Conditions: Atopic Dermatitis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 13
Healthy volunteers: no

Brief summary:
This clinical trial will investigate the effectiveness and safety of a new active ingredient (LEO 138559) in the treatment of moderate to severe atopic dermatitis (AD). It is given by subcutaneous injection. Some people in the trial will instead receive Dupixent® which is an approved treatment for moderate to severe AD. Dupixent® is also given by subcutaneous injection.

The main aim of this clinical trial is to investigate which changes in biomarkers in the skin are caused by LEO 138559 and Dupixent®.

The trial includes a screening phase of up to 4 weeks, followed by a treatment period of 16 weeks, and a safety follow-up period of 16 weeks.

Detailed description:

Arms:
arm 1: Participants received injections of LEO 138559 from Week 0 (baseline) to Week 16 (end of treatment). arm 2: Participants received injections of Dupixent® from Week 0 (baseline) to Week 16 (end of treatment).

Interventions: intervention 1: LEO 138559 intervention 2: Dupixent®
Intervention descriptions: intervention 1: LEO 138559 is an antibody given by subcutaneous injection. intervention 2: Dupixent® is an antibody given by subcutaneous injection.

Protocol document:
Prot_SAP_000.pdf: 
Cover Page 
Study title: A Randomized, Double-blinded, Active Comparator-controlled, 16-week, Single-site, 
Exploratory, Mechanistic Trial to Assess the Effect of LEO 138559 on the Molecular Signature and 
Safety in Adults With Moderate to Severe Atopic Dermatitis.  
LEO Pharma number: LP0145-2274
NCT number: NCT05470114
Date: 04-Jan-2023 


CONFIDENTIAL 
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THE PRIOR WRITTEN CONSENT OF THE LEO PHARMA GROUP 
 
Clinical trial protocol 
 
LP0145-2274 
 
 
A randomized, double-blinded, active comparator-controlled, 16-week, single-site, exploratory, 
mechanistic trial to assess the effect of LEO 138559 on the molecular signature and safety in adults 
with moderate to severe atopic dermatitis 
 
Phase 2a - exploratory mechanistic trial 
This clinical trial will be conducted in compliance with the clinical trial protocol, ICH GCP, 
and the applicable regulatory requirement(s). 
LEO Pharma A/S 
Trial ID: 
LP0145-2274 
 
Date: 
 
04-Jan-2023 
 
EudraCT no: 
2021-006211-28 
 
Version: 
5.0 
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Clinical trial protocol statements 
Approval statement LEO Pharma A/S 
Electronic signatures made within LEO Pharma Clinical Vault are legally binding equivalent 
of traditional handwritten signatures. The following persons have approved this clinical trial 
protocol by using electronic signatures as presented on the last page of this document: 
 M.Sci., Ph.D 
 
 
 
 
 
 
 MMath, PhD 
 
 
 
 
 
 
 MD, DMSc 
 
 
 
 
 
 
 
 MD, PhD 
 
 
 
 
 
 
 
 MSc. Pharm. 
 
 
 
 
 
 
Approval statement Signatory Investigator 
Assoc.-Prof. PD 
 MD, MSc 
 
Signatory investigator 
 
 
Acknowledgement statement investigator(s) 
Each participating investigator must agree to the approved clinical trial protocol by signing a 
clinical trial protocol acknowledgement form or similar document.
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Protocol amendment summary of changes table 
Document history 
Document 
Date 
Type of protocol amendment 
Amendment 3 
(substantial) 
04-Jan-2023 
Global 
Amendment 2 
(substantial) 
14-Apr-2022 
Global 
Amendment 1 
(substantial) 
08-Mar-2022 
Global 
Original protocol 
13-Jan-2022 
NA 
 
Amendment 3 (04-Jan-2023) 
This amendment is considered substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union or 
subsequent regulation. 
Overall rationale for the amendment: 
A new serum biomarker in atopic dermatitis has been identified in the literature. This 
amendment is intended to include this new biomarker. In addition, this amendment is intended 
to clarify that randomization will be continued until 12 patients who are evaluable for the 
primary endpoint i.e., for whom lesional skin biopsies at baseline and week 4 are available, 
are included in the study.  
 
 
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Section no.  
and name 
Description of change 
Brief rationale 
11.6.2 Blood 
biomarkers 
Addition of newly identified 
biomarker IL-22BP to the list of 
blood serum biomarkers that 
will be analysed. 
Formerly (First paragraph): 
Evaluation of effects of treatment 
of AD patients with LEO 138559 
or Dupixent® on protein 
biomarkers in blood, including but 
not limited to E- selectin, 
PI3/Elafin, CCL7, and IL-16, will 
be performed on serum samples. 
… 
New: 
Evaluation of effects of treatment 
of AD patients with LEO 138559 
or Dupixent® on protein 
biomarkers in blood, including but 
not limited to E-selectin, 
PI3/Elafin, CCL7, and IL-16, and 
newly identified IL-22BP [50] 
will be performed on serum 
samples. … 
With the identification of a new blood 
serum biomarker for atopic dermatitis, 
LEO Pharma A/S has decided to add 
this biomarker to the set of biomarkers 
that will be analysed in this clinical 
trial. 
 
 
 
 
 
 
 
 
 
 
 
Wording regarding the number 
of patients to be randomised 
rephrased: 
 
 
 
 
Originally a replacement of patients 
was planned if more than 3 patients left 
the study before the end of the 4th week 
of treatment.  
However, it was always the intention to 
achieve 12 subjects evaluable for the 
primary endpoint i.e., for whom a 
lesional biopsy is available at baseline 
and week 4.  
Wording has been revised for clarity.  
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Section no.  
and name 
Description of change 
Brief rationale 
 
Protocol 
Synopsis 
 
 
 
 
 
 
 
 
 
 
 
 
7.2 Number of 
subjects 
needed 
Formerly: 
A total of 12 subjects will be 
randomised 2:1 to: 
• 
LEO 138559 (8 subjects). 
• 
Dupixent® (4 subjects). 
 
New: 
Approximately 12 subjects will 
be randomised 2:1 to: 
• 
LEO 138559 (8 subjects). 
• 
Dupixent® (4 subjects). 
 
 
Formerly: 
… A total of 12 subjects will be 
randomised in a 2:1 ratio to LEO 
138559 450 mg Q2W (8 subjects) 
and comparator 300 mg Q2W 
(4 subjects). In case more than 3 
subjects prematurely terminate the 
trial before week 4, replacement of 
subjects may be considered after 
consultation with the sponsor. 
New: 
…Approximately 12 subjects will 
be randomised in a 2:1 ratio to 
LEO 138559 450 mg Q2W (8 
subjects) and comparator 300 mg 
Q2W (4 subjects) to be able to 
achieve 12 subjects evaluable for 
the primary endpoint i.e., for 
whom a lesional biopsy is 
available at baseline and week 4. 
In case more than 3 subjects 
prematurely terminate the trial 
 
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Section no. 
and name 
Description of change 
Brief rationale 
before week 4, replacement of 
subjects may be considered after 
consultation with the sponsor. 
10.1 General 
principles 
The third paragraph of this 
section (“Subjects who withdraw 
from the trial and subjects who 
permanently discontinue IMP can 
be considered to be replaced after 
consultation with the sponsor if 
withdrawal or permanent 
discontinuation in more than 3 
subjects occurred before week 4. 
Otherwise, subjects will not be 
replaced.”) has been deleted 
without replacement. 
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Section no.  
and name 
Description of change 
Brief rationale 
14.1 Sample 
size 
The wording regarding the 
sample size has been rephrased 
to precisely describe that it is 
intended to continue with 
randomisation until a number of 
12 patients evaluable for the 
primary endpoint is achieved. 
Formerly: 
The sample size of 12 subjects (8 
receiving LEO 138559 and 4 
receiving comparator) is based on 
the trial design for the exploratory 
comparison of the molecular 
signature changes of LEO 138559 
and the comparator. The sample 
size is not based on power 
calculations. 
New: 
The sample size of 12 subjects 
evaluable for the primary 
endpoint i.e., for whom a 
lesional biopsy is available at 
baseline and week 4 (8 receiving 
LEO 138559 and 4 receiving 
comparator) is based on the trial 
design for the exploratory 
comparison of the molecular 
signature changes of LEO 138559 
and the comparator. The sample 
size is not based on power 
calculations. 
 
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Section no.  
and name 
Description of change 
Brief rationale 
4 Schedule of 
trial 
procedures 
Link to footnote has been 
corrected 
Formerly: 
 
End of 
treatmentc) 
Skin biopsiesr) 
Xr) 
… 
r) 
Photographs will be taken of the 
biopsy sites prior to each biopsy 
sampling 
s) 
Suture removal in week 18, i.e., 2 
weeks after the last biopsy can 
either be performed on site or 
alternatively at general 
practitioner as being most 
convenient for the subject. 
New: 
 
End of 
treatmentc) 
Skin biopsiesr) 
Xr) 
… 
r) 
Photographs will be taken of the 
biopsy sites prior to each biopsy 
sampling 
s) 
Suture removal in week 18, i.e., 2 
weeks after the last biopsy can 
either be performed on site or 
alternatively at general 
practitioner as being most 
 
In reviewing this amendment, it was 
noticed that the hyperlink to the 
footnote regarding the biopsy at the 
end of the treatment was incorrect. 
This mistake has been corrected now. 
 
 
 
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Table of contents 
Clinical trial protocol statements ............................................................................................ 2 
Protocol amendment summary of changes table ................................................................... 3 
Table of contents ..................................................................................................................... 10 
List of panels ........................................................................................................................... 14 
List of abbreviations ............................................................................................................... 15 
1 
Protocol synopsis ........................................................................................................... 18 
2 
Trial identification ........................................................................................................ 23 
3 
Schematic of trial design .............................................................................................. 23 
4 
Schedule of trial procedures ........................................................................................ 24 
5 
Introduction and trial rationale .................................................................................. 33 
5.1 
Atopic dermatitis.................................................................................................... 33 
5.2 
Experience with investigational medicinal product ............................................... 34 
5.3 
Trial rationale ......................................................................................................... 36 
5.4 
Ethical considerations ............................................................................................ 37 
5.5 
Benefit/risk assessment .......................................................................................... 37 
6 
Trial objectives and endpoints ..................................................................................... 41 
7 
Trial design .................................................................................................................... 43 
7.1 
Overall trial design................................................................................................. 43 
7.2 
Number of subjects needed .................................................................................... 44 
7.3 
End-of-trial definition ............................................................................................ 45 
8 
Trial population ............................................................................................................ 46 
8.1 
Subject eligibility ................................................................................................... 46 
8.2 
Inclusion criteria .................................................................................................... 46 
8.3 
Exclusion criteria ................................................................................................... 47 
8.4 
Screening and screening failures ........................................................................... 50 
9 
Treatments ..................................................................................................................... 53 
9.1 
Trial product description ........................................................................................ 53 
9.2 
Administration of investigational medicinal products ........................................... 53 
9.3 
Treatment assignment and blinding ....................................................................... 56 
9.3.1 
Treatment assignment .................................................................................. 56 
9.3.2 
Blinding ....................................................................................................... 56 
9.3.3 
Emergency unblinding of individual subject treatment ............................... 57 
9.4 
Background treatment ............................................................................................ 58 
9.5 
Rescue treatment .................................................................................................... 58 
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9.6 
Concomitant medication and concurrent procedures............................................. 58 
9.7 
Prohibited medication(s) and procedures .............................................................. 60 
9.8 
Treatment logistics and accountability .................................................................. 61 
9.8.1 
Labelling and packaging of trial products ................................................... 61 
9.8.2 
Storage of trial products ............................................................................... 61 
9.8.3 
Investigational medicinal product accountability ........................................ 62 
9.8.4 
Treatment compliance .................................................................................. 63 
9.8.5 
Trial product destruction .............................................................................. 63 
9.9 
Provision for subject care following trial completion ........................................... 63 
9.10 
Reporting product complaints ................................................................................ 64 
10 
Discontinuation and withdrawal ................................................................................. 65 
10.1 
General principles .................................................................................................. 65 
10.2 
Reasons for discontinuation of IMP ...................................................................... 65 
10.2.1 
Reasons for permanent discontinuation of IMP .......................................... 65 
10.2.2 
Reasons for temporary discontinuation of IMP ........................................... 66 
10.3 
Early termination assessments ............................................................................... 67 
10.4 
Lost to follow-up ................................................................................................... 67 
11 
Trial assessments and procedures ............................................................................... 69 
11.1 
Overview ................................................................................................................ 69 
11.2 
Assessments performed only at screening/baseline ............................................... 70 
11.2.1 
Demographics .............................................................................................. 70 
11.2.2 
Medical history ............................................................................................ 70 
11.2.3 
Height ........................................................................................................... 70 
11.3 
Efficacy assessments .............................................................................................. 71 
11.3.1 
Validated Investigator Global Assessment Scale for Atopic Dermatitis ...... 71 
11.3.2 
Body surface area involvement .................................................................... 71 
11.3.3 
Eczema Area and Severity Index ................................................................. 71 
11.4 
Safety assessments ................................................................................................. 73 
11.4.1 
Vital signs .................................................................................................... 73 
11.4.2 
Physical examination ................................................................................... 74 
11.4.3 
Weight .......................................................................................................... 75 
11.4.4 
Electrocardiography ..................................................................................... 75 
11.4.5 
Laboratory testing ........................................................................................ 76 
11.4.6 
Anti-drug antibodies measurements ............................................................ 79 
11.5 
Pharmacokinetic assessments ................................................................................ 80 
11.5.1 
Blood sampling for analysis of PK .............................................................. 80 
11.6 
Pharmacodynamics assessments ............................................................................ 81 
11.6.1 
Overview ...................................................................................................... 81 
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11.6.2 
Blood biomarkers ......................................................................................... 81 
11.6.3 
Skin biopsies ................................................................................................ 81 
11.6.4 
Skin tape strips ............................................................................................. 82 
11.7 
Other assessments .................................................................................................. 83 
11.7.1 
Patient-reported outcomes ........................................................................... 83 
11.8 
End of trial ............................................................................................................. 84 
11.9 
Estimate of total blood volume collected .............................................................. 85 
11.10 Storage of biological samples ................................................................................ 85 
12 
Scientific rationale for trial design and appropriateness of assessments ................ 86 
12.1 
Scientific rationale for trial design......................................................................... 86 
12.2 
Appropriateness of assessments............................................................................. 87 
13 
Adverse events .............................................................................................................. 88 
13.1 
Definition and classification of adverse events ..................................................... 88 
13.2 
Collection of adverse event reports ....................................................................... 88 
13.3 
Reporting of adverse events ................................................................................... 88 
13.4 
Reporting of serious adverse events ...................................................................... 89 
13.4.1 
Investigator reporting responsibilities ......................................................... 89 
13.4.2 
LEO Pharma reporting responsibilities ........................................................ 90 
13.5 
Other events that require expedited reporting ........................................................ 90 
13.5.1 
Pregnancy ..................................................................................................... 90 
13.6 
Reporting of other events ....................................................................................... 91 
13.6.1 
Medication error .......................................................................................... 91 
13.6.2 
Misuse or abuse ........................................................................................... 91 
13.6.3 
Aggravation of condition ............................................................................. 92 
13.7 
Follow-up for final outcome of adverse events ..................................................... 92 
13.8 
Handling of an urgent safety measure ................................................................... 92 
14 
Statistical methods ........................................................................................................ 94 
14.1 
Sample size ............................................................................................................ 94 
14.2 
Trial analysis sets ................................................................................................... 94 
14.3 
Statistical analysis .................................................................................................. 94 
14.3.1 
Disposition of subjects ................................................................................. 94 
14.3.2 
Demographics and other baseline characteristics ........................................ 94 
14.3.3 
Exposure and treatment compliance ............................................................ 95 
14.3.4 
Testing strategy ............................................................................................ 95 
14.3.5 
Primary endpoint analysis ............................................................................ 95 
14.3.6 
Secondary endpoint analysis ........................................................................ 95 
14.3.7 
Analysis of exploratory efficacy endpoints ................................................. 96 
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14.3.8 
Pharmacodynamics analysis ........................................................................ 97 
14.3.9 
Safety analysis ............................................................................................. 97 
14.3.10 
Pharmacokinetic analysis ............................................................................. 99 
14.3.11 
Interim analysis .......................................................................................... 100 
14.3.12 
General principles ...................................................................................... 100 
14.3.13 
Handling of missing values ........................................................................ 100 
15 
References .................................................................................................................... 102 
Appendix 1: Definitions of adverse events and serious adverse events ..................... 106 
Appendix 2: Classification of adverse events ............................................................ 108 
Appendix 3: Trial governance considerations ............................................................ 110 
Appendix 3A: Regulatory and ethical considerations ................................................ 110 
Appendix 3B: Informed consent process ................................................................... 110 
Appendix 3C: Subject and data confidentiality .......................................................... 111 
Appendix 3D: Record keeping, quality control, and data handling ........................... 112 
Appendix 3E: Registration, reporting, and publication policy ................................... 115 
Appendix 3F: Insurance ............................................................................................. 116 
Appendix 3G: Financial disclosure ............................................................................ 117 
Appendix 3H: Committee structure ........................................................................... 117 
Appendix 3I: Trial and trial site closure ..................................................................... 117 
Appendix 3J: Responsibilities .................................................................................... 118 
Appendix 4: Country-specific requirements .............................................................. 119 
Appendix 5: Short version and justification for eligibility criteria ............................ 120 
Appendix 6: Contact list ............................................................................................. 125 
Appendix 7: Protocol Amendment history ................................................................. 125 
Amendment 1 (08-Mar-2022) .................................................................................... 125 
Amendment 2 (14-Apr-2022) ..................................................................................... 128 
 
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List of panels 
Panel 1: Trial design ................................................................................................................. 23 
Panel 2: Schedule of trial procedures ....................................................................................... 24 
Panel 3: Objectives and endpoints ........................................................................................... 41 
Panel 4: Identification of investigational medicinal products .................................................. 53 
Panel 5: Prohibited medication(s) and/or procedure(s) ............................................................ 60 
Panel 6: Sequence of assessments ............................................................................................ 69 
Panel 7: Validated Investigator Global Assessment Scale for Atopic Dermatitis .................... 71 
Panel 8: Calculation of the EASI score .................................................................................... 72 
Panel 9: EASI severity score scale and area score scale .......................................................... 73 
Panel 10: Clinical laboratory tests ............................................................................................ 76 
 
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List of abbreviations 
AAD 
American Academy of Dermatology  
AD 
atopic dermatitis 
ADA 
anti-drug antibodies 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BMI 
body mass index 
BP 
blood pressure 
BSA 
body surface area 
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
confidence interval 
CMO 
contract manufacturing organisation 
CONSORT 
Consolidated Standards of Reporting Trials 
COVID-19 
coronavirus disease 2019 
CRA 
clinical research associate 
CRO 
contract research organisation 
CTR 
clinical trial report 
EASI 
Eczema Area and Severity Index 
EASI50 
at least 50% reduction in EASI score 
EASI75 
at least 75% reduction in EASI score 
EASI90 
at least 90% reduction in EASI score 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EMA 
European Medicines Agency 
FDA 
United States Food and Drug Administration 
FU 
follow-up visit 
GCP 
Good Clinical Practice 
GINA 
Global Initiative for Asthma 
HB 
hepatitis B 
HCP 
healthcare professional 
HIV 
human immunodeficiency virus 
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HV 
Healthy volunteer 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
ID 
identification number 
IEC 
independent ethics committee 
IFN 
interferon 
IGA 
investigator global assessment 
IL-22BP 
interleukin 22 binding protein 
IMP 
investigational medicinal product 
IRB 
institutional review board 
IUD 
intrauterine device 
IUS 
intrauterine hormone-releasing system 
JAK 
janus kinase 
KLH 
keyhole limpet hemocyanin 
LOCF 
last observation carried forward 
mAb 
monoclonal antibody 
MedDRA 
Medical Dictionary for Regulatory Activities 
MoA 
mode of action 
NA 
not applicable 
NRS 
numeric rating scale 
NSAID 
nonsteroidal anti-inflammatory drug 
NBUVB 
narrow band ultraviolet B 
PD 
pharmacodynamics 
PDE-4 
phosphodiesterase-4  
PK 
pharmacokinetics 
PPD 
purified protein derivative 
PRO 
patient-reported outcome 
PT 
preferred term 
PUVA 
psoralen + ultraviolet A 
Q2W 
every second week 
QT 
QT interval, time from start of the Q wave to the end of the T wave on an 
ECG tracing 
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RNA 
ribonucleic acid 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SC 
subcutaneous(ly) 
SD 
standard deviation 
SmPC 
summary of product characteristics 
SOC 
system organ class 
SUSAR 
suspected unexpected serious adverse reaction 
TCI 
topical calcineurin inhibitor(s) 
TCS 
topical corticosteroid(s) 
Th2 
T-helper 2 
UVA1 
ultraviolet A1 
UVB 
ultraviolet B 
vIGA-AD 
validated Investigator Global Assessment Scale for Atopic Dermatitis 
WHO 
World Health Organization 
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1 
Protocol synopsis 
 
Trial ID 
EudraCT no 
 
LP0145-2274 
2021-006211-28 
Title of trial 
A randomized, double-blinded, active comparator-controlled, 16-week, 
single-site, exploratory, mechanistic trial to assess the effect of LEO 138559 
on the molecular signature and safety in adults with moderate to severe atopic 
dermatitis. 
Short title of trial 
A multi-omics disease signature trial in adult patients with moderate - severe 
AD  
Main objectives, 
and endpoints 
Objectives 
Endpoints 
Primary objective 
Primary endpoint 
To investigate the 
molecular signature 
changes in subjects with 
moderate to severe atopic 
dermatitis (AD) following 
treatment with LEO 138559 
and Dupixent® 
• 
Change in biomarkers typically 
associated with atopic dermatitis in 
lesional skin biopsies from baseline to 
week 4.  
Secondary objective 
Secondary endpoints 
To evaluate the safety of 
LEO 138559 in subjects with 
moderate to severe AD 
Secondary endpoint 
• 
Number of treatment-emergent adverse 
events from baseline to week 16 per 
subject. 
Exploratory endpoint (ADA) 
• 
Having a positive ADA response at 
weeks 0, 4, 8, 12, 16, 32, assessed 
separately. 
Exploratory objectives 
Exploratory endpoints 
To evaluate the efficacy of 
LEO 138559 and Dupixent® 
in subjects with moderate to 
severe AD 
Exploratory endpoints (efficacy) 
• 
Change in EASI score from baseline to 
week 1, 2, 4, 6, 8, 12, and 16. 
• 
Having a decrease in EASI of at least 
50% (EASI 50) from baseline to week 1, 
2, 4, 6, 8, 12, and 16, assessed 
separately. 
• 
Having a decrease in EASI of at least 
75% (EASI 75) from baseline to week 1, 
2, 4, 6, 8, 12, and 16, assessed 
separately. 
• 
Having a decrease in EASI of at least 
90% (EASI 90) from baseline to week 1, 
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2, 4, 6, 8, 12, and 16, assessed 
separately. 
• 
 Having vIGA-AD score of 0 (clear) or 
1 (almost clear) at week 1, 2, 4, 6, 8, 12, 
and 16, assessed separately. 
• 
Change in Worst Daily Pruritus NRS 
(weekly average) from baseline to 
weeks 1, 2, 4, 6, 8, 12, and 16. 
To evaluate the 
pharmacokinetics of 
LEO 138559 in subjects with 
moderate to severe AD 
• 
Serum concentration of LEO 138559 at 
weeks 0, 1, 4, 8, 12, 16, and 32. 
To evaluate the effect of 
treatment with LEO 138559 
or Dupixent® on disease 
biomarkers in subjects with 
moderate to severe AD 
• 
Change in expression of AD disease 
biomarkers in skin biopsies from 
baseline to week 1 and 16. 
• 
Change in expression of additional AD 
disease biomarkers in serum from 
baseline to week 1, 4, and 16. 
• 
Change in expression of additional AD 
disease biomarkers in skin tape strips 
from baseline to week 1, 4, and 16. 
Final collection 
of data for the 
primary endpoint 
Visit 6 (week 4) 
 
Trial design 
LP0145-2274 is a phase 2a randomized, double-blinded, active comparator-
controlled, single-site trial conducted in Austria. 
The screening phase of up to 4 weeks (weeks -4 to 0) includes a washout 
phase of 7 days (week -1 to 0). Subjects must stop treatment with topical 
corticosteroids (TCS), topical calcineurin inhibitors (TCI), topical 
phosphodiesterase (PDE)-4 inhibitors, or other topical prescription treatments 
1 week prior to baseline. Washout periods for systemic treatments will be 
checked at the screening visit. At baseline, subjects will be randomised to one 
of two treatment groups. Treatments will be administered at the trial site in a 
Q2W dosing schedule during the treatment period of 16 weeks. While 
subjects in the LEO 138559 treatment group will receive additional dosing at 
week 1 visit, subjects in the comparator group will receive injections with 
saline solution at this visit for blinding purposes. During a safety follow-up 
period of 16 weeks after end of treatment 3 phone contacts and a safety 
follow-up visit (week 32) will be performed.  
 
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Main assessments 
• 
Differentially expressed genes via single cell RNA sequencing 
(scRNASeq) from lesional skin biopsies 
• 
Multi-omics from lesional tape stripping and serum 
• 
Adverse events 
• 
Vital signs (resting blood pressure, pulse, and body temperature) 
• 
Physical examination 
• 
ECG (12-lead resting digital ECG) 
• 
Central / Local laboratory testing (haematology, blood chemistry, 
serology, pregnancy test). 
Main criteria for 
inclusion 
• 
18 – 64 years old at screening (both included). 
• 
Diagnosis of AD [as defined by the American Academy of Dermatology 
(AAD) Consensus Criteria] that has been present for ≥1 year prior to 
screening. 
• 
Subjects who have a recent history (within 6 months before screening) of 
inadequate response to treatment with topical medication, or for whom 
topical treatments are otherwise medically inadvisable. 
• 
EASI score ≥12 at screening and ≥16 at baseline. 
• 
vIGA-AD score ≥3 at screening and baseline. 
• 
Body surface area (BSA) of AD involvement ≥10% at screening and 
baseline. 
• 
Worst Daily Pruritus NRS (weekly average) of ≥3 points at baseline. 
Main criteria for 
exclusion 
• 
Treatment with systemic immunosuppressive/immunomodulating 
medication (excluding systemic antihistamines if taken at stable dose 
already before baseline), e.g., JAK inhibitors, immunoglobulin/blood 
products, or phototherapy within 2 weeks or 5 half-lives prior to baseline, 
whichever is longer. 
• 
Treatment with systemic corticosteroids within 4 weeks prior to baseline 
(NOTE: Inhaled or intranasal steroids equivalent to doses including and 
up to 500 µg beclometasone (or equivalent) daily is allowed). 
• 
Treatment with biologics within 5 half-lives (if known) or 16 weeks prior 
to baseline, whichever is longer. 
• 
Treatment with TCS, TCI, or topical PDE-4 inhibitor within 1 week prior 
to baseline (NOTE: Patient may be rescreened (one time) if failed for this 
criterion. 
• 
Intake of nonsteroidal anti-inflammatory drugs (NSAIDs) within 1 week 
prior to baseline. Intake of paracetamol will be allowed. 
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• 
Treatment with a live (attenuated) vaccine within 12 weeks prior to 
baseline. 
• 
Clinically significant active chronic or acute infection requiring systemic 
treatment within 4 weeks prior to baseline that may compromise the 
safety of the subject. 
• 
Clinically significant abnormalities detected on vital signs or ECG (apart 
from 1st degree atrioventricular (AV) block that is allowed). 
• 
Serious heart conditions, chronic lung diseases. 
• 
Acute asthma, acute bronchospasm, moderate to severe asthma. 
• 
Skin infection within 1 week prior to the baseline visit. 
• 
Presence of hepatitis B or C infection at screening. 
• 
Active inflammatory bowel disease (IBD) or history of IBD, anaphylaxis, 
immune complex disease, pancreatic disease or known or suspected 
history of immunosuppressive disorder. 
• 
History of human immunodeficiency virus (HIV) infection or positive 
HIV serology at screening. 
• 
Subject has a positive test for tuberculosis at screening. 
• 
Subject is pregnant or lactating. 
Investigational 
medicinal 
products 
 
Test Drug: 
• 
Name of IMP: LEO 138559 
• 
Active substance: LEO 138559 
• 
Dosage form: Lyophilised powder for reconstitution (using 1.0 mL 
sterilised water) adding up to a volume of 1.2 mL/vial 
• 
Concentration: 150 mg/mL 
• 
Dose and frequency: 450 mg once every 2 weeks (Q2W) i.e., 3 
injections per administration. In addition to the Q2W dosing schedule 
during the treatment phase, subjects randomised to LEO 138559 
treatment group will receive a dose of LEO 138559 at visit 4 (week 1) 
• 
Method of administration: Subcutaneous. 
 
Comparator: 
• 
Name of IMP: Dupixent® 
• 
Active substance: dupilumab 
• 
Dosage form: Solution for injection, 2 mL prefilled syringe 
• 
Concentration: 150 mg/mL 
• 
Dose and frequency: Initial 600 mg once (administered as two 
300 mg injections) followed by 300 mg Q2W (to compensate for the 
difference in treatment regimen between test drug and comparator, 
subjects randomised to Dupixent® will receive additional injections 
with saline solution). 
• 
Method of administration: Subcutaneous. 
Duration of trial 
participation 
Up to 36 weeks in total: 
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• 
Up to 4 weeks screening period including a washout phase of 1 week 
(week -1 to 0). 
• 
16 weeks treatment period 
• 
16 weeks safety follow-up 
Number of 
subjects 
Approximately 12 subjects will be randomised 2:1 to: 
• 
LEO 138559 (8 subjects). 
• 
Dupixent® (4 subjects). 
Number and 
distribution of 
trial sites 
Single site study performed in Austria 
Statistical 
methods 
All endpoints will be analysed using appropriate descriptive summary 
measures. No formal statistical tests will be applied. 
Signatory 
investigator 
Sponsor 
LEO Pharma A/S, Industriparken 55, DK 2750 Ballerup, Denmark 
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2 
Trial identification 
EudraCT number: 2021-006211-28 
The clinical trial protocol will be registered in local registries if required by local legislation. 
3 
Schematic of trial design 
Panel 1: Trial design 
 
Screening period of up to 4 weeks (weeks -4 to 0) including a washout phase of 7 days (week -1 to 0). Subjects 
must stop treatment with TCS, TCI, topical PDE-4 inhibitors, or other topical prescription treatments 1 week 
prior to baseline.  Washout periods for systemic treatments have to be checked at the screening visit. All subjects 
must use an emollient twice daily (or more frequently, if needed) for at least 7 days before day 1 (baseline) and 
throughout the treatment period (until week 16). 
In addition to the Q2W dosing schedule during the treatment phase, subjects randomised to LEO 138559 
treatment group will receive a dose of LEO 138559 at visit 4 (week 1), whereas subjects in the comparator 
treatment group will receive saline injections for blinding purposes. 
 
Abbreviations: AD = Atopic dermatitis; PDE-4 = phosphodiesterase-4; Q2W = every second week; 
TCI = topical calcineurin inhibitor(s); TCS = topical corticosteroid(s). 
 
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4 
Schedule of trial procedures 
Panel 2: Schedule of trial procedures 
 
Screeninga) 
Washout  
phone calla) 
Baseline/ 
Start of treatment 
Treatment 
End of treatmentc) 
 
SFU phone calls 
SFU site visit 
End of trial visitc) 
Early terminatione)  
Unscheduled. visitf) 
 
 References 
(protocol section) 
 
 
Primary endpoint 
visitb) 
 
 
 
 
 
Visit 
1 
2a) 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13, 14, 15 
16 
 
 
 
Week 
-4 
-1 
0 
1 
2 
4 
6 
8 
10 
12 
14 
16 
20, 24, 28 
32 
Day 
Up to -
28 
-7 
1 
8 
15 
29 
43 
57 
71 
85 
99 
113 
141, 169, 197 
225 
Visit window (days)  
NA 
NA 
NA 
±1 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
Trial population and eligibility 
Informed consentg)  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix 3B: 
Informed 
consent 
process 
Subjects' eligibility 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.2 and 8.3 
Investigator assessments at screening and/or baseline only 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
11.2.1 
Body assessment 
(height)  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
11.2.3 
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Screeninga) 
Washout  
phone calla) 
Baseline/ 
Start of treatment 
Treatment 
End of treatmentc) 
 
SFU phone calls 
SFU site visit 
End of trial visitc) 
Early terminatione)  
Unscheduled. visitf) 
 
 References 
(protocol section) 
 
 
Primary endpoint 
visitb) 
 
 
 
 
 
Visit 
1 
2a) 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13, 14, 15 
16 
 
 
 
Week 
-4 
-1 
0 
1 
2 
4 
6 
8 
10 
12 
14 
16 
20, 24, 28 
32 
Day 
Up to -
28 
-7 
1 
8 
15 
29 
43 
57 
71 
85 
99 
113 
141, 169, 197 
225 
Visit window (days)  
NA 
NA 
NA 
±1 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
Medical history 
X 
 
(X)h) 
 
 
 
 
 
 
 
 
 
 
 
 
 
11.2.2 
Hepatitis B, C, HIV 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
11.4.5 
Tuberculosis 
(Mycobacterium 
tuberculosis IFN-γ 
release assay)i)  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
11.4.5 
Serum pregnancy test 
(females only)j)  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
11.4.5 
Randomisation and treatments 
Randomisationk)  
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.3.1 
IMP administration 
at the trial sitek) 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
(X) 
9.2 
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Screeninga) 
Washout  
phone calla) 
Baseline/ 
Start of treatment 
Treatment 
End of treatmentc) 
 
SFU phone calls 
SFU site visit 
End of trial visitc) 
Early terminatione)  
Unscheduled. visitf) 
 
 References 
(protocol section) 
 
 
Primary endpoint 
visitb) 
 
 
 
 
 
Visit 
1 
2a) 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13, 14, 15 
16 
 
 
 
Week 
-4 
-1 
0 
1 
2 
4 
6 
8 
10 
12 
14 
16 
20, 24, 28 
32 
Day 
Up to -
28 
-7 
1 
8 
15 
29 
43 
57 
71 
85 
99 
113 
141, 169, 197 
225 
Visit window (days)  
NA 
NA 
NA 
±1 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
Treatmentk) 
compliance at the 
trial site 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
(X) 
9.2 
Drug accountabilityk) 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
(X) 
9.8.3 
Background 
treatment 
(emollients)l)  
 
At least twice daily 
 
 
 
 
9.4 
Concomitant 
medications/ 
concurrent 
proceduresm) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
9.6 
Subject assessments (Paper Diary) 
Paper Diary hand-out 
/ training 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
11.7.1.1 
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Screeninga) 
Washout  
phone calla) 
Baseline/ 
Start of treatment 
Treatment 
End of treatmentc) 
 
SFU phone calls 
SFU site visit 
End of trial visitc) 
Early terminatione)  
Unscheduled. visitf) 
 
 References 
(protocol section) 
 
 
Primary endpoint 
visitb) 
 
 
 
 
 
Visit 
1 
2a) 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13, 14, 15 
16 
 
 
 
Week 
-4 
-1 
0 
1 
2 
4 
6 
8 
10 
12 
14 
16 
20, 24, 28 
32 
Day 
Up to -
28 
-7 
1 
8 
15 
29 
43 
57 
71 
85 
99 
113 
141, 169, 197 
225 
Visit window (days)  
NA 
NA 
NA 
±1 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
Diary check by site 
staff/collection of 
completed pages 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(X) 
 
 
Return of Paper 
Diary 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
(X) 
 
 
Investigator assessments of efficacy 
EASI 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
 
(X) 
(X) 
11.3.3 
vIGA-AD 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
 
(X) 
(X) 
11.3.1 
BSA involvement 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
 
(X) 
(X) 
11.3.2 
Subject assessments of efficacy 
Worst Daily Pruritus 
NRSn) 
 
Daily 
 
 
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Screeninga) 
Washout  
phone calla) 
Baseline/ 
Start of treatment 
Treatment 
End of treatmentc) 
 
SFU phone calls 
SFU site visit 
End of trial visitc) 
Early terminatione)  
Unscheduled. visitf) 
 
 References 
(protocol section) 
 
 
Primary endpoint 
visitb) 
 
 
 
 
 
Visit 
1 
2a) 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13, 14, 15 
16 
 
 
 
Week 
-4 
-1 
0 
1 
2 
4 
6 
8 
10 
12 
14 
16 
20, 24, 28 
32 
Day 
Up to -
28 
-7 
1 
8 
15 
29 
43 
57 
71 
85 
99 
113 
141, 169, 197 
225 
Visit window (days)  
NA 
NA 
NA 
±1 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
Investigator assessments of safety 
Vital signso) 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
(X) 
(X) 
11.4.1 
Physical examination 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
(X) 
(X) 
11.4.2 
Weight 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
(X) 
(X) 
11.4.3 
ECGp) 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
(X) 
(X) 
11.4.4 
Clinical chemistry, 
haematology (central 
laboratory) 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
(X) 
(X) 
11.4.5.1 
Urinalysisq) 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
(X) 
(X) 
11.4.5.1 
Urine pregnancy test 
(females only)j)  
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
(X) 
(X) 
11.4.5.1 
ADA 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
(X) 
(X) 
11.4.6 
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Screeninga) 
Washout  
phone calla) 
Baseline/ 
Start of treatment 
Treatment 
End of treatmentc) 
 
SFU phone calls 
SFU site visit 
End of trial visitc) 
Early terminatione)  
Unscheduled. visitf) 
 
 References 
(protocol section) 
 
 
Primary endpoint 
visitb) 
 
 
 
 
 
Visit 
1 
2a) 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13, 14, 15 
16 
 
 
 
Week 
-4 
-1 
0 
1 
2 
4 
6 
8 
10 
12 
14 
16 
20, 24, 28 
32 
Day 
Up to -
28 
-7 
1 
8 
15 
29 
43 
57 
71 
85 
99 
113 
141, 169, 197 
225 
Visit window (days)  
NA 
NA 
NA 
±1 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
13.2 
Pharmacokinetic assessment 
PK blood samples 
 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
(X) 
(X) 
11.5.1 
Pharmacodynamic assessments 
Blood biomarkers 
(PD serum sample) 
 
 
X 
X 
 
X 
 
 
 
 
 
X 
 
 
(X) 
(X) 
11.6.2 
Skin biopsiesr) 
 
 
X 
X 
 
X 
 
 
 
 
 
Xr) 
 
 
(X) 
(X) 
11.6.3 
Skin tape strips 
 
 
X 
X 
 
X 
 
 
 
 
 
X 
 
 
(X) 
(X) 
11.6.4 
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Screeninga) 
Washout  
phone calla) 
Baseline/ 
Start of treatment 
Treatment 
End of treatmentc) 
 
SFU phone calls 
SFU site visit 
End of trial visitc) 
Early terminatione)  
Unscheduled. visitf) 
 
 References 
(protocol section) 
 
 
Primary endpoint 
visitb) 
 
 
 
 
 
Visit 
1 
2a) 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13, 14, 15 
16 
 
 
 
Week 
-4 
-1 
0 
1 
2 
4 
6 
8 
10 
12 
14 
16 
20, 24, 28 
32 
Day 
Up to -
28 
-7 
1 
8 
15 
29 
43 
57 
71 
85 
99 
113 
141, 169, 197 
225 
Visit window (days)  
NA 
NA 
NA 
±1 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
End of treatment/trial 
End-of-treatment 
form 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
10.3 
End-of-trial form 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
a) Screening will be performed up to 4 weeks before the baseline visit. If the screening visit is performed close to the beginning of the washout period, no 
additional washout phone call is necessary, at the discretion of the investigator. 
b) Subjects who permanently discontinue IMP treatment prior to week 4 will be asked to return to the trial site for a primary endpoint (nominal week 4) visit.  
c) An end-of-treatment form must be completed in the eCRF for all randomised subjects.  
d) An end-of-trial form must be completed in the eCRF for all randomised subjects.  
e) Subjects who permanently discontinue IMP prior to week 16 and subjects who withdraw from the trial will be asked to come to an early termination visit. As 
an early termination visit will only be performed in case of subjects permanently discontinuing the IMP, the visit has been marked with an (X).  
f) 
Unscheduled visit(s) between planned visits may be added to the subject’s visit schedule if judged necessary by the investigator, e.g. due to an AE, a significant 
change in disease state, or difficulty complying with the clinical trial protocol requirements. At an unscheduled visit, the investigator should at least collect AEs 
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data. Other assessments/procedures to be conducted at an unscheduled visit will be at the discretion of the investigator. As unscheduled visits will only be 
performed if judged necessary by the investigator, the assessments/procedures have been marked with an (X).  
g) The informed consent form must be signed prior to performing any protocol-related procedures, including but not limited to screening evaluations and washout 
of disallowed medications.  
h) In case medical history is incomplete at the screening visit because prior and concomitant diseases were not communicated by patient before or e.g. in case of 
abnormal lab values from screening assessments, missing data will be documented at week 0 (baseline). 
i) 
Mycobacterium tuberculosis IFN-γ release assay (or a PPD test if it is a requirement from the local health authorities). 
j) 
For women of childbearing potential 
k) Preparation, administration and handling of IMPs will only be performed by unblinded site staff 
l) 
All subjects must use an emollient twice daily (or more frequently, if needed) for at least 7 days before day 1 (baseline) and throughout the treatment period 
(until week 16). 
m) Relevant concomitant medications/ concurrent procedures should be included from 3 months prior to baseline (day 1) until end of trial (week 32). 
n) Completion of the Paper Diary for Worst Daily Pruritus NRS will be initiated at least 1 week prior to baseline (day 1). Compliance with the Paper Diary 
completion will be reviewed by the trial site staff throughout the trial. Subjects who discontinue IMP but remain in the trial will continue completing the Paper 
Diary until the safety follow-up visit (visit 16). 
o) For the first 3 treatment visits (i.e. visits 3, 4, and 5) subjects will be monitored after IMP/saline administration for immediate drug reactions for a minimum of 
1 hour with vital signs taken immediately after the injections as well as after 30 minutes (± 5 minutes) and after 1 hour (± 5 minutes), or until stable, whichever 
is later. 
p) ECG should be recorded in triplicate for each time point and will be centrally evaluated. 
q) Urinalysis is performed by a urine dipstick.  
r) 
Photographs will be taken of the biopsy sites prior to each biopsy sampling 
s) Suture removal in week 18, i.e., 2 weeks after the last biopsy can either be performed on site or alternatively at general practitioner as being most convenient 
for the subject. 
 
 
 
Abbreviations: ADA = anti-drug antibodies; AE = adverse event; BSA = body surface area; EASI = Eczema Area and Severity Index; 
ECG = electrocardiogram; eCRF = electronic case report form; HIV = human immunodeficiency virus; IFN-γ = interferon gamma; IMP = investigational 
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medicinal product; NRS = Numeric Rating Scale; PD = pharmacodynamics; PK = pharmacokinetics; PPD = purified protein derivative; Q2W = every second 
week; SFU = safety follow-up; vIGA-AD = validated Investigator Global Assessment Scale for Atopic Dermatitis.
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5 
Introduction and trial rationale 
5.1 
Atopic dermatitis 
Atopic dermatitis (AD) is a chronic inflammatory disease characterized by recurrent, 
erythematous, and xerotic lesions with exudation at acute stages and fissuring and 
lichenification at chronic stages. 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 pain leading to poor quality of life, sleep deprivation, mood 
changes, and lost productivity [1-4]. AD is the most common inflammatory skin disorder with 
a lifetime prevalence of 15–20% [5]. 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 [6, 7]. 
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 antigen presenting cells 
(APCs) and recruit Th2 cells and innate lymphoid cells [8, 9]. These cells amplify the type 2 
immune response by secreting IL-4, IL-5, and IL-13 [10-12]. As AD progresses from acute to 
chronic, a mixed T-cell infiltrate including Th17 and Th22 cells develops [13]. These cells 
secrete IL-17 and IL-22, which have been purported to play a role in AD pathogenesis [14, 
15]. Whether IL-22 is a key driver of AD pathogenesis remains unknown. 
Topical therapies are the mainstay of treatment for AD and include moisturisers, TCS, TCI, 
and PDE-4 inhibitors [16]. In addition, topical JAK inhibitors (cream) are in development for 
the treatment of AD [17, 18] and the topical JAK inhibitor delgocitinib (ointment) has 
received marketing approval in Japan [19]. If disease control cannot be achieved with topical 
treatments, phototherapy can be considered [20]. For patients with moderate to severe AD, 
topical therapy and phototherapy are often insufficient or impractical, and therefore systemic 
therapy is indicated. Systemic non-biologic therapies 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. In addition, 
azathioprine, methotrexate, and mycophenolate mofetil have demonstrated varying levels of 
efficacy [21, 22] and are used off-label [23]. In 2017, the first biologic was approved for the 
treatment of moderate to severe AD (dupilumab, anti-IL4Ra mAb) and there are several 
targeted biologic therapies in development for AD including lebrikizumab and nemolizumab 
[24-26], as well as oral JAK inhibitors [27-29] . Of note, tralokinumab and baricitinib were 
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recently approved by the European Medicines Agency (EMA) for the treatment of moderate 
to severe AD [30], however, their position in the treatment paradigm is not yet fully 
understood [31].  
Despite promising efficacy with dupilumab, approximately 60% of patients with AD do not 
achieve clinical remission (i.e. IGA 0/1, clear/almost clear). Therefore, there is a remaining 
unmet need to develop new therapies with improved efficacy. Further, it is increasingly 
recognised 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 patients with moderate to severe AD [32, 33]. 
5.2 
Experience with investigational medicinal product 
As LEO 138559 is still at an early stage of development only non-clinical and limited clinical 
data are available. 
Nonclinical data 
LEO 138559, originally known as ARGX-112 (clone 230C9), is a humanised IgG1 mAb with 
high affinity for the IL-22R1 chain of the IL-22R, thereby blocking the binding of the ligand, 
dimerisation of IL-22R1 with IL-10R2, and downstream signaling via JAK1-STAT3 [34]. 
Given the binding of LEO 138559 to IL-22R1, it is hypothesised to prevent not only the 
effects of IL-22 but also the effect of IL-20 and IL-24 on the IL22/24 Type II receptor (IL-
20R2/IL-22R1 dimer). 
Further, LEO 138559 does not bind to IL-22BP, an endogenous negative regulator of IL-22, 
and thereby leaves IL-22BP free to further inhibit IL-22 activity [35].  
LEO 138559 has been modified to avoid Fc effector functions (binding of its Fc region to Fc 
receptors on e.g., effector cells) that can induce unwanted effects of the IMP. It is expected 
that LEO 138559 Q2W will offer an acceptable safety profile in combination with an 
efficacious treatment option for the benefit of patients with moderate to severe AD. 
Toxicology 
The LEO 138559 nonclinical studies conducted to date (4- and 26-week repeat dose 
toxicology studies in cynomolgus monkeys with 5 weekly SC or IV doses up to 100 mg/kg) 
showed no signs of local or systemic toxicities in nonhuman primates (cynomolgus monkeys).  
The LEO 138559 nonclinical data indicated a toxicity profile that is amenable to clinical 
monitoring, is of low concern for human risk, and provides an approximate 16-fold margin of 
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exposure between the observed NOAELs and the exposure at steady state for 450 mg Q2W 
dosing (planned dosing regimen in LP0145-2274). 
The nonclinical results did not indicate a need to perform specific clinical trials (typically 
conducted for small molecule drugs) investigating effects on QT prolongation, implication of 
hepatic or renal impairment and, cytochrome P450 induction/inhibition potential.  
Based on nonclinical pharmacology and toxicology studies, LEO 138559 is expected to be a 
safe and efficacious treatment for the benefit of patients with moderate to severe AD. 
From the mode of action (MoA), target expression, class effects of other biologics, and 
literature review, potential risks have been identified which are included in the investigator’s 
brochure (Section 7.3.2) [36]. 
A detailed overview of nonclinical data on LEO 138559 is available in the current 
investigator’s brochure [36]. 
Clinical data 
One first-in-human (FiH) clinical trial with LEO 138559 was completed (LP0145-1315) and 
further trials (PK and proof of concept) with LEO 138559 are ongoing.  
The FiH trial was a randomised, double-blind, placebo-controlled, multi-centre trial to 
evaluate the safety, tolerability, PK, and PD of LEO 138559 in healthy volunteers (HV) and 
subjects with moderate to severe AD. The trial contained a single-ascending dose (SAD) and 
multiple-ascending dose (MAD) part with overall 51 subjects. SAD were administered 
intravenously (IV) and subcutaneously (SC) in healthy volunteers (HV). MAD were 
administered SC in HV and patients with AD. In patients with AD (data from 8 patients were 
available), a reduction in disease severity based on individual EASI scores was observed for 
LEO 138559 compared with placebo.  
No fatal events, no SAEs, and no severe AEs were reported during the trial. No AE patterns 
giving rise to any concerns have been reported from the 35 subjects who received LEO 
138559. 19 HV were exposed to single doses of LEO 138559 (IV in 11 HV, and SC in 8 HV), 
and 12 patients with AD and 4 HV were exposed to multiple SC doses of LEO 138559. 
Among a total of 17 adverse events considered as possibly or probably related to the 
treatment reported in 8 subjects either receiving single or multiple doses of LEO 138559, the 
most frequently reported adverse events were infections and infestations observed in 6 of 35 
subjects exposed to LEO 138559 and considered mild to moderate in severity at most. 
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Furthermore, nervous system disorders were reported for a total of 3 subjects, 2 of them 
having a single episode of headache and a 3rd subject reported to suffer from dizziness. In 
addition, 2 subjects developed skin and subcutaneous disorders. All other adverse events were 
reported only once without any clustering or trends for a special type of events. 
Overall, there were no clinically relevant treatment effects on vital signs and clinical 
laboratory parameters. No severe AEs were reported. No risks for humans have been 
identified at the dose levels of up to 450 mg LEO 138559 dosed weekly (the selected dose for 
biweekly dosing in the present trial) tested to date. 
Pharmacokinetics  
Based on the human PK data from the FiH trial, the PK of LEO 138559 is as expected for a 
mAb (IgG1) directed toward a membrane-bound target, and the target-mediated drug 
disposition (TMDD) characteristics are also visible in the observed human data as it was in 
the cynomolgus data. 
After SC administration, LEO 138559 is slowly absorbed with a mean time to maximum 
concentration of approximately 7.5 days. After multiple dosing, the elimination half-life was 
observed to be between 21–25 days. At and above the exposure level relevant for clinical 
testing (150 mg Q2W), the elimination is dominated by linear clearance and close to 
dose-proportionality is expected at steady state. The exposure at steady state following 
administration of 450 mg Q2W is expected to result in lower exposure than 450 mg every 
week for 5 weeks (the highest dose in the LP0145-1315 trial). 
A detailed overview of clinical data on LEO 138559 is available in the current investigator’s 
brochure [36]. 
5.3 
Trial rationale 
There remains an unmet need for effective treatment options in patients with moderate to 
severe AD. Building on the knowledge of increased IL-22 expression in AD, it is 
hypothesized that inhibition of the IL-22 pathway via LEO 138559 may be an effective 
treatment in patients with moderate to severe AD. The primary goal of this exploratory 
mechanistic trial will be to evaluate changes in biomarkers in skin and blood in atopic 
dermatitis patients after treatment either with LEO 138599 or with comparator.  
As comparator dupilumab (Dupixent®) will be used, a biologic treatment approved for the 
treatment of moderate-to-severe AD. This monoclonal IgG4 antibody selectively inhibits 
IL-4R. 
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5.4 
Ethical considerations 
This trial will be conducted in accordance with the ethical principles originating from the 
Declaration of Helsinki [37] and ICH GCP [38] and in compliance with the approved protocol 
and applicable regulatory requirements. 
The trial design is considered scientifically justified and to adhere to ethical standards 
ensuring the rights, safety, and well-being of the subjects. 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 as 
explained in Section 5.5 below. 
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 
detect any pregnancies. 
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 readily be 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 subject. 
5.5 
Benefit/risk assessment 
LEO 138559 
No risks have been observed in nonclinical studies or clinical trials with LEO 138559. 
According to the results from the FiH (LP0145-1315), single IV doses up to 75 mg, single SC 
doses up to 300 mg, and multiple SC doses up to 450 mg LEO 138559 are considered safe 
and well tolerated. No severe or serious AEs were reported in this trial.  
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The following are considered important potential risks for LEO 138559 based on mechanism 
of action and class effects of other biologics.  
IL-22 has been shown to mediate cutaneous and mucosal host defence in the skin, lung, and 
intestine and induce expression of epithelial antimicrobial peptides. Therefore, when blocking 
IL-22R, there is a potential for increased risk of infection. However, based on the data 
reported in subjects with AD treated with the monoclonal antibody targeting IL-22 
(fezakinumab) and the available data from LEO138559, no increased risk of infections has 
been observed by blocking the IL- 22 pathway. 
IL-22 is known to play a role in tissue regeneration and wound healing and blocking IL-22R 
could potentially delay skin, lung, intestine, and pancreas healing. The risk is considered low 
as many growth factors and cytokines have overlapping roles for tissue regeneration and 
wound healing.  
Immunogenicity is a class effect of mAbs, though the risk of immunogenicity of LEO 138559 
is predicted to be lower than current biologics as predicted by the in silico Epibase scanning 
system [39]. 
Anaphylaxis and serious allergic reactions have been observed after the administration of 
mAbs and other foreign proteins. In addition, AD subjects are at an increased risk of 
hypersensitivity reactions.  
However, in the FiH trial, no trends for impaired wound healing, no anaphylaxis or serious 
allergic reactions were observed. 
The FiH trial revealed promising efficacy results in AD patients for the 300 mg and 450 mg 
treatment groups. Treatment- and dose-related reductions in mean EASI and IGA scores were 
observed. Reductions from baseline in EASI score ≥90% occurred in 3 out of 4 subjects 
following administration of 450 mg LEO 138559. 
Dupixent® 
As comparator dupilumab (Dupixent®) was chosen, a systemic targeted immunomodulatory 
agent approved for the treatment of moderate-to-severe AD since 2017. Dupilumab is a 
human monoclonal IgG4 antibody that inhibits interleukin-4 (IL-4) and interleukin-13 (IL-13) 
signaling by specifically binding to the IL-4Rα subunit shared by the IL-4 and IL-13 receptor 
complexes. Blocking IL-4Rα with dupilumab inhibits IL-4 and IL-13 cytokine-induced 
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responses, including the release of proinflammatory cytokines, chemokines and IgE and 
modulated the Type 2 pathway. 
Dupixent® will be used in this trial in a dosing scheme as per approved label in Austria. 
Side effects are injection site reactions (includes erythema, oedema, pruritus, pain, and 
swelling), conjunctivitis, arthralgia, oral herpes, and eosinophilia. Rare cases of serum 
sickness, serum sickness-like reaction, anaphylactic reaction, and ulcerative keratitis have 
been reported as described in the summary of product characteristics (SmPC) for Dupixent®. 
Trial-related procedures 
Blood sampling presents the same low risk as normally associated with this procedure (i.e. 
infection, bleeding into the surrounding tissue, and, very rarely, inflammation of the vein, or 
formation of blood clots). Blood sampling will only be conducted by qualified medical 
personnel.  
Subjects may experience discomfort associated with the collection of the skin biopsy samples. 
To minimize discomfort, the subject will receive an injection of a local anesthetic to numb the 
area where the biopsy will be taken. Subjects who have previously had reactions to an 
anesthetic medication will not be included in this trial. Complications of skin biopsies may 
include bleeding, infection, bruising and/or pain at the biopsy site. Pressure dressings and ice 
may be used to help alleviate these symptoms. Wound healing at the biopsy site will be 
checked at a subsequent visit and sutures removed as needed. The subject will be informed 
that they may retain small scars after the procedure. 
Collection of tape strips is a non-invasive technique with no or very limited risks to the 
subject. 
Participation in clinical trials may currently be associated with increased risks and challenges 
due to the COVID-19 pandemic caused by SARS-CoV-2. Based on non-clinical studies, LEO 
138559 is considered a mild immunomodulatory compound and its mechanism of action is 
not believed to present a risk of a decreased antiviral immunity in subjects infected by 
COVID-19. In addition, LEO 138559 is not believed to increase the susceptibility of the 
subject to contract COVID-19 or other infections. However, a risk of exposure to infected 
people cannot be excluded as the subject may enter public areas (e.g., commute to the trial 
site) and have human contacts (e.g., with the site staff). Therefore, risks must appropriately be 
assessed, and mitigation measures taken to protect the subject and site staff and to ensure the 
integrity of the trial data. Several exclusion criteria have been chosen to reduce the risk for 
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participants for infection with SARS-CoV-2 (Appendix 5: Short version and justification for 
eligibility criteria). Vaccination with mRNA vaccines for SARS-CoV-2 will be allowed during 
the trial.  
Both EMA and as well as national and local health authorities in Europe have issued new 
guidelines aiming at providing recommendations for conduct of clinical trials during the 
COVID-19 pandemic [40-42]. Given the potential for the pandemic situation to relapse in 
relation to spread of COVID-19 in the future, special attention will be paid to protecting 
subjects and site staff involved in the trial against infection with SARS-CoV2. 
During the trial, the investigators will be trusted to take appropriate action to ensure 
individual subject safety according to the recommendations and preventive measures issued 
by their local authorities.  
Mitigation measures that are currently planned to be implemented in this clinical trial in case 
of an escalation of pandemic situation are detailed in a separate document (“Mitigation 
Measures due to COVID-19 Pandemic”), that will be part of the submission package send to 
the relevant Ethics Committee and the Competent Regulatory Authority for approval. 
As a result of the ongoing risk evaluation, further mitigation measures may come into force, 
resulting in an update of the above-mentioned document. If additional mitigation measures 
require approval, a substantial amendment will be submitted to the relevant Ethics Committee 
and the Competent Regulatory Authority and will not be implemented until approved. 
Exceptions to this are amendments made to eliminate immediate hazards to the patients 
(“urgent safety measures”). In this case the relevant Ethics Committee and the Competent 
Regulatory Authority will be notified about changes as soon as possible considering national 
and local circumstances. 
Conclusion 
The study population consists of subjects with moderate to severe AD. Since all subjects will 
receive active treatment (either the investigational drug (LEO138559) or an approved drug for 
comparison (Dupixent®) it is likely that they will benefit from study participation. With the 
above provisions in place, 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 favour of conducting the present trial. 
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6 
Trial objectives and endpoints 
Trial objectives and endpoints are presented in Panel 3. Further details about the statistical 
analyses of the endpoints are presented in Section 14.3. 
Panel 3: Objectives and endpoints 
Objectives 
Endpoints 
Primary objective 
 
To investigate the molecular 
signature changes in subjects with 
moderate to severe atopic dermatitis 
(AD) following treatment with LEO 
138559 and Dupixent® 
Primary endpoint 
• 
Change in biomarkers typically associated with atopic 
dermatitis in lesional skin biopsies from baseline to 
week 4.  
Secondary objective 
 
To evaluate the safety of LEO 138559 
in subjects with moderate to severe 
AD 
Secondary endpoint 
Secondary endpoint 
• 
Number of treatment-emergent adverse events from 
baseline to week 16 per subject. 
Exploratory endpoint (ADA) 
• 
Having a positive ADA response at weeks 0, 4, 8, 12, 
16, 32, assessed separately. 
Exploratory objectives 
 
To evaluate the efficacy of LEO 
138559 and Dupixent® in subjects 
with moderate to severe AD 
Exploratory endpoints (efficacy) 
• 
Change in EASI score from baseline to week 1, 2, 4, 6, 
8, 12, and 16. 
• 
Having a decrease in EASI of at least 50% (EASI 50) 
from baseline to week 1, 2, 4, 6, 8, 12, and 16, 
assessed separately. 
• 
Having a decrease in EASI of at least 75% (EASI 75) 
from baseline to week 1, 2, 4, 6, 8, 12, and 16, 
assessed separately. 
• 
Having a decrease in EASI of at least 90% (EASI 90) 
from baseline to week 1, 2, 4, 6, 8, 12, and 16, assessed 
separately. 
• 
 Having vIGA-AD score of 0 (clear) or 1 (almost clear) 
at week 1, 2, 4, 6, 8, 12, and 16, assessed separately. 
• 
Change in Worst Daily Pruritus NRS (weekly average) 
from baseline to weeks 1, 2, 4, 6, 8, 12, and 16.Change 
in EASI score from baseline to week 1, 2, 4, 6, 8, 12, 
and 16. 
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Objectives 
Endpoints 
• 
Having a decrease in EASI of at least 50% (EASI 50) 
from baseline to week 1, 2, 4, 6, 8, 12, and 16, 
assessed separately. 
• 
Having a decrease in EASI of at least 75% (EASI 75) 
from baseline to week 1, 2, 4, 6, 8, 12, and 16, 
assessed separately. 
• 
Having a decrease in EASI of at least 90% (EASI 90) 
from baseline to week 1, 2, 4, 6, 8, 12, and 16, 
assessed separately. 
• 
Having vIGA-AD score of 0 (clear) or 1 (almost clear) 
at week 1, 2, 4, 6, 8, 12, and 16, assessed separately. 
• 
Change in Worst Daily Pruritus NRS (weekly average) 
from baseline to weeks 1, 2, 4, 6, 8, 12, and 16. 
 
To evaluate the pharmacokinetics of 
LEO 138559 in subjects with 
moderate to severe AD 
Exploratory endpoint (pharmacokinetics) 
• 
Serum concentration of LEO 138559 at weeks 0, 1, 4, 
8, 12, 16, and 32. 
To evaluate the effect of treatment 
with LEO 138559 or Dupixent® on 
disease biomarkers in subjects with 
moderate to severe AD 
Exploratory endpoints (pharmacodynamics) 
• 
Change in expression of AD disease biomarkers in 
skin biopsies from baseline to week 1 and 16. 
• 
Change in expression of additional AD disease 
biomarkers in serum from baseline to week 1, 4, and 
16. 
• 
Change in expression of additional AD disease 
biomarkers in skin tape strips from baseline to week 1, 
4, and 16. 
Abbreviations: AD = atopic dermatitis; EASI = Eczema Area and Severity Index; EASI 50/75/90 = at least 
50%/75%/90% decrease in EASI score; NRS = numeric rating scale; vIGA-AD = validated 
Investigator Global Assessment for AD 
 
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7 
Trial design 
7.1 
Overall trial design 
This is a randomised, double-blinded, active comparator-controlled, 16-week, single-site, 
exploratory, mechanistic trial to assess the effect of LEO 138559 on the molecular signature 
and safety in adults with moderate to severe AD. A schematic overview of the trial design is 
presented in Panel 1. 
The trial will consist of:  
• A screening period of up to 4 weeks (weeks -4 to 0) including an applicable washout 
period of 7 days (week -1 to 0). 
• A treatment period of 16 weeks (weeks 1 to 16). 
• A follow-up period of 16 weeks (weeks 17 to 32). 
On day 1 (visit 3) subjects will be randomised to either LEO 138559 or the comparator. The 
primary endpoint will be assessed at week 4. The final safety assessments will be conducted 
at week 16 (end of treatment). 
The subject’s visit schedule and the procedures and assessments to be conducted at each visit 
are presented in Section 4. If necessary, an unscheduled visit can be performed at any time 
and for any reason at the discretion of the investigator. 
Screening period (up to 4 weeks prior to the baseline visit [day 1]) 
Subjects’ eligibility to enter the clinical trial will be evaluated at a screening visit (visit 1) 
including the check of washout periods for systemic treatments. This visit will be performed 
up to 4 weeks before the baseline visit (visit 3).  
Subjects will be reminded with a phone call (visit 2) at the beginning of the washout period 
(7 days before the baseline visit [visit 3, day1]), to stop any treatment with TCS, TCI, PDE-4 
inhibitors, or other topical prescription AD treatments, and start application of an emollient to 
all affected areas of the skin twice daily (or more frequently, if needed). The daily application 
of the emollient should continue throughout the treatment period. At the screening visit 
(visit 1), the subjects will be provided with a diary and will be instructed to record the Worst 
Daily Pruritus NRS and the application of the above-mentioned daily application of 
emollients. Completion of the diary will be initiated at the latest 1 week prior to the baseline 
visit (visit 3, day 1). 
All procedures will be performed as specified in Panel 2. 
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Treatment period (week 1 to week 16) 
After confirmation of the eligibility at the visit 3 (day 1) the assessments as specified in 
Panel 2 and Panel 6 (sequence of assessments) will be performed and the subjects will be 
randomised. LEO 138559 or comparator injections will be administered at the trial site by site 
staff Q2W for 16 weeks (Section Administration of investigational medicinal products9.2). 
Only site staff responsible for handling of IMPs and preparation and administration of the 
injections will be unblinded and will not be involved in the efficacy and safety assessments 
during the trial. In addition to the Q2W dosing schedule, the LEO 138559 treatment group 
will receive an additional dose of their allocated treatment at visit 4 (week 1). Subjects 
randomised in the comparator treatment group will receive the same number of injections as 
subjects in the LEO 138559 treatment group to keep the blinding (as further detailed in a 
separate trial product handling manual and the blinding plan). The additional injections will 
include saline solution. During the treatment period, the subject will be asked to continue 
applying the emollient twice daily (or more frequently, if needed). The subject will be asked 
to visit the clinic for assessments and procedures for 9 visits (until week 16) as specified in 
Panel 2. Final dosing will be administered at week 14, regardless of AD improvement.  
Safety follow-up period (week 17 to week 32) 
In the safety follow-up period, the subject will not receive any treatment with LEO 138559 or 
comparator injections. The safety of the subject will further be assessed at 3 safety follow-up 
phone calls (weeks 20, 24, and 28) and at a final safety follow-up visit at week 32. Topical 
treatment for AD will be permissible during the safety follow-up period. At the end of trial 
visit the diary will be collected and assessments will be conducted as specified in Panel 2. 
Subjects who require treatment with other biologics will prematurely discontinue the trial. 
Subjects who discontinue the trial early should be requested to return for an early 
termination / end of trial visit (see also Section 10.3) at the time of the decision to withdraw 
from the study.  
7.2 
Number of subjects needed 
This trial will be conducted at one site in Austria. Approximately 12 subjects will be 
randomised in a 2:1 ratio to LEO 138559 450 mg Q2W (8 subjects) and comparator 300 mg 
Q2W (4 subjects) to be able to achieve 12 subjects evaluable for the primary endpoint i.e., for 
whom a lesional biopsy is available at baseline and week 4.  
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The statistical considerations for this sample size are described in Section 14.1.  
7.3 
End-of-trial definition 
A subject is considered to have completed the trial if they have completed all periods of the 
trial including the safety follow-up visit at week 32 (see Section 11.8 for data to be recorded 
on the end-of-trial form). 
The end of the trial is defined as the date of the last visit of the last subject in the trial. 
Final collection of data for the primary endpoint occurs at week 4. Therefore, the primary 
completion date is defined as the date of last week 4 visit for the last subject in the trial. 
 
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8 
Trial population 
8.1 
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 Panel 2. It will be recorded in the electronic case report 
form (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. 
8.2 
Inclusion criteria 
The subjects must fulfil all of the following criteria to be eligible for the trial: 
1. Signed and dated informed consent has been obtained prior to any protocol-related 
procedures. 
2. 18 – 64 years old (both included) at screening. 
3. Diagnosis of AD [as defined by the AAD Consensus Criteria [43] that has been present for 
≥1 year prior to screening. 
4. Subjects who have a recent history (within 6 months before screening) of inadequate 
response to treatment with topical medication, or for whom topical treatments are 
otherwise medically inadvisable.  
• 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 (±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 
6 months are considered as inadequate responders to topical treatment and are 
potentially eligible for trial inclusion after appropriate washout. 
5. EASI score ≥12 at screening and ≥16 at baseline. 
6. vIGA-AD score ≥3 at screening and baseline. 
7. Body surface area (BSA) of AD involvement ≥10% at screening and baseline. 
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8. Worst Daily Pruritus NRS (weekly average) of ≥3 points at baseline.  
NOTE: The baseline weekly average will be calculated from daily assessments of itch 
severity during the 7 days immediately preceding randomisation. A minimum of 4 daily 
itch scores out of the 7 days is required to calculate the baseline average score. Only for 
subjects who do not have at least 4 daily itch scores reported during the 7 days 
immediately preceding the planned randomisation date, randomisation can be postponed 
until the requirement of 4 daily entries is met, but without exceeding the 28-day maximum 
duration for screening. 
9. Subject agrees to apply an emollient twice daily (or more frequently, if needed) to AD 
lesional and non-lesional skin for at least 7 days before baseline. 
10. A woman of childbearing potential* must have a negative serum pregnancy test at 
screening and a negative urine pregnancy test at baseline. 
11. A woman of childbearing potential* must use a highly effective** form of birth control 
throughout the trial and at least for 18 weeks after last administration of IMP. 
* A woman of childbearing potential is defined as a female subject aged ≥12 years old 
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 without an alternative 
medical cause prior to screening), 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, intrauterine 
device (IUD), intrauterine hormone-releasing system (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 vasectomised 
partner (given that the subject is monogamous). 
8.3 
Exclusion criteria 
Subjects are not eligible for the trial if they violate any of the following criteria: 
1. Treatment with systemic immunosuppressive/immunomodulating medication (excluding 
systemic antihistamines if taken at stable dose already before baseline), e.g., JAK 
inhibitors, immunoglobulin/blood products within 2 weeks or 5 half-lives prior to 
baseline, whichever is longer. 
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2. Treatment with systemic corticosteroids within 4 weeks prior to baseline  
NOTE: Inhaled or intranasal steroids equivalent to doses including and up to 500 µg 
beclometasone (or equivalent) daily is allowed. 
3. Intake of nonsteroidal anti-inflammatory drugs (NSAIDs) within 1 week prior to 
baseline. 
NOTE: Intake of paracetamol will be allowed. 
4. Treatment with biologics within 5 half-lives (if known) or 16 weeks prior to baseline, 
whichever is longer. 
5. Allergen immunotherapy within 4 weeks prior to baseline. 
6. Treatment with TCS, TCI, topical PDE-4 inhibitor, or other topical prescription 
treatments (i.e., medications or prescription emollients/moisturisers (other than the ones 
allowed during treatment period) used for the treatment of AD) within 1 week prior to 
baseline.  
NOTE: Subject may be rescreened (once) if failed for this criterion (see Section 8.4). 
7. Use of tanning beds or phototherapy (narrow band ultraviolet B [NBUVB], ultraviolet B 
[UVB], ultraviolet A1 [UVA1], psoralen + ultraviolet A [PUVA]) within 4 weeks prior to 
baseline. 
8. Treatment with a live (attenuated) vaccine within 12 weeks prior to baseline. 
9. Active dermatologic condition that could confound the diagnosis of AD or interfere with 
assessment of the treatment. 
10. History of malignancy within 5 years prior to baseline, apart from non-metastatic basal 
cell carcinoma, squamous cell carcinoma of the skin, or cervical carcinoma in-situ, 
considered cured by the standard of care. 
11. Clinically significant active chronic or acute infection requiring systemic treatment 
within 4 weeks prior to baseline that may compromise the safety of the subject.  
NOTE: Subject may be rescreened (once) after infection resolves (see Section 8.4). 
12. Skin infection within 1 week prior to the baseline visit.  
NOTE: Subject may be rescreened (once) after infection resolves (see Section 8.4). 
13. Current or recent (within 2 years prior to baseline) gastrointestinal ulcers. 
14. History of any of the following: anaphylaxis, immune complex disease, pancreatic 
disease, inflammatory bowel disease or known or suspected history of 
immunosuppressive disorder. 
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15. Known or suspected hypersensitivity to any component(s) of the IMPs. 
16. Known or suspected hypersensitivity to local anesthetics. 
17. Presence of hepatitis B or C infection at screening. These are defined as: 1) Positive 
hepatitis C Ab, or 2) Positive HBsAg, or 3) Negative anti-HBs Ab AND positive 
anti-HBc Ab. 
18. History of human immunodeficiency virus (HIV) infection or positive HIV serology at 
screening. 
19. Subject has a positive or indeterminate Mycobacterium tuberculosis IFN-γ release assay 
test or a positive purified protein derivative (PPD) test at screening.  
NOTE: The PPD test is only accepted if it is a requirement from local health authorities. 
20. Current diagnosis of diabetes. 
21. Clinically significant abnormalities detected on vital signs or ECG (apart from 1st degree 
atrioventricular (AV) block that is allowed). 
22. Serious heart conditions (e.g., heart failure, coronary artery disease, congenital heart 
disease, cardiomyopathies, and/or pulmonary hypertension). 
23. Chronic lung diseases (e.g., chronic obstructive pulmonary disease, idiopathic pulmonary 
fibrosis, and/or cystic fibrosis). 
24. Acute asthma, acute bronchospasm, moderate to severe asthma [as defined by GINA 
guidelines [44]]. 
25. Obesity (BMI ≥35). 
26. Subject has laboratory abnormalities that, in the opinion of the investigator, will prevent 
the subject from completing the trial or interfere with the analysis of results. 
27. Subject is pregnant or lactating. 
28. Subject has a history of chronic alcohol or drug abuse within 12 months prior to 
screening, or any condition associated with poor compliance as judged by the 
investigator. 
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. Any disorder* at screening and/or baseline, which is not stable in the opinion of the 
investigator, and could: 
a. 
Affect the safety of the subject throughout the trial. 
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b. Influence the findings of the trial. 
c. 
Impede the subject’s ability to complete the trial. 
*Examples include but are not limited to endocrine, gastrointestinal, hepatic, 
immunological, infectious, metabolic, musculoskeletal, neurological, and major 
physical impairment. 
31. Any significant abnormal finding* at baseline and/or screening which may in the opinion 
of the investigator: 
a. 
Put the subject at risk because of their participation in the trial. 
b. Influence the results of the trial. 
c. 
Influence the subject’s ability to complete the trial. 
*Examples include clinically significant abnormal vital sign, physical examination, 
ECG, and laboratory result. 
32. 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 baseline, whichever is longer. 
33. Current participation in any other interventional clinical trial. 
34. Previously randomised in this clinical trial. 
35. Subjects who are legally institutionalised. 
8.4 
Screening and screening failures 
Subject identification number 
Trial participation begins once written informed consent is obtained. Refer to Appendix 3B 
for details on the informed consent process. Once informed consent is obtained, subjects will 
be assigned to ascending subject identification numbers (subject ID) in the order of their 
appearance at screening and the screening evaluations to assess eligibility criteria may begin. 
The subject ID will be automatically generated by the eCRF system. The generation and 
composition of the subject ID will be described in the Completion Guide for the eCRF. The 
date of first screening activity could be on the same day or a later date than the informed 
consent was signed. 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.  
The investigator will maintain a log of all consented subjects at the trial site (subject 
identification list) including subjects who are not randomised in the trial/ treatment assigned. 
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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 date of screening and the 
status (screening failure or randomised) should also be documented. The log must not be 
copied or retained by LEO Pharma. All subjects who signed the informed consent form must 
be entered into the eCRF. 
Screening failures 
Screening failures are defined as subjects who consent to participate in the trial but are not 
subsequently [randomly] assigned to trial treatment. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure subjects to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements [43] and to 
respond to queries from regulatory authorities. As a minimum, the following data will be 
collected in the eCRF for screening failures: 
• Date of informed consent(s). 
• Demographics (age, sex, ethnicity, race). 
• Reason for screen failure. 
- 
Failure to meet eligibility criteria. 
- 
Lost to follow-up. 
- 
Withdrawal by subject. 
- 
Other. 
• Date of screen failure. 
• Re-screening of the subject, if applicable 
• Any adverse events (AEs) and serious AEs (SAEs). 
In case of any SAEs, these must be followed up as described in Section 13. 
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.  
• if the reason for screening failure is administrative and not due to the subject not meeting 
the eligibility criteria (e.g., delayed test results), 
• an infection resolves after initially not having met exclusion criteria no. 11 (active chronic 
or acute infection requiring systemic treatment) or no. 12 (skin infection), 
• if the subject failed exclusion criterion no. 6 (treatment with TCS, TCI, or topical PDE-4 
inhibitor, or other topical prescription treatments within 7 days 1 week prior to baseline). 
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Rescreening may be permitted once and 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. Rescreened subjects will get a new subject ID. 
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9 
Treatments 
9.1 
Trial product description 
In this trial the test drug LEO 138559 and the comparator Dupixent® will be used. 
LEO 138559 is presented as a lyophilised powder for reconstitution and administration as 
injection. The comparator will be used as commercially available product and is presented as 
pre-filled syringe for injection. 
Refer to Panel 4 for further details. 
Panel 4: Identification of investigational medicinal products 
Investigational 
medicinal 
product 
Dosage form 
 
Active ingredients 
and concentration 
Pack sizes 
Manufacturer 
responsible 
for batch 
release  
LEO 138559 
Lyophilised powder for 
reconstitution (using 
1.0 mL sterilised water) 
adding up to a volume of 
1.2 mL/vial to achieve a 
solution for SC injection 
LEO 138559, 
150 mg/mL 
(following 
reconstitution) 
1 vial for 
150 mg/mL 
(following 
reconstitution) 
LEO Pharma 
Dupixent® 
Pre-filled syringe with 
300 mg in 2 ml solution 
for SC injection 
Dupilumab, 
150 mg/mL. 
300 mg pre-
filled syringe 
Sanofi-Aventis 
Groupe 
Note: To ensure that 1.0 mL can be withdrawn by a syringe, there will be a small overfill in the test drug vial 
after reconstitution, of approximately 0.2 mL per vial.  
Abbreviation: SC = subcutaneous(ly). 
9.2 
Administration of investigational medicinal products 
The IMP will be administered to the subject according to the schedule of trial procedures 
(Section 4). The first day of dosing is considered day 1. For blinding purposes all subjects will 
receive the same number of injections i.e., subjects in the comparator treatment group will 
receive injections with saline solution in addition to their injection of Dupixent®. Sterile water 
for reconstitution of LEO 138559 and saline solution for additional injections will be taken 
from the stock at the trial site. Details on the handling of the IMP and related procedures to 
maintain blinding will be described separately (trial product handling manual and blinding 
plan). 
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To further ensure blinding of subjects, subjects will be asked to cover their eyes (e.g., with a 
sleep mask or a loose bandage) prior to the administration of the IMP. 
IMP will be administered by subcutaneous injections every other week (Q2W) during the 
treatment period.  While subjects in the LEO 138559 treatment group will receive an 
additional dose in week 1 (visit 4), subjects in the comparator group will receive injections 
with saline solution at visit 4.  
During the treatment period, final dosing will be administered at week 14 and the clinical 
assessment will occur at week 16. IMP administration will continue until week 14, regardless 
of AD improvement. 
IMPs will be prepared and administered at the site by qualified, unblinded site staff as the two 
IMPs are distinct in appearance and dosing scheme (for details about blinding see 
section 9.3.2). IMP (or saline solution) will be injected SC in the upper legs (thighs), stomach 
area (abdomen, except in an area of 5 cm around the navel) 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. The anatomical location of the injection, and if it was on the right or left side, 
must be recorded in the source documents at each treatment visit and recorded in the eCRF.  
At each treatment visit, the 3 injections (of IMP or saline solution) must be administered 
within a maximum of 10 minutes. The 3 injections should be administered in the same 
injection site area (e.g., upper right arm) separated by at least 3 cm. The site of injection 
should be rotated such that the subject receives IMP at a different anatomical site at each 
treatment visit. If for some reason the injection site was not rotated, this should be 
documented, and a reason should be recorded in the eCRF. 
If any issues with the IMPs (e.g., damaged kit or vial/syringe) or a malfunction during 
administration should arise, please refer to the trial product handling manual supplied by LEO 
Pharma. 
LEO 138559 administration: 
Each subject in the LEO 138559 treatment group will receive 3 SC injections (each 1.0 mL) 
of 150 mg LEO 138559 to receive a total dose of 450 mg LEO 138559. In addition to the 
Q2W dosing schedule, LEO 138559 treatment group will receive an additional dose at visit 4 
(week 1). Further details on preparation and administration of LEO 138559 will be provided 
in an instruction for use and trial product handling manual. IMP administration must be 
carried out according to these instructions. 
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Comparator (Dupixent®) administration: 
Dupixent® is approved for the treatment of moderate to severe AD in adults in Austria and 
will be administered according to the prescribing information. On day 1 each subject in the 
comparator treatment group will receive 2 SC injections (each 2.0 mL) of the comparator 
300 mg Dupixent® to receive an initial dose of 600 mg dupilumab. On subsequent dosing 
days the comparator will be administered by site staff as 1 SC injection of 2 mL (300 mg 
dupilumab). For blinding purposes, subjects will receive 1 additional SC injection with 1 mL 
saline solution on day 1 and 3 SC injections with saline solution (each 1.0 mL) at visit 4. On 
subsequent dosing days subjects will receive 2 SC injections with saline solution (each 
1.0 mL) in addition to the injection of the comparator. 
After IMP administration 
For the first 3 treatment visits (i.e., visits 3, 4, and 5), subjects will be monitored after their 
injections for immediate drug reactions for a minimum of 1 hour with vital signs taken 
immediately after the injections as well as after 30 minutes (± 5 minutes) and after 1 hour 
(± 5 minutes), or until stable, whichever is later. Vital signs will be documented in the eCRF. 
As with any antibody, allergic reactions to dose administration are possible. The World 
Allergy Organisation has categorised anaphylaxis into 2 subgroups: allergic anaphylaxis 
(mediated by an immunologic mechanism) and nonallergic anaphylaxis (which has a 
nonimmunologic cause) [44]. The clinical criteria for defining anaphylaxis for this trial are 
listed in Appendix 5 and [45]. 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 recognise and 
respond to anaphylaxis according to local guidelines. 
If an anaphylactic reaction occurs, a blood sample will be drawn from the subject as soon as 
possible after the event, at 60 minutes ± 30 minutes after the event, and 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 (e.g. viral illnesses). 
• The subject is febrile (defined as ≥38°C; ≥100.4°F) within 72 hours prior to IMP 
administration. 
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If the trial visit cannot be rescheduled in order to maintain minimum of 7 days to subsequent 
dose, the sponsor’s medical expert should be contacted. 
There are no specific treatment recommendations in relation to overdose of the IMP. The 
investigator will monitor the subject for any signs or symptoms of adverse reactions and 
institute appropriate symptomatic treatment immediately according to clinical judgement to 
treat any overdose if necessary. For reporting of overdose, see Section 13.6.1. 
9.3 
Treatment assignment and blinding 
9.3.1 
Treatment assignment 
Treatment assignment will be pre-planned according to a computer-generated randomisation 
schedule. This randomisation schedule randomly allocates subjects who have been found to 
comply with all the inclusion criteria and not to violate any of the exclusion criteria on day 1 
(visit 3) in a 2:1 ratio to one of the two treatments, LEO 138559 or comparator. 
Randomisation envelopes will be provided to the site. The randomisation number has to be 
documented in the CRF. 
9.3.2 
Blinding 
This is a double-blinded trial in which LEO 138559 and comparator are visually distinct from 
each other and have a different dosing scheme. Neither the subject nor any of the investigators 
or LEO Pharma staff (except unblinded CRAs) who are involved in the clinical evaluation 
and monitoring of the subjects will be aware of the treatment received. IMP and syringes will 
be prepared and administered by a qualified, unblinded trial site staff who will not be 
involved in the management of trial subjects and who will not perform any of the 
assessments. 
Three syringes will be prepared by unblinded site staff for each subject at each dosing visit 
containing either LEO 138559 or, for subjects in the comparator group, Dupixent® and saline 
solution (to account for 3 syringes in total). Before administration of the injections, subjects 
will be blinded i.e., their eyes will be covered (e.g., by a sleep mask) as specified in a blinding 
plan, so they are not able to identify which treatment they receive. 
In the event that the treatment allocation for a subject becomes known to the investigator or 
other trial staff involved in the management of trial subjects, LEO Pharma must be notified 
immediately.  
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The trial site will maintain a written plan (site blinding plan) that specifies which staff 
members are blinded or unblinded and the procedures used to maintain blinding including the 
measures to keep the blinding for the subjects. 
9.3.3 
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, health care professionals (HCPs) who are not members of the trial 
staff, or authorised LEO Pharma personnel. 
Provisions are in place for 24-hour emergency unblinding of individual subject treatment. If 
emergency unblinding is required, the requesting person can directly contact the emergency 
unblinding CRO via a corresponding local emergency unblinding telephone number, that can 
be found in the Investigator Site File (ISF). 
The investigator or delegated site staff will need to provide the trial ID, the subject ID and the 
randomisation code number of the subject to the emergency unblinding CRO who will 
immediately reveal the individual treatment allocation. 
For a requester who is not a member of the site staff (e.g., a physician in an emergency room), 
the local contact number for the emergency unblinding CRO will be provided on the subject 
card (Appendix 3B) to be used if the investigator or delegated site staff cannot be reached. 
The requester need to provide the trial ID, the subject ID and the randomisation code number 
to the emergency unblinding CRO, that will immediately reveal the individual treatment 
allocation. 
The emergency unblinding CRO will clarify that the requester requires immediate unblinding 
without further medical consultation. 
Unblinding should only be done in case of an emergency and when it is essential for effective 
treatment of the subject. Most often, trial drug discontinuation and knowledge of the possible 
treatment assignments are sufficient to treat the subject. The Sponsor is to be informed 
immediately about any unblinding event. 
Documentation of any emergency unblinding by the assessor should include the date of the 
unblinding and the reasons that led to unblinding. It has to be reported on the blind break form 
filed in the Investigators site file. In addition, AEs or SAEs related to the unblinding have to 
be reported appropriately. 
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LEO Pharma Global Safety will receive a set of emergency envelopes, including the identity 
of the product codes for potential unblinding for regulatory purpose. 
9.4 
Background treatment 
All subjects must use an emollient twice daily (or more frequently, if needed) for at least 
7 days before day 1 (baseline) and throughout the treatment period (until week 16). Subjects 
should use the same emollient throughout the trial.  
Subjects may continue using stable doses of their moisturizers if initiated before the screening 
visit. Subjects may not initiate treatment with prescription moisturizers or moisturizers 
containing additives (ceramide, hyaluronic acid, urea, filaggrin degradation products) during 
the screening period or during the treatment period. To ensure use of a suitable emollient, the 
investigator should provide guidance to the subject as to which locally available emollient to 
use. 
The function of the emollient is to: 
• Keep the subject’s skin well moisturised in the absence of systemic and/or topical AD 
treatment(s) in the washout period (week -1 to week 0). 
• Act as a complement to systemic treatment with the IMP (standard of care) and keep the 
subject’s skin well moisturised in the treatment period (week 1 to week 16). 
The subjects will document the use of the emollients in the diary. It will be recorded in the 
eCRF if background treatment (emollient) has been used daily; if not, a reason should be 
provided. 
9.5 
Rescue treatment 
In case subjects require additional treatment for atopic dermatitis during the treatment phase, 
as a first step, TCS / TCIs are recommended, and administration of study drug will be 
continued. Should other systemic AD therapy be required (e.g., cyclosporin A, oral JAK 
inhibitors, oral corticosteroids), the IMP administration should be stopped, and the subject 
will be withdrawn from the trial. Any use of AD therapy other than the trial treatment (see 
also section 9.7) needs to be documented in detail in the eCRF including use of emollients 
(see also section 9.4.) 
9.6 
Concomitant medication and concurrent procedures 
Any medication or vaccine that the subject receives from 3 months prior to screening through 
to safety follow-up must be recorded in the subject’s medical record and the eCRF along with 
details such as: 
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• Medication name or therapy (generic or brand name). 
• Indication. 
• Start and stop date of administration (it will also be recorded if the medication is 
ongoing). 
• Dosage information, including dose per administration, unit, and frequency. 
• Route of administration: oral, topical, subcutaneous, transdermal, intraocular, 
intramuscular, respiratory (inhalation), intralesional, intraperitoneal, nasal, vaginal, rectal, 
intravenous, or other (if other, a specification must be provided).  
For topical treatments, the dosage form (cream, lotion, ointment, other) will also be 
recorded.  
For topical, SC, transdermal, intramuscular, and intralesional treatments, the location of 
administration including laterality will also be recorded (e.g. left upper arm). 
Similarly, any concurrent procedure must also be recorded in the subject’s medical record and 
the eCRF. The following details will be recorded: 
• Procedure name (including anatomical area, if relevant),  
• Body location (upper limb, lower limb, trunk, head)  
• Indication 
• Start and stop date (it will also be recorded if the procedure is ongoing). 
It should be included whether the procedure is inside the area of injection or the area of an AD 
lesion. 
Investigators may prescribe concomitant medications or treatments to provide adequate 
supportive care as deemed necessary, except for medications listed in Section 9.7. The 
sponsor’s medical expert should be contacted if there are any questions regarding concomitant 
or prior therapy. 
The following concomitant medications are permitted from screening through safety follow-
up: 
• Paracetamol use (maximum 2 g/day).  
• Systemic antihistamines, if taken at a stable dose before baseline 
• Concomitant therapies taken for the long-term treatment of pre-existing conditions 
can continue during the trial provided they are in accordance with the exclusion 
criteria (see Section 8.3). 
• Inhaled or intranasal steroids equivalent to doses including and up to 500 µg 
beclometasone (or equivalent) daily 
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9.7 
Prohibited medication(s) and procedures 
The medications and/or procedures listed in Panel 5 are prohibited during the trial. Details 
regarding prohibited medications and/or procedures prior to screening and during wash-out(s) 
are described in Section 8.3.  
Panel 5: Prohibited medication(s) and/or procedure(s) 
Medication or procedure 
Prohibited from 
Prohibited to 
TCS, TCI or topical PDE-4 
inhibitors. 
7 days prior to baseline 
(Washout). 
Week 16. 
Other topical prescription 
medications or prescription 
emollients/moisturisers (other 
than the ones allowed during 
treatment period) used for the 
treatment of AD. 
7 days prior to baseline 
(Washout). 
Week 16. 
Intake of nonsteroidal anti-
inflammatory drugs 
(NSAIDs), except 
Paracetamol  
7 days prior to baseline 
Week 16. 
Use of UVA, UVB, PUVA, 
other phototherapy, or tanning 
beds. 
4 weeks prior to baseline. 
Week 16. 
Immunoglobulin or blood 
products. 
4 weeks or 5 half-lives prior 
to baseline, whichever is 
longer. 
Safety follow-up (week 32). 
Systemic corticosteroids 
(excluding inhaled or intra-
nasal steroids). 
4 weeks prior to baseline. 
Safety follow-up (week 32). 
If medically indicated and deemed 
necessary at investigator’s 
discretion a patient may receive 
therapies with systemic 
corticosteroids during the safety 
follow-up. 
Systemic 
immunosuppressive/immuno- 
modulating medication, 
(excluding systemic 
antihistamines if taken at a 
stable dose before baseline), 
e.g., JAK inhibitors. 
2 weeks or 5 half-lives prior 
to baseline, whichever is 
longer.  
Safety follow-up (week 32). 
If medically indicated and deemed 
necessary at investigator’s 
discretion a patient may receive 
therapies with systemic 
corticosteroids during the safety 
follow-up. 
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Medication or procedure 
Prohibited from 
Prohibited to 
Biologics 
16 weeks or 5 half-lives prior 
to baseline, whichever is 
longer. 
Safety follow-up (week 32). 
If medically indicated and deemed 
necessary at investigator’s 
discretion a patient may receive 
therapies with systemic 
corticosteroids during the safety 
follow-up. 
Allergen immunotherapy. 
4 weeks prior to baseline. 
Safety follow-up (week 32). 
If medically indicated and deemed 
necessary at investigator’s 
discretion a patient may receive 
therapies with systemic 
corticosteroids during the safety 
follow-up. 
Live (attenuated) vaccine. 
12 weeks prior to baseline. 
Safety follow-up (week 32). 
Abbreviations: AD = atopic dermatitis; PDE-4 = phosphodiesterase-4; PUVA = psoralen ultraviolet A; TCI = 
topical calcineurin inhibitor(s); TCS = topical corticosteroid(s); UVA = ultraviolet A; UVB = ultraviolet B. 
In case any prohibited treatments are used during the trial, they must be recorded as 
concomitant medication and the sponsor’s medical expert must be notified immediately if a 
subject receives any of these prohibited medications during the trial.  
9.8 
Treatment logistics and accountability 
9.8.1 
Labelling and packaging of trial products 
IMPs will be packed open label in individually numbered kits. 
Primary and secondary packaging materials (vial or prefilled syringe and outer carton, 
respectively) will be individually labelled. 
The labelling of IMPs will be in accordance with the EU guidelines for Good Manufacturing 
Practices for Medicinal Products for Human and Veterinary use, Annex 13 [46], local 
regulations, and trial requirements. Label text will be translated into local languages as 
required.  
9.8.2 
Storage of trial products 
Storage of IMP 
All LEO Pharma supplied IMPs must be stored in a secure and restricted area under the 
conditions specified on the label and remain in the original container until dispensed. 
The IMPs must be stored protected from light at 2 to 8°C and remain in the original container 
until used at the site. The temperature during storage must be monitored by a calibrated, 
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stationary, and continuously monitoring system. Minimum requirement is a calibrated 
min/max thermometer.  
A temperature log must be kept documenting the storage within the right temperature interval. 
Storage facilities should be checked at least every working day. In case of temperature 
excursions upon receipt or during storage, please refer to the Trial Product Handling Manual 
supplied by LEO Pharma. 
Storage of IMPs may be delegated, e.g., to a hospital pharmacy, as locally and must be 
documented in the site signature and designation of responsibility log. 
Note that in the cases listed below, the site staff should not use the affected IMP and should 
immediately contact their CRA for further guidance: 
• Temperature excursion upon receipt or during storage at the trial site. 
• Damaged kit upon receipt. 
• Damaged vial/syringe. 
Damaged IMP should not be used.  
9.8.3 
Investigational medicinal product accountability 
The investigator is fully responsible for the IMPs at the trial site and for maintaining adequate 
control of the IMPs and for documenting all transactions with them. 
Dispensing of IMPs 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. 
Documentation of IMP accountability must be kept for the IMPs administered to each 
individual subject randomised in the trial. This documentation must be available during 
monitoring visits and will be checked by an unblinded CRA to verify correct administration of 
the IMPs. Drug accountability information will be recorded by unblinded site staff for 
individual drug accountability per subjects as well as for the inventory status of all IMPs at 
the trial site on paper forms.  
All [unused] IMPs (including packaging material) supplied by the contract manufacturing 
organisation (CMO) on behalf of LEO Pharma will be returned to the CMO. Prior to their 
return, the IMP must be fully accounted for by the unblinded CRA with the help of the 
unblinded site staff. Accountability must be documented on drug accountability forms.  
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IMPs will be returned from the trial site to the CMO directly. For more information about 
handling of IMPs at site, including drug accountability and reconciliation, please refer to the 
Trial Product Handling Manual. 
9.8.4 
Treatment compliance 
IMP injections will be performed by unblinded site staff who will document the total number 
of injections administered per treatment day in the eCRF. 
In case of non-compliance, details which injection was not administered in the comparator 
treatment group (i.e., Dupixent® or saline) will be documented as specified in the blinding 
plan. 
Reporting in eCRF 
The following data will be recorded in the eCRF: 
• IMP application according to dosing schedule (yes, no); If no, a reason will be given. 
• Primary reason for non-compliance – lack of time, adverse event, other (if other, a 
specification should be provided). 
• Date and time of injections (stated for each of the injections per visit separately). 
• Site of injection: For the site (upper leg [thigh], stomach area [abdomen] or in the upper, 
outer arm) the laterality should be specified (right or left). 
 
9.8.5 
Trial product destruction 
All used LEO 138559 vials and unused IMP must be returned to the CMO and will be 
destroyed by the CMO according to approved procedures and/or local requirements.  
Empty comparator syringes and syringes used for administration of IMP and saline solution 
can be destroyed at site provided the trial site has procedures in place for such destruction. 
Trial sites which do not have such IMP destruction procedures in place will dispose used IMP 
syringes in sharps bins which will be shipped to the CMO. 
9.9 
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. 
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9.10 Reporting product complaints 
Any defects or issues with the IMP must be reported to the Quality department via Global 
Safety at LEO Pharma on the trial-specific (paper) complaint form within 3 days of first 
knowledge.  
Critical complaints (defined as any defect, issue, that has or potentially could have a serious 
impact on the subject [e.g. SAE or large particles in the vial) must be reported to the Quality 
department via Global Safety within 24 hours of knowledge.  
Complaint forms should contain a detailed description of the defect, issue, including whether 
it led to an AE. (S)AEs which occur due to a defect or issue with the IMP will be reported by 
the investigator as described in Sections 13.3 and 13.4.  
During the investigation of the product complaint, the IMP must be stored at labelled 
conditions unless otherwise instructed; the trial site will be notified whether the IMP 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 
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10 Discontinuation and withdrawal 
10.1 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 10.3. Early termination assessments to be conducted for both events are described 
in Section 10.3. 
If a subject withdraws from the trial, they may request destruction of any samples taken and 
not tested. The investigator must document this in the subject’s medical record and inform 
LEO Pharma. 
10.2 Reasons for discontinuation of IMP 
10.2.1 
Reasons for permanent discontinuation of IMP 
Subjects will permanently discontinue IMP in the event of: 
• Withdrawal by subject 
• An AE that, in the opinion of the investigator or sponsor’s medical expert, 
contraindicates further dosing. 
• Confirmed clinically significantly abnormal ECG or change in ECG.  
• Initiation of prohibited medication which cannot be safely replaced by other 
non-prohibited medications. 
• Evidence of pregnancy, or if the subject is noncompliant with the contraception 
requirements (see Section 8.2). 
• Symptomatic infection with SARS-CoV-2 that is likely to have an impact on efficacy or 
safety data (i.e., patients with a SARS-CoV-2 infection without or very mild symptoms 
only (e.g., rhinitis or sore throat) might continue with the study at investigator’s 
discretion and in accordance with the applicable local regulations).. 
• Other reasons, at the discretion of the investigator. If other, a specification should be 
provided. 
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It is not allowed to restart IMP treatment after discontinuation of IMP. 
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 where the following options are available:  
• Death. 
• Pregnancy. 
• Adverse event. 
• Use of prohibited concomitant medication 
• Lack of efficacy. 
• Withdrawal by subject. 
• Lost to follow-up. 
• Other. 
If ‘adverse event’ or ‘other’ is selected, a specification must be provided in the eCRF. If 
adverse event is selected, the AE in question will be linked to the IMP discontinuation. 
If ‘withdrawal by subject’ is selected, it will be recorded whether the subject withdrew 
informed consent or not. 
Discontinuation of IMP due to COVID-19 pandemic will be collected and specified in the 
‘Other’ category. 
10.2.2 
Reasons for temporary discontinuation of IMP 
IMP dosing may be temporarily suspended in the event of: 
• COVID-19 related disruption leading to site closure. 
A decision to discontinue IMP temporarily or to reinstitute IMP treatment must be discussed 
with sponsor’s medical expert. However, the investigator may suspend trial treatment at any 
time, even without consultation with sponsor’s medical expert if the urgency of the situation 
requires immediate action and if 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. 
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10.3 Early termination assessments 
Permanent discontinuation of IMP 
Subjects who permanently discontinue IMP for any reason will be asked to attend an early 
termination visit as soon as possible after last administration of IMP and return to the trial site 
for additional visits as indicated below:   
• An early IMP termination visit as soon as possible after last dose of IMP (in case of 
early termination before week 4: a nominal week 4 visit) 
• An end of trial visit (safety follow-up visit 16 weeks after last administration of IMP). 
See the schedule of trial procedures (Section 4) for data to be collected at these visits. The 
subjects will be asked to complete the diary until end of trial visit. The investigator will 
review any AEs which will be followed up according to Section 13.7, if the subject agrees. 
Details on data to be recorded in the eCRF for subjects who permanently discontinue IMP can 
be found in Section 11.8. 
Withdrawal from trial 
Subjects who withdraw from the trial after first dose of IMP for any reason will be asked to 
attend an early termination visit as soon as possible after last administration of IMP (see the 
schedule of trial procedures [Section 4] for data to be collected at an early termination visit). 
The investigator will review any AEs which will be followed up according to Section 13.7, if 
the subject agrees. 
Details on data to be recorded in the eCRF for subjects who withdraw from the trial can be 
found in Section 11.8. 
10.4 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. 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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11 Trial assessments and procedures 
11.1 Overview 
Assessments and procedures to be conducted at each visit are listed in the schedule of trial 
procedures (Section 4) and will be conducted in the order presented in Panel 6.  
Panel 6: Sequence of assessments 
 
Abbreviations: IMP = investigational medicinal product. 
a. Laboratory assessments include PK and PD samples. PD samples include serum biomarkers, skin biopsies 
and tape strips. 
b. For the first 3 treatment visits (i.e., Visits 3, 4, and 5) subjects will be monitored after injections for 
immediate drug reactions for a minimum of 1 hour with vital signs taken immediately after injections as well 
as after 30 minutes (± 5 minutes) and after 1 hour (± 5 minutes), or until stable, whichever is later. 
 
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 physicians and 
have experience in treating AD as well as documented experience with and/or training in the 
assessments used in this trial. All dermatologic assessments must be performed by a 
dermatologist or an adequately qualified medical doctor (defined as someone with at least 
1 year post graduate experience).  
AEs must be assessed by a physician (see details in Section 13.2). 
To reduce inter-rater variability, the same investigator should, whenever possible, perform all 
the efficacy assessments for a given subject throughout the entire trial period. 
Efficacy, safety and laboratorya
assessments
Administration of  IMPb
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The investigators performing the assessments must not be involved in the preparation and 
administration of IMP (Section 9.3.2).  
11.2 Assessments performed only at screening/baseline 
11.2.1 
Demographics 
The following demographic data will be recorded: 
• Age. 
• Sex: female, male. 
• Race: American Indian or Alaska native, Asian, Black or African American, native 
Hawaiian or other Pacific islander, White, other (if other, a specification should be 
provided). 
• Ethnic origin (self-reported by the subject): “Hispanic” or “Latino”, not “Hispanic 
or Latino”. 
11.2.2 
Medical history 
Relevant medical history must be recorded:  
• Skin disease history and atopy history including: 
- 
Age at first onset of AD. 
- 
Asthma. 
- 
Food allergy. 
- 
Hay fever. 
For each condition or diagnosis, the start date and stop date will be recorded (it will also 
be recorded if the diagnosis is ongoing).  
• Other medical and surgical history including concurrent diagnoses within the previous 
12 months. For each condition, diagnosis, or surgical procedure, the start date and stop 
date will be recorded (it will also be recorded if the condition, diagnosis, or surgical 
procedure is ongoing). 
Relevant medical history also includes diseases which are specifically listed as exclusion 
criteria and diseases for which specific treatments are listed as exclusion criteria. 
11.2.3 
Height  
The subject’s height (without shoes) will be measured according to the schedule of trial 
procedure (Section 4).  
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11.3 Efficacy assessments 
11.3.1 
Validated Investigator Global Assessment Scale for Atopic Dermatitis 
The validated Investigator Global Assessment Scale for Atopic Dermatitis (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 7) [47]. The vIGA-AD score will be 
assessed according to the schedule of trial procedures (Section 4). 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 disease severity assessment score will be recorded in the 
eCRF. 
Panel 7: Validated Investigator Global Assessment Scale for Atopic Dermatitis 
Score 
Morphological description 
0 – Clear 
No inflammatory signs of atopic dermatitis (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. 
 
11.3.2 
Body surface area involvement 
The total BSA score will be assessed according to the schedule of procedures (Section 4). 
The investigator will assess the total AD involvement for the whole body, i.e. head/neck, 
upper extremities, trunk, genitalia, and lower extremities, 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.  
11.3.3 
Eczema Area and Severity Index 
The Eczema Area and Severity Index (EASI) is a validated measure used in clinical practice 
and clinical trials to assess the severity and extent of AD [48]. The EASI score will be 
assessed according to the schedule of trial procedures (Section 4). 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. 
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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 8. Briefly, the investigator will assess the severity of 4 AD disease characteristics 
(erythema, induration/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 9. For each body region, a severity sum score will be calculated 
which will be multiplied by an area score (Panel 9) and by a weighting factor. The EASI score 
equals the sum of the scores obtained for each body region (Panel 8).  
The body region, severity of the disease characteristics (erythema, induration/papulation, 
excoriation, and lichenification), and the area score will be recorded in the eCRF.  
Panel 8: Calculation of the EASI score 
Body region 
Erythema 
Induration/ 
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 [49]. 
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Panel 9: 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-steps (0.5, 1.5, 2.5) are 
allowed. 
 
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. 
11.4 Safety assessments 
11.4.1 
Vital signs 
Vital signs (blood pressure, pulse, and body temperature) will be assessed according to the 
schedule of trial procedures (Section 4). At an unscheduled visit, it will be at the discretion of 
the investigator if vital signs should be assessed.  
For the first 3 IMP treatment visits (i.e. visits 3, 4, and 5) subjects will be monitored after IMP 
administration for immediate drug reactions for a minimum of 1 hour with vital signs taken 
immediately after IMP administration as well as after 30 minutes (± 5 minutes) and after 1 
hour (± 5 minutes), or until stable, whichever is later.  
 Vital signs (blood pressure, pulse, and body temperature) will be assessed following at least 
5 minutes of rest. If a subject presents with an abnormal vital sign, the measurement of the 
vital sign can be repeated approximately 2–5 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 third 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 third measurement should be recorded in the eCRF. Only 
the last measurement considered true should be recorded in the eCRF. 
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 
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with exclusion criterion 31. 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; if not, a reason should be 
provided. Vital signs, arm used to measure blood pressure, the temperature measuring method 
(axillary, ear, oral, rectal, other), and the date and time vital signs were measured will be 
recorded in the eCRF. Clinically significant abnormal vital signs at the screening visit and 
baseline (as the subjects has not been administered treatment) will be documented as medical 
history in the eCRF. At subsequent visits, any clinically significant deterioration of a pre-
existing condition as well as any new clinically significant sign, symptom, or illness occurring 
after randomisation will be reported as an AE in accordance with Section 13.3. 
11.4.2 
Physical examination 
A physical examination of the subject including general appearance, regional lymph nodes, 
and dermatologic examination of the skin will be performed according to the schedule of trial 
procedures (Section 4). 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. 31. 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 and 
baseline will be documented as medical history in the eCRF. At subsequent visits, any new 
clinically significant abnormal findings, symptoms, or illnesses, as well as any clinically 
significant deterioration of a pre-existing condition after randomisation will be reported as an 
AE in accordance with Section 13.3. 
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11.4.3 
Weight 
Weight will be recorded according to the schedule of trial procedures (Section 4). The 
subject’s weight (in indoor clothing and without shoes) will be measured. At an unscheduled 
visit, it will be at the discretion of the investigator if weight should be measured. 
11.4.4 
Electrocardiography 
ECGs must be measured according to the schedule of trial procedures in (Section 4). At an 
unscheduled visit, it will be at the discretion of the investigator if an ECG should be 
measured.  
At the respective visit, the individual measurements as well as the average of 3 consecutive 
12-lead resting digital ECG will be recorded after the subject has been in supine position for 
at least 5 minutes. ECGs must be measured before any blood samples scheduled at the same 
visit.  
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 analyse and interpret the ECG data. The ECG 
service company will provide ECG evaluation reports to the trial sites.  
The investigator must evaluate all abnormal ECG results (‘clinically significant’ or ‘not 
clinically significant’) and sign and date. The investigator is responsible for taking the final 
decision about the clinical significance of any abnormal ECG.  
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 enrolled into the trial (respecting exclusion criteria no. 21 and 31). If a subject with 
an abnormal and clinically significant ECG result is enrolled, the investigator should provide 
a justification in the medical record. 
During the trial, if a subject presents with a clinically significant abnormal ECG or a clinically 
significant abnormal change in ECG from baseline, the ECG should be repeated. If the ECG 
or change in ECG is confirmed clinically significantly abnormal, the subject must 
permanently discontinue IMP, and be withdrawn from the trial. 
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The collection and transmission of ECG data will be described in a separate ECG manual. 
Reporting in eCRF 
It will be recorded in the eCRF if an ECG was performed and, if applicable, the investigator’s 
assessment of ECG results (‘normal’, ‘abnormal, not clinically significant’, ‘abnormal, 
clinically significant’). If an ECG was not performed, a reason should be given. 
Clinically significant abnormal ECG findings at the screening visit will be documented as 
medical history in the eCRF. At subsequent visits, any clinically significant deterioration of a 
pre-existing condition as well as any new clinically significant sign, symptom, or illness 
occurring after randomisation will be reported as an AE in accordance with Section 13.3. 
11.4.5 
Laboratory testing 
11.4.5.1 
Overview 
Pregnancy tests in female subjects of child-bearing potential must be performed at visits 
according to the schedule of trial procedures (Section 4). At visit 1 (screening), a serum hCG 
test is to be made, on the other visits, urine hCG dip tests will be made. At visit 3 (baseline), 
the test must be made prior to randomisation. Pregnant women must not be randomised into 
the trial. 
Blood and urine samples will be collected according to the schedule of trial procedures 
(Section 4) and the evaluations listed in Panel 10 will be performed. 
Panel 10: Clinical laboratory tests 
Clinical chemistry 
Haematology P2 
Sodium 
Potassium 
Creatinine 
Urea nitrogen 
Calcium  
Alkaline phosphatase  
Aspartate aminotransferase (AST) 
Alanine aminotransferase (ALT) 
Gamma glutamyl transferase  
Bilirubin1 
(Direct bilirubin)1 
(Indirect bilirubin)1 
Cholesterol 
LDL cholesterol 
Haematocrit 
Haemoglobin 
Leukocytes  
Neutrophils   
Neutrophils/leukocytes5 
Lymphocytes  
Lymphocytes/leukocytes5 
Monocytes  
Monocytes/leukocytes5 
Eosinophils  
Eosinophils/leukocytes5 
Basophils  
Basophils/leukocytes5 
Thrombocytes 
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HDL cholesterol 
Triglycerides 
Glucose (non-fasting) 
Albumin 
Protein 
Tryptase2 
Lactate dehydrogenase 
C-reactive protein 
Amylase 
Serology3 
Hepatitis B virus surface antigen 
Hepatitis B virus surface antibody 
Hepatitis B virus core antibody 
Hepatitis C virus antibody 
HIV-1 antibody 
HIV-2 antibody 
Tuberculosis test3, 7 
Mycobacterium tuberculosis IFN-γ release assay 
Urinalysis4 
Serum pregnancy test3,6 
Protein 
Glucose 
Ketones 
Occult blood 
Leukocytes 
Nitrite 
Choriogonadotropin beta 
Urine pregnancy test6, 7 
Choriogonadotropin beta dip stick 
1) 
If bilirubin is above upper limit of normal, direct and indirect bilirubin will also be measured. 
2) 
In case of reactions to SC IMP administration, tryptase can be tested at the discretion of the investigator. 
3) 
Conducted at screening only. 
4) 
The analytes listed will be measured locally with a urine dipstick but must be measured at the central lab if the urine 
dipstick is abnormal. 
5) 
The symbol ‘/’included in the table represents ‘a ratio’. 
6) 
Only women of childbearing potential. 
7) 
Measured locally 
Abbreviations: HDL = high density lipoprotein; HIV = human immunodeficiency virus; IMP = investigational medicine 
product; LDL = low density lipoprotein;  SC = subcutaneous. 
 
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11.4.5.2 
Investigator evaluation of laboratory samples 
Central laboratory 
Chemistry, haematology, serology, and serum pregnancy tests will be analysed by a central 
laboratory which will provide results to the trial sites. The investigator must evaluate all 
results outside the reference range (‘clinically significant’ or ‘not clinically significant’) and 
sign and date the evaluation. The signed and dated version will be filed with the investigator’s 
trial documentation. Clinically significant abnormal tests must be repeated to confirm the 
abnormality. 
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 randomised in the trial. 
During the trial, if a subject presents with an abnormal clinically significant laboratory result, 
the investigator must take appropriate action, at their discretion. 
If a screening laboratory result is abnormal and of clinical significance, it will be at the 
investigator’s discretion to decide if the subject should be randomised into the trial. During 
the trial, if a subject presents with a clinically significant abnormal laboratory result, 
appropriate action, as judged by the investigator, must be taken.  
Serum pregnancy tests for women of childbearing potential will be analysed by a central 
laboratory, which will provide results to the trial sites. A positive serum pregnancy test at 
screening is an exclusion criterion. 
A laboratory manual will be provided to the trial sites specifying the procedures for 
collection, processing, storage, and shipment of samples, as well as laboratory contact 
information specific to this trial. 
Tests performed at the trial site 
Subjects will have a test on tuberculosis (Mycobacterium tuberculosis IFN-γ release assay) at 
screening (Visit 1). A positive or indeterminate test result is an exclusion criterion. 
Urine samples will be tested with a dipstick according to the schedule of trial procedures 
(Section 4). 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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Women of childbearing potential will have a urine pregnancy test performed at the trial site at 
baseline prior to randomisation. The test will be repeated as shown in the schedule of trial 
procedures in Section 4. A positive urine pregnancy test must be verified with a serum 
pregnancy test. A woman with a positive urine pregnancy test during the trial must 
immediately discontinue IMP and must be withdrawn from the trial after confirmation by 
positive serum pregnancy test. 
Reporting in eCRF 
At each visit, the site staff will record 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 be recorded in the eCRF. 
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 performed. If not, a reason should be provided. Also, the date and 
the outcome of the urine pregnancy test will be recorded in the eCRF (‘positive’, ‘negative’). 
Clinically significant abnormal laboratory results at the screening visit will be documented as 
medical history in the eCRF. At subsequent visits, any clinically significant deterioration of a 
pre-existing condition will be reported as an AE. Any new clinically significant sign, 
symptom, or illness occurring after screening will be reported as an AE in accordance with 
Section 13.3. 
11.4.6 Anti-drug antibodies measurements  
Blood samples will be collected to determine ADA levels at pre-determined time points 
according to the schedule of trial procedures (Section 4). At an unscheduled visit, it will be at 
the discretion of the investigator if a blood sample to determine ADA levels should be 
collected. In case a blood sample for ADA levels determination is drawn, also a PK blood 
sample should be taken. 
Serum samples for determination of presence or absence of ADA will be analysed by a 
laboratory using a validated bioanalytical method. A tiered testing scheme will be employed, 
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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 titre 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. 
Reporting in eCRF 
It will be recorded in the eCRF if an ADA blood sample was taken. If not, a reason should be 
provided. 
11.5 Pharmacokinetic assessments 
11.5.1 
Blood sampling for analysis of PK 
Blood samples for PK assessments will be collected at the time points specified in the 
schedule of trial procedures (Section 4). PK blood sampling should be performed prior to IMP 
administration at site. Date and time of sample collection will be captured on the laboratory 
requisition forms.  
Serum samples for determination of LEO 138559 concentrations will be analysed 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.  
Reporting in eCRF 
It will be recorded in the eCRF if the PK sample was taken; if not, a reason will be provided.  
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11.6 Pharmacodynamics assessments 
11.6.1 
 Overview 
Biomarker expression in blood and skin (skin biopsies and tape strips) will be measured to 
evaluate treatment effect of LEO 138559 on disease biomarkers and investigate gene 
expression in the skin related to the mechanism of action of LEO 138559 and Dupixent®. 
Blood and skin samples for PD assessment must be collected at the time points specified in 
the schedule of trial procedures (Section 4). 
The biomarker 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 
pharmacodynamics/biomarker results will be reported in an addendum to the CTR. 
11.6.2 
Blood biomarkers 
Evaluation of effects of treatment of AD patients with LEO 138559 or Dupixent® on protein 
biomarkers in blood, including but not limited to E- selectin, PI3/Elafin, CCL7, IL-16, and 
newly identified IL-22BP [50] will be performed on serum samples. Changes in blood 
biomarkers have been linked to atopic dermatitis in previous disease signature studies [51]. 
Serum samples for biomarker analyses will be taken according to the schedule of trial 
procedures (Section 4). 
Collection, handling, and shipment instructions for serum samples will be provided in a 
separate laboratory manual. 
Serum biomarker data will be described in a separate report appended to the CTR.  
Reporting in eCRF 
It will be recorded in the eCRF if PD blood samples were taken. If not, a reason should be 
provided. 
11.6.3 
 Skin biopsies 
Lesional skin biopsies from subjects treated with LEO 138559 or Dupixent® will be 
evaluated by single-cell RNASeq analysis, a technique which enables evaluation of global 
gene expression in single cells and which has previously been used in a study in subjects 
with AD treated with Dupixent® [52]. Effects of LEO 138559 on single-cell 
transcriptomics have not been evaluated to date. Histological analysis will also be 
performed, on the same biopsies. 
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One 5 mm skin punch biopsy will be taken at each time-point specified in the schedule of 
trial procedures (Section 4) for analysis of differentially expressed genes analysed by 
single cell RNA sequencing and for AD biomarker analysis.  
At baseline, the biopsy will be taken from a representative lesional area. At the 
end-of-treatment visit (or early IMP termination visit, if applicable) the same lesional area as 
at baseline (“original lesional area”) will be sampled. Note that the lesion sample at the 
end-of-treatment (or early IMP termination visit, if applicable) should be taken from the 
original lesional area, even if this lesion clears during the trial. At the other sampling 
timepoint a biopsy may be taken from any other representative lesion. 
Photographs will be taken of the biopsy sites prior to each biopsy sampling. 
A check of skin biopsy wound healing including removal of suture, if applicable, will be 
performed at the next trial visit. After the biopsy at week 16 visit, subjects will be asked to 
return to site for suture removal two weeks later (week 18) or alternatively to have the sutures 
removed by their general practitioner, as preferred by subject. 
Collection, handling, and shipment instructions for skin biopsy samples for single cell RNA 
sequencing and evaluation of biomarkers are provided in a separate laboratory manual. 
Skin biopsy single cell RNA sequencing and biomarker data will be described in detail in a 
separate report appended to the CTR 
Reporting in eCRF 
For each skin biopsy it will be recorded in the eCRF from which body location (upper limb, 
lower limb, trunk) it was taken. If a skin biopsy was not taken, a reason will be provided. 
 
11.6.4 
Skin tape strips 
The effects of treatment of AD patients with LEO 138559 and Dupixent® on biomarkers that 
have been linked to the integrity of the skin barrier will be evaluated by analysis of non-
invasive tape strips from lesional skin, a technique that has been used to demonstrate a link 
between decreased levels of ceramides in the stratum corneum and barrier- disrupted dry skin 
in AD patients [53]. 
Tape stripping will be performed according to the schedule of trial procedures (Section 4).  
Non-invasive tape stripping will be done for biomarker analyses in the skin. At baseline, the 
samples will be taken from a representative lesional area. At the end-of-treatment visit (or 
early IMP termination visit, if applicable) the same lesional area as at baseline (“original 
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lesional area”) will be sampled. Note that the lesion sample at the end-of-treatment (or early 
IMP termination visit, if applicable) should be taken from the original lesional area, even if 
this lesion clears during the trial. At the other sampling timepoint tape stripping will be 
performed from any other representative lesion. 
Subjects will be instructed not to apply any emollients for at least 2 hours prior to visits that 
include tape stripping. 
Collection, handling, and shipment instructions for tape strips samples are provided in a 
laboratory manual. 
Reporting in eCRF 
For each tape strip visit it will be recorded in the eCRF from which body location (upper 
limb, lower limb, trunk) the tape strips were collected. If a tape stripping was not performed, a 
reason will be provided 
11.7 Other assessments 
11.7.1 
Patient-reported outcomes 
11.7.1.1 
Diary 
The subjects will receive a paper diary at screening (visit 1) and must complete the diary each 
day throughout the trial starting at least 7 days before baseline (visit 3, day 0). Subjects should 
document the use of emollients as well as use of other medications (except usual ongoing 
medication). Compliance with the diary completion will be reviewed by the trial site staff at 
the site visits and completed diary pages will be collected and the corresponding information 
from the diary will be entered into the eCRF by trial site staff. The diary should be returned to 
the trial site as outlined in the schedule of trial procedures (Section 4). 
11.7.1.2 
Worst Daily Pruritus numeric rating scale 
Subjects will assess their worst itch severity over the past 24 hours using an 11-point NRS 
(‘Worst Daily Pruritus NRS’) with 0 indicating ‘no itch’ and 10 indicating ‘worst itch 
imaginable’. Subjects will complete the Worst Daily Pruritus NRS as part of a paper diary 
each day in the morning starting at least 7 days prior to baseline (visit 3) until week 32 
(visit 16). 
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11.8 End of trial 
End-of-treatment form 
An end-of-treatment form will be completed in the eCRF for all subjects 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 (see Section 10.3 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. If not, the primary reason 
for permanent discontinuation of IMP must be recorded (see Section 10.2.1). 
End-of-trial form 
An end-of-trial form must be completed in the eCRF for all screened subjects. The following 
data will be collected:  
• Screening failure. 
• Did the subject complete the trial? 
• Which was the last visit (including phone calls) the subject attended in this trial? 
• Date of last contact. 
• Primary reason for withdrawing from the trial (death, pregnancy, adverse event, lack of 
efficacy, screening failure, withdrawal by subject, lost to follow-up, or other [if other, a 
specification should be provided]).  
• If the subject attended the primary endpoint visit (visit 6). If not, the primary reason for 
not attending the visit (death, pregnancy, adverse event, lack of efficacy, withdrawal by 
subject, lost to follow-up, or other [if other, a specification should be provided]). 
• If the subject attended the end-of-treatment visit (visit 12). If not, the primary reason for 
not attending the visit (death, pregnancy, adverse event, lack of efficacy, withdrawal by 
subject, lost to follow-up, or other [if other, a specification should be provided]). 
• If the subject attended the safety follow-up visit (visit 16). If not, the primary reason for 
not attending the visit (death, pregnancy, adverse event, lack of efficacy, withdrawal by 
subject, lost to follow-up, or other [if other, a specification should be provided]). 
The end of trial form will be completed when the subject turned out to be a screening failure 
or has had their last visit (that is the safety follow-up visit 16, or early IMP termination visit). 
 
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11.9 Estimate of total blood volume collected 
Blood samples will be drawn for haematology, biochemistry, serology, PK, PD, ADA, and 
safety assessments. The total volume of blood to be drawn is approximately 200 mL. If 
additional blood samples are required, the amount of blood drawn may be more than this 
stated value; however, the total volume of blood drawn will be less than that taken during a 
blood donation (approximately 500 mL).  
11.10 Storage of biological samples 
Laboratory samples (chemistry/haematology/serology) will not be stored for more than a few 
days after sampling and analysis. 
Primary samples for PK will be discarded by the bioanalytical lab upon finalisation of the 
CTR whereas backup samples stored at the Central Lab will be retained for as long as the 
quality of the material permits evaluation but for no longer than 6 months after completion of 
the CTR. Any backup samples that have been sent to the Bioanalytical Lab will also be 
discarded upon finalisation of the CTR. 
Primary samples (set A samples) for ADA evaluation will be discarded by the bioanalytical 
lab upon finalisation of the CTR whereas backup samples (set B samples) stored at the central 
laboratory will be stored at least until approval in first major market (US or EU or JP) or until 
10 years after final CTR– which ever comes last. 
Biomarker samples (skin biopsies, skin tape strips and PD blood samples) will be retained for 
as long as the quality of the material permits evaluation but for no longer than 12 months after 
completion of the CTR. 
 
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12 Scientific rationale for trial design and appropriateness of 
assessments 
12.1 Scientific rationale for trial design 
LP0145-2274 is a randomized, double-blinded, active comparator-controlled, 16-week, 
single-site exploratory, mechanistic trial designed to evaluate the effect on the molecular 
signature of SC administered LEO 138559 450 mg Q2W compared with Dupixent® Q2W in 
adults with moderate to severe AD.  
The primary endpoint is selected to gain information about the mode of action of LEO 
138559 and the influence of blocking of IL-22 pathway on gene expression in lesional skin.  
Based on PK, PD, and safety results of the FiM trial with LEO 138559 (LP0145-1315), the 
dose regimen LEO 138559 450 mg Q2W was selected for investigation in this trial. In 
addition to the Q2W dosing schedule, an additional dose of IMP will be given to the subjects 
at week 1 to reach steady state exposure early in the treatment period. According to a PK 
model developed based on preliminary data from the FiM trial, the additional dose given at 
week 1 should allow 75% of steady state exposure to be reached already after 3 weeks of 
treatment. The 16-week treatment period was selected to ensure sufficient time to evaluate the 
impact of LEO 138559 on disease severity as AD. Further, given the expected half-life, 
dosage, and dosing frequency of LEO 138559, it is expected that LEO 138559 achieve steady 
state concentration before the end of this period and a maximum therapeutic effect will be 
achieved by this time. A safety follow-up period of 16-week after last dose of IMP is 
considered an appropriate length as serum concentrations of LEO 138559 are expected to be 
declined to nondetectable levels (below the lower limit of quantification) in most subjects at 
that timepoint. 
The use of Dupixent® as a comparator will serve as reference to evaluate the mode of action, 
efficacy and safety of LEO 138559. The comparison with an approved immunoregulatory 
agent that selectively and simultaneously inhibits IL-4 and IL-13 allows for an evaluation of 
similarity or differences in the mechanistic effect. Dupixent® will be administered according 
to the prescription instructions (standard of care) for adult subjects with moderate to severe 
AD with an initial dose of 600 mg followed by Q2W injections with 300 mg. 
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Since both IMPs are distinguishable in appearance and dosing requirements (number of 
injections) this study will be performed as an assessor- and patient blinded trial. Only the 
person responsible for handling and administration of IMPs will be unblinded. The 
investigator responsible for assessment of safety and efficacy and the patient will be blinded 
throughout the study, to ensure that the clinical assessments will be carried out without bias. 
Therefore, certain blinding procedures are in place (see section 9.3.2)   
The trial population is adult subjects with moderate to severe AD with documented 
inadequate response to topical AD treatments or being a subject for whom topical treatment is 
medically inadvisable. This trial population represents the subjects with highest remaining 
unmet clinical need and can be applied to the general population. The other eligibility criteria 
have been chosen to ensure inclusion of the targeted patient population and safety of the 
subjects and to minimize factors which could interfere with the efficacy and safety 
assessments. 
12.2 Appropriateness of assessments 
In order to gain more information about the mechanism of action of LEO138559, analysis of 
biomarkers in skin and blood will be performed to evaluate effects of treatment of subjects 
with atopic dermatitis with LEO 138559 or a comparator (Dupixent®). Lesional skin biopsies 
will be analyzed using single-cell RNASeq and histology while serum samples will be 
assessed for protein biomarkers. 
Serum concentration of LEO 138559 will be measured to further characterise the PK of 
LEO 138559 in subjects with moderate to severe AD. 
Efficacy will be evaluated by investigators assessment of EASI and vIGA-AD which are 
validated measures used in clinical practice and clinical trials [47-49]. 
Standard clinical methods of subject evaluations, such as AE monitoring, vital signs, physical 
examinations, ECG, laboratory testing including pregnancy testing, and ADA will be used to 
assess subject safety. Given some large proteins may cause indirect adverse cardiac effects 
upon long term exposure, data on ECG will be collected and evaluated. Data on ADA will be 
collected in order to evaluate the potential immunogenicity of LEO 138559. 
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13 Adverse events 
13.1 Definition and classification of adverse events 
Adverse events (AEs) and serious adverse events (SAEs) are defined in Appendix 1. 
Classification of AEs in terms of severity, causality, and outcome is defined in Appendix 2. 
13.2 Collection of adverse event reports 
AE data must be collected from time of first trial-related activity after the subject has signed 
the informed consent form (ICF) until subject’s completion of the clinical trial (safety 
follow-up visit at week 32 see Section 7.3) 
AEs must be assessed by a physician.  
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?” No specific symptoms should be asked for. 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 11.4.1 to 11.4.5 
13.3 Reporting of adverse events 
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’). 
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 if the AE started prior to first administration of IMP. 
AEs must be classified in terms of severity, causality, and outcome according to the 
definitions in Appendix 2. 
Action taken with IMP: any action taken with IMP as a consequence of the AE must be 
recorded (dose not changed, drug interrupted, drug withdrawn, not applicable, unknown). 
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Other action taken: any other action taken as a result of the AE must be recorded (none, 
concomitant medication, concurrent procedure). 
It must be recorded in the eCRF if the AE led to permanent discontinuation of IMP and/or 
withdrawal from trial. 
Withdrawn from trial due to this AE: it must be recorded whether the AE led to withdrawal 
from the trial. 
13.4 Reporting of serious adverse events 
The criteria that define an AE as serious (that is, an SAE) are defined in Appendix 1. SAE 
criteria are also listed on the SAE form. 
13.4.1 
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, comparator 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 
anonymised reports of diagnostic procedures, hospital records, autopsy reports, etc. 
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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, including any protocol-required 
post-treatment follow-up period, should not be routinely sought or recorded. However, such 
events should be reported immediately without undue delay and no later than 24 hours of 
obtaining knowledge to Global Safety at LEO Pharma (see contact details above) if the 
investigator becomes aware of them. 
13.4.2 
LEO Pharma reporting responsibilities 
Global Safety at LEO Pharma is responsible for assessing whether an SAE is expected. The 
relevant reference safety information documents for this clinical trial are: 
• For the drug product LEO 138559, the investigator’s brochure Section 7.3.8, edition 4 and 
subsequent updates must be used.  
• For the comparator Dupixent® the latest version of the SmPC [54] must be used. 
Global Safety at LEO Pharma will notify the regulatory authorities and concerned 
investigators of SAEs according to the current applicable legislation for the concerned 
country.  
The IRB(s)/IEC(s) will be notified of SAEs according to the current applicable legislation for 
the concerned country.  
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 [55], 
and which are unexpected (suspected, unexpected serious adverse reactions [SUSARs]), are 
subject to expedited reporting to regulatory authorities and 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. 
13.5 Other events that require expedited reporting 
13.5.1 
Pregnancy 
Any pregnancy, occurring after first exposure to IMP and until the subject has completed the 
trial must be reported to LEO Pharma within 24 hours of first knowledge using the (paper) 
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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 Section 13.4.1. 
Pregnant subjects must immediately discontinue IMP permanently (Sections 10.2.1 and 10.3). 
13.6 Reporting of other events 
13.6.1 
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. 
Inappropriate schedule of product administration where a clinical consequence occurred or 
could have occurred should be recorded based on investigator judgement. Treatment 
non-compliance (incl. missed doses) where no clinical consequence occurred or could have 
occurred should not be recorded as medication errors. See Section 9.8.4 for recording of 
treatment compliance. 
Reporting in eCRF 
Medication error must be recorded on the AE from 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 
(Section 13.4). 
13.6.2 
Misuse or abuse 
The terms misuse and abuse are similar in that they both represent the intentional use of a 
drug in a way other than intended. 
Misuse refers to situations where the IMP is intentionally and inappropriately used for 
therapeutic purposes not in accordance with the protocol. 
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Abuse refers to intentional use of an IMP for what could be considered desirable non-
therapeutic effects (e.g. sedative, stimulant, euphoric effects). 
Misuse and abuse must be recorded on the AE form in the eCRF. In addition, any clinical 
consequences of misuse or abuse must be recorded as separate AEs on the AE form. If the AE 
originating from the misuse or abuse qualifies as an SAE, expedited reporting is required 
(Section 13.4).] 
13.6.3 
Aggravation of condition 
Any clinically significant aggravation/exacerbation/worsening of any medical condition(s) 
(including the trial disease), compared to screening, must be reported as an (S)AE in 
accordance with Sections 13.3 and 13.4. 
Atopic dermatitis 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.  
13.7 Follow-up for final outcome of adverse events 
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 after visit 16 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 stabilised 
and from which the subject cannot be expected to recover during the trial or the safety 
follow-up periods, e.g. chronic or stabilised conditions, the final outcome at the investigator’s 
discretion should be reported as ‘recovering/resolving’ or ‘not recovered/not resolved’. In 
addition, a statement detailing why the subject cannot be expected to recover during the trial, 
e.g. that the SAE has stabilised or is chronic, should be added to the narrative description of 
the SAE on the SAE form. 
13.8 Handling of an urgent safety measure 
An urgent safety measure is a measure taken to implement an action/protocol deviation under 
an emergency. This is defined as “…the occurrence of any new event relating to the conduct 
of the trial or the development of the investigational medicinal product where that new event 
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is likely to affect the safety of the subjects, the sponsor and the investigator shall take 
appropriate urgent safety measures to protect the subjects against any immediate 
hazard.” [56]. 
If the investigator becomes aware of information that requires an immediate change in a 
clinical trial procedure or a temporary halt of the clinical trial to protect clinical trial subjects 
from any immediate hazard to their health and safety, the investigator can do so without prior 
approval from LEO Pharma, regulatory authorities, or IRBs/IECs. 
The investigator must immediately inform LEO Pharma – by contacting the clinical project 
manager or medical expert – of this change in a clinical trial procedure or of the temporary 
halt; the investigator will provide full details of the information and the decision-making 
process leading to the implementation of the urgent safety measure. 
LEO Pharma must act immediately upon receipt of the urgent safety measure notification in 
accordance with internal procedures and local legislation. 
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14 Statistical methods 
14.1 Sample size 
The sample size of 12 subjects evaluable for the primary endpoint i.e., for whom a lesional 
biopsy is available at baseline and week 4 (8 receiving LEO 138559 and 4 receiving 
comparator) is based on the trial design for the exploratory comparison of the molecular 
signature changes of LEO 138559 and the comparator. The sample size is not based on power 
calculations.  
14.2 Trial analysis sets 
All screened subjects will be accounted for in the CTR. 
All subjects randomised and exposed to IMP will be included in the full analysis set and will 
be analysed for efficacy based on the planned (randomized) treatment allocation. Exclusions 
from the full analysis set 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 randomised subject from the full analysis 
set, 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 were exposed to LEO 138559 and 
provided at least one sample for measuring serum concentrations of LEO 138559.  
The decisions regarding inclusion/exclusion of subjects or subject data from the trial analysis 
sets will be documented in the clinical trial report. 
14.3 Statistical analysis 
14.3.1 
Disposition of subjects 
The reasons for permanent discontinuation of IMP or withdrawal from trial will be presented 
for all randomised subjects by last visit attended and by treatment group and overall. 
A subject disposition summary table will be made including information of number of 
subjects who were screened, randomised, exposed and who completed the trial, permanently 
discontinued IMP, and/or were withdrawn from the trial (by treatment group and overall) 
14.3.2 
Demographics and other baseline characteristics 
Descriptive statistics of demographics and other baseline characteristics will be presented for 
all randomised subjects and by treatment group and overall. Presentations of age, sex, 
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ethnicity, race, and baseline EASI score by treatment group will be reported for all 
randomised subjects. Other baseline characteristics include height, weight, BMI, duration of 
AD, concurrent diagnoses (from medical history and indications for concomitant medication), 
concomitant medication, and previous AD treatments.  
14.3.3 
Exposure and treatment compliance 
Exposure to treatment will be presented for the safety analysis set as days of exposure per 
treatment group and overall.  
The cumulated dose administered to each subject will be determined and summarised 
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. In addition, the percentage of subjects who received IMP 
application according to dosing schedule will be presented per treatment group.  
14.3.4 
Testing strategy 
No formal statistical significance tests will be carried out. 
14.3.5 
Primary endpoint analysis 
The primary endpoint 
• Change in biomarkers in lesional skin biopsies typically associated with atopic 
dermatitis from baseline to week 4 
will be analyzed descriptively by computing the following statistics by treatment group: 
minimum and maximum value, lower and upper quartile, median, mean, standard deviation 
and median absolute deviation. 
Individual and mean data as well as boxplots will be plotted by treatment group.  
14.3.6 
Secondary endpoint analysis 
The secondary endpoint 
• Number of treatment-emergent adverse events from baseline to week 16 per subject 
will be analysed descriptively on the safety analysis set by computing the number of 
treatment-emergent adverse events per subject by treatment group. 
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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. 
14.3.7 
Analysis of exploratory efficacy endpoints 
Binary endpoints 
The endpoints 
• Having a decrease in EASI of at least 50% (EASI 50) from baseline to week 1, 2, 4, 6, 8, 
12, and 16, assessed separately. 
• 
Having a decrease in EASI of at least 75% (EASI 75) from baseline to week 1, 2, 4, 6, 8, 12, 
and 16, assessed separately. 
• Having a decrease in EASI of at least 90% (EASI 90) from baseline to week 1, 2, 4, 6, 8, 
12, and 16, assessed separately. 
• Having vIGA-AD score of 0 (clear) or 1 (almost clear) at week 1, 2, 4, 6, 8, 12, and 16, 
assessed separately. 
 
will be analysed on the full analysis set by computing frequency tables for each time point by 
treatment group. 
Proportions with respect to these endpoints will be plotted by treatment group.  
 
Continuous endpoints  
The endpoints 
• Change in EASI score from baseline to week 1, 2, 4, 6, 8, 12, and 16. 
• Change in Worst Daily Pruritus NRS (weekly average) from baseline to weeks 1, 2, 4, 6, 
8, 12, and 16. 
 
will be analysed on the full analysis set by computing descriptive summary statistics for each 
time point by treatment group. 
Individual and mean data as well as boxplots with respect to these endpoints will be plotted 
by treatment group. 
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14.3.8 
Pharmacodynamics analysis 
For the following endpoints; 
• Change in expression of AD disease biomarkers in serum from baseline to week 1, 4, 
and 16. 
• Change in expression of AD disease biomarkers in skin biopsies from baseline to week 
1, 4, and 16. 
• Change in expression of AD disease biomarkers in skin tape strips from baseline to 
week 1, 4, and 16. 
explorative analyses will be performed for the total population. 
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. 
14.3.9 
Safety analysis 
The analysis of safety will be based on the safety analysis set. 
14.3.9.1 
Adverse events 
AEs will be coded during the course of the trial according to Medical Dictionary for 
Regulatory Activities (MedDRA). AEs will be presented by preferred term and primary 
system organ class (SOC). 
Treatment-emergent AEs will be summarised; however, all AEs recorded during the course of 
the trial will be included in subject data listings. The tabulations described in the following 
will only include the treatment-emergent AEs. In each of the tabulations, AEs are defined by 
MedDRA preferred terms within primary SOC. 
AEs will be summarised 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’. 
An overall summary of the number of events and the number (percentage) of subjects with 
any treatment-emergent AEs, deaths, SAEs, permanent discontinuations from IMP, and/or 
withdrawals from the trial due to AEs, treatment-related AEs, mild and moderate AEs, and 
severe AEs will be presented. 
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Tabulations by SOC and preferred term will be presented for all AEs, SAEs, related AEs, 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. 
The number of AEs and number of subjects with each type of AEs will be tabulated by 
treatment group from baseline to week 16, from baseline to week 32, and from week 17 to 
week 32.  
AEs leading to withdrawal from trial and/or permanent discontinuation of IMP will be 
tabulated and listed. The detailed listing will provide an overview of the individual cases and 
include the age and sex of the subject, treatment received at the time of AE onset, the AE 
preferred and reported terms, causality and severity of the AE, the action taken with the IMP, 
AE outcome, start and stop date of AE, duration of AE, and number of days since first and last 
IMP administration. No narratives will be given. 
SAEs will be evaluated separately, and a narrative will be given. 
14.3.9.2 
Vital signs and physical examination 
The change in vital signs (blood pressure, pulse, and body temperature) from baseline to each 
relevant visit will be summarized by treatment group as mean, standard deviation (SD), 
median, minimum and maximum values for the safety analysis set. 
Subjects with abnormal, clinically significant physical findings will be listed. Furthermore, a 
shift table for physical findings showing the change from baseline to week 16 in clinical 
assessments (normal; abnormal, not clinically significant; abnormal, clinically significant) 
will be performed. 
14.3.9.3 
ECG 
The change in ECG from baseline to each visit will be summarized by treatment group as 
mean, SD, median, minimum and maximum values for the safety analysis set. 
Subjects with abnormal, clinically significant ECG will be listed. Furthermore, a shift table 
for ECG showing the change from baseline to week 16 in clinical assessments (normal; 
abnormal, not clinically significant; abnormal, clinically significant) will be performed. 
14.3.9.4 
Clinical laboratory evaluation 
The change in each of the laboratory parameters from baseline to each visit will be 
summarized by treatment group as mean, SD, median, minimum and maximum values for the 
safety analysis set. 
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Laboratory parameters will be classified as ‘low’, ‘normal’, or ‘high’, depending on whether 
the value is below, within, or above the reference range, respectively. A shift table will be 
produced showing the categories at baseline against those at the end of treatment. Subjects 
with laboratory parameters outside the reference range will be listed. 
14.3.9.5 
Anti-drug antibodies 
 For the exploratory endpoint 
• Having a positive ADA response at weeks 0, 4, 8, 12, 16, 32, assessed separately. 
the ADA status (positive vs. negative) including actual ADA titre at each assessment time 
point will be summarised. If considered relevant, descriptive statistics including number of 
subjects, mean, SD, median, and range of the actual ADA titres and visit will be provided. The 
ADA status across the trial for each subject (positive vs. negative) will also be classified and 
summarised.  
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 
summarised 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. 
14.3.10 
Pharmacokinetic analysis 
The endpoint 
• Serum concentration of LEO 138559 at weeks 0, 1, 4, 8, 12, 16, and 32, assessed 
separately. 
will be evaluated based on the PK analysis set.  
LEO 138559 serum concentrations will be listed and summarized by visit. The serum 
concentrations will be included in a cross-trial population PK analysis and reported separately. 
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14.3.11 
Interim analysis 
No interim analysis is planned. 
14.3.12 
General principles 
All data will be analysed descriptively. No formal significance tests will be performed. 
Efficacy analyses will be based on the FAS, and safety analyses will be based on the safety 
analysis set. PK summary will be based on the PK analysis set. 
If not mentioned otherwise, endpoints will be summarised descriptively at each visit by 
treatment. For endpoints evaluated over time, plots will be made to explore the trajectories 
with time.  
An observed cases approach will be used for tabulations of data by visit (that is, involving 
only those subjects who attended each specific visit). The number of subjects for whom data 
was not collected at each specific visit will also be provided. 
Categorical data will be summarised by treatment group, using the number and percentage of 
subjects in each category. Continuous data will be summarised using the mean, median, 
standard deviation (SD), 1st quartile, 3rd quartile, minimum, and maximum values. 
Additionally, geometric mean and coefficient of variation (CV) will be provided for the PK 
endpoint.  
In general, for endpoints evaluated as change from baseline and/or where a baseline 
adjustment is applied, baseline is defined as assessments conducted at the randomisation visit 
(visit 3), if not otherwise stated. If the information is not available at the randomisation visit 
but at the (re)screening visit (visit 1) then this will be used instead.  
All the analyses specified in the protocol will be reviewed in relation to the blinded data 
actually obtained, and the statistical analysis plan will be finalised before breaking the 
randomisation code.  
Any changes from the statistical analyses planned in this clinical trial protocol will be 
described and justified in a protocol amendment, the statistical analysis plan, and/or in the 
CTR, dependent on the type of change. 
14.3.13 
Handling of missing values 
Handling of missing values will be specified in the statistical analysis plan (SAP). 
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For the weekly average of worst daily pruritus NRS, a minimum of four measurements per 
week must be available, otherwise the score for this week will be set to missing. 
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15 References 
 
1. 
Weidinger, S., et al., Atopic dermatitis. Nat Rev Dis Primers, 2018. 4(1): p. 1-20. 
2. 
LEO Pharma A/S. Investigator’s Brochure - LEO 39652 (Atopic Dermatitis). 0.2 nd 
ed. 2014. 
3. 
Dalgard, F.J., et al., The psychological burden of skin diseases: a cross-sectional 
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Kiebert, G., et al., Atopic dermatitis is associated with a decrement in health-related 
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Deckers, I.A., et al., Investigating international time trends in the incidence and 
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Abuabara, K., et al., The prevalence of atopic dermatitis beyond childhood: A 
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Silverberg, J.I. and J.M. Hanifin, Adult eczema prevalence and associations with 
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Salimi, M., et al., A role for IL-25 and IL-33-driven type-2 innate lymphoid cells in 
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Mashiko, S., et al., Increased frequencies of basophils, type 2 innate lymphoid cells 
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Brüggen, M.C., et al., In Situ Mapping of Innate Lymphoid Cells in Human Skin: 
Evidence for Remarkable Differences between Normal and Inflamed Skin. J Invest 
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Maggi, L., et al., Human circulating group 2 innate lymphoid cells can express CD154 
and promote IgE production. J Allergy Clin Immunol, 2017. 139(3): p. 964-976.e4. 
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Gittler, J.K., et al., Progressive activation of T(H)2/T(H)22 cytokines and selective 
epidermal proteins characterizes acute and chronic atopic dermatitis. J Allergy Clin 
Immunol, 2012. 130(6): p. 1344-54. 
14. 
Nograles, K.E., et al., IL-22-producing "T22" T cells account for upregulated IL-22 in 
atopic dermatitis despite reduced IL-17-producing TH17 T cells. J Allergy Clin 
Immunol, 2009. 123(6): p. 1244-52 e2. 
15. 
Suarez-Farinas, M., et al., Intrinsic atopic dermatitis shows similar TH2 and higher 
TH17 immune activation compared with extrinsic atopic dermatitis. J Allergy Clin 
Immunol, 2013. 132(2): p. 361-70. 
16. 
Eichenfield, L.F., et al., Guidelines of care for the management of atopic dermatitis: 
section 2. Management and treatment of atopic dermatitis with topical therapies. J Am 
Acad Dermatol, 2014. 71(1): p. 116-32. 
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17. 
Kim, B.S., et al., Treatment of atopic dermatitis with ruxolitinib cream (JAK1/JAK2 
inhibitor) or triamcinolone cream. Journal of Allergy and Clinical Immunology, 2020. 
145(2): p. 572-582. 
18. 
Nakagawa, H., et al., Delgocitinib ointment, a topical Janus kinase inhibitor, in adult 
patients with moderate to severe atopic dermatitis: A phase 3, randomized, double-
blind, vehicle-controlled study and an open-label, long-term extension study. J Am 
Acad Dermatol, 2020. 82(4): p. 823-831. 
19. 
Japan Tobacco Inc, Japan Tobacco delgocitinib (Corectim®) PMDA approval 
(30200AMX00046000). 2020. 
20. 
Sidbury, R., et al., Guidelines of care for the management of atopic dermatitis: section 
3. Management and treatment with phototherapy and systemic agents. J Am Acad 
Dermatol, 2014. 71(2): p. 327-49. 
21. 
Haeck, I.M., et al., Enteric-coated mycophenolate sodium versus cyclosporin A as 
long-term treatment in adult patients with severe atopic dermatitis: a randomized 
controlled trial. J Am Acad Dermatol, 2011. 64(6): p. 1074-84. 
22. 
Schram, M.E., et al., A randomized trial of methotrexate versus azathioprine for severe 
atopic eczema. J Allergy Clin Immunol, 2011. 128(2): p. 353-9. 
23. 
Davari, D.R., et al. Current Perspectives on the Systemic Management of Atopic 
Dermatitis. Journal of asthma and allergy, 2021. 14, 595-607 DOI: 
10.2147/jaa.s287638. 
24. 
Guttman-Yassky, E., Lebrikizumab, a High-Affinity IL-13 Inhibitor, Improves Clinical 
Manifestations in Moderate-to-Severe Atopic Dermatitis: Primary Results From a 
Randomized, Double-Blinded, Placebo-Controlled, Dose-Ranging, Phase 2b Study. 
2019. 
25. 
Kabashima, K., et al., Nemolizumab in patients with moderate-to-severe atopic 
dermatitis: Randomized, phase II, long-term extension study. J Allergy Clin Immunol, 
2018. 142(4): p. 1121-1130.e7. 
26. 
Wollenberg, A., et al., Treatment of atopic dermatitis with tralokinumab, an anti-IL-13 
mAb. J Allergy Clin Immunol, 2019. 143(1): p. 135-141. 
27. 
Silverberg, J.I., et al., Efficacy and Safety of Abrocitinib in Patients With Moderate-to-
Severe Atopic Dermatitis: A Randomized Clinical Trial. JAMA Dermatology, 2020. 
156(8): p. 863-873. 
28. 
Guttman-Yassky, E., et al., Baricitinib in adult patients with moderate-to-severe atopic 
dermatitis: a phase 2 parallel, double-blinded, randomized placebo-controlled 
multiple-dose study. J Am Acad Dermatol, 2018. S0190-9622(18): p. 30129-4. 
29. 
Guttman-Yassky, E., et al., Upadacitinib in adults with moderate to severe atopic 
dermatitis: 16-week results from a randomized, placebo-controlled trial. J Allergy 
Clin Immunol, 2020. 145(3): p. 877-884. 
30. 
European Medicines Agency, Baricitinib; assessment report (EMA/13493/2017 and 
EMEA/H/C/004085/0000). 2016. 
31. 
Simpson, E.L., et al., Baricitinib in patients with moderate-to-severe atopic dermatitis 
and inadequate response to topical corticosteroids: results from two randomized 
monotherapy phase III trials. Br J Dermatol, 2020. 183(2): p. 242-255. 
32. 
Thijs, J.L., et al., Moving toward endotypes in atopic dermatitis: Identification of 
patient clusters based on serum biomarker analysis. J Allergy Clin Immunol, 2017. 
140(3): p. 730-737. 
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33. 
Bieber, T., et al., Clinical phenotypes and endophenotypes of atopic dermatitis: Where 
are we, and where should we go? J Allergy Clin Immunol, 2017. 139(4s): p. S58-s64. 
34. 
Wolk, K., et al., Biology of interleukin-22. Semin Immunopathol, 2010. 32(1): p. 17-
31. 
35. 
Kotenko, S.V., et al., Identification, cloning, and characterization of a novel soluble 
receptor that binds IL-22 and neutralizes its activity. J Immunol, 2001. 166(12): p. 
7096-103. 
36. 
LEO Pharma A/S, Investigator's Brochure, LEO 138559 in Atopic Dermatitis, project 
LP0145 (edition 4.0). 2021. 
37. 
WMA, World Medical Association. Declaration of Helsinki – ethical principles for 
medical research involving human subjects. Amended by the 64th WMA General 
Assembly, Fortaleza, Brazil. 2013. 
38. 
ICH, International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use: Integrated Addendum to ICH E6(R1): Guideline for 
Good Clinical Practice. (E6)(R2), Step 4; 09-Nov. 2016. 
39. 
Argenx, B.V., Summary of all the in vitro and in silico characteristics of ARGX112 
(230C9_N297Q). 
40. 
FDA: Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 
Public Health Emergency. March 2020;  Updated on August 30, 2021. 
41. 
EMA: Points to consider on implications of Coronavirus disease (COVID-19) on 
methodological aspects of ongoing clinical trials. 25-MAR-2020. DRAFT. 
42. 
FAQ - COVID-19 Studien  - BASG 
(https://www.basg.gv.at/gesundheitsberufe/klinische-studien/klinische-studien-und-
covid-19/haeufige-fragen)  
43. 
Schulz, K.F., D.G. Altman, and D. Moher, CONSORT 2010 statement: updated 
guidelines for reporting parallel group randomised trials. Bmj, 2010. 340: p. c332. 
44. 
Johansson, S.G., et al., Revised nomenclature for allergy for global use: Report of the 
Nomenclature Review Committee of the World Allergy Organization, October 2003. J 
Allergy Clin Immunol, 2004. 113(5): p. 832-6. 
45. 
Sampson, H.A., et al., Second symposium on the definition and management of 
anaphylaxis: summary report--Second National Institute of Allergy and Infectious 
Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy Clin Immunol, 
2006. 117(2): p. 391-7. 
46. 
European Commission. EudraLex: The Rules Governing Medicinal Products in the 
European Union. Guidelines for good manufacturing practices for medicinal products 
for human and veterinary use. Volume 4. 2010  
47. 
Eli Lilly and Company, Validated Investigator Global Assessment scale for Atopic 
Dermatitis. vIGA-AD™. 2017. 
48. 
Hanifin, J.M., et al., The eczema area and severity index (EASI): assessment of 
reliability in atopic dermatitis. EASI Evaluator Group. Exp Dermatol, 2001. 10(1): p. 
11-8. 
49. 
HOME, Harmonising Outcome Measures for Eczema. Eczema Area and Severity 
Index (EASI) case report form. Aged 8 and over. 2017. 
50. 
Varandas, C., et al., Serum IL-22 binding protein as a marker for atopic dermatitis 
activity and response to dupilumab treatment. Clinical & Experimental Allergy, 2022. 
52(6): p. 820-823. 
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51. 
Brunner, P.M., et al., The atopic dermatitis blood signature is characterized by 
increases in inflammatory and cardiovascular risk proteins. Sci Rep, 2017. 7(1): p. 
8707. 
52. 
Bangert, C., et al., Persistence of mature dendritic cells, T<sub>H</sub>2A, and Tc2 
cells characterize clinically resolved atopic dermatitis under IL-4R&#x3b1; blockade. 
Science Immunology, 2021. 6(55): p. eabe2749. 
53. 
Imokawa, G., et al., Decreased level of ceramides in stratum corneum of atopic 
dermatitis: an etiologic factor in atopic dry skin? J Invest Dermatol, 1991. 96(4): p. 
523-6. 
54. 
Dupixent®, Summary of Product Characteristics (SmPC), Nov-2021. 
55. 
ICH, International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use. Integrated addendum to ICH E6(R1): Guideline for 
good clinical practice E6(R2). 2016. 
56. 
European Parliament Union and C.o.T. European, Directive 2001/20/EC of the 
European Parlament and of the Council of 4 April 2001 on the approximation of the 
laws, regulations and administrative provisions of the Member States relating to the 
implementation of good clinical practice in the conduct of clinical trials on medicinal 
products for human use, 2001, Ema, Editor. 2001. 
57. 
ICH, International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use: Clinical Safety Data Management. Definitions and 
Standards for Expected Reporting (E2A), Step 4; 27-Oct. 1994. 
58. 
CIOMS, International Ethical Guidelines for Health-related Research Involving 
Humans. Council for International Organizations of Medical Sciences. 2016: Geneva. 
 
 
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Appendix 1: Definitions of adverse events and serious adverse events 
Adverse event 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 unfavourable 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 [57]. 
This definition includes: 
• Accidental injuries. 
• Events related to trial procedures. 
• Reasons for any unfavourable 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 11.4.5.2). 
Serious adverse event 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 hospitalisation or prolongation of existing hospitalisation*. 
• 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 hospitalisation but may jeopardise the subject or may require 
intervention to prevent one 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 hospitalisation, development of drug 
dependency, or drug abuse.  
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*Hospitalisation 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. 
*Hospitalisation 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. 
*Hospitalisation 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. 
*Hospitalisation 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 hospitalisation are (S)AEs. If a complication prolongs 
hospitalisation, the event is an SAE. 
*When in doubt as to whether hospitalisation occurred or was necessary, the AE should be 
considered serious. 
 
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Appendix 2: Classification of adverse events 
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. 
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. 
 
Causality 
The causal relation of the AE to the use of the IMP should be described in terms of probably, 
possibly, or not related according to the investigator’s clinical judgement.  
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. 
 
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. 
 
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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’. 
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. 
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Appendix 3: Trial governance considerations 
Appendix 3A: 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 [37] and Council for International Organizations of 
Medical Sciences (CIOMS) International Ethical Guidelines [58]. 
• Current version of applicable International Council for Harmonisation Good Clinical 
Practice (ICH GCP) Guidelines [55]. 
• 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 fulfil its responsibilities (such as the trial 
protocol, protocol amendments, investigator’s brochure [as applicable], subject information 
sheet, and informed consent form(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 favourable 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. 
• Providing oversight of the conduct of the trial at the trial site and ensuring adherence to 
applicable national and international legislation. 
Appendix 3B: Informed consent process 
Subjects will receive written and verbal information concerning the clinical trial. This 
information will emphasise 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. 
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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 authorised 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 randomisation, subjects will be provided with a card stating that they are participating in a 
clinical trial and which contains contact address and telephone numbers 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 used if 
the investigator or delegated site staff cannot be. 
Appendix 3C: Subject and data confidentiality 
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.   
Trial subjects must be informed and consent to that their medical records may be examined by 
clinical quality assurance auditors or other authorised personnel appointed by LEO Pharma, 
by appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
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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. 
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. 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 asked to consent to 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 authorisations for products/services, marketing of products/services, 
and other related activities. 
LEO Pharma has obtained the necessary authorisations for the processing of personal data 
collected in the trial. 
Appendix 3D: Record keeping, quality control, and data handling 
Source data at trial sites 
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 
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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. 
• Randomisation code number. 
• The fact that the subject is participating in a clinical trial in AD including treatment with 
LEO 138559 or Dupixent® for 16 weeks.  
• Other relevant medical information. 
Trial monitoring 
The trial will be monitored on an ongoing basis to verify that (i) the rights and well-being of 
the trial subjects is protected; (ii) the reported trial data are accurate, complete, and verifiable 
from source documents; and (iii) the conduct of the trial is in compliance with the currently 
approved protocol/amendment(s), ICH GCP, and all applicable regulatory requirement(s). 
The monitoring will be performed in a systematic, prioritised, risk-based approach, and as a 
combination of on-site, remote, and centralised monitoring. For more details, please refer to 
the trial-specific monitoring guideline and data review plan.  
In order to perform their role effectively, CRAs and persons involved in quality assurance and 
inspections will need direct access to source data, e.g. medical records, laboratory reports, 
appointment books, etc. If the electronic medical record does not have a visible audit trail, the 
investigator must provide the CRA with signed and dated printouts. In addition, relevant site 
staff should be available for discussions at monitoring visits and between monitoring visits 
(e.g. by telephone). 
Protocol compliance 
Protocol deviations will be documented and notified to the investigator. Protocol deviations 
will be assessed by LEO Pharma and important protocol deviations described in the CTR. 
Sponsor audits, IRB/IEC review, and regulatory agency inspections 
The clinical trial will be subject to audits conducted by LEO Pharma or inspections from 
domestic or foreign regulatory authorities or from IRBs/IECs. Audits and inspections may 
take place during or after the trial. The investigator and the site staff as well as LEO Pharma 
staff have an obligation to cooperate and assist in audits and inspections. This includes giving 
auditors and inspectors direct access to all source documents and other documents at the trial 
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site relevant to the clinical trial. This includes permission to examine, verify, and reproduce 
any records and reports that are important to the evaluation of the trial. 
If the trial site is contacted for an inspection by competent authorities, LEO Pharma must be 
notified immediately. 
Data handling 
Data will be collected by means of electronic data capture unless transmitted electronically to 
LEO Pharma or designee (e.g. laboratory data). The investigator or staff authorised by the 
investigator will enter subject data into an electronic CRF (eCRF). Data recorded in the eCRF 
will be accessible to the trial site and LEO Pharma personnel immediately after entry. The 
eCRF must be maintained in an up-to-date state by the trial site at all times. 
The investigator must verify the correctness of the data entered by the site by electronically 
dating and signing the eCRF. This signature information will be kept in the audit trail and 
cannot be altered. Any correction(s) made by the investigator or authorised site staff to the 
eCRF after original entry will be documented in the audit trail. Changes to data already 
approved will require re-signature by the investigator. The person making the change to the 
data, and the date, time, and reason for the change will be identified in the audit trail. 
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 
electronic data capture system. This systematic validation will ensure that a clean and 
consistent database is provided for the statistical analysis. 
External data transfers from vendors to LEO Pharma will be transmitted and handled via a 
secure file transfer protocol site.  
Transmissions of data are documented in more detail in a data flow plan which is part of the 
trial master file.  
Statistical programming standards 
CDISC controlled terminology version 06‑Nov‑2020 or newer was used for definition of 
controlled terminology throughout this protocol. Latest version of standard data tabulation 
model (SDTM) available at FSFV will be used for data. 
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Archiving of trial documentation 
The investigator at each trial site must make arrangements to store the essential trial 
documents, including the investigator trial file [55]. Essential trial documents must be stored 
until LEO Pharma informs the investigator that the documents are no longer to be retained, or 
longer if required by local regulations. 
In addition, the investigator is responsible for the archiving of all relevant source documents 
so that the trial data can be compared against source data after the completion of the trial (e.g., 
in case of an inspection from regulatory authorities). 
The investigator is required to ensure the continued storage of the documents even if the 
investigator leaves the trial site or retires before the end of the required storage period. 
No documents may be destroyed during the retention period without the written approval of 
LEO Pharma. No documents may be transferred to another location or party without written 
acceptance from LEO Pharma. 
The destruction process must ensure confidentiality of data and must be done in accordance 
with local regulatory requirements. 
For archiving purposes, each investigator will be supplied with an electronic copy of the 
eCRFs for all screened subjects at the trial site. This is done after completion of the trial and 
before access to the eCRF is revoked. Audit trail information will be included. eCRFs must be 
available for inspection by authorised representatives from LEO Pharma, from regulatory 
authorities and/or IRBs/ IECs. 
Appendix 3E: Registration, reporting, and publication policy 
Trial disclosure 
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 into 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 at leopharmatrials.com in accordance with our 
Position on Public Access to Clinical Trial Information no later than 12 months after trial 
completion. Trial results may also become reported in www.ClinicalTrials.gov, 
www.clinicaltrialsregister.eu, and national data registries in accordance with applicable law 
and regulations after clinical trial completion or premature termination. 
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Publications 
The investigator shall be entitled to make publications of the results generated by the 
investigator in accordance with the process described here. 
A publication will be submitted for publication within 12 months after the clinical trial has 
been completed or terminated at the trial site and all data have been received, defined as final 
database lock of the clinical trial. 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 
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.  
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 [43]. 
Appendix 3F: 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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Appendix 3G: 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 update 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. 
Appendix 3H: Committee structure 
Not applicable. 
Appendix 3I: Trial and trial site closure 
Premature termination of trial or trial site 
LEO Pharma, the investigator, the IRBs/IECs, or competent authorities may decide to stop the 
clinical trial, part of the trial, or a trial site at any time, but agreement on procedures to be 
followed must be obtained. 
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. 
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 
unfavourable 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 of subjects by the investigator. 
Completion of trial 
Investigators will be informed when subject recruitment is to cease. Screening activities will 
be stopped at a trial site when the total requested number of subjects for the clinical trial has 
been obtained, irrespective of the specific site’s planned inclusion number. 
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Trial sites will be closed upon trial completion. LEO Pharma will undertake arrangements for 
the collection and disposal of any unused trial material that the investigator is not required to 
keep in his/her files. 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. 
When the randomisation code has been broken, the investigators will receive information 
about the treatment allocation for the subjects randomised at their respective sites and will be 
asked to record this in the subject’s medical record. 
Appendix 3J: Responsibilities 
The signatory investigator is responsible for the approval of the clinical trial protocol and 
the CTR on behalf of all clinical trial investigators and as agreed to in a signatory investigator 
agreement. 
Each participating investigator is responsible for all aspects of the clinical trial conduct at 
his/her trial site as agreed to in a clinical trial agreement.  
 
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Appendix 4: Country-specific requirements 
Not applicable 
 
 
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Appendix 5: Short version and justification for eligibility criteria 
Inclusion criteria 
No. 
Short version 
Justification 
1 
Signed and dated informed consent has been obtained prior to 
any protocol-related procedures 
To ensure compliance with Declaration of Helsinki and GCP. 
2 
18-64 years old (both included) at screening. 
To ensure only adults are included given the early stage of development. 
Subjects older than 65 years are excluded to ensure safety of subjects by 
decreasing the risk of enrolling subjects who may be at increased risk of 
severe COVID-19 infection. 
3 
Diagnosis of AD that has been present for ≥1 year prior to 
screening. 
To ensure that the subject has AD 
4 
Subjects who have a recent history (within 6 months before 
screening) of inadequate response to treatment with topical 
medication, or for whom topical treatments are otherwise 
medically inadvisable. 
To ensure that the subject is a candidate for systemic treatment with 
LEO 138559. 
5 
EASI score ≥12 at screening and ≥16 at baseline. 
To ensure that the subject has a severity of disease that makes assessment 
of improvement possible. 
6 
vIGA-AD score ≥3 at screening and baseline. 
To ensure that the subject has a severity of disease that makes assessment 
of improvement possible. 
7 
Body surface area (BSA) of AD involvement ≥10% at screening 
and baseline. 
To ensure that the subject has a BSA involvement that makes assessment 
of improvement possible. 
8 
Worst Daily Pruritus NRS (weekly average) of ≥3 points at 
baseline. 
To ensure that the subject has a severity of itch that makes assessment of 
improvement possible. 
9 
Subject agrees to apply an emollient twice daily (or more 
frequently, if needed) to AD lesional and non-lesional skin for at 
least 7 days before baseline. 
To provide subjects with background standard of care therapy 
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10 
A woman of childbearing potential must have a negative serum 
pregnancy test at screening and a negative urine pregnancy test 
at baseline. 
For the safety of the fetus/ newborn child. 
11 
A woman of childbearing potential must use a highly effective 
form of birth control throughout the trial and at least for 
18 weeks after last administration of IMP. 
For the safety of the fetus/newborn child. 
 
 
Exclusion criteria  
No. 
Short version  
Justification 
1 
Treatment with systemic 
immunosuppressive/immunomodulating medication (excluding 
systemic antihistamines if taken at stable dose already before 
baseline) e.g JAK inhibitors, immunoglobulin/blood products 
within 2 weeks or 5 half-lives prior to baseline, whichever is 
longer. 
To not interfere with primary endpoint and efficacy assessments. 
2 
Treatment with systemic corticosteroids within 4 weeks prior to 
baseline 
To not interfere with primary endpoint and efficacy assessments 
3 
Intake of nonsteroidal anti-inflammatory drugs (NSAIDs) within 
1 week prior to baseline. Intake of paracetamol will be allowed. 
To not interfere with primary endpoint and efficacy assessments 
4 
Treatment with biologics within 5 half-lives (if known) or 16 
weeks prior to baseline, whichever is longer. 
To not interfere with primary endpoint and efficacy assessments 
5 
Allergen immunotherapy within 4 weeks prior to baseline 
To not interfere with primary endpoint and efficacy assessments 
6 
Treatment with TCS, TCI, topical PDE-4 inhibitor, or other 
topical prescription treatments within 1 week prior to baseline. 
To not interfere with primary endpoint and efficacy assessments 
7 
Use of tanning beds or phototherapy (narrow band ultraviolet B 
[NBUVB], ultraviolet B [UVB], ultraviolet A1 [UVA1], 
psoralen + ultraviolet A [PUVA]) within 4 weeks prior to 
baseline 
To not interfere with efficacy assessments 
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8 
Treatment with a live (attenuated) vaccine within 12 weeks prior 
to baseline. 
To ensure safety of subjects as LEO 138559 could potentially interact 
with this. 
9 
Active dermatologic condition that could confound the diagnosis 
of AD or interfere with assessment of the treatment. 
To exclude conditions that are likely to interfere with the assessment of 
severity of AD. 
10 
History of malignancy within 5 years prior to randomization, 
apart from nonmetastatic BCC, SCC of the skin, or cervical 
carcinoma in-situ, considered cured by the standard of care. 
To ensure safety of subjects. 
11 
Clinically significant active chronic or acute infection requiring 
systemic treatment within 4 weeks prior to baseline that may 
compromise the safety of the subject 
To ensure safety of subjects  
12 
Skin infection within 1 week prior to the baseline visit. 
To ensure safety of subjects  
13 
Current or recent (within 2 years prior to baseline) 
gastrointestinal ulcers 
To ensure safety of subjects 
14 
History of any of the following: anaphylaxis, immune complex 
disease, pancreatic disease, inflammatory bowel disease or 
known or suspected history of immunosuppressive disorder 
Anaphylaxis: To ensure safety of subjects given the potential increased 
risk of anaphylaxis and serious allergic reactions after administration of 
foreign proteins. 
Immune complex disease: To ensure safety of subjects given the potential 
increased risk that antibody-antigen complexes can accumulate and cause 
a Type III allergic reaction. 
Pancreatic disease: To ensure safety of subjects given the potential 
increased risk of impaired wound healing of pancreas with LEO 138559. 
Inflammatory bowel disease: To ensure safety of subjects given the 
potential increased risk of impaired wound healing of intestine with 
LEO 138559. 
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Known or suspected history of immunosuppressive disorder: To ensure 
safety of subjects given the potential increased risk of infections of the 
skin, lung, and intestines with LEO 138559s 
15 
Known or suspected hypersensitivity to any component(s) of the 
IMPs  
To ensure safety of subjects 
16 
Known or suspected hypersensitivity to local anesthetics 
To ensure safety of subjects 
17 
Presence of hepatitis B or C infection at screening. These are 
defined as: 1) Positive hepatitis C Ab, or 2) Positive HBsAg, or 
3) Negative anti-HBs Ab AND positive anti-HBc Ab 
To ensure safety of subjects 
18 
History of human immunodeficiency virus (HIV) infection or 
positive HIV serology at screening 
To ensure safety of subjects 
19 
Subject has a positive or indeterminate Mycobacterium 
tuberculosis IFN-γ release assay test or a positive purified 
protein derivative (PPD) test at screening 
To ensure safety of subjects given the potential increased risk of 
infections of the lung with LEO 138559. 
20 
Current diagnosis of diabetes. 
 
To ensure safety of subjects by decreasing the risk of enrolling subjects 
who may be at increased risk of severe COVID-19 infection. 
21 
Clinically significant abnormalities detected on vital signs or 
ECG (apart from 1st degree atrioventricular (AV) block that is 
allowed 
To ensure safety of subjects 
22 
Serious heart conditions (e.g., heart failure, coronary artery 
disease, congenital heart disease, cardiomyopathies, and/or 
pulmonary hypertension). 
 
To ensure safety of subjects by decreasing the risk of enrolling subjects 
who may be at increased risk of severe COVID-19 infection. 
23 
 
Chronic lung diseases (e.g., chronic obstructive 
pulmonary disease, idiopathic pulmonary fibrosis, and/or cystic 
fibrosis) 
To ensure safety of subjects by decreasing the risk of enrolling subjects 
who may be at increased risk of severe COVID-19 infection. 
24 
Acute asthma, acute bronchospasm, moderate to severe asthma 
[as defined by GINA guidelines] 
To ensure safety of subjects by decreasing the risk of enrolling subjects 
who may be at increased risk of severe COVID-19 infection. 
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25 
Obesity (BMI ≥35) 
To ensure safety of subjects by decreasing the risk of enrolling subjects 
who may be at increased risk of severe COVID-19 infection. 
26 
Subject has laboratory abnormalities that, in the opinion of the 
investigator, will prevent the subject from completing the trial or 
interfere with the analysis of results 
To ensure safety of subjects 
27 
Subject is pregnant or lactating 
For the safety of the unborn/newborn child. 
28 
Subject has a history of chronic alcohol or drug abuse within 
12 months prior to screening, or any condition associated with 
poor compliance as judged by the investigator. 
To ensure safety of the subjects, and integrity and validity of the trial 
data. 
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. 
To ensure integrity of trial data. 
30 
Any disorder at screening and/or baseline, which is not stable in 
the opinion of the investigator 
To ensure safety of the subjects, and integrity and validity of the trial 
data. 
31 
Any significant abnormal finding at baseline and/or screening 
which may in the opinion of the investigator 
To ensure safety of the subjects, and integrity and validity of the trial 
data. 
32 
Treatment with any non-marketed drug substance within the last 
4 weeks or 5 half-lives prior to baseline, whichever is longer. 
To ensure safety of subjects and ensure lack of confounding of 
measurements (e.g. efficacy, PK, and PD). 
33 
Current participation in any other interventional clinical trial. 
To ensure safety of subjects and ensure lack of confounding of 
measurements (e.g. efficacy, PK, and PD). 
34 
Previously randomised in this clinical trial. 
To ensure integrity and validity of the trial data due to the possibility of 
duplicate subject entries. 
35 
Subjects who are legally institutionalised. 
To ensure compliance with Declaration of Helsinki [37]. 
 
 
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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 
Assoc.-Prof. PD Patrick M. Brunner, MD, MSc 
Department of Dermatology 
Medical University of Vienna  
Währinger Gürtel 18-20 
1090 Vienna 
Austria 
 
Appendix 7: Protocol Amendment history 
Amendment 1 (08-Mar-2022) 
This amendment is considered substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union or 
subsequent regulation. 
Overall rationale for the amendment: 
The Clinical Trial Protocol Version 2.0 became necessary in order to take account of 
objections raised by the Ethics Committee (EC) of the Medical University of Vienna 
(Ethikkommission der Medizinischen Universität Wien) the relevant Austrian Ethics 
Committee (EC) received on 22-Feb-2022. 
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Section no. 
and name 
Description of change 
Brief rationale 
Synopsis 
8.2 
Exclusion 
criteria 
9.7 
Prohibited 
medications 
and 
procedures 
 
Appendix 5 
Exclusion criterion #1 has been 
modified, shortening the wash-out 
period for the treatment with systemic 
immunosuppressive/immunomodulating 
medication from 4 weeks to only 2 
weeks. 
The information on the length of the 
washout period for treatment with 
systemic immunosuppressive / 
immunomodulatory drugs was also 
adjusted in Panel 5 (Prohibited 
medication(s) and/or procedure(s)). 
Short version of eligibility criteria was 
updated accordingly. 
Based on the limited data 
available for LEO 138559, the 
EC requested to add another 
inclusion criterion that only 
allows the inclusion of patients 
on systemic therapy who have 
not responded adequately to a 
conventional systemic therapy. 
As the original protocol 
already intended to only 
include patients who either 
qualify for systemic therapy or 
who have already failed to 
respond adequately to 
conventional local and 
systemic therapies (refer to 
inclusion criterion #4), no new 
inclusion criterion have been 
added. Nonetheless, as a wash-
out period of 4 weeks in 
patients with prior 
unsuccessful Janus kinase 
inhibitor or ciclosporin A 
therapy seems to be very long 
in relation to their short half-
life’s (half-life 10-16 hours) 
the wash-out period for these 
therapies is shortened to only 2 
weeks or to 5x the half-life, 
whichever is longer, to avoid 
any unnecessary withhold. 
Synopsis 
Exclusion criterion #14 has been 
changed by taking out the history of 
Furthermore, the EC requested 
to clarify, if it is intended to 
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Section no. 
and name 
Description of change 
Brief rationale 
8.2 
Exclusion 
criteria 
Appendix 5 
zoster infection and viral skin 
infections. 
Short version of eligibility criteria was 
in addition updated accordingly. 
exclude patients with a history 
of viral skin infections. 
As this is neither intended nor 
necessary, the respective 
exclusion criterion (No. #14) 
has been adapted accordingly. 
Section 11.10 
As no biobanking is planned the 
respective phrase in section 11.10, 
inserted by mistake, has been deleted. 
The Ethics Committee has also 
objected that the information 
on whether a biobank is 
planned remains unclear in the 
protocol. 
In fact, no biobank is planned. 
All biological samples 
collected will only be used 
according to the investigations 
outlined in the protocol and 
will be destroyed afterwards. 
Clinical trial 
protocol 
statements 
Per Sørensen has been replaced by Kyle 
Raymond, the new lead statistician at 
LEO Pharma A/S 
As the lead statistician has 
changed, the signatory page 
needed to be updated 
Whole trial 
protocol 
Individual corrections throughout the 
protocol can be traced back via the 
track change mode and are not listed 
here. 
Mistakes, such as typos or 
incorrect cross-references that 
were noticed during the review 
of this protocol amendment, 
were corrected in order to be 
as unambiguous and precise as 
possible 
 
 
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Amendment 2 (14-Apr-2022) 
This amendment is considered substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union or 
subsequent regulation. 
Overall rationale for the amendment: 
With the introduction of COVID-19 vaccines, COVID-19 may now be considered more like 
other influenza-like diseases – and COVID-19 (confirmed by a positive SARS-CoV-2 test 
result) is no longer deemed a major health risk as disease symptoms are commonly only mild 
and patients rapidly recover from COVID-19. This amendment is intended to take account for 
the changed status of the COVID-19 pandemic. 
Section no.  
and name 
Description of change 
Brief rationale 
10.2.1 Reasons 
for permanent 
discontinuation 
of IMP 
Rewording of the reason for 
permanent discontinuation of IMP 
due to SARS-CoV-2 infection 
Formerly: 
Subjects will permanently 
discontinue IMP in the event of: 
• 
…. 
• 
Infection with SARS-CoV-2 
(COVID -19). 
• 
…. 
 
New: 
Subjects will permanently 
discontinue IMP in the event of: 
• 
…. 
• 
Symptomatic infection with 
SARS-CoV-2 that is likely to 
have an impact on efficacy or 
safety data (i.e., patients with 
a SARS-CoV-2 infection 
without or very mild 
symptoms only (e.g., rhinitis 
or sore throat) might continue 
with the study at investigator’s 
The adjustment was made in the light of 
the changing course of disease in case of 
infection with SARS-CoV-2, which 
currently tends to show milder courses 
and shorter durations due to the 
vaccination status but also the dominant 
viral variant. 
It is important to note the investigational 
drug is not believed to present a risk of a 
decreased antiviral immunity in subjects 
infected with SARS-CoV-2. In addition, it 
is not believed that the investigational 
drug increase the susceptibility of a 
subject to contract COVID-19 or other 
infections. The infection situation will 
continue to be monitored and necessary 
adjustments will be implemented as 
needed. 
TMF-000709974 - Version 5.0


Trial ID: LP0145-2274 
Date: 04-Jan-2023 
Version: 5.0 
Page 129 of 129 
 
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 
 
Section no.  
and name 
Description of change 
Brief rationale 
discretion and in accordance 
with the applicable local 
regulations). 
• 
…. 
Clinical trial 
protocol 
statements 
 has been replaced by 
 as 
Senior Director, Medical 
Department at LEO Pharma A/S 
Due to personnel changes and changes in 
project responsibility at LEO Pharma A/S, 
it is necessary to adapt the Approval 
Statement accordingly 
 
 
 
TMF-000709974 - Version 5.0
PPD
PPD