similar document at each trial site. There must only be 1 source defined at any time for any 
data elements. 
Source data should as a general rule be recorded in the subject’s medical record or other 
defined document normally used at the trial site. Source data not normally collected as a 
routine part of the clinical practice at the site may be entered on a worksheet. Safety 
evaluations must be signed and dated by a physician. Clinical assessments must be signed and 
dated by the investigator. 
If the worksheet does not become part of the subject’s medical record, the following should as 
a minimum be added to the subject’s medical record: 
• Subject ID. 
• A statement from the investigator to verify that each of the eligibility criteria were met 
and documented. 
• Randomization code number. 
• The fact that the subject is participating in a clinical trial in AD including treatment with 
LEO 138559 or placebo for 16 weeks. 
• Other relevant medical information. 
12.1.10 
Trial and trial site start and closure 
First act of recruitment 
The trial start date is the date on which the clinical trial will be open for recruitment of 
subjects. 
The first act of recruitment is the first subject first visit.  
Trial/site termination 
LEO Pharma or designee reserves the right to close the trial site or terminate the trial at any 
time for any reason at the sole discretion of LEO Pharma. Trial sites will be closed upon trial 
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completion. A trial site is considered closed when all required documents and trial supplies 
have been collected and a trial site closure visit has been performed. 
The investigator may initiate trial site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
The trial must be terminated if the perception of the benefit/risk ratio (judged from clinical 
signs and symptoms, [S]AEs, and/or remarkable safety laboratory changes) becomes 
unfavorable for the continuation of the trial. 
Reasons for the premature closure of a trial site by LEO Pharma or investigator may include 
but are not limited to: 
• Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, LEO Pharma procedures, or GCP guidelines. 
• Inadequate recruitment (evaluated after a reasonable amount of time) of subjects by the 
investigator. 
• Total number of subjects included earlier than expected (irrespective of the specific site’s 
planned inclusion number). 
Responsibilities following suspension or termination 
If a clinical trial is suspended or prematurely terminated, the investigator must inform the 
subjects promptly and ensure appropriate therapy and follow-up. As specified by applicable 
regulatory requirements, the investigator or LEO Pharma must promptly inform IRBs/IECs 
and provide a detailed written explanation. Relevant competent authorities must be informed. 
12.1.11 
Publication policy 
The investigator shall be entitled to make publications of the results generated by the 
investigator in accordance with the process described here. 
A multi-site publication will be submitted for publication within 12 months after the clinical 
trial has been completed or terminated at all trial sites and all data have been received, defined 
as final database lock of the clinical trial. After such multi-site publication is made public, or 
if no multi-site publication has been submitted with the above-described deadline, the 
investigator shall have the right to publish the results from the clinical trial generated by the 
investigator, subject to the following notice requirements: 
Prior to submission for publication or presenting a manuscript relating to the clinical trial, the 
investigator shall provide to LEO Pharma a copy of all such manuscripts and/or presentations. 
LEO Pharma shall have rights to review and comment. The investigator shall consider 
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comments provided by LEO Pharma but is not required to modify the manuscript and/or 
presentation based on such comments, provided, however, that the investigator upon the 
request of LEO Pharma remove any confidential information (other than results generated by 
the investigator) prior to submitting or presenting the manuscripts. The investigator shall, 
upon the request of LEO Pharma withhold the publication or presentation to allow LEO 
Pharma to protect its inventions and other intellectual property rights described in any such 
manuscripts.  
In case no multi-site publication has been made public at the time of investigator’s 
notification of an independent publication to LEO Pharma, LEO Pharma and the writing 
group may also delay the publication or presentation if the manuscript is deemed to harm the 
ongoing multi-site publication. 
In case of publications made by the investigator after the first multi-site publication has been 
published, the above-mentioned requirements must still be followed. 
Any publication must comply with Good Publication Practice (GPP3) standards. 
LEO Pharma complies with GPP3 standards and the recommendations from the International 
Committee of Medical Journal Editors. LEO Pharma complies with the positions of the 
International Federation of Pharmaceutical Manufacturers & Associations (IFPMA), 
European Federation of Pharmaceutical Industries and Associations (EFPIA), Japan 
Pharmaceutical Manufacturers Association (JPMA), Pharmaceutical Research and 
Manufacturers of America (PhRMA), and the joint position statement by the American 
Medical Writers Association (AMWA), the European Medical Writers Association (EMWA), 
and the International Society for Medical Publication Professionals (ISMPP) on disclosure of 
information about clinical trials, trial results, and authorship. LEO Pharma also follows the 
CONSORT reporting guidelines (63). 
12.1.12 
Insurance 
LEO Pharma has taken out relevant insurances covering the subjects in the present clinical 
trial in accordance with applicable laws and regulations. 
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12.2 Appendix 2: AEs and SAEs: Definitions and procedures for 
recording, evaluating, follow-up, and reporting 
12.2.1 
AE definition 
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with 
the use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product (82). 
This definition includes: 
• Accidental injuries. 
• Events related to trial procedures. 
• Reasons for any unfavorable and unplanned change in medication (drug and/or dose). 
• Clinically significant worsening of pre-existing conditions. 
• Reasons for admission to hospital or surgical procedures*.  
• AEs commonly observed and AEs anticipated based on the pharmacological effect of the 
IMP.  
• Any laboratory abnormality assessed as clinically significant by the investigator (see 
Section 8.4.5.2). 
12.2.2 
SAE definition 
An SAE is any untoward medical occurrence that: 
• Results in death. 
• Is life-threatening – at risk of death at the time of the SAE (not an event that 
hypothetically might have caused death if more severe). 
• Requires inpatient hospitalization or prolongation of existing hospitalization*. 
• Results in persistent or significant disability or incapacity. 
• Is a congenital anomaly or birth defect. 
• Is a medically important condition. Events that may not be immediately life-threatening or 
result in death or hospitalization but may jeopardize the subject or may require 
intervention to prevent 1 of the other outcomes listed in the definition above. Examples 
are intensive treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias, and convulsions that do not result in hospitalization, development of drug 
dependency, or drug abuse.  
Additionally, all malignancies, including skin malignancies, should be reported as SAEs. 
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*Hospitalization for procedures or treatments planned prior to the subject consented to trial 
participation does not constitute an AE and should therefore not be reported as an AE or SAE. 
*Hospitalization for elective treatment of a pre-existing condition which did not worsen from 
the subject consented to trial participation is not considered an AE and should therefore not be 
reported as an AE or SAE, even if not planned before consent to trial participation. 
*Hospitalization for routine scheduled treatment or monitoring of the studied indication not 
associated with any aggravation of the condition does not constitute an AE and should 
therefore not be reported as an AE or SAE. 
*Hospitalization for administrative, trial-related, or social purpose does not constitute an AE 
and should therefore not be reported as an AE or SAE. 
*Complications that occur during hospitalization are (S)AEs. If a complication prolongs 
hospitalization, the event is an SAE. 
*When in doubt as to whether hospitalization occurred or was necessary, the AE should be 
considered serious. 
 
12.2.3 
Definition of AESIs 
An AESI (serious or non-serious) is an event type of scientific and medical concerns specific 
to the product or development program, for which additional monitoring may be appropriate. 
Such an event might warrant further investigation to characterize and understand it. 
Depending on the nature of the event, rapid communication by the investigator to LEO 
Pharma and/or from LEO Pharma to other parties (e.g. regulators) might also be warranted. 
AESIs are described in Section 10.7.1. 
12.2.4 
Recording and follow-up of AEs 
AE recording 
When an AE occurs, it is the responsibility of the investigator to review all documentation 
(e.g. hospital progress notes, laboratory, and diagnostics reports) related to the event. 
AEs reported by the subject or observed by the investigator must be recorded on the AE form 
of the eCRF and should be described in the following manner: 
The AE term must be in precise English medical terminology (that is, not necessarily the 
exact words used by the subject). Whenever possible, a specific diagnosis should be stated 
(e.g. ‘allergic contact dermatitis’). 
Any clinically significant aggravation/exacerbation/worsening of any medical condition(s) 
(including the trial disease), compared to screening, must be reported as an AE. 
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AD is a fluctuating disease with possible periods of remission. In case of relapses/recurrences, 
only aggravations/exacerbations exceeding normal disease fluctuation or lesions appearing in 
a body area normally not affected by AD should be reported as an AE. 
The duration of the AE must be reported by the start date and stop date of the event unless the 
event is ongoing. If the event is ongoing, it will be marked as ongoing. In addition, it will be 
recorded whether the AE started on the same day as IMP was administered and if so, whether 
before or after IMP dosing. 
AEs must be classified in terms of severity, causality, and outcome according to the 
definitions below. 
Action taken with IMP: any action taken with IMP as a consequence of the AE must be 
recorded in the eCRF (dose not changed, drug interrupted, drug discontinued, not applicable, 
unknown). 
For subjects participating in the qualitative interview, AEs reported during the interview may 
be reported retrospectively. 
Any potential AE reported by the subjects during the qualitative interview must be collected 
by the interviewer on the Potential Adverse Event Collection Form. The interviewer must 
forward the completed form to the investigator within 24 hours of the interview. The 
investigator must evaluate if the potential AEs are indeed to be considered as AEs and 
whether they were already recorded in the eCRF and date and sign their evaluation within 
24 hours of receipt of the form. Investigator should confirm review of the form directly in the 
secure IT portal within those 24 hours. If the confirmed AEs were not recorded in the eCRF, 
or if the investigator is in doubt, they must record the AEs in the eCRF. If considered relevant, 
the investigator should follow up on the AEs with the subject at the safety follow-up visit. If a 
potential AE qualifies as an SAE, the SAE must be reported within 24 hours of receipt by the 
site/investigator as described in Section 12.2.5. 
Assessment of severity 
The severity of the AE should be described in terms of mild, moderate, or severe according to 
the investigator’s clinical judgement. If the AE worsens in severity, the new severity, 
including date of worsening, should be recorded. However, if an AE with onset prior to IMP 
initiation worsens after IMP administration, a new AE should be recorded.  
Mild 
An AE 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. 
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Moderate 
An AE 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 subject. 
Severe 
An AE 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 trial treatment and each 
occurrence of each AE/SAE. The investigator will use clinical judgement 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 trial treatment administration will be 
considered and investigated. 
The investigator will also consult the LEO 138559 investigator’s brochure in their assessment. 
For each AE, the investigator must document in the medical notes that he/she has reviewed 
the AE and has provided an assessment of causality. 
There may be situations in which an SAE has occurred, and the investigator has minimal 
information to include in the initial SAE form. However, it is very important that the 
investigator always assesses causality for every event before the initial recording of the SAE 
data. 
The investigator may change their opinion of causality in light of follow-up information and 
send an SAE follow-up report with the updated causality assessment. 
The following decision choices will be used by the investigator to describe the causality 
assessment: 
Probably 
related 
Follows a reasonable temporal sequence from administration of the IMP. 
 
Could not be reasonably explained by the subject’s clinical state, environmental or toxic 
factors, or other therapies administered to the subject. 
 
Follows a known pattern of response to the IMP. 
 
Disappears or decreases on cessation or reduction in dose of the IMP. 
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Reappears or worsens upon re-challenge. 
Possibly 
related 
 
Follows a reasonable temporal sequence from the administration of the IMP. 
 
Could also be reasonably explained by the subject’s clinical state, environmental or toxic 
factors, or other therapies administered to the subject. 
 
Follows a known pattern of response to the IMP. 
Not related 
 
Does not follow a reasonable temporal sequence from administration of the IMP. 
 
Is better explained by other factors like the subject’s clinical state, environmental or toxic 
factors, or other therapies administered to the subject. 
 
Does not reappear or worsen upon re-challenge. 
 
Does not follow a known pattern of response to the IMP. 
Assessment of outcome 
The outcome of the event according to the investigator’s clinical judgement should be 
classified using the categories below. 
Fatal 
The subject has died as a consequence of the event. Date of death is recorded as stop date for 
the AE. 
Not recovered/ 
not resolved 
Event is still ongoing.  
Recovering/ 
resolving 
The subject is clearly recovering from an event. The event is not yet completely resolved.  
Recovered/ 
resolved 
The event has stopped. The stop date of the event must be recorded. 
Recovered/         
resolved with 
sequelae 
The event has reached a state where no further changes are expected and the residual 
symptoms are assumed to persist. An example is hemiparesis after stroke. 
 
The stop date of the event must be recorded. In case of an SAE, the sequelae should be 
specified. 
Unknown 
Unknown to investigator, e.g. subject lost to follow-up. 
LEO Pharma definitions versus CDISC definitions 
Note that as per the above definition, LEO Pharma uses ‘recovered/resolved’ only if an event 
has actually stopped. According to the CDISC definition, the category ‘recovered/resolved’ 
also includes events which have improved. However, following the LEO Pharma definitions 
above, such an improved event will instead be classified as ‘not recovered/not resolved’ or 
‘recovering/resolving’. 
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Similarly, it should be noted that as per the above definition, LEO Pharma uses 
‘recovered/resolved with sequelae’ only if an event has reached a state where the residual 
symptoms are assumed to persist. According to CDISC, an event is considered ‘with 
sequelae’, if it has ‘retained pathological conditions’. Consequently, it is likely that some of 
the events classified by LEO Pharma with the outcome ‘recovered/resolved with sequelae’ 
could have been classified with the outcome ‘recovered/resolved’ according to the CDISC 
definition. 
In summary, the definitions used by LEO Pharma are more conservative than those used by 
CDISC. 
Follow-up of AE 
During the trial, the investigator should follow up for final outcome on all AEs (including 
SAEs). Once a subject leaves the clinical trial, the investigator should follow up on the 
outcome of all non-serious AEs classified as possibly or probably related to the IMP for 
2 weeks or until the final outcome is determined, whichever comes first. Non-serious AEs 
classified as not related to the IMP do not need to be followed up for the final outcome. 
All SAEs must be followed up until a final outcome has been established, that is, the 
follow-up may continue beyond the end of the clinical trial. For SAEs which have stabilized 
and from which the subject cannot be expected to recover during the trial or the safety 
follow-up periods, e.g. chronic or stabilized conditions, the final outcome should be reported 
as ‘recovering/resolving’ or ‘not recovered/not resolved’ at the investigator’s discretion. In 
addition, a statement detailing why the subject cannot be expected to recover during the trial, 
e.g. that the SAE has stabilized or is chronic, should be added to the narrative description of 
the SAE on the SAE form. 
The investigator is obligated to arrange for the conduct of supplemental measurements and/or 
evaluations as medically indicated or as requested by LEO Pharma 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 subject dies during participation in the trial or during a recognized follow-up period, the 
investigator will provide LEO Pharma with a copy of any post-mortem findings including 
histopathology, if available. 
New or updated information will be recorded in the originally completed form. 
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The investigator will submit any updated SAE data to LEO Pharma within 24 hours of receipt 
of the information. 
12.2.5 
Reporting of SAEs 
Investigator reporting responsibilities 
Any SAE must be reported to LEO Pharma on the (paper) SAE form immediately, without 
undue delay and no later than U24 hours of obtaining knowledge. This report should contain 
amongst others an assessment of available information on seriousness, severity, causal 
relationship to the IMP or trial procedure, the action taken, the outcome to date, and a 
narrative description of the course of the event. For more details regarding reporting of any 
SAE, please see the guidance text on the SAE form. 
By signing and dating the SAE form, the investigator acknowledges that he/she is aware of 
the SAE and has assessed the causal relationship of the IMP(s) and any of the other 
medications to the SAE. 
The actual reporter, if not the investigator, should also sign and date the SAE form. 
The completed SAE form must be faxed or scanned and e-mailed to Global Safety at LEO 
Pharma using the e-mail address or fax number below: 
UGlobal Safety at LEO Pharma 
E-mail address: drug.safety@leo-pharma.com  
Fax number: +45 6910 2468 
If relevant, the investigator will enclose other information with the SAE form, such as 
anonymized reports of diagnostic procedures, hospital records, autopsy reports, etc. 
Additionally, Global Safety at LEO Pharma may request further information in order to fully 
assess the SAE. The investigator must forward such information to LEO Pharma upon request 
by fax or e-mail (see contact details above). 
The investigator must notify the local IRB(s)/IEC(s) of SAEs, as required by current 
applicable legislation for the concerned country. 
SAEs occurring after the completion of the clinical trial should not be routinely sought or 
recorded. If the investigator becomes aware of an SAE with a suspected causal relationship to 
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the IMP that occurs after the end of the clinical trial in a subject treated by him or her, the 
investigator shall, without undue delay, report the SAE to Global Safety at LEO Pharma (see 
contact details above).  
LEO Pharma reporting responsibilities 
Global Safety at LEO Pharma is responsible for assessing whether an SAE is expected. The 
relevant reference safety information document for this clinical trial is the investigator’s 
brochure Section 7.3, edition 5.0 and subsequent updates (49). 
Global Safety at LEO Pharma will notify the regulatory authorities and concerned 
investigators of SAEs according to the current applicable legislation for the concerned 
countries.  
The IRB(s)/IEC(s) will be notified of SAEs according to the current applicable legislation for 
the concerned countries.  
For all non-US countries, the following reporting requirements apply: all SAEs which are 
assessed as causally related to the IMP(s) by either the investigator or LEO Pharma (1), and 
which are unexpected (SUSARs), are subject to expedited reporting to regulatory authorities, 
IEC(s)/IRB(s) according to the current applicable legislation in the concerned countries. 
Investigators will be notified of the evolving safety profile of the IMP on an ongoing basis. 
For the US, the following reporting requirements apply: all SAEs which are assessed as 
causally related to the IMP(s) by LEO Pharma (83, 84) and which are unexpected (serious and 
unexpected suspected adverse reactions [IND safety report]) are subject to expedited reporting 
to regulatory authorities, IRB(s). Investigators will be notified of the evolving safety profile 
of the IMP on an ongoing basis. 
12.2.6 
Narratives 
In the CTR, narratives will be provided for the following: 
• SAEs. 
• Deaths. 
• AESIs 
 
 
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12.3 Appendix 3: Hanifin and Rajka (1980) diagnostic criteria for AD 
Major Features: must have 3 or more of the following: 
• Pruritus. 
• Typical morphology and distribution: 
- 
Flexural lichenification or linearity in adults. 
- 
Facial and extensor involvement in infants and children. 
• Chronic or chronically-relapsing dermatitis. 
• Personal or family history of atopy (asthma, allergic rhinitis, AD). 
Minor Features: should have 3 or more of the following: 
• Xerosis. 
• Ichthyosis, palmar hyperlinearity, or keratosis pilaris. 
• Immediate (type 1) skin-test reactivity. 
• Raised serum IgE. 
• Early age of onset. 
• Tendency toward cutaneous infections (especially S. aureus and herpes 
simplex) or impaired cell-mediated immunity. 
• Tendency toward non-specific hand or foot dermatitis. 
• Nipple eczema. 
• Cheilitis. 
• Recurrent conjunctivitis. 
• Dennie-Morgan infraorbital fold. 
• Keratoconus. 
• Anterior subcapsular cataracts. 
• Orbital darkening. 
• Facial pallor or facial erythema. 
• Pityriasis alba. 
• Anterior neck folds. 
• Itch when sweating. 
• Intolerance to wool and lipid solvents. 
• Perifollicular accentuation. 
• Food intolerance. 
• Course influenced by environmental or emotional factors. 
• White dermographism or delayed blanch. 
 
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12.4 Appendix 4: Guidance for anaphylaxis diagnosis 
The National Institute of Allergy and Infectious Diseases (NIAID) and Food Allergy and 
Anaphylaxis Network Guidance for Anaphylaxis Diagnosis (FAAN) define anaphylaxis as a 
serious allergic reaction that is rapid in onset and may cause death. They recognize 
3 categories of anaphylaxis, with criteria designated to capture from 80% of cases 
(category 1) to >95% of all cases of anaphylaxis (for all 3 categories). 
Clinical criteria for diagnosing anaphylaxis 
Anaphylaxis is highly likely when any one of the following 3 criteria are fulfilled: 
1) Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue, or both (e.g. generalized hives, pruritus or flushing, swollen lips-
tongue-uvula). 
AND AT LEAST ONE OF THE FOLLOWING: 
• Respiratory compromise (e.g. dyspnoea, wheeze-bronchospasm, stridor, 
reduced PEF, hypoxemia). 
• Reduced BP or associated symptoms of end-organ dysfunction (e.g. hypotonia 
[collapse], syncope, incontinence). 
2) Two or more of the following that occur rapidly after exposure to a likely allergen for 
that patient (minutes to several hours): 
• Involvement of the skin-mucosal tissue (e.g. generalized hives, itch-flush, 
swollen lips-tongue-uvula). 
• Respiratory compromise (e.g. dyspnoea, wheeze-bronchospasm, stridor, 
reduced PEF, hypoxemia). 
• Reduced BP or associated symptoms (e.g. hypotonia [collapse], syncope, 
incontinence). 
• Persistent gastrointestinal symptoms (e.g. crampy abdominal pain, vomiting). 
3) Reduced BP after exposure to known allergen for that patient (minutes to several 
hours): 
• Infants and children: low systolic BP (age specific) or greater than 30% 
decrease in systolic BP. 
• Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from 
that person’s baseline. 
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12.5 Appendix 5: Country-specific requirements 
12.5.1 
Specific requirements for all EU countries 
This section describes requirements and procedures that are specific for all EU countries 
i.e. CZ, DE, ES, FR, HU, PL and RO.  
The schedule of trial activities specific for EU countries is presented in Section 12.5.1.1 
(Panel 18). The list of eligibility criteria specific for EU countries is presented in 
Section 12.5.1.2. 
For each section, the text from the protocol is presented in normal font. The country-specific 
requirements or procedures are presented below in bold and deleted text has a line through it.  
Section 1.3 Schedule of activities 
Panel 18: Schedule of trial activities for EU countries 
Assessments of vital signs should also be performed at Week 6 (Visit 8), Week 10 
(Visit 10), and Week 14 (Visit 12). 
Panel 18: Schedule of trial activities for EU countries, footnote o) related to vital signs will 
be: Vital signs must be assessed prior to IMP administration. In addition, at Weeks 0, 
1, 2, 3, and 4, subjects will be monitored after IMP administration for potential immediate 
drug reactions for a minimum of 2 hours with vital signs taken immediately (within 
5 minutes) after last IMP administration as well as after 30 minutes (± 5 minutes), after 
1 hour (± 5 minutes), and after 2 hours (± 5 minutes), or until stable, whichever is later. 
From Week 5 onwards, subjects will be monitored after IMP administration for 
potential immediate drug reactions for a minimum of 20 minutes with vital signs 
assessed within 5 minutes after last IMP administration as well as after 20 minutes 
(± 5 minutes), or until stable, whichever is later. 
Panel 18: Schedule of trial activities for EU countries 
Assessments of hepatitis B and hepatitis C should also be performed at Week 12 
(Visit 11), and Week 24 (Visit 15). 
Panel 18: Schedule of trial activities for EU countries, an additional footnote p) related to 
hepatitis B, hepatitis C and HIV will be added: For subjects who at screening have a 
negative HBV-DNA reflex test (i.e. HBV-DNA is not detected), and negative HBsAg, 
negative anti-HBc, positive anti-HBs and without documentation of prior HBV 
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vaccination or negative HBsAg and positive anti-HBc, repeat HBV-DNA will be done 
at Weeks 12 and 24. For subjects who at screening have positive anti-HCV but 
negative HCV-RNA (i.e. HCV-RNA is not detected), repeat HCV-RNA will be done at 
Weeks 12 and 24. 
Panel 18: Schedule of trial activities for EU countries 
Assessments of chemistry and hematology (central laboratory) should also be 
performed at Week 1 (Visit 4), Week 2 (Visit 5), and Week 3 (Visit 6). 
Section 2.4 Ethical considerations 
In addition, at Weeks 0, 1, 2, 3, and 4, subjects will be monitored for a period of 2 
hours to detect potential immediate drug reactions, and from Week 5 onwards, 
subjects will be monitored for a period of 20 minutes. 
Section 5.3 Exclusion criteria 
Exclusion criterion #8 
Positive HBsAg or positive anti-HCV AND positive HCV-RNA at screening. 
- 
Subjects with a negative HBsAg and a positive anti-HBc or anti-HBs at screening 
will have reflex testing for HBV-DNA. Subjects who have a positive HBV-DNA 
test (i.e. HBV-DNA is detected) will be excluded. 
- 
For subjects who at screening have a negative HBV-DNA reflex test (i.e. 
HBV-DNA is not detected), and 
Negative HBsAg, negative anti-HBc, positive anti-HBs and without 
documentation of prior HBV vaccination  
or  
Negative HBsAg and positive anti-HBc 
repeat HBV-DNA testing must be done at Weeks 12 and 24. If HBV-DNA is 
positive (i.e. HBV-DNA is detected) at Week 12, subjects must permanently 
discontinue IMP.  
- 
Subjects who at screening have a negative HBV-DNA reflex test (i.e. HBV-DNA 
is not detected), negative HBsAg, negative anti-HBc, positive anti-HBs and 
provide documentation of prior HBV vaccination will not require regular 
monitoring by HBV-DNA repeat testing in the trial. 
- 
For subjects who at screening have positive anti-HCV but negative HCV-RNA 
(i.e. HCV-RNA is not detected), repeat HCV-RNA will be done at Weeks 12 and 
24. If HCV-RNA is positive (i.e. HCV-RNA is detected) at Week 12, subjects 
must permanently discontinue IMP. 
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Exclusion criterion #14 
Any disorder* at screening and/or baseline, which is not stable in the opinion of the 
investigator, and could: 
-Affect the safety of the subject throughout the trial. 
- Influence the results of the trial. 
- Impede the subject’s ability to complete the trial. 
 
 
 
 
 
 
 
Exclusion criterion #15 
Any significant abnormal finding* at screening and/or baseline which may in the opinion of 
the investigator:  
- Put the subject at risk because of their participation in the trial. 
- Influence the results of the trial. 
- Influence the subject’s ability to complete the trial. 
*The abnormal finding must be clinically significant and observed during the screening 
period. Examples include but are not limited to abnormal findings in physical 
examination, vital signs, ECG, hematology (e.g. hemoglobin <100 g/L, neutrophils <1.5 x 
109/L, thrombocytes <75 x 109/L), biochemistry (e.g. serum creatinine >1.5 times the 
ULN, bilirubin >1.5 times the ULN; subjects with a history of Gilbert’s syndrome are 
eligible for this trial provided direct bilirubin is < the ULN), or urinalysis. 
Exclusion criterion #30 
Subjects who are legally institutionalized or legally protected (e.g. those under 
guardianship, curatorship, safeguard of justice) or other subjects incapable of giving 
informed consent according to the law of his/her residing country. 
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Section 6.2 Administration of IMP 
At Weeks 0, 1, 2, 3, and 4, subjects will be monitored for potential immediate drug 
reactions for a minimum of 2 hours after IMP administration. Vital signs will be taken 
immediately (within 5 minutes) after last IMP administration, as well as after 30 minutes (± 
5 minutes), after 1 hour (± 5 minutes), and after 2 hours (± 5 minutes), or until stable, 
whichever is later. From Week 5 onwards, subjects will be monitored after IMP 
administration for potential immediate drug reactions for a minimum of 20 minutes 
with vital signs assessed within 5 minutes after last IMP administration as well as after 
20 minutes (± 5 minutes), or until stable, whichever is later. Vital signs will be 
documented in the eCRF. 
Section 7.2.1 Reasons for permanent discontinuation of IMP 
• Positive HBV-DNA test (i.e. HBV-DNA is detected) at Week 12 (see exclusion 
criterion no. 8). 
• Positive HCV-RNA test (i.e. HCV-RNA is detected) at Week 12 (see exclusion 
criterion no. 8). 
Section 8.4.1 Vital signs 
At Weeks 0, 1, 2, 3, and 4, subjects will be monitored after IMP administration for 
immediate drug reactions for a minimum of 2 hours with vital signs taken immediately 
(within 5 minutes) after last IMP administration, after 30 minutes (± 5 minutes), after 
1 hour ± 5 minutes), and after 2 hours ± 5 minutes), or until stable, whichever is later. From 
Week 5 onwards, subjects will be monitored after IMP administration for potential 
immediate drug reactions for a minimum of 20 minutes with vital signs assessed 
within 5 minutes after last IMP administration as well as after 20 minutes ± 
5 minutes), or until stable, whichever is later. 
Section 8.4.5.2 Investigator evaluation of laboratory samples 
If the urine pregnancy test is positive but not confirmed by the repeated serum pregnancy 
test, the subject may continue IMP treatment, but the LEO medical expert should be 
consulted. 
 
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12.5.1.1 
Schedule of activities specific for EU countries 
Panel 18: Schedule of trial activities for EU countries 
 
 
 
 
Early 
term, 
if 
app.b),
c),d)  
 
Protocol 
section 
 
Screeninga) 
Treatment period 
Follow-up 
Uns. 
visit
e) 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13/ 
EoTb) 
14 
15 
16 
17b),c)  
 
 
 
Week 
-4 
-1 
0 
1 
2 
3 
4 
6 
8 
10 
12 
14 
16b) 
20 
24 
28 
32 
 
 
 
Day 
-28 
-7 
1 
8 
15 
22 
29 
43 
57 
71 
85 
99 
113 
14
1 
16
9 
197 
225 
 
 
 
Visit window 
(days)f) 
NA 
-3 
NA 
±1 
±1 
±1 
±1 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
 
 
 
Administrative and baseline procedures 
Informed consentg) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
App 1 
(12.1.3) 
Subject eligibility 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.2 and 
5.3 
Demographics  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.2.1 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.2.2 
Body measurement 
(height)  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.2.3 
Serum pregnancy 
testh) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.2.5 
C-SSRS 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.2.4 
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Early 
term, 
if 
app.b),
c),d)  
 
Protocol 
section 
 
Screeninga) 
Treatment period 
Follow-up 
Uns. 
visit
e) 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13/ 
EoTb) 
14 
15 
16 
17b),c)  
 
 
 
Week 
-4 
-1 
0 
1 
2 
3 
4 
6 
8 
10 
12 
14 
16b) 
20 
24 
28 
32 
 
 
 
Day 
-28 
-7 
1 
8 
15 
22 
29 
43 
57 
71 
85 
99 
113 
14
1 
16
9 
197 
225 
 
 
 
Visit window 
(days)f) 
NA 
-3 
NA 
±1 
±1 
±1 
±1 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
 
 
 
Treatments and randomization 
Randomization 
 
 
Xk) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.3 
IMP 
administrationo) and 
compliance 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
(X) 
6.2 and 
6.8.3 
Background 
treatment 
(moisturizer)i) 
<================================================================================> 
 
 
6.4 
Concomitant 
medicationj) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(X) 
6.6 
Concurrent 
proceduresj) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(X) 
6.6 
Assessments of efficacy: Investigator assessments 
EASI 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(X) 
8.3.1 
SCORAD 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(X) 
8.3.2 
vIGA-AD 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(X) 
8.3.3 
Assessments of efficacy: Subject assessments 
eDiary hand-
out/training 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Early 
term, 
if 
app.b),
c),d)  
 
Protocol 
section 
 
Screeninga) 
Treatment period 
Follow-up 
Uns. 
visit
e) 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13/ 
EoTb) 
14 
15 
16 
17b),c)  
 
 
 
Week 
-4 
-1 
0 
1 
2 
3 
4 
6 
8 
10 
12 
14 
16b) 
20 
24 
28 
32 
 
 
 
Day 
-28 
-7 
1 
8 
15 
22 
29 
43 
57 
71 
85 
99 
113 
14
1 
16
9 
197 
225 
 
 
 
Visit window 
(days)f) 
NA 
-3 
NA 
±1 
±1 
±1 
±1 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
 
 
 
Return of eDiary 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
eDiary completionl) 
 
<================================================================================> 
===> 
 
8.3.5.1 
DLQI 
 
 
X 
X 
 
 
X 
 
X 
 
X 
X 
X 
 
 
 
 
(X) 
(X) 
8.3.5.6 
POEM 
 
 
X 
X 
 
 
X 
 
X 
 
X 
X 
X 
 
 
 
 
(X) 
(X) 
8.3.5.7 
EQ-5D-5L  
 
 
X 
 
 
 
X 
 
X 
 
X 
X 
X 
 
 
 
 
(X) 
(X) 
8.3.5.8 
WPAI-SHP 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
(X) 
(X) 
8.3.5.9 
HADS 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
(X) 
(X) 
8.3.5.10 
PGI-Sm) 
 
 
X 
 
 
 
X 
 
X 
 
X 
X 
X 
 
 
 
 
(X) 
(X) 
8.3.5.11 
PGI-Cn) 
 
 
 
 
 
 
X 
 
X 
 
X 
X 
X 
 
 
 
 
(X) 
(X) 
8.3.5.12 
Assessments of safety 
Vital signso) 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
(X) 
(X) 
8.4.1 
Physical 
examination 
X 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
(X) 
(X) 
8.4.2 
Body measurement 
(weight) 
X 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
(X) 
(X) 
8.4.3 
ECG 
X 
 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
(X) 
(X) 
8.4.4 
AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
10 
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Early 
term, 
if 
app.b),
c),d)  
 
Protocol 
section 
 
Screeninga) 
Treatment period 
Follow-up 
Uns. 
visit
e) 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13/ 
EoTb) 
14 
15 
16 
17b),c)  
 
 
 
Week 
-4 
-1 
0 
1 
2 
3 
4 
6 
8 
10 
12 
14 
16b) 
20 
24 
28 
32 
 
 
 
Day 
-28 
-7 
1 
8 
15 
22 
29 
43 
57 
71 
85 
99 
113 
14
1 
16
9 
197 
225 
 
 
 
Visit window 
(days)f) 
NA 
-3 
NA 
±1 
±1 
±1 
±1 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
 
 
 
Laboratory tests 
Hepatitis B and C, 
HIV 
X 
 
 
 
 
 
 
 
 
 
Xp) 
 
 
 
Xp) 
 
 
 
 
8.2.5 
Tuberculosis test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.2.5 
Chemistry and 
hematology (central 
laboratory)   
X 
 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
 
 
X 
(X) 
(X) 
8.4.5 
IgE 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
X 
 
 
X 
(X) 
(X) 
8.4.5 
Urinalysis (urine 
dipstick) 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
X 
 
 
X 
(X) 
(X) 
8.4.5 
Urine pregnancy 
test 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
(X) 
(X) 
8.4.5 
ADA 
 
 
X 
 
X 
 
 
 
 
 
 
 
X 
X 
 
 
X 
(X) 
(X) 
8.4.6 
Other assessments: Pharmacokinetics 
Blood sample 
(LEO 138559 serum 
concentration)q) 
 
 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
 
X 
(X) 
(X) 
8.5 
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Early 
term, 
if 
app.b),
c),d)  
 
Protocol 
section 
 
Screeninga) 
Treatment period 
Follow-up 
Uns. 
visit
e) 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13/ 
EoTb) 
14 
15 
16 
17b),c)  
 
 
 
Week 
-4 
-1 
0 
1 
2 
3 
4 
6 
8 
10 
12 
14 
16b) 
20 
24 
28 
32 
 
 
 
Day 
-28 
-7 
1 
8 
15 
22 
29 
43 
57 
71 
85 
99 
113 
14
1 
16
9 
197 
225 
 
 
 
Visit window 
(days)f) 
NA 
-3 
NA 
±1 
±1 
±1 
±1 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
 
 
 
Other assessments: Pharmacodynamics 
Blood sample  
(biomarkers) 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
 
(X) 
(X) 
8.6 
Skin swabs 
(Staphylococcus 
aureus abundance) 
and microbiome 
profiling 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
(X) 
(X) 
8.6 
Skin tape strips 
(molecular profile)r) 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
(X) 
(X) 
8.6 
Skin biopsies 
(biomarker 
expression)s) 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
8.6 
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Early 
term, 
if 
app.b),
c),d)  
 
Protocol 
section 
 
Screeninga) 
Treatment period 
Follow-up 
Uns. 
visit
e) 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13/ 
EoTb) 
14 
15 
16 
17b),c)  
 
 
 
Week 
-4 
-1 
0 
1 
2 
3 
4 
6 
8 
10 
12 
14 
16b) 
20 
24 
28 
32 
 
 
 
Day 
-28 
-7 
1 
8 
15 
22 
29 
43 
57 
71 
85 
99 
113 
14
1 
16
9 
197 
225 
 
 
 
Visit window 
(days)f) 
NA 
-3 
NA 
±1 
±1 
±1 
±1 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
 
 
 
Other assessments: Photography 
Photographyt) 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
(X) 
(X) 
8.7.1 
Other assessments: Qualitative interviews in DE and PLu) 
Scheduling 
interview 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
8.7.2 
Clinigma to conduct 
trial interviews 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
8.7.2 
End of treatment/trial 
End of treatmentv) 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
(X) 
8.8 
End of trialw) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Xx) 
(X) 
8.8 
a) The screening period has a maximum duration of 4 weeks, with 2 planned visits. Visit 2 can be conducted by phone or on site. 
b) Subjects who permanently discontinue IMP for any reason will be asked to attend an early termination visit as soon as possible after discontinuation of 
IMP. Subjects should be encouraged to attend all trial visits and be assessed for safety and efficacy according to the schedule of assessments. For subjects 
who no longer wish to attend all trial visits, the following visits should be prioritized: The primary endpoint visit (i.e. the Week 16 visit) and a final follow-
up visit 18 weeks after last administration of IMP (with assessments identical to those to be done at the regular Week 32 visit).  
c) Subjects who withdraw from the trial prior to Week 16 will be asked to attend an early termination visit as soon as possible after withdrawal (with 
assessments identical to those to be done at the regular Week 32 visit). 
d) Some assessments to be performed at early termination visits will be at the discretion of the investigator. These are marked with an (X) in the table. 
e) Assessments to be performed at unscheduled visits will be at the discretion of the investigator (marked with an (X) in the table). 
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f) 
If the date of a trial visit does not conform to the clinical trial protocol, subsequent visits should be planned to maintain the visit schedule relative to 
randomization/baseline. 
g) The ICF must be signed prior to performing any protocol-related procedures, including, but not limited to, screening evaluations and washout of prohibited 
medications. 
h) Only for women of childbearing potential (as defined in inclusion criterion no. 10). 
i) 
Subjects should continue using their current daily skin care moisturizing routine from screening throughout the trial (until Week 32), if approved by the 
investigator, who will otherwise make an alternative suggestion. 
j) 
Any medication, vaccine, or procedure received/performed from 3 months (12 months for medications related to AD) prior to screening through end of 
trial must be recorded. 
k) In order to ensure a sufficient number of subjects naive for biologics and systemic JAK inhibitors used for their AD, there will be a capping at 50% of 
subjects who received prior treatment with such therapies. 
l) 
Nocturnal 
, Difficulty 
, and Frequency of 
 During the Night (to be completed in the morning), and ADSD (to be 
completed in the evening) will be initiated at least 7 days prior to baseline (Day 1) and will be completed in the eDiary daily. After Week 16, only ADSD 
will be completed. Subjects who discontinue IMP, but remain in the trial, will continue completing the eDiary until the Week 16 visit. 
m) PGI-S includes: 
, ADSD, Nocturnal 
, Difficulty 
, and Frequency of 
 During the Night. 
n) PGI-C includes: 
, ADSD, Nocturnal 
, Difficulty 
, and Frequency of 
 During the Night. 
o) Vital signs must be assessed prior to IMP administration. In addition, at Weeks 0, 1, 2, 3, and 4, subjects will be monitored after IMP administration for 
potential immediate drug reactions for a minimum of 2 hours with vital signs taken immediately (within 5 minutes) after last IMP administration as well as 
after 30 minutes (± 5 minutes), after 1 hour (± 5 minutes), and after 2 hours (± 5 minutes), or until stable, whichever is later. From Week 5 onwards, 
subjects will be monitored after IMP administration for potential immediate drug reactions for a minimum of 20 minutes with vital signs assessed within 
5 minutes after last IMP administration as well as after 20 minutes (± 5 minutes), or until stable, whichever is later. 
p) For subjects who at screening have a negative HBV-DNA reflex test (i.e. HBV-DNA is not detected), and negative HBsAg, negative anti-HBc, positive 
anti-HBs and without documentation of prior HBV vaccination or negative HBsAg and positive anti-HBc, repeat HBV-DNA will be done at 
Weeks 12 and 24. For subjects who at screening have positive anti-HCV but negative HCV-RNA (i.e. HCV-RNA is not detected), repeat HCV-RNA will be 
done at Weeks 12 and 24. 
q) Samples to be collected pre-dose. 
r) 
Skin tape strips will be collected at selected trial sites. 
s) 
Skin biopsies will be collected at selected trial sites. It is voluntary for subjects at these sites to have skin biopsies collected, and if done, they will need to 
have provided informed consent to this component. Paired lesional and non-lesional biopsies will be collected at baseline. At the post-baseline visit, 
1 biopsy will be collected from the original lesion; no skin biopsy will be collected from non-lesional skin at the post-baseline visit. 
t) 
Photography will be performed at selected trial sites. It is voluntary for subjects at these sites to have photographs taken, and if done, they will need to 
have provided informed consent to this component. 
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u) Interviews will be conducted at selected trial sites. The interview will be scheduled to occur as soon as possible and within 14 days after Week 14 
(Visit 12). 
v) An end-of-treatment form must be completed once in the eCRF for all subjects exposed to IMP either at Week 16 or early termination.  
w) An end-of-trial form must be completed in the eCRF for all subjects randomized and/or exposed to IMP. 
x) Only applicable to subjects who withdraw from the trial prior to Week 16. 
Abbreviations: AD = atopic dermatitis; ADA = anti-drug antibodies; ADSD = Atopic Dermatitis Symptom Diary; AE = adverse event; anti-HCV = hepatitis C 
virus antibody; app = applicable; C-SSRS = Columbia-Suicide Severity Rating Scale; DE = Germany; DLQI = Dermatology Life Quality Index; DNA = 
deoxyribonucleic acid; EASI = Eczema Area and Severity Index; ECG = electrocardiogram; eCRF = electronic case report form; eDiary = electronic diary; 
EoT = end-of-treatment; EQ-5D-5L = EuroQoL 5-Dimension Health Questionnaire 5 Level; HADS = Hospital Anxiety and Depression Scale; HBsAg = 
hepatitis B surface antigen; HIV = human immunodeficiency virus; ICF = informed consent form; IgE = immunoglobulin E; IMP = investigational medicinal 
product; JAK = janus kinase; LLQ = lower level of quantification; NA = not applicable; PGI-C = Patient Global Impression of Change; PGI-S =  Patient Global 
Impression of Severity; PL = Poland; POEM = Patient-Oriented Eczema Measure; RNA = ribonucleic acid; SCORAD = SCORing Atopic Dermatitis; term = 
termination; Uns = unscheduled; vIGA-AD = validated Investigator’s Global Assessment for atopic dermatitis; WPAI-SHP = Work Productivity and Activity 
Impairment: Specific Health Problem.
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12.5.1.2 
Eligibility criteria specific for EU countries 
INCLUSION CRITERIA 
Subjects are eligible to be included in the trial only if all of the following criteria apply: 
Informed consent 
1. Signed and dated informed consent as described in Appendix 1 (Section 12.1.3) has been 
obtained prior to any protocol-related procedures. 
Age 
2. 18–75 years old (both included) at screening (Visit 1).  
Compliance 
3. Willingness to comply with the clinical trial protocol.  
Type of subject and disease characteristics 
4. At screening, diagnosis of AD as defined by the Hanifin and Rajka (1980) criteria for AD 
((62) and Appendix 3 [Section 12.3]). 
- 
History of AD for ≥1 year. 
5. Subjects who have a recent history (within 12 months before screening) with documented 
inadequate response to treatment with TCS (±TCI as appropriate) or for whom these 
topical AD treatments are medically inadvisable (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 IGA 0=clear to 2=mild) despite treatment with a 
daily regimen of TCS of medium to higher potency (EU class II-IV, JP ≥ Medium, US 
class I-V) (±TCI as appropriate), applied for at least 28 days or for the maximum 
duration recommended by the product prescribing information (e.g. 14 days for super 
potent TCS), whichever is shorter. 
- 
Subjects with documented systemic treatment or phototherapy for AD in the past 
1 year are considered as inadequate responders to TCS treatment and are potentially 
eligible for trial inclusion after appropriate washout. 
*Important side effects or safety risks are those that outweigh the potential treatment 
benefits and include intolerance to treatment, hypersensitivity reactions, significant skin 
atrophy, and systemic effects, as assessed by the investigator, or by the subject’s treating 
physician. 
6. EASI score ≥12 at screening and ≥16 at baseline. 
7. vIGA-AD score ≥3 at screening and baseline. 
8. BSA of AD involvement ≥10% at screening and baseline. 
9. ADSD Worst 
 score (weekly average) ≥4 at baseline. The baseline weekly average 
will be calculated from daily assessments of 
 severity during the 7 days immediately 
preceding the baseline visit (Day -7 to Day -1). A minimum of 4 
 scores out of the 
7 days is required to calculate the baseline average score. 
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Contraceptive/barrier requirements 
10. A woman of childbearing potential* must use a highly effective** form of birth control 
throughout the trial and for at least 18 weeks after last administration of IMP. 
* A woman of childbearing potential is defined as a female subject aged ≥12 years or a 
younger girl who, at the discretion of the investigator, is deemed to be of reproductive 
potential. A woman is defined as not being of childbearing potential if she is 
postmenopausal (at least 12 months with no menses prior to screening without an 
alternative medical cause), or surgically sterile (hysterectomy, bilateral salpingectomy, 
or bilateral oophorectomy). 
**A highly effective method of birth control is defined as one which results in a low 
failure rate (less than 1% per year) such as bilateral tubal occlusion, IUD, IUS, 
combined (oestrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation (oral, intravaginal, transdermal), progestogen-only 
hormonal contraception associated with inhibition of ovulation (oral, injectable, 
implantable), sexual abstinence (when this is in line with the preferred and usual life 
style of the subject and not just being without a current partner), same-sex partner, or 
vasectomized partner (given that the subject is monogamous). 
EXCLUSION CRITERIA 
Subjects are excluded from the trial if any of the following criteria apply: 
Medical conditions 
1. Major* surgery within 8 weeks prior to screening, or planned inpatient surgery or 
hospitalization during the trial period (*at the discretion of the investigator). 
2. Active dermatologic condition that could confound the diagnosis of AD or interfere with 
assessment of the treatment (e.g. scabies, contact dermatitis, rosacea, urticaria, or 
psoriasis). 
3. History of cancer, with the following exceptions: 
- 
Subjects who have had basal cell carcinoma, localized squamous cell carcinoma of the 
skin or in situ carcinoma of the cervix are eligible provided that the subject is in 
remission and curative therapy was completed at least 12 months prior to screening. 
- 
Subjects who have had other malignancies are eligible provided that the subject is in 
remission and curative therapy was completed at least 5 years prior to screening. 
4. History of or current immunodeficiency syndrome. 
5. History of anaphylaxis following any biologic therapy. 
6. History of clinically significant infection within 4 weeks prior to baseline which, in the 
opinion of the investigator, may compromise the safety of the subject in the trial, interfere 
with evaluation of the IMP, or reduce the subject’s ability to participate in the trial. 
Clinically significant infections are defined as: 
- 
a systemic infection. 
- 
a serious skin infection requiring parenteral (IV or intramuscular) antibiotics, antiviral, 
or antifungal medication. 
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NOTE: Subject may be rescreened (once) after infection resolves. However, rescreening 
will require approval by the sponsor’s medical expert (see Section 5.4). 
7. Non-serious skin infection within 7 days prior to baseline. NOTE: Subject may be 
rescreened (once) after infection resolves. However, rescreening will require approval by 
the sponsor’s medical expert (see Section 5.4). 
8. Positive HBsAg or positive anti-HCV AND positive HCV-RNA at screening. 
- 
Subjects with a negative HBsAg and a positive anti-HBc or anti-HBs at screening will 
have reflex testing for HBV-DNA. Subjects who have a positive HBV-DNA test (i.e. 
HBV-DNA is detected) will be excluded. 
- 
For subjects who at screening have a negative HBV-DNA reflex test (i.e. HBV-DNA is 
not detected), and 
Negative HBsAg, negative anti-HBc, positive anti-HBs and without 
documentation of prior HBV vaccination  
or  
Negative HBsAg and positive anti-HBc 
repeat HBV-DNA testing must be done at Weeks 12 and 24. If HBV-DNA is positive 
(i.e. HBV-DNA is detected) at Week 12, subjects must permanently discontinue IMP.  
- 
Subjects who at screening have a negative HBV-DNA reflex test (i.e. HBV-DNA is not 
detected), negative HBsAg, negative anti-HBc, positive anti-HBs and provide 
documentation of prior HBV vaccination will not require regular monitoring by 
HBV-DNA repeat testing in the trial. 
- 
For subjects who at screening have positive anti-HCV but negative HCV-RNA (i.e. 
HCV-RNA is not detected), repeat HCV-RNA will be done at Weeks 12 and 24. If 
HCV-RNA is positive (i.e. HCV-RNA is detected) at Week 12, subjects must 
permanently discontinue IMP. 
9. History of HIV infection or positive HIV serology at screening. 
10. Evidence of active or latent tuberculosis according to local standard of care for patients 
requiring initiation of a biologic treatment. 
- 
A tuberculosis test can be performed at the central or local laboratory. Subjects with a 
positive or indeterminate test at screening will be excluded. NOTE: Subject may be 
retested (once) if the initial test was indeterminate. 
11. ALT or AST level ≥2.0 times the ULN at screening. 
12. Uncontrolled/untreated clinically significant depression or history of attempted suicide or 
is at significant risk of suicide (either in the opinion of the investigator or defined as a 
“yes” to suicidal ideation questions no. 4 or 5 or answering “yes” to suicidal behavior on 
the C-SSRS Screening version). 
13. Known or suspected hypersensitivity to any component(s) of the IMP. 
14. Any disorder* at screening and/or baseline, which is not stable in the opinion of the 
investigator, and could: 
- 
Affect the safety of the subject throughout the trial. 
- 
Influence the results of the trial. 
- 
Impede the subject’s ability to complete the trial. 
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15. Any significant abnormal finding* at screening and/or baseline which may in the opinion 
of the investigator:  
- 
Put the subject at risk because of their participation in the trial. 
- 
Influence the results of the trial. 
- 
Influence the subject’s ability to complete the trial. 
*The abnormal finding must be clinically significant and observed during the screening 
period. Examples include but are not limited to abnormal findings in physical 
examination, vital signs, ECG, hematology (e.g. hemoglobin <100 g/L, neutrophils <1.5 x 
109/L, thrombocytes <75 x 109/L), biochemistry (e.g. serum creatinine >1.5 times the 
ULN, bilirubin >1.5 times the ULN; subjects with a history of Gilbert’s syndrome are 
eligible for this trial provided direct bilirubin is < the ULN), or urinalysis. 
16. Current or recent chronic alcohol or drug abuse, or any other condition associated with 
poor compliance as judged by the investigator. 
17. Women who are pregnant or breastfeeding. 
Prior/concomitant therapy 
18. Previous treatment with LEO 138559. 
19. Previous exposure to fezakinumab (anti-IL-22 Ab). 
20. Systemic treatment with immunosuppressive drugs (e.g. methotrexate, cyclosporine, 
azathioprine), immunomodulating drugs, retinoids (e.g. alitretinoin), corticosteroids 
(steroid eyedrops and inhaled or intranasal steroids are allowed), or JAK inhibitors within 
28 days or 5 half-lives prior to baseline, whichever is longer. 
21. Use of tanning beds or phototherapy (NBUVB, UVB, UVA1, PUVA), within 4 weeks 
prior to baseline. 
22. Receipt of blood products within 28 days prior to screening. 
23. Treatment with: 
- 
 Any marketed or investigational biologic agents within 3 months or 5 half-lives, 
whichever is longer, prior to baseline. 
- 
Any cell-depleting agents including but not limited to rituximab: within 6 months 
prior to baseline, or until lymphocyte count returns to normal, whichever is longer. 
24. Treatment with TCS, TCI, topical PDE-4 inhibitors, topical JAK inhibitors, or other 
medicated topical treatments within 7 days prior to baseline. NOTE: Subject may be 
rescreened (once) if failed for this criterion. However, rescreening will require approval 
by the sponsor’s medical expert (see Section 5.4). 
25. Receipt of live attenuated vaccines 30 days prior to baseline or longer if recommended so 
by local guidelines. 
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26. Treatment with any non-marketed drug substance (that is, an agent which has not yet been 
made available for clinical use following registration) within the last 4 weeks or 
5 half-lives prior to randomization, whichever is longer. 
Prior/concurrent clinical trial experience 
27. Current participation in any other interventional clinical trial. 
28. Previously randomized in this clinical trial. 
Other exclusion criteria 
29. Employees of the trial site, or any other individuals directly involved with the planning or 
conduct of the trial, or immediate family members of such individuals. 
30. Subjects who are legally institutionalized or legally protected (e.g. those under 
guardianship, curatorship, safeguard of justice) or other subjects incapable of giving 
informed consent according to the law of his/her residing country. 
 
 
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12.5.2 
Specific requirements for Czech Republic 
This section describes requirements and procedures that are specific only for CZ. The 
text from the protocol is presented in normal font. The country-specific requirements or 
procedures are presented below in bold. 
Section 8.1 Overview 
Subjects participating in the trial will be under careful supervision of a qualified principal 
investigator who must be a dermatologist or an allergist. Investigators must be experienced 
in treating AD and have documented experience and/or training in use of the assessments 
required by the protocol and must be either a physician, a certified physician’s assistant, or 
an advanced registered nurse practitioner. 
In CZ, according to Act no. 378/2007 Coll., only a physician can be an investigator. 
 
 
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12.5.3 
Specific requirements for France 
This section describes requirements and procedures that are specific only for FR. The 
text from the protocol is presented in normal font. The country-specific requirements or 
procedures are presented below in bold. 
Section 5.2 Inclusion criteria 
In FR, the following inclusion criterion is to be added: 
• Subject affiliated with or a beneficiary of a social security scheme. 
Section 8.2.1 Demographics 
• Ethnic origin (self-reported by the subject): ‘Hispanic or Latino’, ‘not Hispanic or 
Latino’, not reported (not provided or available). 
• Race (self-reported by the subject, more than 1 race may be reported): American Indian 
or Alaska native, Asian Japanese, Asian Chinese, Asian other, Black or African 
American, native Hawaiian or other Pacific Islander, White, not reported (not provided 
or available). 
In FR, race and ethnicity data will not be collected from the subjects.  
 
 
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12.5.4 
Specific requirements for Japan 
This section describes requirements and procedures that are specific only for JP. The text 
from the protocol is presented in normal font. The country-specific requirements or 
procedures are presented below in bold. 
Section 5.2 Inclusion criteria 
Inclusion criterion #2 
18–75 years old (both included) at screening (Visit 1).  
In JP, inclusion criterion #2 will be: Japanese adults, 18–75 years old (both included) at 
screening (Visit 1). 
Inclusion criterion #10 
A woman of childbearing potential* must use a highly effective** form of birth control 
throughout the trial and for at least 18 weeks after last administration of IMP. 
* A woman of childbearing potential is defined as a female subject aged ≥12 years or a 
younger girl who, at the discretion of the investigator, is deemed to be of reproductive 
potential. A woman is defined as not being of childbearing potential if she is 
postmenopausal (at least 12 months with no menses prior to screening without an 
alternative medical cause), or surgically sterile (hysterectomy, bilateral salpingectomy, or 
bilateral oophorectomy). 
**A highly effective method of birth control is defined as one which results in a low failure 
rate (less than 1% per year) such as bilateral tubal occlusion, IUD, IUS, combined 
(oestrogen- and progestogen-containing) hormonal contraception associated with inhibition 
of ovulation (oral, intravaginal, transdermal), progestogen-only hormonal contraception 
associated with inhibition of ovulation (oral, injectable, implantable), sexual abstinence 
(when this is in line with the preferred and usual life style of the subject and not just being 
without a current partner), same-sex partner, or vasectomized partner (given that the subject 
is monogamous). 
In JP, ** will be: A highly effective method of birth control is defined as one which 
results in a low failure rate (less than 1% per year) such as bilateral tubal occlusion, 
IUD, IUS, combined (oestrogen- and progestogen-containing) hormonal contraception 
associated with inhibition of ovulation (oral), sexual abstinence (when this is in line 
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with the preferred and usual lifestyle of the subject and not just being without a 
current partner), same-sex partner, or vasectomized partner (given that the subject is 
monogamous). 
Section 5.3 Exclusion criteria 
Exclusion criterion #8 
Positive HBsAg or positive anti-HCV AND positive HCV-RNA at screening. 
- Subjects with a negative HBsAg and a positive anti-HBc or anti-HBs at screening will 
have reflex testing for HBV-DNA. Subjects who have HBV-DNA above LLQ will be 
excluded. 
In JP, in addition to the above, repeat HBV-DNA testing must be done at trial Weeks 
8, 16 and 32 for Japanese subjects who at screening have a negative HBV-DNA reflex 
test (i.e. below LLQ), and  
- Negative HBsAg, negative anti-HBc, positive anti-HBs and without documentation of 
prior HBV vaccination 
or 
- Negative HBsAg and positive anti-HBc. 
If HBV-DNA is above LLQ at Week 8 subjects must discontinue IMP. 
Japanese subjects who at screening have a negative HBV-DNA reflex test (i.e. below 
LLQ), negative HBsAg, negative anti-HBc, positive anti-HBs and provide 
documentation of prior HBV vaccination will not require regular monitoring by 
HBV-DNA repeat testing in the trial. 
Section 6.8.2 Storage and accountability of trial products 
The investigator or authorized site staff is responsible for IMP accountability, and record 
maintenance (e.g. receipt, and final disposition records). 
In JP, the Head of Institute will be responsible for the IMPs at the trial site. 
Section 6.10 Reporting product complaints 
Global Safety, LEO Pharma contact information for reporting product complaints: 
E-mail address: drug.safety@leo-pharma.com. 
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In JP, product complaints must be reported to Pharmacovigilance, LEO Pharma K.K. 
using the contact information below: 
E-mail address: clinical_trial_jp@leo-pharma.com. 
Fax number: +81 3 4243 3311. 
Note: Reports sent to the above email address and fax number will be manually 
forwarded to Global Safety, LEO Pharma. 
Section 8.1 Overview 
Subjects participating in the trial will be under careful supervision of a qualified principal 
investigator who must be a dermatologist or an allergist. Investigators must be experienced 
in treating AD and have documented experience and/or training in use of the assessments 
required by the protocol and must be either a physician, a certified physician’s assistant, or 
an advanced registered nurse practitioner. 
In JP, principal investigators must be board-certified dermatologists. 
Section 10.5 Pregnancy 
The completed pregnancy forms must be faxed or scanned and e-mailed to Global Safety at 
LEO Pharma. Contact details are given in Section 12.2.5. 
In JP, any pregnancy must be reported to Pharmacovigilance, LEO Pharma K.K. 
using the contact information below: 
E-mail address: clinical_trial_jp@leo-pharma.com. 
Fax number: +81 3 4243 3311. 
Note: Reports sent to the above email address and fax number will be manually 
forwarded to Global Safety, LEO Pharma. 
Section 12.2.5, Appendix 1 Investigator reporting responsibilities 
Contact details for Global Safety at LEO Pharma as stated in Section 12.2.5 are as follows: 
Global Safety at LEO Pharma 
E-mail address: drug.safety@leo-pharma.com. 
Fax number: +45 6910 2468. 
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In JP, SAEs must be reported to Pharmacovigilance, LEO Pharma K.K. using the 
contact information below: 
E-mail address: clinical_trial_jp@leo-pharma.com. 
Fax number: +81 3 4243 3311. 
Note: Reports sent to the above email address and fax number will be manually 
forwarded to Global Safety, LEO Pharma. 
Section 12.2.5, Appendix 1 LEO Pharma reporting responsibilities 
Global Safety at LEO Pharma will notify the regulatory authorities and concerned 
investigators of SAEs according to the current applicable legislation for the concerned 
countries. 
In JP, Pharmacovigilance, LEO Pharma K.K. will notify the regulatory authorities 
and concerned investigators of SAEs. 
 
 
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12.5.5 
Specific requirements for the United Kingdom 
This section describes requirements and procedures that are specific only for the UK. 
The text from the protocol is presented in normal font. The country-specific requirements or 
procedures are presented below in bold. 
Section 6.8.4 Trial product destruction 
In the UK, the following clarification is to be added: 
All IMP (i.e. used, partly used, and unused vials) must be returned to the CMO, where it 
will be destroyed according to approved procedures and/or local requirements. 
Alternatively, if due to local requirements used vials cannot be returned to the CMO, 
used vials can be destroyed at the trial site, provided the trial site has procedures in 
place for such IMP destruction. 
 
 
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12.6 Appendix 6: Contact list 
Contact details for the clinical project manager, national lead CRA, and sponsor’s medical 
expert are provided to the trial sites as a separate contact list. 
Sponsor 
ULEO Pharma A/SU (referred to as ‘LEO Pharma’ or ‘the sponsor’ in this clinical trial protocol) 
is the sponsor of the clinical trial: 
LEO Pharma A/S  
Industriparken 55 
DK-2750 Ballerup 
Denmark 
Coordinating investigator 
Stephan Weidinger, MD. 
Department of Dermatology and Allergy. 
University Hospital Schleswig-Holstein. 
Arnold-Heller-Str. 3. 
24105 Kiel, Germany. 
 
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12.7 Appendix 7: Pandemic contingency plan (e.g. COVID-19) 
Without compromising subject and site staff safety as well as trial integrity, it is expected that 
all efforts will be made to ensure subject attendance to the planned trial visits and thereby 
ensure the conduct of important safety and efficacy assessments. 
As protective/preventive measures to be taken in the context of the COVID-19 pandemic (or 
any pandemic) can differ across countries and regions, no general instructions from the 
sponsor can be provided and the investigators will be trusted to take appropriate action. This 
includes but is not limited to complying with recommendations and regulations issued by 
their local health authorities, the increase of protective safety and hygiene measures (e.g. 
wearing mask, disinfecting hands, social distancing) for both subject and site staff, and the 
frequent monitoring of the subject’s health. 
To minimize subject exposure in public transportation and public areas, LEO Pharma will 
reimburse travel cost of subjects using taxis or their own vehicle (including parking fees) to 
commute to and from the trial site. 
If on-site visits are not possible due to preventive measures issued by local health 
authority(ies) or site obligations, the affected site(s) will postpone screening and 
randomization of subjects until on-site visits can be conducted again. 
Safety monitoring is an obligation of LEO Pharma and in case the subject, due to local 
restrictions, is prevented from coming to the trial site, the investigator can convert on-site 
visits into phone visits for the primary purpose of safety monitoring. At a phone visit, the 
following data may be collected:  
• AEs. 
• Concomitant medication and concurrent procedures. 
• POEM, DLQI, EQ-5D-5L, WPAI-SHP, HADS, PGI-S, and PGI-I collected on the 
web-based solution by remote transfer to the vendor. 
The phone visits must not be used for conducting the investigator’s assessments of efficacy. 
Reporting in eCRF 
It will be recorded in the eCRF if a visit was conducted remotely (phone visit) and the reason 
why it was done remotely (due to COVID-19 or for other reasons). If the visit was not 
conducted at all, the reason will also be recorded in the eCRF. 
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12.8 Appendix 8: Protocol amendment history 
The Protocol amendment summary of changes for the current amendment is located directly 
before the table of contents. 
Amendment 1 (05-Feb-2024, non-substantial, local UK) 
Overall rationale for the amendment 
The main purpose of this protocol amendment was to clarify aspects related to destruction of 
IMP specific for the UK. Changes to the protocol are summarized in the table below. 
Section no. and 
title 
Description of change 
Brief rationale 
Section 12.5.5 
Specific 
requirements for 
the United 
Kingdom 
In the UK, Section 6.8.4 has been updated to allow destruction 
of IMP at sites. 
To clarify 
procedures for IMP 
destruction. 
Section 12.8 
Appendix 8: 
Protocol 
amendment 
history 
Section updated. Amendment 1 (13-Nov-2023, non-substantial, 
global) has been moved from Protocol amendment summary of 
changes to Section 12.8. 
Administrative 
change. 
Abbreviations: please refer to the list of abbreviations. 
Amendment 1 (13-Nov-2023, non-substantial, global) 
This amendment is considered to be non-substantial based on the criteria set forth in 
Article 2 (13) of Regulation 536/2014 of the European Parliament and the Council of the 
European Union or subsequent regulation because it neither is likely to have a substantial 
impact on the safety or rights of the subjects or on the reliability and robustness of the data 
generated in the clinical trial. 
Overall rationale for the amendment 
The main purpose of this protocol amendment was to introduce qualitative interviews that 
will be performed as other assessments at selected trial sites. This global protocol amendment 
also includes some changes implemented in the local (European Union and Japan) protocol 
amendments and will serve as global consolidated protocol for the trial going forward. 
Changes to the protocol are summarized in the table below (text added to the protocol is 
written in bold and deleted text has a line through it). 
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Section no. and 
title 
Description of change 
Brief rationale 
Section 1.3 
Schedule of 
activities 
Panel 2: Schedule of trial activities, footnote o) related to vital 
signs was edited: Vital signs must be assessed prior to IMP 
administration. In addition, at Weeks 0, 1, 2, 3, and 4, subjects 
will be monitored after IMP administration for potential 
immediate drug reactions for a minimum of 2 hours with vital 
signs taken immediately (within 5 minutes) after last IMP 
administration as well as after 30 minutes (± 5 minutes), after 
1 hour (± 5 minutes), and after 2 hours (± 5 minutes), or until 
stable, whichever is later. 
To specify vital 
signs assessment 
procedure. 
Section 1.3 
Schedule of 
activities 
Panel 2: Schedule of trial activities 
Other assessments: Qualitative interviews in CA, UK and US 
were added with reference to Section 8.7.2 as: 
Scheduling interview at Week 10 (Visit 10) 
Clinigma to conduct trial interviews at Week 14 (Visit 12). 
To add qualitative 
interviews as other 
assessments. 
Panel 2: Schedule of trial activities, footnote t) related to 
scheduling and conduction of the interviews was added: 
Interviews will be conducted at selected trial sites. The 
interview will be scheduled to occur as soon as possible and 
within 14 days after Week 14 (Visit 12). 
To add qualitative 
interviews as other 
assessments. 
Section 5.3 
Exclusion criteria 
Exclusion criterion #7 
Non-serious skin infection within 7 days prior to baseline. 
NOTE: Subject may be rescreened (once) after infection 
resolves. However, rescreening will require approval by the 
sponsor’s medical expert (see Section 5.4). 
Updated due to 
authority request in 
the EU CTIS 
clinical trial 
application 
procedure. 
Exclusion criterion #10 
Evidence of active or latent tuberculosis according to local 
standard of care for patients requiring initiation of a biologic 
treatment.  
- A tuberculosis test can be performed at the central or local 
laboratory. Subjects with a positive or indeterminate test at 
screening will be excluded. NOTE: Subject may be retested 
(once) if the initial test was indeterminate. 
To clarify exclusion 
of subjects with 
indeterminate 
tuberculosis test. 
Exclusion criterion #12  
Uncontrolled/untreated clinically significant depression or 
history of attempted suicide or is at significant risk of suicide 
(either in the opinion of the investigator or defined as a “yes” to 
suicidal ideation questions no. 4 or 5 or answering “yes” to 
suicidal behavior on the C-SSRS Screening version). 
Updated due to 
authority request in 
the EU CTIS 
clinical trial 
application 
procedure. 
Exclusion criterion #25 
Receipt of live attenuated vaccines 30 days prior to baseline or 
longer if recommended so by local guidelines. 
Updated due to 
authority request in 
the EU CTIS 
clinical trial 
application 
procedure. 
Section 6.2 
Administration of 
IMP 
‘IMP will be administered by a qualified, unblinded HCP site 
staff as the active drug is visually distinct from placebo…’. 
To specify IMP 
administration 
procedure. 
Section 6.3.2 
Blinding 
‘IMP will be prepared, handled, and administered by a qualified, 
unblinded HCP site staff at the site who will not be involved in 
the management…’. 
To specify IMP 
administration 
procedure. 
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Section no. and 
title 
Description of change 
Brief rationale 
‘Should an issue arise with the IMP (e.g. damaged kit or syringe 
that has been assigned to a subject prior to administration, or any 
other unexpected event with the kit or syringe [e.g. a 
malfunction during IMP administration]), the unblinded HCP 
site staff at the site will contact the…’. 
Section 6.7 
Prohibited 
medications and 
procedures 
4. Use of UVA or UVB, PUVA, other phototherapy, or tanning 
beds, or prolonged sun exposure. 
Updated due to 
authority request in 
the EU CTIS 
clinical trial 
application 
procedure. 
Section 6.8.3 
Treatment 
compliance 
‘IMP injections will be performed by unblinded HCP site staff 
who will also keep…’. 
To specify IMP 
administration 
procedure. 
Section 7.2.2 
Reasons for 
temporary 
discontinuation of 
IMP 
In case an urgent situation requires immediate action, IMP 
dosing may be temporary discontinued if, at the investigator’s 
discretion, this is determined to be in the subject’s best interest. 
In such cases, sponsor’s medical expert should be informed as 
soon as possible. 
A decision to re-initiate IMP must always be discussed with 
and approved by the sponsor’s medical expert. 
Updated due to 
authority request in 
the EU CTIS 
clinical trial 
application 
procedure. 
Section 8.4.1 
Vital signs 
Vital signs (resting BP, pulse, and body temperature) must be 
assessed prior to IMP administration according to the 
schedule of trial activities (Section 1.3). 
To specify vital 
signs assessment 
procedure. 
Section 8.4.5.1 
Overview 
Panel 12: Clinical laboratory tests, footnote 3) related to hepatitis 
B, hepatitis C and HIV was edited: Conducted at screening only. 
Edited to align with 
EU and Japanese 
authority requests 
for additional 
assessments of 
hepatitis. 
Section 8.7.2 
Qualitative 
interviews 
(selected sites) 
Section added to describe the procedure for conducting 
qualitative interviews. 
To provide 
guidance for 
performing 
qualitative 
interviews. 
Section 12.2.4 
Recording and 
follow-up of AEs 
Text added to describe recording of potential AEs reported by 
the subjects during qualitative interviews. 
To provide 
guidance on 
handling of AEs 
reported during 
interviews. 
Section 12.5.1 
Specific 
requirements for 
all EU countries 
In CZ, DE, ES, FR, HU, PL and RO, Panel 2: Schedule of trial 
activities has been updated with regards to additional 
assessments of vital signs, hepatitis B, hepatitis C, and chemistry 
and hematology. 
Panel 18 Schedule of trial activities for EU countries was added. 
Updated due to 
authority request in 
the EU CTIS 
clinical trial 
application 
procedure. 
In CZ, DE, ES, FR, HU, PL and RO, Section 2.4 has been 
updated with regards to additional assessments of vital signs. 
Updated due to 
authority request in 
the EU CTIS 
clinical trial 
application 
procedure. 
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Section no. and 
title 
Description of change 
Brief rationale 
Section 12.5.1 
Specific 
requirements for 
all EU countries 
In CZ, DE, ES, FR, HU, PL and RO, exclusion criteria #8, #14, 
#15 and #30 (Section 5.3) have been updated. 
Section 12.5.1.2 Eligibility criteria specific for EU countries was 
added. 
Updated due to 
authority request in 
the EU CTIS 
clinical trial 
application 
procedure. 
In CZ, DE, ES, FR, HU, PL and RO, Section 6.2 has been 
updated with regards to additional assessments of vital signs. 
Updated due to 
authority request in 
the EU CTIS 
clinical trial 
application 
procedure. 
In CZ, DE, ES, FR, HU, PL and RO, Section 7.2.1 has been 
updated with regards to additional assessments of hepatitis B and 
hepatitis C. 
Updated due to 
authority request in 
the EU CTIS 
clinical trial 
application 
procedure. 
In CZ, DE, ES, FR, HU, PL and RO, Section 8.4.1 has been 
updated with regards to additional assessments of vital signs. 
Updated due to 
authority request in 
the EU CTIS 
clinical trial 
application 
procedure. 
In CZ, DE, ES, FR, HU, PL and RO, Section 8.4.5.2 has been 
updated with regards to pregnancy testing procedure. 
Updated due to 
authority request in 
the EU CTIS 
clinical trial 
application 
procedure. 
Section 12.5.2 
Specific 
requirements for 
Czech Republic 
In CZ, Section 8.1 has been updated in accordance with 
applicable local laws and regulations. 
Updated due to 
authority request in 
the EU CTIS 
clinical trial 
application 
procedure. 
Section 12.5.3 
Specific 
requirements for 
France 
In FR, Section 8.2.1 has been updated in accordance with 
applicable local laws and regulations. 
Updated due to 
authority request in 
the EU CTIS 
clinical trial 
application 
procedure. 
Section 12.5.4 
Specific 
requirements for 
Japan 
In JP, inclusion criterion #10 (Section 5.2) and exclusion 
criterion #8 (Section 5.3) have been updated. 
Updated due to 
Japanese authority 
request. 
Section 12.8 
Appendix 8: 
Protocol 
amendment 
history 
Section added. 
Classification of previous EU amendments with reference to 
Article 10(a) of Directive 2001/20/EC has been corrected to refer 
to Article 2 (13) of EU Clinical Trial Regulation 536/2014. 
To list all the 
country-specific 
amendments 
preceding this 
global amendment. 
Throughout 
document 
Wording ‘rescue medication’ changed to ‘rescue treatment’. 
For consistency. 
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Section no. and 
title 
Description of change 
Brief rationale 
Throughout 
document 
Minor editorial revisions including references to respective 
subsections of Section 12.5 for details on the country-specific 
requirements and procedures. 
Minor, have 
therefore not been 
summarized. 
Abbreviations: please refer to the list of abbreviations. 
Amendment 3 (05-Oct-2023, non-substantial, local Czech Republic, Germany, France, 
Hungary, Poland, Romania and Spain) 
This amendment is considered to be non-substantial based on the criteria set forth in 
Article 2 (13) of Regulation 536/2014 of the European Parliament and the Council of the 
European Union or subsequent regulation because it neither is likely to have a substantial 
impact on the safety or rights of the subjects or on the reliability and robustness of the data 
generated in the clinical trial. 
Overall rationale for the amendment 
The main purpose of this protocol amendment was to address the request from the regulatory 
authorities of the European Union countries included in this trial via the Clinical Trials 
Information System procedure after their review of the European Union protocol version 2.0. 
Changes to the protocol are summarized in the table below (text added to the protocol is 
written in bold). 
Section no. and 
title 
Description of change 
Brief rationale 
Section 5.3 
Exclusion criteria 
Exclusion criterion #7 
Non-serious skin infection within 7 days prior to baseline. 
NOTE: Subject may be rescreened (once) after infection 
resolves. However, rescreening will require approval by the 
sponsor’s medical expert (see Section 5.4). 
Added due to 
authority request. 
Section 5.3 
Exclusion criteria 
Exclusion criterion #12  
Uncontrolled/untreated clinically significant depression or 
history of attempted suicide or is at significant risk of suicide 
(either in the opinion of the investigator or defined as a “yes” to 
suicidal ideation questions no. 4 or 5 or answering “yes” to 
suicidal behavior on the C-SSRS Screening version). 
Added due to 
authority request. 
Section 12.8 
Appendix 8: 
Protocol 
amendment 
history 
This section has been updated. Amendment 2 has been moved 
from Protocol amendment summary of changes to Section 12.8. 
Administrative 
change. 
Throughout 
document 
Minor editorial revisions. 
Minor, have 
therefore not been 
summarized. 
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Amendment 2 (28-Sep-2023, non-substantial, local France) 
This amendment is considered to be non-substantial based on the criteria set forth in 
Article 2 (13) of Regulation 536/2014 of the European Parliament and the Council of the 
European Union or subsequent regulation because it neither is likely to have a substantial 
impact on the safety or rights of the subjects or on the reliability and robustness of the data 
generated in the clinical trial. 
Overall rationale for the amendment 
The main purpose of this protocol amendment was to address the request from the French 
Committees of Protection of Persons (Comités de Protection des Personnes, CPP) via the 
Clinical Trials Information System procedure. Changes to the protocol are summarized in the 
table below (text added to the protocol is written in bold). 
Section no. and 
title 
Description of change 
Brief rationale 
Section 5.4 
Screening and 
subjects excluded 
prior to 
randomization 
• 
Date of birth (day, month, and year; only month and year; or 
only year, as per local legislation), age, sex, ethnicity, race 
(for details on the country-specific requirements, see 
Section 12.5). 
Added as requested. 
Section 8.2.1 
Demographics 
• 
Ethnic origin (self-reported by the subject): ‘Hispanic or 
Latino’, ‘not Hispanic or Latino’, not reported (not provided 
or available). For details on the country-specific 
requirements, see Section 12.5. 
• 
Race (self-reported by the subject, more than 1 race may be 
reported): American Indian or Alaska native, Asian 
Japanese, Asian Chinese, Asian other, Black or African 
American, native Hawaiian or other Pacific Islander, White, 
not reported (not provided or available). For details on the 
country-specific requirements, see Section 12.5. 
Added as requested. 
Section 12.1.5 
Data protection 
This clinical trial protocol as well as all other information, data, 
and results relating to this clinical trial and/or to the IMP is 
confidential information of LEO Pharma and shall not be used 
by the investigator for purposes other than this clinical trial. For 
details on the country-specific requirements for personal 
data collection, see Section 12.5. 
Added as requested. 
Section 12.5 
Appendix 5: 
Country-specific 
requirements 
In France, race and ethnicity data will not be collected from 
the subjects. 
Added as requested. 
Section 12.8 
Appendix 8: 
Protocol 
amendment 
history 
This section has been added. Amendment 1 has been moved 
from Protocol amendment summary of changes to Section 12.8. 
Administrative 
change. 
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Section no. and 
title 
Description of change 
Brief rationale 
Throughout 
document 
Minor editorial revisions. 
Minor, have 
therefore not been 
summarized. 
Amendment 1 (16-Sep-2023, non-substantial, local Czech Republic, Germany, France, 
Hungary, Poland, Romania and Spain) 
This amendment is considered to be non-substantial based on the criteria set forth in 
Article 2 (13) of Regulation 536/2014 of the European Parliament and the Council of the 
European Union or subsequent regulation because it neither is likely to have a substantial 
impact on the safety or rights of the subjects or on the reliability and robustness of the data 
generated in the clinical trial. 
Overall rationale for the amendment 
The main purpose of this protocol amendment was to address requests from the regulatory 
authorities of the European Union countries included in this trial via the Clinical Trials 
Information System procedure after their review of the global protocol v1.0. Changes to the 
protocol are summarized in the table below (text added to the protocol is written in bold and 
deleted text has a line through it). 
Section no. and 
title 
Description of change 
Brief rationale 
Section 1.3 
Schedule of 
activities 
Panel 2: Schedule of trial activities 
Assessments of vital signs were 
added for Week 6 (Visit 8), Week 10 
(Visit 10), and Week 14 (Visit 12). 
 
Panel 2: Schedule of trial activities, 
footnote o) related to vital signs was 
edited: At Weeks 0, 1, 2, 3, and 4, 
subjects will be monitored after IMP 
administration for potential 
immediate drug reactions for a 
minimum of 2 hours with vital signs 
taken immediately (within 5 minutes) 
after last IMP administration as well 
as after 30 minutes (± 5 minutes), 
after 1 hour (± 5 minutes), and after 
2 hours (± 5 minutes), or until stable, 
whichever is later. From Week 5 
onwards, subjects will be 
monitored after IMP 
administration for potential 
immediate drug reactions for a 
minimum of 20 minutes with vital 
signs assessed within 5 minutes 
Added as requested. 
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Section no. and 
title 
Description of change 
Brief rationale 
after last IMP administration as 
well as after 20 minutes 
(± 5 minutes), or until stable, 
whichever is later. 
Section 1.3 
Schedule of 
activities 
Panel 2: Schedule of trial activities 
Assessments of hepatitis B, 
hepatitis C and HIV were added for 
Week 12 (Visit 11) and Week 24 
(Visit 15). 
 
Panel 2: Schedule of trial activities, 
footnote p) related to hepatitis B, 
hepatitis C and HIV was added: For 
subjects who at screening have a 
negative HBV-DNA reflex test (i.e. 
HBV-DNA is not detected), and 
negative HBsAg, negative anti-HBc, 
positive anti-HBs and without 
documentation of prior HBV 
vaccination or negative HBsAg and 
positive anti-HBc, repeat 
HBV-DNA will be done at 
Weeks 12 and 24. For subjects who 
at screening have positive 
anti-HCV but negative HCV-RNA 
(i.e. HCV-RNA is not detected), 
repeat HCV-RNA will be done at 
Weeks 12 and 24. 
Added as requested. 
Section 1.3 
Schedule of 
activities 
Panel 2: Schedule of trial activities 
Assessments of chemistry and 
hematology (central laboratory) were 
added for Week 1 (Visit 4), Week 2 
(Visit 5), and Week 3 (Visit 6). 
Added as requested. 
Section 2.4 
Ethical 
considerations 
In addition, at Weeks 0, 1, 2, 3, and 4, 
subjects will be monitored for a 
period of 2 hours to detect potential 
immediate drug reactions, and from 
Week 5 onwards, subjects will be 
monitored for a period of 
20 minutes. 
Added as requested for additional assessments 
of vital signs. 
Section 5.3 
Exclusion criteria 
Exclusion criterion #8 
Positive HBsAg or positive anti-HCV 
AND positive HCV-RNA at 
screening. 
- Subjects with a negative HBsAg and 
a positive anti-HBc or anti-HBs at 
screening will have reflex testing for 
HBV-DNA. Subjects who have a 
positive HBV-DNA test (i.e. 
HBV-DNA is detected) will be 
excluded. 
- For subjects who at screening 
have a negative HBV-DNA reflex 
Added as requested. 
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Section no. and 
title 
Description of change 
Brief rationale 
test (i.e. HBV-DNA is not detected), 
and 
     Negative HBsAg, negative  
anti-HBc, positive anti-HBs and 
without documentation of prior 
HBV vaccination  
or  
     Negative HBsAg and positive 
anti-HBc 
repeat HBV-DNA testing must be 
done at Weeks 12 and 24. If 
HBV-DNA is positive (i.e. 
HBV-DNA is detected) at Week 12, 
subjects must permanently 
discontinue IMP.  
- Subjects who at screening have a 
negative HBV-DNA reflex test (i.e. 
HBV-DNA is not detected), 
negative HBsAg, negative anti-HBc, 
positive anti-HBs and provide 
documentation of prior HBV 
vaccination will not require regular 
monitoring by HBV-DNA repeat 
testing in the trial. 
- For subjects who at screening 
have positive anti-HCV but 
negative HCV-RNA (i.e. HCV-RNA 
is not detected), repeat HCV-RNA 
will be done at Weeks 12 and 24. If 
HCV-RNA is positive (i.e. 
HCV-RNA is detected) at Week 12, 
subjects must permanently 
discontinue IMP. 
Section 5.3 
Exclusion criteria 
Exclusion criterion #14 
Any disorder* at screening and/or 
baseline, which is not stable in the 
opinion of the investigator, and could: 
-Affect the safety of the subject 
throughout the trial. 
- Influence the results of the trial. 
- Impede the subject’s ability to 
complete the trial. 
Added as requested. 
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Section no. and 
title 
Description of change 
Brief rationale 
Section 5.3 
Exclusion criteria 
Exclusion criterion #15 
Any significant abnormal finding* at 
screening and/or baseline which may 
in the opinion of the investigator:  
- Put the subject at risk because of 
their participation in the trial. 
- Influence the results of the trial. 
- Influence the subject’s ability to 
complete the trial. 
*The abnormal finding must be 
clinically significant and observed 
during the screening period. 
Examples include but are not 
limited to abnormal findings in 
physical examination, vital signs, 
ECG, hematology (e.g. hemoglobin 
<100 g/L, neutrophils <1.5 x 109/L, 
thrombocytes <75 x 109/L), 
biochemistry (e.g. serum creatinine 
>1.5 times the ULN, bilirubin >1.5 
times the ULN; subjects with a 
history of Gilbert’s syndrome are 
eligible for this trial provided direct 
bilirubin is < the ULN), or 
urinalysis. 
Added as requested. 
Section 5.3 
Exclusion criteria 
Exclusion criterion #25 
Receipt of live attenuated vaccines 
30 days prior to baseline or longer if 
recommended so by local 
guidelines. 
Added as requested. 
Section 5.3 
Exclusion criteria 
Exclusion criterion #30 
Subjects who are legally 
institutionalized or legally protected 
Clarified as requested. 
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Section no. and 
title 
Description of change 
Brief rationale 
(e.g. those under guardianship, 
curatorship, safeguard of justice) 
or other subjects incapable of 
giving informed consent according 
to the law of his/her residing 
country. 
Section 6.2 
Administration of 
IMP 
At Weeks 0, 1, 2, 3, and 4, subjects 
will be monitored for potential 
immediate drug reactions for a 
minimum of 2 hours after IMP 
administration. Vital signs will be 
taken immediately (within 5 minutes) 
after last IMP administration, as well 
as after 30 minutes (± 5 minutes), 
after 1 hour (± 5 minutes), and after 
2 hours (± 5 minutes), or until stable, 
whichever is later. From Week 5 
onwards, subjects will be 
monitored after IMP 
administration for potential 
immediate drug reactions for a 
minimum of 20 minutes with vital 
signs assessed within 5 minutes 
after last IMP administration as 
well as after 20 minutes 
(± 5 minutes), or until stable, 
whichever is later. Vital signs will 
be documented in the eCRF. 
Added as requested for additional assessments 
of vital signs. 
Section 6.7 
Prohibited 
medications and 
procedures 
4. Use of UVA or UVB, PUVA, other
phototherapy, or tanning beds, or
prolonged sun exposure.
Added as requested. 
Section 7.2.1 
Reasons for 
permanent 
discontinuation of 
IMP 
Added to the list: 
• Positive HBV-DNA test (i.e.
HBV-DNA is detected) at Week 12
(see exclusion criterion no. 8).
• Positive HCV-RNA test (i.e.
HCV-RNA is detected) at Week 12
(see exclusion criterion no. 8).
Added as requested. 
Section 7.2.2 
Reasons for 
temporary 
discontinuation of 
IMP 
In case an urgent situation requires 
immediate action, IMP dosing may be 
temporary discontinued if, at the 
investigator’s discretion, this is 
determined to be in the subject’s best 
interest. In such cases, sponsor’s
medical expert should be informed as 
soon as possible.  
A decision to re-initiate IMP must 
always be discussed with and 
approved by the sponsor’s medical 
expert. 
Added as requested. 
Section 8.4.1 
Vital signs 
At Weeks 0, 1, 2, 3, and 4, subjects 
will be monitored after IMP 
Added as requested for additional assessments 
of vital signs. 
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Section no. and 
title 
Description of change 
Brief rationale 
administration for immediate drug 
reactions for a minimum of 2 hours 
with vital signs taken immediately 
(within 5 minutes) after last IMP 
administration, after 30 minutes 
(± 5 minutes), after 1 hour 
± 5 minutes), and after 2 hours 
± 5 minutes), or until stable, 
whichever is later. From Week 5 
onwards, subjects will be 
monitored after IMP 
administration for potential 
immediate drug reactions for a 
minimum of 20 minutes with vital 
signs assessed within 5 minutes 
after last IMP administration as 
well as after 20 minutes 
± 5 minutes), or until stable, 
whichever is later. 
Section 8.4.5.1 
Overview 
Panel 12: Clinical laboratory tests, 
footnote 3) related to hepatitis B, 
hepatitis C and HIV was edited: 
Conducted at screening only. 
Edited as requested for additional assessments 
of hepatitis. 
Section 8.4.5.2 
Investigator 
evaluation of 
laboratory 
samples 
If the urine pregnancy test is positive 
but not confirmed by the repeated 
serum pregnancy test, the subject may 
continue IMP treatment, but the LEO 
medical expert should be consulted. 
Added as requested. 
Section 12.5 
Appendix 5: 
Country-specific 
requirements 
Information added for the Czech 
Republic regarding Section 8.1 
Overview 
In Czech Republic, according to 
Act no. 378/2007 Coll., only a 
physician can be an investigator. 
Added as requested and to comply with 
Act no. 378/2007 Coll.. 
Throughout 
document 
Minor editorial revisions. 
Minor, have therefore not been summarized. 
Amendment 1 (12-Jul-2023, non-substantial, local Japan) 
This protocol amendment was to address comments from the Health Authority in Japan after 
their review of the global protocol v1.0. The purpose of the amendment was mainly to clarify 
aspects related to the inclusion and exclusion criteria. Changes to the protocol are summarized 
in the table below. 
Section no. and 
title 
Description of change 
Brief rationale 
Section 12.5 
Appendix 5: 
Country-specific 
requirements 
Inclusion criterion #10 
The definition of highly effective 
form of birth control was updated. 
The following contraception methods 
were removed from the definition: 
Deleted as requested. 
 
 
 
 
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Section no. and 
title 
Description of change 
Brief rationale 
• Combined (oestrogen and 
progestogen) hormonal contraceptives 
(intravaginal and transdermal) with 
ovulation inhibitory effects. 
• Progestogen-only hormonal 
contraceptives (oral, intravaginal, or 
transdermal) that suppress ovulation. 
 
Exclusion criterion #8 
It was included that repeat 
HBV-DNA testing must be done at 
trial Weeks 8, 16 and 32 for Japanese 
subjects who at screening have a 
negative HBV-DNA reflex test (i.e. 
below LLQ), and  
- Negative HBsAg, negative anti-
HBc, positive anti-HBs and without 
documentation of prior HBV 
vaccination 
or  
- Negative HBsAg and positive anti-
HBc. 
If HBV-DNA is above LLQ at Week 
8 subjects must discontinue IMP. 
Japanese subjects who at screening 
have a negative HBV-DNA reflex test 
(i.e. below LLQ), negative HBsAg, 
negative anti-HBc, positive anti-HBs 
and provide documentation of prior 
HBV vaccination will not require 
regular monitoring by HBV-DNA 
repeat testing in the trial. 
 
 
 
 
 
 
 
 
Added as requested. 
 
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