A Phase 2a, Randomized, Double-blind, Placebo-controlled, Multi-site, Proof of Concept Trial to Evaluate the Efficacy and Safety of LEO 138559 in Adult Subjects With Moderate to Severe Atopic Dermatitis (AD).
Phase: PHASE2
Conditions: Atopic Dermatitis
Sponsor: LEO Pharma

CONFIDENTIAL 
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Clinical Trial Protocol 
 
 
LP0145-1376 
 
 
A phase 2a, randomised, double-blind, placebo-controlled, multi-site, proof of concept trial 
to evaluate the efficacy and safety of LEO 138559 in adult subjects with moderate to severe 
atopic dermatitis (AD). 
 
Phase 2a Proof of Concept  
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: 
LP0145-1376 
 
Date: 
 
31-Jan-2022 
 
EudraCT no: 
2020-005541-16  
 
Version: 
4.0 
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Clinical trial protocol statements 
Approval statement LEO Pharma A/S 
Electronic signatures made within eTMF LEO Pharma are considered to be a 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: 
, MMath, PhD 
 
Biostatistics lead, Medical Sciences 
 
 
 
, MD 
 
Vice president, Medical Sciences 
 
 
 
, MD, PhD 
 
Vice president, Translational Medicine 
 
 
 
, PhD 
 
Clinical operations lead, Global Clinical Operations 
 
 
 
, MD 
 
Signatory investigator 
 
 
 
 
 
 
 
Acknowledgement statement investigators 
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 
Document history 
Document 
Date 
Type of protocol amendment 
Amendment 3 (substantial) 
31-Jan-2022 
Global 
Amendment 2 (non-substantial) 
17-Nov-2021 
Global 
Amendment 1 (substantial) 
07-May-2021 
Global 
Original protocol 
12-Mar-2021 
NA 
Abbreviations: NA = not applicable. 
Note that protocol amendment summary of changes tables for the previous amendments are 
provided in Appendix10. 
Amendment 3 (31-Jan-2022) 
This amendment is considered to be 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 main purpose for this protocol amendment is to change the event of a positive 
SARS-CoV-2 test (COVID-19) from leading to permanent discontinuation of IMP 
(Section 10.2.1) to leading to a possible temporary discontinuation of IMP (Section 10.2.2).  
At the time of protocol preparation, COVID-19 was considered a disease with lower 
respiratory tract involvement in many people infected. However, even though the IL-22R is 
expressed in the lungs, the role of LEO 138559 in the context of COVID-19 disease was 
unknown. It was expected that the number of people infected with SARS-CoV-2 during the 
conduct of the trial would be low, and therefore not anticipated to affect data integrity of the 
trial. These assumptions led to a conservative approach of permanently discontinuing IMP for 
subjects testing positive for SARS CoV-2. 
During trial conduct, the COVID-19 situation in many countries including Germany, Poland, 
US, and Canada, has changed. At the beginning of the pandemic, the number of infected 
patients was lower than now, but with a higher risk of severe illness. Now, a very high number 
of newly infected people each day is observed (possibly due to a combination of more 
contagious mutations and a higher test capacity), but with an overall lower number of patients 
with severe illness (possibly due to the introduction of vaccines and virus variants leading to 
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milder symptoms in the majority of the infected people). Based on this, a potential safety 
concern for the patients in relation to SARS CoV-2 infection is now reduced.  
The observed development in the SARS CoV-2 infection rates, results in a risk of a potential 
higher trial attrition rate than previously expected. With the current knowledge of COVID-19 
disease course, presenting with many cases of mild disease, it is considered reasonable to not 
per default discontinue subjects with a SARS CoV-2 infection from IMP treatment. Based on 
local guidelines and regulations on handling of SARS CoV-2 infection, it is considered 
relevant to allow temporary, instead of per default permanent discontinuation of IMP similar 
to other COVID-19 related disruptions (Section 10.2.2 and Appendix 9). Note that as per 
investigator discretion, the IMP can still be permanently discontinued. 
Introducing this amendment increases the possibility of retaining patients in the trial, thereby 
fulfilling our ethical obligation to all the participating subjects and investigators. Furthermore, 
the amendment does not affect the total number of subjects, statistical analysis, and 
interpretation of the trial results, and has no impact on patient safety, thus no impact on the 
scientific value or integrity of the trial.  
All changes to the protocol are presented in the summary of changes table below except for a 
few minor editorial changes (e.g. spelling errors). 
Summary of changes 
Section no. and name 
Description of change 
Brief rationale 
Section 9.10 Reporting 
product complaints 
Fax number: +45 7226 32876910 2468 
Editorial. 
Section 10.2.1 Reasons 
for permanent 
discontinuation of IMP 
• Infection with SARS-CoV-2 (COVID-19). 
Due to change in the global SARS 
CoV-2 (COVID-19) situation. 
Section 10.2.2 Reasons 
for temporary 
discontinuation of IMP 
• COVID-19 related disruption leading to 
site closure. 
Due to change in the global SARS 
CoV-2 (COVID-19) situation. 
Section 13.4.1 
Investigator reporting 
responsibilities 
Fax number: +45 7226 32876910 2468 
Editorial.  
Appendix 3C Subject 
and data confidentiality 
Processing of personal data on behalf of 
LEO Pharma requires a written agreement 
between LEO Pharma and the relevant party 
which covers collection, processing, and 
transfer of personal data in the clinical trial 
as well as reporting obligations in the 
event of any data breach. In certain cases, 
an agreement on transfer of personal data 
may also be required. 
Editorial. 
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Section no. and name 
Description of change 
Brief rationale 
Appendix 9 COVID-19 
pandemic contingency 
plan 
A subject testing positive for COVID 19 
after randomisation must be permanently 
discontinued from IMP and withdrawn from 
the trial. A subject testing positive for 
COVID-19 after randomisation may be 
temporarily discontinued from IMP. IMP 
treatment may be reinstituted at the 
investigator’s discretion. 
Due to change in the global SARS 
CoV-2 (COVID-19) situation. 
Appendix 10 Protocol 
amendment history 
Protocol amendment 2, Summary of changes 
table moved to Appendix 10. 
Editorial. 
Appendix 10 Protocol 
amendment history 
Amendment 2 (197-Nov-2021) 
Editorial. 
 
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Table of contents 
Table of contents ....................................................................................................................... 6 
List of panels ........................................................................................................................... 11 
List of abbreviations ............................................................................................................... 12 
1 Protocol synopsis ................................................................................................................ 16 
2 Trial identification ............................................................................................................. 20 
3 Schematic of trial design ................................................................................................... 20 
4 Schedule of trial procedures ............................................................................................. 21 
5 Introduction and trial rationale ....................................................................................... 31 
5.1 Atopic dermatitis ........................................................................................................ 31 
5.2 Experience with investigational medicinal product .................................................... 32 
5.3 Trial rationale .............................................................................................................. 34 
5.4 Ethical considerations ................................................................................................. 34 
5.5 Benefit/risk assessment ............................................................................................... 35 
6 Trial objectives and endpoints .......................................................................................... 38 
7 Trial design ......................................................................................................................... 40 
7.1 Overall trial design ..................................................................................................... 40 
7.2 Number of subjects needed ......................................................................................... 41 
7.3 End-of-trial definition ................................................................................................. 42 
8 Trial population ................................................................................................................. 43 
8.1 Subject eligibility ........................................................................................................ 43 
8.2 Inclusion criteria ......................................................................................................... 43 
8.3 Exclusion criteria ........................................................................................................ 45 
8.4 Screening and screening failures ................................................................................ 47 
9 Treatments .......................................................................................................................... 49 
9.1 Trial product description ............................................................................................. 49 
9.2 Administration of investigational medicinal product ................................................. 50 
9.3 Treatment assignment ................................................................................................. 51 
9.3.1 
Blinding ......................................................................................................... 52 
9.3.2 
Emergency unblinding of individual subject treatment ................................ 52 
9.4 Background treatment (emollients) ............................................................................ 53 
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9.5 Rescue treatment ......................................................................................................... 53 
9.6 Concomitant medication and concurrent procedures ................................................. 54 
9.7 Prohibited medication and procedures........................................................................ 56 
9.8 Treatment logistics and accountability ....................................................................... 57 
9.8.1 
Labelling and packaging of trial products ..................................................... 57 
9.8.2 
Storage of trial products ................................................................................ 57 
9.8.3 
Drug accountability ....................................................................................... 58 
9.8.4 
Treatment compliance ................................................................................... 58 
9.8.5 
Trial product destruction ............................................................................... 58 
9.9 Provision for subject care following trial completion ................................................ 59 
9.10 Reporting product complaints..................................................................................... 59 
10 Discontinuation and withdrawal ...................................................................................... 60 
10.1 General principles ....................................................................................................... 60 
10.2 Reasons for discontinuation of IMP ........................................................................... 60 
10.2.1 Reasons for permanent discontinuation of IMP ............................................ 60 
10.2.2 Reasons for temporary discontinuation of IMP ............................................ 61 
10.3 Early termination assessments .................................................................................... 61 
10.4 Lost to follow-up ........................................................................................................ 62 
11 Trial assessments and procedures .................................................................................... 64 
11.1 Overview..................................................................................................................... 64 
11.2 Assessments performed only at screening/baseline .................................................... 65 
11.2.1 Demographics................................................................................................ 65 
11.2.2 Body assessment (height) .............................................................................. 65 
11.2.3 Medical history .............................................................................................. 65 
11.2.4 Other assessments ......................................................................................... 66 
11.3 Efficacy assessments .................................................................................................. 66 
11.3.1 Eczema Area and Severity Index (EASI) ...................................................... 66 
11.3.2 Validated Investigator Global Assessment Scale for Atopic Dermatitis 
(vIGA-AD) .................................................................................................... 68 
11.3.3 Body surface area involvement ..................................................................... 68 
11.3.4 Patient-reported outcomes ............................................................................. 69 
11.4 Safety assessments ...................................................................................................... 70 
11.4.1 Vital signs ...................................................................................................... 70 
11.4.2 Physical examination..................................................................................... 71 
11.4.3 Weight ........................................................................................................... 72 
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11.4.4 ECG ............................................................................................................... 72 
11.4.5 Laboratory testing ......................................................................................... 73 
11.4.6 Anti-drug antibodies measurements .............................................................. 76 
11.5 Pharmacokinetic assessments ..................................................................................... 77 
11.5.1 Blood sampling for analysis of PK ............................................................... 77 
11.6 Pharmacodynamics assessments ................................................................................. 77 
11.6.1 Overview ....................................................................................................... 77 
11.6.2 Blood biomarkers .......................................................................................... 78 
11.6.3 Skin swabs ..................................................................................................... 78 
11.6.4 Tape strips ..................................................................................................... 79 
11.7 End-of-trial ................................................................................................................. 79 
11.8 Estimate of total blood volume collected ................................................................... 80 
11.9 Storage of biological samples ..................................................................................... 80 
12 Scientific rationale for trial design and appropriateness of assessments ..................... 82 
12.1 Scientific rationale for trial design ............................................................................. 82 
12.2 Appropriateness of assessments ................................................................................. 84 
13 Adverse events ................................................................................................................... 86 
13.1 Definition and classification of adverse events .......................................................... 86 
13.2 Collection of adverse event reports ............................................................................ 86 
13.3 Reporting of adverse events........................................................................................ 86 
13.4 Reporting of serious adverse events ........................................................................... 87 
13.4.1 Investigator reporting responsibilities ........................................................... 87 
13.4.2 LEO Pharma reporting responsibilities ......................................................... 88 
13.5 Other events that require expedited reporting ............................................................ 89 
13.5.1 Pregnancy ...................................................................................................... 89 
13.6 Reporting of other events............................................................................................ 89 
13.6.1 Adverse events of special interest ................................................................. 89 
13.6.2 Overdose........................................................................................................ 89 
13.6.3 Medication error ............................................................................................ 90 
13.6.4 Misuse or abuse ............................................................................................. 90 
13.6.5 Aggravation of condition .............................................................................. 91 
13.7 Follow-up for final outcome of adverse events .......................................................... 91 
13.8 Handling of an urgent safety measure ........................................................................ 91 
14 Statistical methods ............................................................................................................. 93 
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14.1 Sample size ................................................................................................................. 93 
14.2 Trial analysis sets ........................................................................................................ 93 
14.3 Statistical analysis ....................................................................................................... 94 
14.3.1 General principles ......................................................................................... 94 
14.3.2 Handling of missing values ........................................................................... 94 
14.3.3 Handling of intercurrent events related to the COVID-19 pandemic ........... 95 
14.3.4 Disposition of subjects .................................................................................. 96 
14.3.5 Demographics and other baseline characteristics.......................................... 96 
14.3.6 Exposure and treatment compliance ............................................................. 96 
14.3.7 Testing strategy ............................................................................................. 96 
14.3.8 Analysis of primary endpoint ........................................................................ 97 
14.3.9 Analysis of secondary endpoint .................................................................. 105 
14.3.10 Analysis of exploratory efficacy endpoints ................................................. 105 
14.3.11 Analysis of patient-reported outcomes ........................................................ 106 
14.3.12 Analysis of pharmacodynamics .................................................................. 107 
14.3.13 Exploratory analyses ................................................................................... 107 
14.3.14 Analysis of safety ........................................................................................ 107 
14.3.15 Analysis of pharmacokinetics ..................................................................... 110 
14.3.16 Interim analysis ........................................................................................... 110 
15 References .......................................................................................................................... 111 
Appendix 1: Definitions of adverse events and serious adverse events ........................... 118 
Appendix 2: Classification of adverse events ..................................................................... 120 
Appendix 3: Trial governance considerations ................................................................... 124 
Appendix 3A: Regulatory and ethical considerations .............................................. 124 
Appendix 3B: Informed consent process ................................................................. 125 
Appendix 3C: Subject and data confidentiality ....................................................... 125 
Appendix 3D: Record keeping, quality control, and data handling ......................... 127 
Appendix 3E: Registration, reporting, and publication policy ................................ 130 
Appendix 3F: Insurance ........................................................................................... 131 
Appendix 3G: Financial disclosure .......................................................................... 131 
Appendix 3H: Committee structure ......................................................................... 131 
Appendix 3I: Trial and trial site closure ................................................................... 131 
Appendix 3J: Responsibilities .................................................................................. 132 
Appendix 4: AAD Consensus Criteria for the diagnosis of AD ........................................ 133 
Appendix 5: Guidance for anaphylaxis diagnosis ............................................................. 135 
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Appendix 6: Country-specific requirements ...................................................................... 137 
Appendix 7: Short version and justification for eligibility criteria ................................. 138 
Appendix 8: Contact list ...................................................................................................... 143 
Appendix 9: COVID-19 pandemic contingency plan........................................................ 144 
Appendix 10: Protocol amendment history ....................................................................... 146 
 
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List of panels 
Panel 1: Trial design ................................................................................................................. 20 
Panel 2: Schedule of trial procedures ....................................................................................... 21 
Panel 3: Objectives and endpoints ........................................................................................... 38 
Panel 4: Identification of investigational medicinal products .................................................. 49 
Panel 5: Prohibited medication(s) and/or procedure(s) ............................................................ 56 
Panel 6: Sequence of assessments ............................................................................................ 64 
Panel 7: Calculation of the Eczema Area and Severity Index .................................................. 67 
Panel 8: Eczema Area and Severity Index severity score scale and area score scale .............. 67 
Panel 9: Validated Investigator Global Assessment Scale for Atopic Dermatitis .................... 68 
Panel 10: Clinical laboratory tests ............................................................................................ 74 
Panel 11: Adverse events of special interest............................................................................. 89 
Panel 12: Objective and estimands for primary endpoint ........................................................ 98 
Panel 13: Handling of intercurrent events and analyses of estimands for the primary endpoint
 ........................................................................................................................ 104 
 
 
 
 
 
 
 
 
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List of abbreviations  
AAD 
American Academy of Dermatology  
Ab 
antibody 
AD 
atopic dermatitis 
ADA 
anti-drug antibodies 
AE 
adverse event 
AESI 
adverse event of special interest 
ANCOVA 
analysis of covariance 
anti-HBc 
hepatitis B core antibody 
anti-HBs 
hepatitis B surface antibody 
BCC 
basal cell carcinoma 
BP 
blood pressure 
BMI 
body mass index 
BSA 
body surface area 
CCL17 
chemokine (C-C motif) ligand 17 
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
confidence interval 
CMH 
Cochran–Mantel–Haenszel 
CMO 
contract manufacturing organisation 
CONSORT 
Consolidated Standards of Reporting Trials 
COVID-19 
coronavirus disease 2019 
CPM 
clinical project manager 
CRA 
clinical research associate 
CRO 
contract research organisation 
CTR 
clinical trial report 
DLQI 
Dermatology Life Quality Index 
DPP4 
dipeptidyl peptidase-4 
EASI 
Eczema Area and Severity Index 
EASI 50 
at least 50% reduction in EASI score 
EASI 75 
at least 75% reduction in EASI score 
EASI 90 
at least 90% reduction in EASI score 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
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eDiary 
electronic diary 
EMA 
European Medicines Agency 
ePRO 
electronic patient-reported outcome 
EU 
European Union 
FAS 
Full analysis set 
Fc 
fragment crystallisable 
FDA 
Unites States Food and Drug Administration 
FiM 
first in man 
FSFV 
first subject first visit 
GCP 
Good Clinical Practice 
GINA 
Global Initiative for Asthma 
HbsAg 
hepatitis B surface antigen 
HCP 
healthcare professional 
HIV 
human immunodeficiency virus 
HRQoL 
health-related quality of life  
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- γ 
interferon gamma 
IGA 
Investigator’s Global Assessment 
IgE 
immunoglobulin E 
IgG 
immunoglobulin G 
IgM 
immunoglobulin M 
IL 
interleukin 
IL-10R2 
interleukin 10 receptor 2 
IL-22BP 
interleukin 22 binding protein 
IL-22R 
interleukin 22 receptor 
IL-22R1 
interleukin 22 receptor 1 
IL4Ra 
interleukin 4 receptor a 
IMP 
investigational medicinal product 
IND 
Investigational New Drug 
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IRB 
institutional review board 
IRT 
interactive response technology 
IUD 
intrauterine device 
IUS 
intrauterine hormone-releasing system 
IV 
Intravenous(ly) 
JAK 
janus kinase inhibitor 
JP 
Japan 
KLH 
keyhole limpet hemocyanin 
LEO 138559 
investigational medicinal product investigated in this trial 
LOCF 
last observation carried forward 
LS 
least squares 
mAb 
monoclonal antibody 
MAD 
multiple ascending dose 
MAR 
missing at random 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
multiple imputation 
MMRM 
mixed model repeated measures 
MoA 
mode of action 
NA 
not applicable 
NCT 
National Clinical Trial 
NOAEL 
no-observed-adverse-effect level 
NRI 
non-responder imputation 
NRS 
numeric rating scale 
PCR 
polymerase chain reaction 
PD 
pharmacodynamics 
PDE-4 
phosphodiesterase-4  
PEF 
peak expiratory flow 
PK 
pharmacokinetics 
PoC 
proof of concept 
POEM 
Patient-Oriented Eczema Measure 
PPD 
purified protein derivative 
PRO 
patient-reported outcome 
Q2W 
every second week 
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qPCR 
Quantitative polymerase chain reaction 
QT 
QT interval, time from start of the Q wave to the end of the 
T wave on an ECG tracing 
RNA 
ribonucleic acid 
rRNA 
ribosomal RNA 
SAD 
single ascending dose 
SAE 
serious adverse event 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SC 
Subcutaneous(ly) 
SCC 
squamous cell carcinoma 
SD 
standard deviation 
SDTM 
standard data tabulation model 
SOC 
system organ class 
STAT 
signal transducer and activator of transcription 
SUSAR 
suspected unexpected serious adverse reaction 
TARC 
thymus and activation-regulated chemokine 
TCI 
topical calcineurin inhibitor(s) 
TCS 
topical corticosteroid(s) 
Th2 
T-helper 2 
TMDD 
target-mediated drug disposition 
US 
United States of America 
vIGA-AD 
Validated Investigator Global Assessment Scale for Atopic 
Dermatitis 
WOCF 
worst observation carried forward 
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1 Protocol synopsis  
Trial ID 
EudraCT no. 
NCT no. 
IND no. 
LP0145-1376 
2020-005541-16 
04922021 
146054 
Title of trial 
A phase 2a, randomised, double-blind, placebo-controlled, multi-site, proof of 
concept trial to evaluate the efficacy and safety of LEO 138559 in adult 
subjects with moderate to severe atopic dermatitis (AD). 
Short title of trial 
An evaluation of LEO 138559 in adults with moderate to severe atopic 
dermatitis. 
Main objectives 
and endpoints 
 Objectives 
Endpoints 
Primary objective 
Primary endpoint 
To compare the efficacy of 
LEO 138559 with placebo 
in subjects with moderate 
to severe AD. 
• 
Change in Eczema Area and Severity 
Index (EASI1) score from baseline to 
Week 16. 
Secondary objective 
Secondary endpoints 
To compare the safety of 
LEO 138559 with placebo in 
subjects with moderate to 
severe AD. 
• 
Number of treatment-emergent adverse 
events from baseline to Week 16 per 
subject. 
 
1 The EASI is a validated measure used in clinical practice and clinical trials 
to assess the severity and extent of AD. The EASI is a composite index with 
scores ranging from 0 to 72, with higher values indicating more severe 
and/or more extensive condition. 
Final collection of 
data for the 
primary endpoint 
Week 16 
Trial design 
The trial design is illustrated in the figure below: 
 
 
aScreening phase of up to 4 weeks (Weeks -4 to 0) including a washout phase of 
1 week (Week -1 to 0). Subjects must stop treatment with TCS, TCI, topical PDE-4 
inhibitors, or other topical prescription treatments 1 week prior to randomisation. All 
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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). 
bIn addition to the Q2W dosing schedule during the treatment phase, both treatment 
groups will receive an additional dose of their allocated treatment (LEO 138559 
450 mg or placebo) at Visit 4 (Week 1). 
cA 16-weeks safety follow-up period including 3 phone visits at Visits 13, 14, and 15 
(Weeks 20, 24, and 28), and 1 safety follow-up visit at the site at Visit 16 (Week 32). 
Abbreviations: PDE-4 = phosphodiesterase-4; Q2W = every second week; TCI = 
topical calcineurin inhibitor(s); TCS = topical corticosteroid(s). 
 
The trial will consist of a screening period of up to 4 weeks (Weeks -4 to -0) 
including an applicable washout period of 1 week (Week -1 to 0), a treatment 
period of 16 weeks (Weeks 0 to 16), and a 16-weeks off-treatment follow-up 
period for the assessment of safety and anti-drug antibodies (ADA) (Weeks 16 
to 32).  
After providing informed consent and successful completion of the screening 
and washout period, subjects will be randomised in a 1:1 ratio to receive 
LEO 138559 450 mg Q2W or placebo Q2W. Each subject will receive  SC 
injections (each 
 mL) of 
 mg LEO 138559 or placebo to receive a total 
dose of 450 mg LEO 138559 (
 mL) or placebo 
 mL). In addition to this 
Q2W dosing schedule, both treatment groups will receive an additional dose of 
their allocated treatment (LEO 138559 450 mg or placebo) at Visit 4 (Week 1). 
Randomisation will be stratified by the disease severity at baseline; one 
stratum, ‘stratum A’, will be defined as having EASI <21 and the other stratum, 
‘stratum B’, will be defined as having EASI ≥21. 
During the treatment period, final dosing will be administered at Week 14, 
regardless of AD improvement. Rescue treatment: if medically necessary (i.e.,  
due to worsening of AD or intolerable AD symptoms), rescue treatment for AD 
in the form of TCS/TCI may be used from Week 4 at the discretion of the 
investigator. The primary endpoint will be assessed at Week 16, and the final 
safety assessment will be conducted at Week 32. 
Main assessments 
• 
EASI. 
• 
Treatment-emergent adverse events. 
Main criteria for 
inclusion 
• 
18-64 years old (both included) at screening. 
• 
Diagnosis of AD [as defined by the AAD Consensus Criteria (1)] 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, immunoglobulin/blood products, or phototherapy within 4 
weeks or 5 half-lives prior to randomisation, whichever is longer. 
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• 
Treatment with biologics within 5 half-lives (if known) or 16 weeks prior 
to randomisation, whichever is longer. 
• 
Treatment with TCS, TCI, topical PDE-4 inhibitor, or other topical 
prescription treatments within 1 week prior to randomisation. 
• 
Treatment with a live (attenuated) vaccine within 12 weeks prior to 
randomisation. 
• 
Clinically significant active chronic or acute infection requiring systemic 
treatment within 4 weeks prior to randomisation that may compromise the 
safety of the subject. 
• 
Skin infection within 1 week prior to randomisation. 
• 
Presence of hepatitis B or C infection at screening. 
• 
History of human immunodeficiency virus (HIV) infection or positive HIV 
serology at screening. 
• 
Subject has a positive or indeterminate test for tuberculosis at screening. 
• 
Subject is pregnant or lactating. 
Investigational 
medicinal 
products  
• 
Name of IMP: LEO 138559.  
• 
Active substance: LEO 138559, 
 mg/mL (following reconstitution). 
• 
Dosage form: Lyophilised powder for reconstitution (using 1.0 mL 
sterilised water) adding up to a volume of 1.2 mL/vial. 
• 
Concentration: 
 mg/mL.  
• 
Dose and frequency: 450 mg Q2W (  injections of 
 mg/mL). 
• 
Method of administration: Subcutaneous. 
 
• 
Name of IMP: Placebo. 
• 
Active substance: Placebo contains the same excipients in the same 
concentration as LEO 138559 only lacking the active ingredient. 
• 
Dosage form: Solution for injection (contains 1.2 mL/vial). 
• 
Concentration: Not applicable. 
• 
Dose and frequency: Not applicable and  injections of  mL placebo 
solution Q2W. 
• 
Method of administration: Subcutaneous. 
Duration of trial 
participation 
Up to 36 weeks 
Number of 
subjects 
A total of 52 subjects will be randomised 1:1 to: 
• 
LEO 138559 450 mg Q2W (26 subjects). 
• 
Placebo Q2W (26 subjects). 
Number and 
distribution of 
trial sites 
Approximately 20 sites in Canada, Germany, Poland, and the US. 
Statistical 
methods 
Primary and secondary endpoints: All subjects randomized and exposed to IMP 
will be included in the full analysis set (FAS) and will be analysed for the 
primary endpoint, based on treatment assigned. All subjects who will be 
exposed to IMP will be included in the safety analysis set and will be analysed 
for the secondary endpoint, based on actual treatment received. 
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A primary and 3 supplementary estimands will be defined for the primary 
endpoint to ensure that occurrence of intercurrent events is taken into account. 
• The primary estimand for the primary endpoint will use a hypothetical 
strategy which attempts to quantify the effect of treatment, in the 
hypothetical situation, where one or more intercurrent events do not 
occur. 
• A first supplementary estimand will use a composite strategy which 
accounts for occurrence of pre-defined intercurrent events (initiation of 
rescue treatment and permanent discontinuation of IMP) as a component 
of the endpoint. 
• A second supplementary estimand will use a pandemic-modified 
composite strategy which follows a composite strategy for intercurrent 
events independent of the COVID-19 pandemic, attempting to quantify 
the effect of the randomised treatment as if the COVID-19 pandemic did 
not happen. 
• A third supplementary estimand will use a treatment policy strategy 
which attempts to quantify the effect of the randomised treatment 
regardless of whether an intercurrent event occurs. 
For the primary analysis of the primary estimand, missing data at Week 16 due 
to an intercurrent event will be imputed using MI (100 iterations) assuming 
MAR within each treatment group and whether the subject has experienced an 
intercurrent event. Within a given treatment group, observed data from subjects 
not experiencing an intercurrent event will be used to impute missing data for 
subjects who experience an intercurrent event. 
For each of the 100 complete datasets after imputation, the change in EASI 
score from baseline to Week 16 will be analysed using an ANCOVA model 
adjusted for treatment, region, baseline EASI score, and baseline disease 
severity. The pooled estimate of the difference in the LS-mean change from 
baseline, along with the associated 95% CIs and nominal p-values will be 
presented based on applying Rubin’s rules to the estimates and standard errors 
from the ANCOVA analysis of the imputed datasets.  
The 3 supplementary estimands will be analysed using the same ANCOVA 
model with different imputation methods for intercurrent events.   
The secondary endpoint (number of treatment-emergent AEs from baseline to 
Week 16 per subject) will be reported descriptively by treatment group. 
Signatory 
investigator 
  
  
 
 
 Germany 
Sponsor 
LEO Pharma A/S, Industriparken 55, DK 2750 Ballerup, Denmark 
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2 Trial identification 
EudraCT number: 2020-005541-16 
NCT number: 04922021 
IND number: 146054 
The clinical trial protocol will be registered in local registries if required by local legislation. 
3 Schematic of trial design 
The trial design is illustrated in Panel 1 and described in Section 7.1. 
Panel 1: Trial design  
 
 
aScreening phase of up to 4 weeks (Weeks -4 to 0) including a washout phase of 1 week (Week -1 to 0). Subjects 
must stop treatment with TCS, TCI, topical PDE-4 inhibitors, or other topical prescription treatments 1 week 
prior to randomisation. 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). 
bIn addition to the Q2W dosing schedule during the treatment phase, both treatment groups will receive an 
additional dose of their allocated treatment (LEO 138559 450 mg or placebo) at Visit 4 (Week 1). 
cA 16-weeks safety follow-up period including 3 phone visits at Visits 13, 14, and 15 (Weeks 20, 24, and 28), 
and 1 safety follow-up visit at the site at Visit 16 (Week 32). 
Abbreviations: 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) 
Washouta) 
Baseline/ 
Start of treatment 
Treatment 
 
End of treatmentb) 
Primary endpointc) 
SFU phone calls 
SFU site visitd) 
Early IMP 
termination, if 
applicablee) 
Unscheduled. Visitf) 
 
References (Section 
in protocol) 
 
Visit 
1 
2 
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 
-28 
-7 
1 
8 
15 
29 
43 
57 
71 
85 
99 
113 
141, 169, 197 
225 
Visit window 
(days)g)  
NA 
NA 
NA 
±1 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
Trial population and eligibility 
Informed consenth)  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix 3B 
Subjects eligibility 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.2 and 8.3 
Investigator assessments at screening and/or baseline only 
Demographicsi) 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
11.2.1 
Body assessment 
(height)  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
11.2.2 
Medical historyj) 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
11.2.3 
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Screeninga) 
Washouta) 
Baseline/ 
Start of treatment 
Treatment 
 
End of treatmentb) 
Primary endpointc) 
SFU phone calls 
SFU site visitd) 
Early IMP 
termination, if 
applicablee) 
Unscheduled. Visitf) 
 
References (Section 
in protocol) 
 
Visit 
1 
2 
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 
-28 
-7 
1 
8 
15 
29 
43 
57 
71 
85 
99 
113 
141, 169, 197 
225 
Visit window 
(days)g)  
NA 
NA 
NA 
±1 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
Hepatitis B, C, HIV 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
11.2.4 and 
Exclusion 
criterion no. 
14 and 15 
Tuberculosis 
(Mycobacterium 
tuberculosis IFN-γ 
release assay)k)  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
11.2.4 and 
Exclusion 
criterion no. 
16 
Serum pregnancy 
test (females only)l)  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
11.4.5 and 
Inclusion 
criterion no. 
10 
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Screeninga) 
Washouta) 
Baseline/ 
Start of treatment 
Treatment 
 
End of treatmentb) 
Primary endpointc) 
SFU phone calls 
SFU site visitd) 
Early IMP 
termination, if 
applicablee) 
Unscheduled. Visitf) 
 
References (Section 
in protocol) 
 
Visit 
1 
2 
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 
-28 
-7 
1 
8 
15 
29 
43 
57 
71 
85 
99 
113 
141, 169, 197 
225 
Visit window 
(days)g)  
NA 
NA 
NA 
±1 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
SARS-CoV-2 PCR 
test  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
11.2.4, 
11.4.5, and 
exclusion 
criterion 
no. 30 
Randomisation and treatments 
Randomisation 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.3 
IMP administration 
at the trial site 
 
 
X 
Xm) 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
(X) 
9.2 
Treatment 
compliance at the 
trial site 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
(X) 
9.8.4 
Drug accountability 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
(X) 
9.8.3 
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Screeninga) 
Washouta) 
Baseline/ 
Start of treatment 
Treatment 
 
End of treatmentb) 
Primary endpointc) 
SFU phone calls 
SFU site visitd) 
Early IMP 
termination, if 
applicablee) 
Unscheduled. Visitf) 
 
References (Section 
in protocol) 
 
Visit 
1 
2 
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 
-28 
-7 
1 
8 
15 
29 
43 
57 
71 
85 
99 
113 
141, 169, 197 
225 
Visit window 
(days)g)  
NA 
NA 
NA 
±1 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
Background 
treatment 
(emollients)n)  
 
At least twice daily 
 
 
 
 
9.4 
Concomitant 
medications/ 
concurrent 
procedureso) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
9.6 
Subject assessments (eDiary) 
eDiary hand-out / 
training 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Return of eDiaryp) 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
(X) 
 
 
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Screeninga) 
Washouta) 
Baseline/ 
Start of treatment 
Treatment 
 
End of treatmentb) 
Primary endpointc) 
SFU phone calls 
SFU site visitd) 
Early IMP 
termination, if 
applicablee) 
Unscheduled. Visitf) 
 
References (Section 
in protocol) 
 
Visit 
1 
2 
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 
-28 
-7 
1 
8 
15 
29 
43 
57 
71 
85 
99 
113 
141, 169, 197 
225 
Visit window 
(days)g)  
NA 
NA 
NA 
±1 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
Investigator assessments of efficacy 
EASI 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
(X) 
(X) 
11.3.1 
vIGA-AD 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
(X) 
(X) 
11.3.2 
BSA involvement 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
(X) 
(X) 
11.3.3 
Subject assessments of efficacy and HRQoL 
Worst Daily Pruritus 
NRSq) 
 
Daily 
 
 
11.3.4.2 
POEMr) 
 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
 
(X) 
(X) 
11.3.4.3 
DLQIr) 
 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
 
(X) 
(X) 
11.3.4.4 
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Screeninga) 
Washouta) 
Baseline/ 
Start of treatment 
Treatment 
 
End of treatmentb) 
Primary endpointc) 
SFU phone calls 
SFU site visitd) 
Early IMP 
termination, if 
applicablee) 
Unscheduled. Visitf) 
 
References (Section 
in protocol) 
 
Visit 
1 
2 
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 
-28 
-7 
1 
8 
15 
29 
43 
57 
71 
85 
99 
113 
141, 169, 197 
225 
Visit window 
(days)g)  
NA 
NA 
NA 
±1 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
Investigator assessments of safety 
Vital signss) 
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 
ECGt) 
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 
IgE 
 
 
X 
 
 
X 
 
 
 
 
 
X 
 
X 
(X) 
(X) 
11.4.5 
Urinalysisu) 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
(X) 
(X) 
11.4.5 
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Screeninga) 
Washouta) 
Baseline/ 
Start of treatment 
Treatment 
 
End of treatmentb) 
Primary endpointc) 
SFU phone calls 
SFU site visitd) 
Early IMP 
termination, if 
applicablee) 
Unscheduled. Visitf) 
 
References (Section 
in protocol) 
 
Visit 
1 
2 
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 
-28 
-7 
1 
8 
15 
29 
43 
57 
71 
85 
99 
113 
141, 169, 197 
225 
Visit window 
(days)g)  
NA 
NA 
NA 
±1 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
Urine pregnancy test 
(females only)l)  
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
(X) 
(X) 
11.4.5 
ADA 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
(X) 
(X) 
11.4.6 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
13 
Pharmacokinetic assessment 
PK blood samples 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
(X) 
(X) 
11.5 
Pharmacodynamic assessments 
Blood biomarkers 
(PD serum sample) 
 
 
X 
 
X 
X 
 
X 
 
 
 
X 
 
 
(X) 
(X) 
11.6.2 
Skin swabs 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
(X) 
(X) 
11.6.3 
Tape strips 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
(X) 
(X) 
11.6.4 
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Screeninga) 
Washouta) 
Baseline/ 
Start of treatment 
Treatment 
 
End of treatmentb) 
Primary endpointc) 
SFU phone calls 
SFU site visitd) 
Early IMP 
termination, if 
applicablee) 
Unscheduled. Visitf) 
 
References (Section 
in protocol) 
 
Visit 
1 
2 
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 
-28 
-7 
1 
8 
15 
29 
43 
57 
71 
85 
99 
113 
141, 169, 197 
225 
Visit window 
(days)g)  
NA 
NA 
NA 
±1 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
End of treatment/trial 
End-of-treatment 
form 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
11.7 
End-of-trial form 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
11.7 
a) Screening will be performed up to 4 weeks before the baseline visit and can be combined with the washout visit (Visit 2) if needed.  
b) An end-of-treatment form must be completed in the eCRF for all randomised subjects. See Section 11.7 for further details. 
c) Subjects who permanently discontinue IMP treatment prior to Week 16 will be asked to return to the trial site at Week 16 for a primary endpoint (nominal 
Week 16) visit.  
d) An end-of-trial form must be completed in the eCRF for all randomised subjects. See Section 11.7 for further details. 
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 and 
will be followed up as described in Section 10.3. 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).  
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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 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 visits have been marked with an (X).  
g) If the date of a trial visit does not conform to the clinical trial protocol, subsequent visits should be planned to maintain the visit schedule relative to 
randomisation/baseline. 
h) 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.  
i) 
At screening, the demographic data listed in Section 11.2.1 will be recorded. At baseline, only age will be recorded. 
j) 
In case medical history is incomplete at the screening visit, missing data will be retrieved at Week 0 (baseline). 
k) Mycobacterium tuberculosis IFN-γ release assay (or a PPD test if it is a requirement from the local health authorities). 
l) 
For women of childbearing potential (as defined in inclusion criterion no. 10 and 11, Section 8.2). 
m) In addition to the Q2W dosing schedule, both treatment groups will receive an additional dose of LEO 138559 450 mg or placebo at Week 1.  
n) 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). 
o) Relevant concomitant medications/ concurrent procedures should be included from 3 months prior to screening until end of trial (Week 32). 
p) At Week 32, subjects will be asked to bring the eDiary back to the clinic.  
q) Completion of the eDiary for Worst Daily Pruritus NRS will be initiated at least 1 week prior to baseline (Day 1). Compliance with the eDiary 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 eDiary until the safety 
follow-up visit (Visit 16). 
r) 
At the screening visit (at the earliest Week -4), the subject's eligibility to participate in the trial must be confirmed before any PROs are completed. PROs will 
be collected in the electronic device at the trial site and should be completed before the investigator’s assessment of efficacy.  
s) 
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. 
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t) 
ECG should be recorded in triplicate for each time point and will be centrally evaluated. 
u) Urinalysis is performed by a urine dipstick. The analytes listed in Section 11.4.5 will only be measured if the urine dipstick is abnormal.  
 
Abbreviations: ADA = anti-drug antibodies; AE = adverse event; BSA = body surface area; DLQI = Dermatology Life Quality Index; EASI = Eczema Area 
and Severity Index; ECG = electrocardiogram; eCRF = electronic case report form; HIV = human immunodeficiency virus; HRQoL = health related quality of 
life; IFN-γ = interferon gamma; IgE = immunoglobulin E; IMP = investigational medicinal product; NRS = Numeric Rating Scale; PCR = polymerase chain 
reaction; PD = pharmacodynamics; PK = pharmacokinetics; POEM = Patient-Oriented Eczema Measure; PPD = purified protein derivative; PRO = patient-
reported outcome; Q2W = every second week; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; 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 
AD is a chronic inflammatory disease characterised 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 (2-4). 
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. 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 tralokinumab, lebrikizumab, and 
nemolizumab (23-25), as well as oral JAK inhibitors (26-28) . Of note, baricitinib was 
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recently approved by the EMA for the treatment of moderate to severe AD (29), however, its 
position in the treatment paradigm is not yet fully understood (30).  
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 moderate to severe AD patients (31, 32). 
5.2 Experience with investigational medicinal product 
Nonclinical data 
LEO 138559, originally known as ARGX-112 (clone 
), 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 signalling via JAK1-STAT3 (33). 
Given the binding of LEO 138559 to IL-22R1, it is hypothesised to prevent not only the 
effects of IL-22 but also partially 
 and 
. 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 cellular activity (34). Therefore, LEO 138559 is considered an optimal 
therapeutic tool to inhibit the IL-22 pathway.  
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 
-fold margin of 
exposure between the observed NOAELs and the exposure at steady state for 450 mg Q2W 
dosing (planned dosing regimen in LP0145-1376). 
As expected for a mAb drug, the nonclinical results did not indicate a need to perform 
specific clinical trials (typically conducted for small molecule drugs) investigating effects on 
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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 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) (35). 
A detailed overview of nonclinical data on LEO 138559 is available in the current 
investigator’s brochure (35). 
Clinical data 
LEO 138559 is in early development with 1 ongoing first-in-human clinical trial: 
LP0145-1315. This is a phase 1, randomised, double-blind, placebo-controlled, multi-centre, 
SAD, and MAD trial to evaluate the safety, tolerability, PK, and PD of LEO 138559 in 
healthy volunteers and subjects with moderate to severe AD. The trial consists of 2 parts: 
SAD and MAD.  
To date in the LP0145-1315 trial, single IV doses up to 
 mg LEO 138559 or placebo and 
single SC doses up to 
 mg LEO 138559 or placebo have been administered to healthy 
subjects. LEO 138559 or placebo are administered SC as once-weekly doses in healthy 
subjects (
 mg) and in AD patients (
 and 
 mg) for 5 weeks. In AD patients, a 
reduction in disease severity based on individual EASI scores was observed for LEO 138559 
compared with placebo. No SAEs and no AE patterns giving rise to any concerns have been 
reported. No risks for humans have been identified at the dose levels tested to date.  
Prior to LP0145-1315, there was no clinical experience of administering of LEO 138559 to 
humans. However, the anti-IL-22 mAb fezakinumab (ILV-094, Pfizer) was well tolerated 
when IV administered to AD patients and improved disease scores in patients with severe AD 
after 12 weeks in a phase 2a trial (36). Fezakinumab was also well tolerated in a safety and 
efficacy trial where it was administered SC in rheumatoid arthritis patients on a stable 
background of methotrexate (37). 
Pharmacokinetics  
Based on the preliminary human PK data, the PK of LEO 138559 is as expected for a mAb 
directed toward a membrane-bound target, and the TMDD characteristics are also visible in 
the observed human data as it was in the cynomolgus data. 
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After SC administration, LEO 138559 is slowly absorbed with a mean time to maximum 
concentration of approximately 
 days. After multiple dosing, the elimination half-life was 
observed to be between 
 days. At and above the exposure level relevant for clinical 
testing (
 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 
 in the LP0145-1315 trial). 
A detailed overview of clinical data on LEO 138559 is available in the current investigator’s 
brochure (35). 
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 excessive IL-22 expression in AD, we hypothesise 
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 the PoC trial will be to evaluate whether 
patients with moderate to severe AD who are treated with LEO 138559 demonstrate improved 
efficacy compared with placebo. 
5.4 Ethical considerations  
This trial will be conducted in accordance with the ethical principles originating from the 
Declaration of Helsinki (38) and ICH GCP (39) 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 subject. The efficacy and safety of 
LEO 138559 will be evaluated in adults with moderate to severe AD who may benefit from 
treatment with LEO 138559. Appropriate measures will be taken to protect the subject from 
potential risks related to treatment with LEO 138559 and to closely monitor the subject 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 
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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 
There is a clear unmet need for safe, long-term treatment options for subjects with moderate 
to severe AD. As a novel IL-22R antagonist, LEO 138559 is expected to be efficacious 
against AD.  
Risks to subjects in the trial will be minimised by inclusion of subjects fulfilling all eligibility 
criteria (Sections 8.1 to 8.3) and by close clinical monitoring (Section 4). Discontinuation and 
withdrawal criteria are also in place (Section 10.2).  
The subject will be informed that changes to their ongoing AD treatment may be required 
during the screening period up to Visit 6 (Week 4) and that their condition may worsen as a 
result. To minimise the negative consequences of this for the subject and ensure subject 
safety, investigators will be asked only to include subjects who are considered able to 
discontinue prohibited medications during the screening period without experiencing 
intolerable worsening of AD. 
The subject will also be informed of the possibility and probability of receiving active or 
placebo treatment. In this trial, approximately 50% of the subjects will receive active 
treatment with LEO 138559. A benefit for all subjects participating in this trial regardless of 
whether they receive active drug or placebo is that they receive close monitoring of their 
disease and easy access to specialist care. 
After randomisation and if medically necessary (i.e., due to worsening of AD or intolerable 
worsening of AD symptoms), rescue treatment of AD may be provided to the subject after 
Week 4 at the discretion of the investigator. All subjects may receive rescue treatment, 
regardless of treatment allocation (Section 9.5). The subject will be instructed to inform the 
investigator if their AD significantly worsens at any time during the trial. 
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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. Collection of tape strips and skin swabs are non-invasive techniques with no or 
very limited risks to the subject. 
LEO Pharma has evaluated currently available safety data on LEO 138559. IL-22R is 
expressed on epithelial cells and not on immune cells. IL-22 has shown to be involved in the 
production of antimicrobial peptides in the skin, lung, and intestines. Therefore, when 
blocking the IL-22 receptor, there is a potential for reduced antimicrobial peptide production 
and consequently a theoretically increased risk of infection. However, based on nonclinical 
studies, LEO 138559 is considered immunomodulatory, and not immunosuppressive. 
Regarding the ability to mount effective antibody immune responses, an assessment of the 
effect of LEO 138559 on the immune response was performed in an immune-toxicological 
study in monkeys. The study concluded that KLH-specific antibody responses (IgG and IgM) 
to the first and second immunisations with KLH occurred in all animals. Importantly, no 
adverse effect on the ability to mount a humoral primary or memory response was noted in 
animals administered up to 100 mg/kg LEO 138559. Further, no indicators of 
immunosuppression (e.g., haematological changes, organ weights, infections, and histology) 
were observed in 4- and 26-week nonclinical toxicology studies.  
Participation in any clinical trial is currently associated with increased risk and added 
challenges due to the COVID-19 pandemic caused by SARS-CoV-2. The proposed trial and 
treatment with LEO 138559 are not believed to put subjects with AD under an increased risk 
for viral infections including SARS-CoV-2. However, the risk of exposure to infected people 
cannot be excluded as the trial subjects may need to expose themselves to public areas (e.g., 
commute to the trial site) and have additional human contact (e.g., with trial site staff). Both 
EMA (40) and FDA (41) as well as national health authorities in Europe have issued 
guidelines aiming at providing recommendations for conducting clinical trials during the 
COVID-19 pandemic. Given the rapidly evolving epidemic situation and the potential for the 
pandemic to relapse in the future, LEO Pharma will carefully monitor the pandemic situation 
and issue risk mitigation measures to protect subjects and staff involved in the trial against 
infection with SARS-CoV-2 and to ensure integrity of the trial data (Appendix 9). A number 
of eligibility criteria have been added to reduce the risk of severe SARS-CoV-2 infections 
(Sections 8.1 to 8.3). 
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 
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by their local authorities. As these can differ across countries and regions, no general 
instructions from the sponsor can be provided in relation to subject safety and the need for 
postponing/cancelling visits during the trial. 
However, safety monitoring is an obligation of LEO Pharma and in case the subject, due to 
local restrictions, is prevented from coming to the trial site, the investigator can convert 
on-site visits into phone visits for the purpose of safety monitoring (for details refer to 
Appendix 9). The phone visits must, however, not be used for the investigator’s assessments 
of efficacy. Other mitigation measures include POEM and DLQI collected on the web-based 
solution by remote transfer to the vendor (see Appendix 3D).  
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. An estimand framework is used for 
the primary endpoint to ensure that occurrence of intercurrent events is taken into account. 
Further details about the estimands and statistical analyses of the endpoints are presented in 
Section 14.3. 
Panel 3: Objectives and endpoints  
Objectives 
Endpoints 
Primary objective 
 
To compare the efficacy of 
LEO 138559 with placebo in subjects 
with moderate to severe AD. 
Primary endpoint 
• 
Change in Eczema Area and Severity Index (EASI) 
score from baseline to Week 16. 
 
Exploratory endpoints (efficacy) 
• 
Having a decrease in EASI of at least 50% (EASI 
50) from baseline to Week 16. 
• 
Having a decrease in EASI of at least 75% (EASI 
75) from baseline to Week 16. 
• 
Having a decrease in EASI of at least 90% (EASI 
90) from baseline to Week 16. 
• 
Having vIGA-AD score of 0 (clear) or 1 (almost 
clear) at Week 16. 
• 
Time to having a decrease in EASI of at least 50% 
(EASI 50) between baseline and Week 16. 
• 
Time to having a decrease in EASI of at least 75% 
(EASI 75) between baseline and Week 16. 
• 
Time to having a decrease in EASI of at least 90% 
(EASI 90) between baseline and Week 16. 
• 
Time to initiation of TCI or TCS rescue treatment 
between baseline and Week 16. 
 
Exploratory endpoints (patient-reported outcomes) 
• 
Change in Worst Daily Pruritus NRS (weekly 
average) from baseline to Weeks 1, 2, 4, 8, 12, and 
16. 
• 
Having a decrease in Worst Daily Pruritus NRS 
(weekly average) of ≥3 points from baseline at 
Weeks 1, 2, 4, 8, 12, and 16, assessed separately. 
• 
Time to reduction of Worst Daily Pruritus NRS 
(weekly average) of ≥3 points between baseline 
and Week 16. 
• 
Having a decrease in Worst Daily Pruritus NRS 
(weekly average) of ≥4 points from baseline at 
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Objectives 
Endpoints 
Weeks 1, 2, 4, 8, 12, and 16, assessed separately, 
among subjects with a baseline Worst Daily 
Pruritus NRS ≥4 points. 
• 
Time to reduction of Worst Daily Pruritus NRS 
(weekly average) of ≥4 points between baseline 
and Week 16 among subjects with a baseline Worst 
Daily Pruritus NRS ≥4 points.  
• 
Change in POEM score from baseline to Week 16. 
• 
Change in DLQI from baseline to Week 16. 
Secondary objective 
 
To compare the safety of LEO 138559 
with placebo 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 
 
To evaluate the pharmacokinetics of 
LEO 138559 for 16 weeks in subjects 
with moderate to severe AD 
Exploratory endpoint (pharmacokinetics) 
• 
Serum concentration of LEO 138559 at Weeks 0, 
1, 2, 4, 6, 8, 10, 12, 14, 16, 32, assessed separately. 
To evaluate the effect of treatment 
with LEO 138559 compared with 
placebo for 16 weeks on disease 
biomarkers in subjects with moderate 
to severe AD 
Exploratory endpoints (pharmacodynamics) 
• 
Change in expression of AD disease biomarkers in 
serum from baseline to Week 16. 
• 
Change in expression of AD disease biomarkers in 
skin from baseline to Week 16. 
Abbreviations: AD = atopic dermatitis; ADA = anti-drug antibodies; DLQI = Dermatology Life Quality Index; 
EASI = Eczema Area and Severity Index; EASI 50 = at least 50% decrease in EASI score; EASI 75 = at least 
75% decrease in EASI score; EASI 90 = at least 90% decrease in EASI score; NRS = numeric rating scale; 
POEM = Patient-Oriented Eczema 
Measure; TCI = topical calcineurin inhibitor(s); TCS = topical corticosteroid(s); vIGA-AD = Validated 
Investigator Global Assessment Scale for Atopic Dermatitis. 
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7 Trial design 
7.1 Overall trial design  
Overview 
This is a phase 2a, randomised, double-blind, placebo-controlled, multi-site, proof of concept 
trial to evaluate the efficacy and safety of SC administered LEO 138559 in adult subjects with 
moderate to severe AD. A schematic overview of the trial design is presented in Panel 1. 
The trial will consist of:  
• A screening period of up to 4 weeks (Weeks -4 to 0) including an applicable washout 
period of 1 week (Week -1 to 0). 
• A treatment period of 16 weeks (Weeks 0 to 16). 
• A follow-up period of 16 weeks (Weeks 16 to 32) for the assessment of safety and ADA. 
Randomisation will take place at Week 0. The primary endpoint will be assessed at Week 16. 
The final safety assessments will be conducted at Week 32 (end of trial). 
The subject’s visit schedule and the procedures and assessments to be conducted at each visit 
are presented in Section 4. The trial rationale is presented in Section 5.3 and the scientific 
rationale for trial design is presented in Section 12.1. 
Screening period (between 0 and 4 weeks prior to the baseline visit [Day 1]) 
In the screening period, eligibility of the subject (Sections 8.1 to 8.3) to participate in the trial 
will be evaluated at a screening visit (Visit 1). This visit will be performed up to 4 weeks 
before the baseline visit (Visit 3) and can be combined with the washout visit (Visit 2) if 
needed. 
At the washout visit (Visit 2, Week -1), subjects will stop any treatment with TCS, TCI, 
PDE-4 inhibitors, or other topical prescription 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. Moreover, at the 
washout visit (Visit 2), the subjects will receive training in completion of an eDiary and will 
be given an electronic device to record the Worst Daily Pruritus NRS. To complete training of 
the eDiary, and as an opportunity to fill out Worst Daily Pruritus NRS before the treatment 
period, subjects will be asked to complete Worst Daily Pruritus NRS at the visit. Completion 
of the eDiary will be initiated at the latest 1 week prior to the baseline visit (Visit 3, Week 0). 
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Randomisation (Week 0) 
At baseline (Visit 3, Week 0), eligible subjects will be randomised 1:1 to 1 of 2 treatment 
groups: LEO 138559 or placebo. Randomisation will be stratified by baseline disease severity. 
One stratum, ‘stratum A’, will be defined as having EASI <21 and the other stratum, 
‘stratum B’, will be defined as having EASI ≥21. IRT will be used to control randomisation 
and stratification factors. 
Treatment period (Week 0 to Week 16) 
In the treatment period, LEO 138559 or placebo injections will be administered at the site by 
site staff Q2W for 16 weeks (Section 9.2). In addition to this Q2W dosing schedule, both 
treatment groups will receive an additional dose of their allocated treatment (LEO 138559 
450 mg or placebo) at Visit 4 (Week 1). During the treatment period, the subject will be asked 
to continue applying the emollient twice daily (or more frequently, if needed). The subject 
will also be asked to visit the clinic for assessments and procedures. Final dosing will be 
administered at Week 14, regardless of AD improvement. If medically necessary (i.e. due to 
worsening of AD or intolerable AD symptoms), rescue treatment for AD in the form of 
TCS/TCI may be used from Week 4 at the discretion of the investigator.  
Safety follow-up period (Week 16 to Week 32) 
In the safety follow-up period, the subject will stop treatment with LEO 138559 or placebo 
injections and 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.  
7.2 Number of subjects needed 
Based on an anticipated screening failure rate of 35%, the planned number of subjects to 
screen is set to 80. 
At Week 0 (baseline), a total of 52 subjects will be randomised 1:1 to: 
• LEO 138559 450 mg (26 subjects). 
• Placebo (26 subjects). 
Based on an anticipated attrition rate of 30% in both treatment groups, this will provide a total 
of 36 subjects for analysis (18 subjects per treatment group). 
The trial will be conducted at approximately 20 sites in Canada, Germany, Poland, and the 
US.  
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The statistical power 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 11.7 for data to be recorded 
on the end-of-trial form).  
The end of the trial is defined as the date of the last safety follow-up visit (Week 32) for the 
last subject in the trial globally. 
Final data collection for evaluation of the primary endpoint will occur at Week 16. Therefore, 
the primary completion date is defined as the date of last Week 16 visit for the last subject in 
the trial globally. 
 
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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 Section 4. It will be recorded in the eCRF if the subject 
has met all the inclusion criteria and none of the exclusion criteria. 
Any implementation of national requirements/law for the subject’s participation in the clinical 
trial will be ensured and described in submission documentation to regulatory authorities and 
IRBs/IECs, as applicable.  
8.2 Inclusion criteria 
For inclusion into this trial, subjects must fulfil all of the following criteria: 
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 (1) and Appendix 4] 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. 
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• Important side effects or safety risks are those that outweigh the potential 
treatment benefits and include intolerance to treatment, hypersensitivity reactions, 
significant skin atrophy, and systemic effects, as assessed by the investigator or by 
the subject’s treating physician. 
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.  
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. 
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). 
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**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 must not enter the trial if they fulfil any of the following exclusion criteria:  
1. Active dermatologic condition that could confound the diagnosis of AD or interfere 
with assessment of the treatment.  
2. Previously randomised in this clinical trial.  
3. Current participation in any other interventional clinical trial.  
4. Treatment with systemic immunosuppressive/immunomodulating medication, 
immunoglobulin/blood products, or phototherapy within 4 weeks or 5 half-lives prior 
to randomisation, whichever is longer. 
5. Treatment with biologics within 5 half-lives (if known) or 16 weeks prior to 
randomisation, whichever is longer. 
6. Treatment with TCS, TCI, topical PDE-4 inhibitor, or other topical prescription 
treatments within 1 week prior to randomisation.  
NOTE: Subject may be rescreened (once) if failed for this criterion (see Section 8.4). 
7. Treatment with a live (attenuated) vaccine within 12 weeks prior to randomisation. 
8. History of malignancy within 5 years prior to randomisation, apart from nonmetastatic 
basal cell carcinoma, squamous cell carcinoma of the skin, or cervical carcinoma in-
situ, considered cured by the standard of care. 
9. Clinically significant active chronic or acute infection requiring systemic treatment 
within 4 weeks prior to randomisation that may compromise the safety of the subject. 
NOTE: Subject may be rescreened (once) after infection resolves (see Section 8.4). 
10. Skin infection within 1 week prior to randomisation.  
NOTE: Subject may be rescreened (once) after infection resolves (see Section 8.4). 
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11. Current or recent (within 2 years prior to randomisation) gastrointestinal ulcers. 
12. History of any of the following: anaphylaxis, immune complex disease, pancreatic 
disease, inflammatory bowel disease, or known or suspected history of 
immunosuppressive disorder. 
13. Known or suspected hypersensitivity to any component(s) of the IMP. 
14. 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. 
15. History of human immunodeficiency virus (HIV) infection or positive HIV serology at 
screening. 
16. 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. 
17. Current diagnosis of diabetes. 
18. Serious heart conditions (e.g., heart failure, coronary artery disease, congenital heart 
disease, cardiomyopathies, and/or pulmonary hypertension). 
19. Chronic lung diseases (e.g., chronic obstructive pulmonary disease, idiopathic 
pulmonary fibrosis, and/or cystic fibrosis). 
20. Moderate to severe asthma [as defined by GINA guidelines (42)]. 
21. Obesity (BMI ≥35). 
22. 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. 
23. Subject is pregnant or lactating. 
24. 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. 
25. 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. 
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26. 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. 
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. 
27. 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. 
28. 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 randomisation, whichever is longer. 
29. Subjects who are legally institutionalised. 
30. Positive SARS-CoV-2 PCR test at screening. 
NOTE: Subject may be rescreened (once) if failed for this criterion (see Section 8.4). 
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, a 10-digit 
subject identification number (subject ID xxxx-xxxx-xx) will be assigned by a central IRT 
system. 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. 
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Investigator logs 
The investigator will maintain a log of all subjects considered for screening, whether they 
have been randomised or not (screening log). This log will be anonymous and will include the 
reason(s) for not entering the trial, if applicable, or the allocated subject ID. In addition, the 
investigator will maintain a log of all consented subjects at the trial site (subject identification 
list). This log will include each subject’s identity, date of consent, and corresponding 
subject ID so that any subject may be identified if required for any reason. The subject 
identification list must not be copied or retained by LEO Pharma.  
Screening failures 
Screen 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 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 screen failures: 
• Date of informed consent(s). 
• Date of screening failure. 
• Reason for screen failure. 
a. Failure to meet eligibility criteria and which eligibility criterion(ia) was (were) not 
met.  
b. Lost to follow-up. 
c. Withdrawal by subject. 
d. Other (if other, a specification should be provided).  
• Demographics (full date of birth [day, month, and year], only month and year, or only 
year, as per local legislation, age, sex, race, ethnicity as per local legislation).  
• Any adverse events (AEs) and serious AEs (SAEs). 
 
Any SAE will require expedited reporting as described in Section 13.7. 
Rescreening of screening failures (subjects who did not meet the eligibility criteria for 
participation in the trial) is not allowed except in specific situations as described below.  
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If the reason for screening failure is administrative and not due to the subject not meeting the 
eligibility criteria (e.g., delayed test results or temporary site closure due to the COVID-19 
pandemic), rescreening may be permitted. In addition, rescreening may be permitted (once) if 
an infection resolves after initially not having met exclusion criteria no. 9 (active chronic or 
acute infection requiring systemic treatment), no. 10 (skin infection), or no. 30 (positive 
SARS-CoV-2 PCR test) or if the subject failed exclusion criterion no. 6 (treatment with TCS, 
TCI, or topical PDE-4 inhibitor, or other topical prescription treatments). Rescreening will 
require approval by the sponsor’s medical expert after thorough review of eCRF data from the 
first screening visit. In all cases, rescreening will only be permitted if the duration of the 
screening period does not exceed 28 consecutive days in total. Subjects to be rescreened must 
sign a new ICF. Rescreened subjects will get a new subject ID. In addition, the subject ID 
from the previous screening will be recorded in the eCRF. 
9 Treatments 
9.1 Trial product description 
LEO 138559 is a human recombinant mAb of the IgG1 subclass that specifically binds to 
human IL-22R1 and inhibits the ligand IL-22 from binding to it. It is presented as a 
lyophilised powder for reconstitution (using 1.0 mL sterilised water) and injection. 
LEO 138559 and placebo will be packaged in individually numbered kits. Refer to Panel 4 for 
further details. 
Panel 4: Identification of investigational medicinal products  
Investigational 
medicinal 
product 
 
Dosage form 
Volume to be 
SC injected 
Active 
ingredient and 
concentration 
Pack size 
 
Source 
 
LEO 138559  
Lyophilised powder for 
reconstitution (using 
1.0 mL sterilised water) 
adding up to a volume of 
1.2 mL/vial 
 (  vials of 
 mL each) 
LEO 138559, 
 mg/mL 
(following 
reconstitution)  
 mg/vial 
LEO Pharma 
Placebo  
Solution for SC injection 
(contains 1.2 mL/vial) 
 mL (  vials of 
 mL each) 
Not applicable 
1.2 mL/vial 
LEO Pharma 
Note: To ensure that 1.0 mL can be withdrawn by a syringe, there will be a small overfill in the placebo vial and in the active 
IMP vial after reconstitution, of approximately 0.2 mL per vial.  
Abbreviation: SC = subcutaneous(ly). 
 
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No active comparators will be used in this trial. 
9.2 Administration of investigational medicinal product 
General 
The IMP will be dispensed to the subject according to the schedule of trial procedures 
(Section 4). Dispensing of the IMP will be handled by an IRT system. The IRT system will 
assign the required kit number(s) for each subject at each dispensing visit. 
The first day of dosing is considered Day 1 (Week 0). Each subject will receive  SC 
injections (each 
 mL) of 
 mg LEO 138559 or placebo to receive a total dose of 
450 mg LEO 138559 or placebo (
 mL). In addition to this Q2W dosing schedule, both 
treatment groups will receive an additional dose of their allocated treatment (LEO 138559 
450 mg or placebo) at Visit 4 (Week 1). 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. 
IMP will be administered by a qualified, unblinded HCP as the preparation of the active drug 
is visually distinct from placebo (see Section 9.3.1 for blinding details). The IMP must be 
injected SC in the upper legs (thighs), stomach area (abdomen) or in the upper, outer arm but 
should not be given into areas where the skin is tender, bruised, red, hard, thick, scaly, or 
affected by AD. 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  injections of IMP must be administered within a maximum of 
10 minutes. The  injections of IMP 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 IMP (e.g., damaged kit or vial/syringe) or a malfunction during 
administration should arise, the unblinded CRA should be contacted, and the issue should be 
documented. 
Further details on IMP preparation and administration will be provided in an instruction for 
use and trial product handling manual. IMP administration must be carried out according to 
these instructions. 
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After IMP administration 
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 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. 
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. 
Overdose is specified in Section 13.6.2. LEO Pharma does not have any specific treatment 
recommendations in relation to overdose. The investigator will use clinical judgement to treat 
any overdose if necessary. 
9.3 Treatment assignment  
Subjects who comply with all the eligibility criteria (Sections 8.1, 8.2, and 8.3) will be 
randomised at baseline (Day 1) to receive treatment with either LEO 138559 450 mg Q2W or 
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placebo Q2W. Treatment assignment will be pre-planned according to a computer generated 
randomisation schedule in a 1:1 ratio (LEO 138559 : placebo) stratified by baseline disease 
severity; one stratum, ‘stratum A’, will be defined as having EASI <21 and the other stratum, 
‘stratum B’, will be defined as having EASI ≥21.  
IRT will be used to control randomisation and stratification factors, along with IMP supply 
chain and expiry tracking. 
9.3.1 Blinding  
This is a double-blinded trial in which LEO 138559 and placebo are visually distinct from 
each other and not matched for viscosity. Neither the subject nor any of the investigators or 
LEO Pharma staff (except unblinded CRAs) who are involved in the clinical evaluation and 
monitoring of the subjects will be aware of the treatment received.  
IMP will be prepared, handled, and administered by a qualified, unblinded HCP at the site 
who will not be involved in the management of trial subjects and who will not perform any of 
the assessments. 
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.  
Should an issue arise with the IMP (e.g., damaged kit or syringe that has been assigned to a 
subject prior to administration, or any other unexpected event with the kit or syringe [e.g. a 
malfunction during IMP administration]), the unblinded HCP at the site will contact the 
unblinded CRA to determine whether any specific actions are required. 
The trial site will maintain a written plan (site blinding plan) detailing which staff members 
are blinded/unblinded and the process of IMP administration used to maintain the blind. 
9.3.2 Emergency unblinding of individual subject treatment 
While the safety of a subject always comes first, it is still important to carefully consider if 
unblinding is necessary to ensure a subject’s safety. An emergency unblinding request can be 
made by the investigators, HCPs who are not members of the trial staff, or authorised LEO 
Pharma personnel. 
Provisions are in place for 24-hour emergency unblinding of individual subject treatment. If 
emergency unblinding is required, the investigator can unblind a subject’s treatment in the 
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IRT. For a requester who is not a member of the trial staff and who does not have access to the 
IRT (e.g., a physician at an emergency room), a local contact number for the emergency 
unblinding CRO is provided on the subject card (see Appendix 3B) to be used if the 
investigator or delegated site staff cannot be reached. The requester will provide the trial ID 
and subject ID to the emergency unblinding CRO who will immediately reveal the individual 
treatment allocation. 
The emergency unblinding CRO will clarify that the requester requires immediate unblinding 
without further medical consultation. Should the requester wish to discuss whether unblinding 
is necessary, the emergency unblinding CRO will provide the requester with the LEO Pharma 
24/7 contact which will be diverted to the medical cover. 
LEO Pharma Global Safety may unblind subject(s) if it is deemed necessary, including for 
regulatory purposes in relation to reporting of SUSARs. 
9.4 Background treatment (emollients) 
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.  
The emollient should preferably not contain additives such as ceramide, hyaluronic acid, or 
urea. 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 0 to Week 16). 
Reporting in eCRF 
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 
If medically necessary (i.e., due to worsening of AD or intolerable AD symptoms), rescue 
treatment for AD in the form of TCS/TCI may be prescribed to trial subjects and used from 
Week 4 at the discretion of the investigator. It is recommended that the investigator starts with 
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a TCI or least potent TCS for the face (e.g., hydrocortisone 2.5% cream/ointment) and 
moderately potent TCS for the body (e.g., triamcinolone acetonide 0.1% cream/ointment). 
If rescue treatment with TCS/TCI is initiated after Week 4, the subject will continue treatment 
and the schedule of trial visits and assessments. However, treatment with IMP will be 
discontinued if a subject receives the following treatment: 
• Rescue treatment with any TCS/TCI before Week 4. 
• Super potent TCS (e.g., clobetasol propionate 0.05% cream) between Week -1 and 
Week 16. 
• Systemic rescue treatment (besides systemic antihistamines and/or anti-infectives) at any 
point during the trial between Week -4 (or from 5 half-lives of Week 0, whichever is 
longer) and Week 16.  
Investigators should make every attempt to conduct efficacy and safety assessments (for 
example disease severity scores, safety labs) immediately before administering any rescue 
treatment. An unscheduled visit may be used for this purpose, if necessary. 
During the safety follow-up period (Weeks 16 to 32), topical therapy (including TCS and TCI) 
may be prescribed to control disease activity at the discretion of the investigator and will not 
be considered as rescue treatment. Any medication taken by the subjects during the follow-up 
period will be reported as concomitant medication using the eCRF. 
Reporting in eCRF 
It will be recorded in the eCRF if and what rescue treatment has been used. 
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: 
• Medication name or therapy (generic or brand name). 
• Whether the medication or therapy is a rescue treatment for AD. 
• Indication. 
• Start and stop date of administration (it will also be recorded if the medication is 
ongoing).  
• Dosage information, including dose per administration, unit, and frequency. 
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• Route of administration: oral, topical, SC, transdermal, intraocular, intramuscular, 
respiratory (inhalation), intralesional, intraperitoneal, nasal, vaginal, rectal, IV, or other (if 
other, a specification must be provided).  
For topical treatments, the dosage form (cream, lotion, ointment, other) and the potency 
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 conducted within 3 months prior to screening must also 
be recorded in the subject’s medical record and the eCRF with details such as: 
• Procedure name.  
• 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 during the trial: 
• Paracetamol use (maximum 2 g/day).  
• Concomitant therapies taken for the long-term treatment of pre-existing conditions 
can continue during the trial provided they are in accordance with the exclusion 
criteria (see Section 8.3). 
• Systemic antihistamines and/or anti-infectives. 
• Emollients allowed during the treatment period. 
For AD patients with mild chronic asthma (42) or mild allergic rhinitis, use of inhaled 
corticosteroids up to and including 500 µg beclometasone (or equivalent) per day is 
acceptable. 
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9.7 Prohibited medication and procedures 
Prohibited medications and/or procedures are listed in Panel 5. Details regarding prohibited 
medications and/or procedures prior to screening and during washout(s) are described in 
Section 8.3. 
If prohibited medications are used during the trial, they must be recorded as concomitant 
medication in the eCRF (Section 9.6). 
Panel 5: Prohibited medication(s) and/or procedure(s) 
Medication or procedure 
Prohibited from 
Prohibited to 
TCS or TCI (other than those 
permitted as rescue treatment). 
Washout (Week -1). 
Week 16. 
Topical PDE-4 inhibitors. 
Washout (Week -1). 
Week 16. 
Other topical prescription 
medications or prescription 
emollients/moisturisers (other 
than the ones allowed during 
treatment period) used for the 
treatment of AD. 
Washout (Week -1). 
Week 16. 
Use of UVA, UVB, PUVA, 
other phototherapy, or tanning 
beds. 
Week -4 prior to randomisation. Week 16. 
Immunoglobulin or blood 
products. 
Week -4 or 5 half-lives prior to 
randomisation, whichever is 
longer. 
Safety follow-up (Week 32). 
Systemic corticosteroids 
(excluding inhaled or intra-nasal 
steroids). 
Week -4 prior to randomisation. Safety follow-up (Week 32). 
Systemic 
immunosuppressive/immuno- 
modulating medication 
(excluding systemic 
antihistamines). 
Week -4 or 5 half-lives prior to 
randomisation, whichever is 
longer.  
Safety follow-up (Week 32). 
Biologics. 
Week -16 or 5 half-lives prior to 
randomisation, whichever is 
longer. 
Safety follow-up (Week 32). 
Allergen immunotherapy. 
Week -4 prior to randomisation. Safety follow-up (Week 32). 
Live (attenuated) vaccine. 
Week -12 prior to 
randomisation. 
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. 
The sponsor’s medical expert must be notified if a subject receives any of these prohibited 
medications during the trial. 
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As described in Section 9.5, TCI and TCS used as rescue treatment for worsening of AD or 
intolerable AD symptoms are allowed from Week 4. 
9.8 Treatment logistics and accountability  
9.8.1 Labelling and packaging of trial products 
IMP will be packed open label in individually numbered kits. 
Primary and secondary packaging materials (vial 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  
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 IMP must be stored at 2 to 8°C at the site. The temperature during storage must be 
monitored by a calibrated, stationary, and continuously monitoring system. Minimum 
requirement is a calibrated min/max thermometer.  
A temperature log must be kept to document the storage within the right temperature interval. 
Storage facilities should be checked at least every working day. 
Storage of IMP may be delegated, e.g., to a hospital pharmacy, as locally applicable. 
Note that in the cases listed below, site staff should not use the affected IMP and should 
immediately contact their unblinded CRA for further guidance: 
• Temperature excursion upon receipt or during storage at the trial site. 
• Damaged kit upon receipt. 
• Damaged vial. 
Damaged IMP should be documented via IRT (refer to the IRT quick reference guide for 
further details). Damaged IMP should not be used.  
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9.8.3 Drug 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. 
Documentation of drug accountability must be kept of the IMPs administered to each 
individual subject randomised in the trial. This documentation must be available during 
monitoring visits and will be checked by the unblinded CRA to verify correct dispensing of 
the IMPs. Drug accountability information will be recorded in the IRT system. The IRT 
system will also maintain the inventory status of all IMPs at the trial site. 
The IMP must be fully accounted for by the unblinded CRA with the help of the unblinded 
HCP. Accountability must be documented in the trial medication inventory log in the IRT.  
For further information about handling of trial product at site, including IMP 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 also keep the accountability 
records up-to-date. Any non-compliance and the reason for it must be recorded in the eCRF. 
 
Reporting in eCRF 
The following data will be recorded in the eCRF:  
Did the subject comply with the IMP dosing schedule (yes, no); If no, a reason will be given. 
It will also be recorded how much IMP the subject received (partial dose, no dose, and the 
total number of IMP applications missed since last visit). 
• Primary reason for non-compliance – lack of time, adverse event, other (if other, a 
specification should be provided). 
• Date and time of IMP administration (stated for each of the  injections). 
• Site of IMP 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 
Used IMP (i.e., empty vials) and unused IMP must be returned to the CMO for destruction. 
Used IMP and unused IMP that is no longer available for dispensation (e.g., expired or 
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damaged IMP) can be returned on an ongoing basis throughout the trial. Unused IMP (i.e., 
IMP that is still available for dispensation) can be returned for destruction after the last dosing 
visit of the last subject at the site.  
Syringes used for administration of IMP can be destroyed at site according to local procedures 
in compliance with local regulations. 
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. 
9.10 Reporting product complaints 
Any defects or issues with the IMP (e.g., inadequate labelling) must be reported to Global 
Safety at LEO Pharma on the trial-specific (paper) complaint form within 3 days of first 
knowledge.  
Critical complaints (defined as any defect or issue that has or potentially could have a serious 
impact for the subject [e.g., SAE or large particles in the vial]) must be reported to Global 
Safety, LEO Pharma within 24 hours.  
Complaint forms should contain a detailed description of the defect or 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.  
Refer to the trial product handling manual and the IRT quick reference guide for information 
on how to update the kit status in the IRT. 
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. 
Subjects who withdraw from the trial and subjects who permanently discontinue IMP will not 
be replaced. 
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 of consent. 
• An AE that, in the opinion of the investigator or sponsor’s medical expert, 
contraindicates further dosing. 
• Initiation of systemic rescue treatment of AD (besides systemic antihistamines 
and/or anti-infectives) at any point during the trial between Week 0 and 16, rescue 
treatment before Week 4, and/or super potent TCS between Week -1 and Week 16. 
• 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). 
• Other reasons, at the discretion of the investigator. If other, a specification should 
be provided. 
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Reporting in 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:  
• Pregnancy. 
• Adverse event (if adverse event, a specification must be provided). 
• Lack of efficacy. 
• Withdrawal by subject. 
• Lost to follow-up. 
• Other (if other, a specification should be provided). 
In case the primary reason is adverse event, the AE in question will be linked to the 
permanent discontinuation of IMP. To support the statistical analysis, it will also be recorded 
if the permanent discontinuation of IMP was due to the COVID-19 pandemic. 
10.2.2 Reasons for temporary discontinuation of IMP  
IMP dosing may be temporarily suspended in the event of: 
• COVID-19 related disruption.  
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.  
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. See the schedule of trial procedures (Section 4) for 
data to be collected at these visits. Subjects who discontinue IMP but remain in the trial will 
continue completing the eDiary until the safety follow-up visit (Visit 16). The investigator 
will review any AEs which will be followed up according to Section 13.7, if the subject 
agrees. 
Subjects who permanently discontinue IMP will be asked to attend: 
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• An early termination visit as soon as possible after last dose of IMP. 
• The primary endpoint visit (16 weeks after randomisation). 
• A safety follow-up visit (16 weeks after last administration of IMP). 
Details on data to be recorded in the eCRF for subjects who permanently discontinue IMP can 
be found in Section 11.7. 
Withdrawal from trial 
Subjects who withdraw/are withdrawn from the trial prior to first dose of IMP 
(randomisation) will be considered screening failures. 
Subjects who withdraw from the trial for any reason should attend an early termination visit 
as soon as possible after last administration of IMP. Assessments/procedures to be conducted 
at this visit are listed in the schedule of trial procedures (Section 4). If the subject agrees, the 
investigator will review any AEs which will be followed up according to Section 13.7. 
Details on data to be recorded in the eCRF for subjects who withdraw from the trial can be 
found in Section 11.7. 
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 or not the subject wishes to continue in 
the trial. 
• Before a subject is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the subject (where possible, 3 telephone calls and, if 
necessary, a certified letter to the subject’s last known mailing address or local 
equivalent method[s]). These contact attempts should be documented in the subject’s 
medical record. 
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• 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. PROs to be 
completed at the trial site and investigator assessments of efficacy should be conducted at the 
same visit.  
Panel 6: Sequence of assessments  
 
a At the screening visit (at the earliest Week -4), the subject’s eligibility to participate in the trial must be 
confirmed before any PROs are completed. PROs will be completed either in the eDiary or on an electronic 
device at the trial site.  
b Laboratory assessments include PK and PD samples. PD samples include serum biomarkers, skin swabs, and 
tape strips. 
c 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. 
 
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 
Patient-reported 
outcomesa
Investigator assessments
Safety and laboratory 
assessmentsb
Administration of IMPc
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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 (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. 
The investigators performing the assessments must not be involved in the administration of 
IMP (Section 9.3.1).  
11.2 Assessments performed only at screening/baseline 
11.2.1 Demographics  
The following demographic data will be recorded at screening (Section 4): 
• Full date of birth (day, month, and year) or partial date of birth (only month and 
year, or only year), as per local legislation. 
• Age (as on the day informed consent is signed, if full date of birth cannot be 
collected due to local legislation). 
• 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), if allowed by the local legislation.  
At baseline, only age will be recorded (Section 4). 
11.2.2 Body assessment (height) 
Height will be recorded according to the schedule of trial procedure (Section 4).  
The subject’s height (without shoes) will be measured.  
11.2.3 Medical history 
Medical history will be recorded according to the schedule of trial procedures (Section 4). 
Relevant past and concurrent medical history must be recorded including all past and current 
skin disease history:  
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• Atopy history: 
- 
Age at first onset of AD. 
- 
Previous AD treatments (e.g., dupilumab, cyclosporine, etc). 
- 
Asthma. 
- 
Food allergy. 
- 
Hay fever. 
• Other medical and surgical history including concurrent diagnoses within the previous 
12 months. For each condition, surgical procedure, or diagnosis, the start and stop dates 
will be recorded. It will also be recorded if the condition or diagnosis is ongoing. 
Relevant medical history also includes diseases which are specifically listed as exclusion 
criteria and diseases for which treatments are listed as exclusion criteria or prohibited 
medications. 
11.2.4 Other assessments 
The following tests will be conducted according to the schedule of trial procedures 
(Section 4): 
• Hepatitis B virus testing (for more detail, see Panel 10). 
• Hepatitis C virus antibody. 
• HIV antibodies. 
• Tuberculosis (Mycobacterium tuberculosis IFN-γ release assay [or a PPD test if a 
requirement from the local health authorities]). 
• SARS-CoV-2 (PCR). 
11.3 Efficacy assessments 
11.3.1 Eczema Area and Severity Index (EASI) 
EASI will be assessed by the investigator according to the schedule of trial procedures 
(Section 4). At an unscheduled visit, it will be at the discretion of the investigator if EASI 
should be assessed. 
EASI is a validated measure used in clinical practice and clinical trials to assess the severity 
and extent of AD (47). 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. To reduce 
inter-assessor variability, the same investigator should, whenever possible, conduct all EASI 
assessments for a given subject during the entire trial. 
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EASI is a composite score ranging from 0 to 72 with higher scores indicating a more severe 
or more extensive condition. The score will be calculated as described in Panel 7. 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, and lower extremities). Severity will be assessed using the severity 
score scale presented in Panel 8. For each body region, a severity sum score will be calculated 
and multiplied by an area score (Panel 8) and a weighting factor. The EASI score equals the 
sum of scores obtained for each body region (Panel 7). 
Reporting in eCRF 
The body region, severity of the disease characteristics (erythema, induration/papulation, 
excoriation, and lichenification), and the area score will be recorded in the eCRF. Refer to 
Appendix 3D for principles for data entry in the eCRF. 
Panel 7: Calculation of the Eczema Area and Severity Index 
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 scores of the 4 body regions 
 
(Range 
0-72) 
Abbreviations: AS = area score; EASI = Eczema Area and Severity Index; SS = severity score.  
Modified from (48). 
Panel 8: Eczema Area and Severity Index severity score scale and area score scale 
Severity score scale a 
 
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 
a Half-scores (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 
 
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11.3.2 Validated Investigator Global Assessment Scale for Atopic Dermatitis 
(vIGA-AD) 
vIGA-AD will be assessed by the investigator according to the schedule of trial procedures 
(Section 4). At an unscheduled visit, it will be at the discretion of the investigator if the 
vIGA-AD should be assessed. 
The vIGA-AD is an instrument used in clinical trials to assess the subject’s global disease 
severity and is based on a 5-point scale ranging from 0 (clear) to 4 (severe) (Panel 9) (49). 
The assessment will be based on the condition of the disease at the time of evaluation and not 
in relation to the condition at a previous visit.  
Reporting in eCRF 
The disease severity assessment score will be recorded in the eCRF. Refer to Appendix 3D for 
principles for data entry in the eCRF. 
Panel 9: 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. 
 
11.3.3 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. 
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11.3.4  Patient-reported outcomes 
11.3.4.1 Overview 
During the trial each subject should make individual assessments relating to their perception 
of their disease and quality of life. These should be performed independently of the 
investigator and prior to the investigator performing his/her efficacy assessments. At the 
screening visit (at the earliest Week -4), the subject’s eligibility to participate in the trial needs 
to be established before the PROs can be completed.  
The subject will be asked to complete the following PROs according to the schedule of trial 
procedures (Section 4). 
• Worst Daily Pruritus NRS.  
• POEM.  
• DLQI. 
Worst Daily Pruritus NRS will be completed daily in an eDiary. At Week -1 subjects will 
receive an eDiary device and eDiary training in using the device. At each visit between 
Week -1 and Week 32, the investigator or site staff will review the eDiary on the eDiary 
vendor portal and check compliance with eDiary completion.  
In case of significant non-compliance, the investigator should remind the subject of the 
importance of adhering to the eDiary completion schedule. Subjects will be asked to return 
the eDiary at Week 32 or at their last visit in the trial. 
POEM and DLQI will be completed in an electronic device by the subjects at the trial sites at 
the visits specified in the schedule of trial procedures (Section 4). At an unscheduled visit, it 
will be at the discretion of the investigator if POEM and/or DLQI should be assessed.  
11.3.4.2 Worst Daily Pruritus NRS 
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 an eDiary each 
day from Week -1 until Week 32. 
11.3.4.3 Patient-Oriented Eczema Measure (POEM) 
The POEM is a validated questionnaire used to assess disease symptoms in AD patients in 
both clinical practice and clinical trials (50). The tool consists of 7 items each addressing a 
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specific symptom (itching, sleep, bleeding, weeping, cracking, flaking, and dryness). Subjects 
will score how often they have experienced each symptom over the previous week on a 
5-point categorical response scale (0 = ‘no days’; 1 = ‘1 to 2 days’; 2 = ‘3 to 4 days’; 3 = ‘5 to 
6 days’; 4 = ‘every day’). The total score is the sum of the 7 items (range 0 to 28) and reflects 
disease-related morbidity; a high score is indicative of a worse disease severity.  
11.3.4.4 Dermatology Life Quality Index (DLQI) 
The DLQI is a validated questionnaire with content specific to those with dermatology 
conditions (51). It consists of 10 items addressing the subject’s perception of the impact of 
their skin disease on different aspects of their quality of life over the last week such as 
dermatology-related symptoms and feelings, daily activities, leisure, work or school, personal 
relationships, and the treatment . Each item is scored on a 4-point Likert scale (0 = ‘not at all 
⁄not relevant’; 1 = ‘a little’; 2 = ‘a lot’; 3 = ‘very much’). The total score is the sum of the 
10 items (0 to 30); a high score is indicative of a poor quality of life.  
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. 
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In case of a clinically significant abnormal vital sign at screening and/or baseline, it will be at 
the discretion of the investigator if the subject should be included in the trial in accordance 
with exclusion criterion no. 27. 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 
Vital signs will be recorded in the eCRF and if not measured, a reason should be provided. 
Clinically significant abnormal vital signs at screening and baseline 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. 
Refer to Appendix 3D for principles for data entry in the eCRF. 
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. 27. 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 as described in Section 13.3. 
Refer to Appendix 3D for principles for data entry in the eCRF. 
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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 ECG 
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 each visit, the individual measurements as well as the average of 3 consecutive 12-lead 
resting digital ECG measurements will be recorded after the subject has been in supine 
position for at least 5 minutes.  
A pre-evaluation of the ECGs will be performed by the investigator to evaluate immediate 
subject safety. At a minimum, the date of ECG pre-evaluation will be recorded in the source 
documents. In case of a suspected abnormal ECG, the investigator must take appropriate 
action, at their discretion. 
The ECG data will be transferred to a central ECG service company for central evaluation. A 
cardiologist at the ECG service company will 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 when the evaluation is performed. The investigator 
has the final decision on the clinical significance of ECG abnormalities.  
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. 18 and 27). 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. In such case, the subject 
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should be monitored until the subject’s ECG returns to a state similar to that of 
screening/baseline at the discretion of the investigator. 
The collection and transmission of ECG data will be described in a separate ECG manual. 
Reporting in eCRF 
It must be recorded in the eCRF if an ECG was measured. If not, a reason must be provided. 
The date of ECG measurement must be recorded. In case of a suspected abnormal ECG, the 
action taken with the subject, if any, must be recorded. The investigator’s assessment of ECG 
result (‘normal’, ‘abnormal, not clinically significant’, ‘abnormal, clinically significant’) must 
also be recorded in the eCRF. 
Clinically significant abnormal ECG findings at screening and baseline before first dose of 
IMP will be documented as medical history in the eCRF. At subsequent visits, any new 
clinically significant abnormal ECG finding, symptoms, or illnesses, as well as any clinically 
significant deterioration of a pre-existing condition after randomisation will be reported as an 
AE as described in Section 13.3. 
Refer to Appendix 3D for principles for data entry in the eCRF. 
11.4.5 Laboratory testing 
11.4.5.1 Overview 
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 conducted by the central laboratory. 
At an unscheduled visit, it will be at the discretion of the investigator if samples should be 
collected. 
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Panel 10: Clinical laboratory tests  
Clinical chemistry 
Haematology 
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 
HDL cholesterol 
Triglycerides 
Glucose (non-fasting) 
Albumin 
Protein 
Tryptase2 
Lactate dehydrogenase 
C-reactive protein 
Haematocrit 
Haemoglobin 
Leukocytes  
Neutrophils   
Neutrophils/leukocytes5 
Lymphocytes  
Lymphocytes/leukocytes5 
Monocytes  
Monocytes/leukocytes5 
Eosinophils  
Eosinophils/leukocytes5 
Basophils  
Basophils/leukocytes5 
Thrombocytes  
Serology 
Tuberculosis test6 
Hepatitis B virus surface antigen3 
Hepatitis B virus surface antibody3 
Hepatitis B virus core antibody3 
Hepatitis C virus antibody3 
HIV-1 antibody3 
HIV-2 antibody3 
Immunoglobulin E 
Mycobacterium tuberculosis IFN-γ release assay  
COVID-19 test 
SARS-CoV-2 (PCR)3 
Urinalysis4 
Serum pregnancy test7  
Protein 
Glucose 
Ketones 
Occult blood 
Leukocytes 
Nitrite 
β-human chorionic gonadotropin 
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 only be measured if the urine dipstick is abnormal. 
5) 
The symbol ‘/’included in the table represents ‘a ratio’. 
6) 
Conducted at screening only. 
7) 
Only women of childbearing potential. 
Abbreviations: HDL = high density lipoprotein; HIV = human immunodeficiency virus; IMP = investigational medicine 
product; LDL = low density lipoprotein; PCR = polymerase chain reaction; SARS-CoV-2 = severe acute respiratory 
syndrome coronavirus 2; SC = subcutaneous. 
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11.4.5.2 Investigator evaluation of laboratory samples 
Laboratory samples sent to the central laboratory 
Clinical chemistry, haematology, urinalysis (if applicable), serology, and serum pregnancy 
tests will be analysed by a central laboratory which will provide results to the trial sites. 
Laboratory parameters will be classified as low, normal, or high, depending on whether the 
value is below, within, or above the reference range. The investigator must evaluate all results 
outside the reference range (clinically significant or not clinically significant) and sign and 
date their evaluation which will be archived in the investigator’s trial file.  
In case of an abnormal clinically significant laboratory result at screening and/or baseline, it 
will be at the discretion of the investigator if the subject should be randomised in the trial in 
accordance with exclusion criterion no. 22. During the trial, if a subject presents with an 
abnormal clinically significant laboratory result, the investigator must take appropriate action, 
at their discretion.  
In case additional analyses are needed to support the interpretation of the initial test results for 
hepatitis B, hepatitis C, or HIV, these will be conducted by the central laboratory, as 
applicable. Subjects with a positive serology, tuberculosis, or SARS-CoV-2 test at screening 
should be referred to a competent health care structure for treatment and follow-up. 
Serum pregnancy tests for women of childbearing potential will be analysed by a central 
laboratory which will provide results to the trial sites. A woman with a positive serum 
pregnancy test at screening must not be included in the trial (inclusion criterion no. 10 and 
exclusion criterion no. 23). 
Instruction for collection, processing, storage, and shipment of laboratory samples, as well as 
laboratory contact information specific to this trial will be provided in a separate laboratory 
manual. 
Laboratory tests performed at the trial site 
Urine samples will be tested at the trial site with a dipstick according to the schedule of trial 
procedures (Section 4). At an unscheduled visit, it will be at the discretion of the investigator 
if urine samples should be collected.  
If a dipstick shows any abnormal reading, a urine sample must always be collected and sent to 
the central laboratory for further analysis, regardless of causality or investigator’s assessment 
of significance. 
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Urine pregnancy tests for women of childbearing potential will be conducted at the trial sites. 
A woman with a positive urine pregnancy test at Week 0 (baseline) must not be randomised in 
the trial (inclusion criterion no. 10 and exclusion criterion no. 23). The test will be repeated 
every 4 weeks until Week 16 and at Week 32 as shown in the schedule of trial procedures in 
Section 4. A woman with a positive urine pregnancy test during the trial must immediately 
and permanently discontinue IMP and be withdrawn from the trial. A positive urine pregnancy 
test must be verified with a serum pregnancy test. 
Reporting in eCRF 
It will be recorded in the eCRF if a blood sample was taken. If not, a reason should be 
provided. The investigator’s assessment of the results (‘normal’, ‘abnormal, not clinically 
significant’, ‘abnormal, clinically significant’) will also be recorded. 
It will be recorded in the eCRF if a urine sample was tested with a dipstick. If not, a reason 
should be provided. It will be recorded if the urine sample was sent to the central laboratory 
for further analysis (urinalysis). In case urinalysis is conducted, the investigator’s assessment 
of the results (‘normal’, ‘abnormal, not clinically significant’, ‘abnormal, clinically 
significant’) will also be recorded. 
It will be recorded in the eCRF if the subject is a woman of childbearing potential and if a 
urine pregnancy test was conducted. If not, a reason should be provided. The date and 
outcome (‘positive’, ‘negative’) of the urine pregnancy test will also be recorded. 
Clinically significant abnormal laboratory results at screening and baseline will be 
documented as medical history in the eCRF. At subsequent visits, any new clinically 
significant abnormal laboratory results, symptoms, or illnesses, as well as any clinically 
significant deterioration of a pre-existing condition after randomisation will be reported as an 
AE as described in Section 13.3. 
Refer to Appendix 3D for principles for data entry in the eCRF. 
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.  
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. 
ADA A samples will be discarded upon finalisation of the CTR, whereas ADA B samples will 
be retained until approval in first major market (EU, US, and JP) or until 10 years after final 
CTR – whichever comes last. 
Reporting in eCRF 
It will be recorded in the eCRF if an ADA blood sample was taken. If not, a reason should be 
provided. Refer to Appendix 3D for principles for data entry in the eCRF. 
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). At an unscheduled visit, it will be at the discretion of 
the investigator if a blood sample to determine PK should be collected.  
Serum samples for determination of LEO 138559 concentrations will be 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. 
Refer to Appendix 3D for principles for data entry in the eCRF. 
11.6 Pharmacodynamics assessments 
11.6.1  Overview 
Biomarker expression in blood and skin (skin swabs and tape strips) will be measured to 
evaluate treatment effect of LEO 138559 on disease biomarkers and biomarkers related to the 
mechanism of action of LEO 138559 as presented in Sections 11.6.2, 11.6.3, and 11.6.4. 
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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 
Serum samples for biomarker analyses will be collected 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 should be collected to determine blood biomarkers.  
The serum biomarkers to be analysed include, but are not limited to 
 
.  
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.  
Refer to Appendix 3D for principles for data entry in the eCRF. 
11.6.3 Skin swabs 
Skin swabs will be taken according to the schedule of trial procedures (Section 4). At an 
unscheduled visit, it will be at the discretion of the investigator if skin swabs should be taken.  
Skin swabs from both lesional and non-lesional skin will be performed to measure the 
abundance of S. aureus colonisation as well as for broad microbiome profiling based on 16 S 
rRNA sequencing at baseline and Week 16. Subjects will be asked not to shower, bathe, or 
wash in general within 12 hours prior to the baseline and Week 16 visits. 
S. aureus colonisation will be analysed by qPCR. In addition, the skin microbiome may be 
characterised using next-generation sequencing. 
Collection, handling, and shipment instructions for skin swabs are provided in a laboratory 
manual. 
Results from skin swabs will be described in a separate report appended to the CTR. 
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Reporting in eCRF 
It will be recorded in the eCRF if skin swabs were taken and from which body location (volar 
arm, elbow pit, trunk, lower limbs, other) it was taken. If skin swabs were not taken, a reason 
should be provided.  
Refer to Appendix 3D for principles for data entry in the eCRF. 
11.6.4 Tape strips  
Tape stripping 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 tape stripping should be 
performed.  
Non-invasive tape stripping will be done to investigate gene expression in the skin. At 
baseline, the assessment will be done in 2 areas: in a representative lesional area and in a 
non-lesional area which is anatomically similar to the lesional area. If an anatomically similar 
non-lesional area cannot be found, the volar forearm may be used instead. At the 
end-of-treatment visit (or early IMP termination visit, if applicable) both the original lesional 
and a non-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.  
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 
It will be recorded in the eCRF if the tape strips were collected and from which body 
locations (volar arm, lower limbs, trunk, other). 
Refer to Appendix 3D for principles for data entry in the eCRF. 
11.7 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). 
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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 
At their last visit in the trial, an end-of-trial form must be completed in the eCRF for all 
randomised subjects. The following data will be collected:  
• Did the subject complete the trial (Section 7.3). If not, it will be recorded if the reason was 
due to the COVID-19 pandemic. 
• Date of last contact. 
• Primary reason for withdrawal from trial (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 primary endpoint visit (Week 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]). 
• If the subject attended the safety follow-up visit (Week 32). If not, the primary reason for 
not attending the visit (see reasons above) should be provided. 
The end-of-trial form will be completed when the subject has had their last visit (that is, the 
follow-up visit at Week 32, or early termination visit, or primary endpoint visit). 
11.8 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).  
11.9 Storage of biological samples 
Primary samples (set A samples) for PK 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 retained no longer than 12 months after completion of the CTR. 
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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 retained until approval in first major market (US, EU, and JP) or until 10 
years after final CTR – whichever comes last. Any B samples that have been sent to the 
bioanalytical lab will also be discarded upon finalisation of the CTR. The B samples stored at 
the central laboratory will be transferred to a central archive facility for long-term storage 
upon finalisation of the CTR. 
Biobank 
This protocol includes the collection and analysis of different biological samples. If consent is 
given by the subject, LEO Pharma will store serum, skin swab, and tape strip samples 
collected in a biobank established by LEO Pharma and hosted by Brooks Life Sciences 
GmbH (Germany). The biobanked biological samples will be used for future research 
performed by LEO Pharma. Donation of the samples for future research is voluntary and 
subjects must give their written consent to confirm donation and storage and the terms 
associated herewith. The samples will be transferred from the relevant laboratory to the 
biobank. The samples will be labelled with the trial ID, subject ID, and the sample date to 
protect the privacy of the subjects and to allow continued blinding for future analyses. The 
samples in this trial will be stored in the biobank for a maximum of 15 years after CTR 
finalisation, and will then be destroyed. 
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12 Scientific rationale for trial design and appropriateness of assessments 
12.1 Scientific rationale for trial design 
The overall trial design is presented in Section 7.1 and illustrated in Section 3.  
The trial is designed to evaluate the efficacy and safety of SC administered LEO 138559 
450 mg Q2W compared with placebo Q2W in adults with moderate to severe AD. The trial 
design is considered appropriate to evaluate the trial objectives (Section 6). 
Population 
The most important inclusion criterion for participation in the trial is an established diagnosis 
of AD (as defined by the AAD Consensus Criteria (1) with a history of AD of at least 1 year 
prior to screening), to ensure correct diagnosis and rule out differential diagnosis 
(Section 8.2). The AAD Consensus Criteria are utilised in clinical trials and in clinical 
practice for the diagnosis of AD. The AAD Consensus Criteria are based on the long standing 
Hanifin and Rajka criteria (52) but are updated to emphasise both childhood and adult aspects 
of AD. 
Another prerequisite for participation in the trial is a recent (within 6 months prior to the 
screening visit) documented history of inadequate response to topical AD treatments or being 
a subject for whom topical treatment is medically inadvisable, to ensure that the subject is 
candidate for the treatment.  
The other eligibility criteria have been chosen to ensure inclusion of the targeted patient 
population and safety of the subjects and to minimise factors which could interfere with the 
efficacy and safety assessments (Sections 8.2 and 8.3). 
Treatment and treatment groups 
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 placebo control group will serve as reference to evaluate the efficacy and safety of 
LEO 138559. The use of a placebo control group allows for an evaluation of similarity to the 
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treatment effect observed in other AD systemic treatment trials, thereby adding to the 
knowledge needed for positioning LEO 138559 in the AD treatment pathway. 
Trial periods 
The screening period should last long enough to allow complete washout of any systemic AD 
treatment by Week 0 (baseline) but should not exceed 4 weeks in total so that the general 
medical condition of the subject, as established by the examinations and laboratory 
measurements conducted at the screening visit, has not significantly changed by Week 0 
(Section 7.1). 
The 1-week washout period is considered an appropriate length to ensure washout of any 
topical AD treatment (TCS/TCI) and establish a baseline for AD symptoms. In this period, the 
subject should apply a background treatment (emollient) on lesional and non-lesional skin at 
least twice daily for at least 7 consecutive days prior to baseline to keep their skin well 
moisturised in the absence of systemic and/or topical AD treatment(s) (Section 7.1). 
AD is a chronic condition with a waxing and waning course. Subjects with moderate to severe 
AD often experience multiple flares during the course of a year and therefore a 16-week 
treatment period ensures sufficient time to evaluate the impact of LEO 138559 on disease 
severity. Further, given the expected half-life, dosage, and dosing frequency of LEO 138559, 
a 16-week treatment period ensures that LEO 138559 will reach its maximum effect. During 
the treatment period, the subject will be asked to continue applying an emollient twice daily 
(or more frequently, if needed) as a complement to the systemic treatment (standard of care) 
and to keep their skin well moisturised (Section 7.1). 
After last dose of IMP, the 16-week safety follow-up period is considered an appropriate 
length before the last safety assessments are conducted (Section 7.1). 
Mitigation of bias 
The combination of randomisation and blinding (Section 9.3.1) minimises the likelihood of 
allocation bias. The risk of allocation bias is further reduced through the use of central 
randomisation. The use of randomisation also ensures that baseline factors will not be 
confounded with treatment. Randomisation within the strata defined by baseline disease 
severity (‘stratum A’ [EASI <21] or ‘stratum B’ [EASI ≥21]) will limit any potential 
imbalance in the allocation of subjects across baseline disease severity.  
Endpoints and estimands 
The endpoints have been selected to evaluate the efficacy of LEO 138559 in improving the 
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severity and extent of AD, including objective signs of the disease, subjective symptoms (e.g., 
itch), as well as HRQoL. 
Change in EASI score from baseline to Week 16 has been chosen as primary endpoint 
because EASI allows capturing change in disease on a continuous scale with a degree of 
precision making it a suitable tool for modelling the exposure-response relationship of 
LEO 138559 (53). 
The primary estimand addressing the primary endpoint follows a hypothetical strategy which 
attempts to quantify the effect of treatment, in the hypothetical situation, where one or more 
intercurrent events (initiation of rescue treatment or permanent discontinuation of IMP) do not 
occur.   
12.2 Appropriateness of assessments 
Efficacy assessments 
EASI and vIGA-AD are validated measures used in clinical practice and clinical trials by 
investigators to assess the severity and/or extent of AD (see Sections 11.3.1 and 11.3.2)  
(47-49). 
PROs 
A range of validated PROs will be used to assess subject perception of AD independently of 
the investigator or trial staff. The PROs have been selected to assess the key symptoms of AD 
(including itch) and HRQoL (11.3.4). 
Safety assessments 
Standard clinical methods of subject evaluations, such as AE monitoring (Section 13), vital 
signs, physical examinations, ECG, laboratory testing including pregnancy testing, and ADA 
will be used to assess subject safety (Section 11.4). Given some large proteins may cause 
indirect adverse cardiac effects upon long term exposure, data on ECG will be collected and 
evaluated (11.4.4). Data on ADA will be collected in order to evaluate the potential 
immunogenicity of LEO 138559 (11.4.6). 
One AESI of lower respiratory tract infection has been identified for this trial as IL-22 has 
been shown to mediate mucosal host defence of the lung and induce expression of epithelial 
antimicrobial peptides (13.6.1). Therefore, when blocking IL-22R, there is a potential for 
increased risk of infection. However, no SAEs were reported in the FiM trial (LP0145-1315) 
nor in subjects with AD treated with a mAb targeting IL‑22 (fezakinumab) (36). Further,  
IL-22R is expressed on epithelial cells and not on immune cells, so immune cell responses to 
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infections are preserved. For further information please refer to the current investigator’s 
brochure (35). 
Pharmacokinetic assessments 
Serum concentration of LEO 138559 will be measured to further characterise the PK of 
LEO 138559 in subjects with moderate to severe AD (Section 11.5). The serum 
concentrations will be summarised and reported in the CTR as well as subjected to population 
PK analysis and reported separately, and may be used in an exploratory exposure-response 
analysis to support dose selection in future clinical trials. 
Pharmacodynamics assessments 
Biomarkers will be evaluated in blood and skin of subjects to assess 1) target engagement in 
the skin, 2) the molecular response of LEO 138559 on inflammatory processes in AD in 
general and more specifically on the IL-22 pathway, and 3) to identify sub-populations of AD 
patients with increased response to treatment. 
Serum samples from all subjects will be collected for assessment of PD markers in the blood. 
Serum samples will be analysed for IL-22 pathway protein biomarkers, protein biomarkers of 
relevance for AD, and for potential new disease or treatment-related protein biomarkers.  
Skin swabs will be taken from both lesional and non-lesional skin to measure the abundance 
of S. aureus colonisation as well as for broad microbiome profiling based on 16 S rRNA 
sequencing. 
Transcriptome profiling of tape strips will be used to further elucidate the pathophysiological 
mechanisms of AD and to expand our understanding of the compound MoA. Biomarkers in 
tape strips will be assessed by RNA expression analysis.  
 
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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 ICF until completion of the clinical trial (all trial periods including safety follow-up visit 
at Week 32, see Section 7.3). 
AEs must be assessed by a physician. In the US only, certain AE assessments can be 
delegated to investigators with other qualifications. However, the diagnosis, seriousness, and 
causality of the AEs must be assessed by a physician. 
At all visits, the subject will be asked a non-leading question by the investigator about AEs, 
for example: “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 (for 
example ‘allergic contact dermatitis’). 
The duration of the AE must be reported by the start date and stop date of the event (if the 
event is ongoing it will also be recorded). 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. 
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Action taken with IMP: any action taken with IMP as a consequence of the AE must be 
recorded in the eCRF (dose not changed, drug interrupted, drug discontinued, not applicable, 
unknown). 
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. 
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 within 24 hours of first 
knowledge. This report should contain an assessment of available information on seriousness, 
severity, causal relationship to the IMP or trial procedure, the action taken, the outcome to 
date, and a narrative description of the course of the event. 
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 report. 
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: 
Global 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 should not be routinely sought or 
recorded. However, such events should be reported 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 or not an SAE is expected. 
The relevant reference safety information document for this clinical trial is the investigator’s 
brochure Section 7.4, edition 4.0 and subsequent updates (35).  
Global Safety at LEO Pharma will notify the regulatory authorities and concerned 
investigators of SAEs according to the current applicable legislation for the concerned 
countries.  
The IRB(s)/IEC(s) will be notified of SAEs according to the current applicable legislation for 
the concerned countries.  
For all non-US countries, the following reporting requirements apply: all SAEs which are 
assessed as causally related to the IMP(s) by either the investigator or LEO Pharma (54), 
and which are unexpected (suspected, unexpected serious adverse reactions [SUSARs]), are 
subject to expedited reporting to regulatory authorities, IEC(s)/IRB(s) according to the current 
applicable legislation in the concerned countries. Investigators will be notified of the evolving 
safety profile of the IMP on an ongoing basis. 
For the US, the following reporting requirements apply: all SAEs which are assessed as 
causally related to the IMP(s) by LEO Pharma (55, 56) and which are unexpected (serious 
and unexpected suspected adverse reactions [IND safety report]) are subject to expedited 
reporting to regulatory authorities and IRB(s). Investigators will be notified of the evolving 
safety profile of the IMP on an ongoing basis. 
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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) 
pregnancy form (part I). All pregnancies must be followed up until delivery or termination 
and final 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 and be withdrawn from the 
trial (Sections 10.2.1 and 10.3). 
13.6 Reporting of other events 
13.6.1 Adverse events of special interest 
The event listed in Panel 11 is considered an AESI in this trial and will require additional 
details to be recorded. LEO Pharma may request that the investigator to forward additional 
test results, as appropriate. An AESI may be serious or non-serious. Serious AESIs require 
expedited reporting as described in Section 13.4.  
Panel 11: Adverse events of special interest 
AESI 
Additional data to be recorded 
Data collection method 
Lower respiratory 
tract infections 
• 
Infectious cause.  
• 
COVID-19 test performed in relation to 
event. 
• 
Known risk factors. 
• 
Smoking. 
eCRF  
Abbreviations: AESI = adverse events of special interest; eCRF = electronic case report form; COVID-19 = 
coronavirus disease 2019. 
13.6.2 Overdose 
An overdose is defined as a subject receiving a dose of IMP in excess of that specified in this 
protocol.  
The term ‘overdose’ including a specification of why it occurred (accidental or intentional) 
must be recorded on the AE form of the eCRF. In addition, AEs originating from overdose 
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must be recorded as separate events. If the AE originating from the overdose qualifies as an 
SAE, expedited reporting is required (Section 13.4). 
LEO Pharma does not recommend specific treatment for an overdose. The investigator will 
use clinical judgement to treat any overdose if necessary. 
13.6.3 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 
The medication error category must be documented on the AE form in the eCRF. In addition, 
AEs originating from a medication error must be recorded as separate events. If the AE 
originating from the medication error qualifies as an SAE, expedited reporting is required 
(Section 13.4). 
13.6.4 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 defined in the protocol. 
Misuse refers to situations where the IMP is intentionally and inappropriately used for 
therapeutic purposes not in accordance with the protocol. 
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/abuse must be recorded as separate AEs on the AE form. If the AE 
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originating from the misuse or abuse qualifies as an SAE, expedited reporting is required 
(Section 13.4). 
13.6.5 Aggravation of condition 
Any clinically significant aggravation/exacerbation/worsening of any medical condition(s) 
(including the trial disease), compared with screening, must be reported as an (S)AE in 
accordance with Sections 13.3 and 13.4. 
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 of possibly or probably related to the IMP for 
2 weeks or until the final outcome is determined, whichever comes first. 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, for 
example chronic or stabilised conditions, the final outcome should be reported as ‘recovering’ 
or ‘not recovered’ as per the investigator’s discretion. In addition, a statement 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 
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.” (57). 
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 
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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 
At baseline, a total of 52 subjects will be randomised 1:1: 
• 26 subjects to LEO 138559 450 mg Q2W. 
• 26 subjects to placebo Q2W. 
The sample size is determined using t-test for pairwise consideration of 2 treatment groups 
based on the following assumptions: 
Treatment 
Expected reduction in EASI (SD)* 
Attrition rate 
LEO 138559 
22.9 (13) 
30% 
Placebo 
7.3 (18) 
30% 
*Expected reduction in EASI for LEO 138559 is based on results from an upadacitinib phase 2b trial (28), and 
for placebo, the expected reduction is based on a dupilumab phase 2b trial (58). 
With a significance level of 5%, 18 subjects per treatment group will provide a nominal 
power of at least 80% to detect a difference between the 2 treatment groups. Assuming a 
maximum attrition rate of 30%, 26 subjects in each treatment group should be randomised 
into the trial. 
Assuming a screening failure rate of 35%, the planned number of subjects to screen is set to 
80. 
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 (FAS) 
and will be analysed for efficacy. Exclusions from the FAS can be considered in special cases 
as described in ICH E9, Section 5.2.1., Full Analysis Set. If it is decided to exclude a subject 
from the FAS, a justification addressing ICH E9 will be given. 
A safety analysis set (SAF) will be defined as all subjects who will be exposed to IMP.  
A PK analysis set will be defined as all subjects who will be exposed to LEO 138559 and 
provide samples 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 analysis set definition document before breaking the 
randomisation code. 
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14.3 Statistical analysis 
14.3.1 General principles 
All significance tests will be two-sided using the 5% significance level. All confidence 
intervals will be presented with 95% degree of confidence, unless otherwise specified. 
Efficacy analyses will be based on the FAS, and safety analyses will be based on the safety 
analysis set. PK analysis 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). For categorical endpoints, the number of 
subjects not attending 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. 
14.3.2 Handling of missing values 
The methods for handling of missing values for the primary endpoint are described in 
Section 14.3.8. 
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For other continuous endpoints for which a MMRM analysis will be used it will be assumed 
that data is missing at random within each treatment group. The missing data will be predicted 
by the MMRM model. 
For the categorical endpoints for which a CMH test will be used, subjects with missing data 
will be considered as non-responders and their missing values will be imputed using NRI. 
14.3.3 Handling of intercurrent events related to the COVID-19 pandemic 
As the implications of the COVID-19 pandemic might, extraordinarily, influence trial events 
and data in manners not foreseen by the clinical trial protocol, this section introduces the 
statistical considerations for handling of intercurrent events related to the pandemic for the 
primary endpoint. 
A supplementary estimand, ‘pandemic-modified composite’, is introduced for analysis of the 
primary endpoint to address permanent discontinuation of IMP due to the pandemic as an 
intercurrent event. Details are described in Section 14.3.8. 
Interruption of IMP administration during the treatment period (Weeks 0–16) is not 
considered as an intercurrent event if only 1 full dose (450 mg) is missed. Observed data from 
subjects missing more than one dose will be ‘treated as missing’. The causal relationship of 
permanent discontinuation of IMP related to the pandemic will be recorded in the eCRF.  
Handling of data affected by the COVID-19 pandemic 
As a consequence of the pandemic and associated local preventive measures, subjects may 
miss an entire visit. At scheduled visits, it will be recorded in the eCRF whether data are 
missing due to the pandemic.  
Observed data after permanent discontinuation of IMP related to the pandemic will be ‘treated 
as missing’ and imputed assuming MAR. Similarly, missing data and/or initiation of rescue 
treatment related to the pandemic will be imputed assuming MAR. 
It should be noted that a subject may have missing data related to the pandemic, even though 
the subject has not experienced an intercurrent event related to the pandemic. 
An overview of how observed and missing data will be handled according to the intercurrent 
events and their relatedness to the pandemic is presented in Section 14.3.7. For the primary 
analysis of estimands, details of the analysis are described in Section 14.3.8. 
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14.3.4 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. 
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).  
14.3.5 Demographics and other baseline characteristics 
Descriptive statistics of demographics and other baseline characteristics will be presented for 
all randomised subjects and by treatment group. Presentations of date of birth, age, sex, 
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.  
14.3.6 Exposure and treatment compliance 
Exposure to treatment will be presented for the safety analysis set as days of exposure per 
treatment group.  
The cumulated dose administered to each subject will be determined and 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. 
14.3.7 Testing strategy 
This is a phase 2a trial with the primary objective to investigate efficacy of LEO 138559. For 
the primary endpoint, change in EASI score from baseline to Week 16, the statistical analysis 
will be controlled by 2-sided alpha value of 5%. There will be no adjustment for the multiple 
testing of primary and secondary endpoints, all p-values will be considered nominal. 
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14.3.8  Analysis of primary endpoint 
A primary and 3 supplementary estimands will be defined for the primary endpoint to ensure 
that occurrence of intercurrent events is taken into account (Panel 12).
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Panel 12: Objective and estimands for primary endpoint  
Objective 
Estimands 
Endpoint 
 
Estimand type 
(Primary/ 
Supplementary) 
Comparison 
groups 
Interpretation of endpoint 
Intercurrent events and strategy 
Population 
level 
summary 
 
Primary 
objective 
To 
compare 
the 
efficacy of 
LEO 
138559 
with 
placebo in 
subjects 
with 
moderate 
to severe 
AD. 
Primary 
Dose of 
LEO 138559 
450 mg Q2W 
vs. placebo. 
Change in EASI from baseline to Week 16 as 
if all subjects adhered to the treatment 
regimen, i.e., they did not permanently 
discontinue IMP and did not use rescue 
treatment before Week 16 (Section 14.3.8.1). 
Events: Permanent discontinuation 
of IMP, initiation of rescue 
treatment 
Strategy: ‘Hypothetical’. 
Difference 
in mean 
change in 
EASI 
from 
baseline to 
Week 16. 
Primary 
endpoint 
Change in 
EASI 
score from 
baseline to 
Week 16. 
First 
supplementary 
Change in EASI from baseline to Week 16 
without intercurrent events (Section 14.3.8.2). 
Events: Permanent discontinuation 
of IMP, initiation of rescue 
treatment 
Strategy: ‘Composite’. 
Second 
supplementary  
Change in EASI from baseline to Week 16 
without intercurrent events and as if 
COVID-19 pandemic did not happen 
(Section 14.3.8.3). 
Events: Permanent discontinuation 
of IMP due to 
non-pandemic-related factors, 
permanent discontinuation of IMP 
due to pandemic-related factors, 
initiation of rescue treatment 
Strategy: ‘Pandemic-modified 
composite’. 
Third 
supplementary  
Change in EASI from baseline to Week 16 
regardless of intercurrent events 
(Section 14.3.8.4). 
Events: Permanent discontinuation 
of IMP, initiation of rescue 
treatment 
Strategy: ‘Treatment policy’. 
Abbreviations: AD = atopic dermatitis; COVID-19 = coronavirus disease 2019; EASI = Eczema Area and Severity Index; IMP = investigational medicinal 
product; Q2W = every second week. 
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The following intercurrent events are considered to affect the interpretation of the estimated 
treatment effects:  
• Initiation of rescue treatment: This event occurs when a subject initiates rescue treatment. 
This event is disallowed during the first 4 weeks of treatment but can occur from week 4 
at the discretion of the investigator. The timing of the event will be taken as the date of 
initiation of the rescue treatment recorded in the eCRF and the event will be handled 
without assessing relatedness to the COVID-19 pandemic. If rescue treatment is initiated 
before week 4, the subject will be withdrawn from the trial.  
• Permanent discontinuation of IMP independent of the COVID-19 pandemic: This event 
occurs when a subject permanently discontinues IMP independently of the pandemic. This 
event can occur at the subject's own initiative, at the discretion of the investigator or the 
sponsor, or if the subject is lost to follow-up. The timing of the event will be taken as the 
date of permanent discontinuation of IMP recorded in the eCRF.  
• Permanent discontinuation of IMP due to the COVID-19 pandemic: This event occurs 
when a subject permanently discontinues IMP due to circumstances related to the 
pandemic; not attributed to lack of efficacy or randomised treatment features considered 
unacceptable by the subject. 
Depending on the estimand strategy selected, the occurrence of an intercurrent event may be 
ignored, lead to the exclusion of data observed after the occurrence of the event, be accounted 
for in the definition of a composite endpoint, or restrict the relevant observation window to 
the time prior to the occurrence of the intercurrent event as described below.  
14.3.8.1 Primary estimand 
The primary estimand will use a hypothetical strategy which attempts to quantify the effect of 
treatment, in the hypothetical situation, where one or more intercurrent events do not occur. In 
this context, an intercurrent event refers to a post-randomisation event that either precludes 
the existence of or affects the interpretation of the measurements of the endpoint e.g., 
permanent discontinuation of IMP.  
This primary estimand evaluates the treatment difference in change in EASI score from 
baseline to Week 16 as if all subjects adhered to the treatment regimen, i.e., they did not 
discontinue IMP permanently and no rescue treatment was made available before Week 16. 
Data collected after permanent discontinuation of IMP or after initiation of rescue treatment 
will not be included in the analysis, but will be ‘treated as missing’ and imputed assuming 
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MAR. Similarly, for subjects who experience a pandemic-related intercurrent event prior to 
Week 16, observed data at Week 16 will be ‘treated as missing’ and imputed assuming MAR. 
If data is missing at Week 16 due to a non-pandemic-related intercurrent event, the data will 
be imputed using MI (100 iterations) assuming MAR within each treatment group and 
whether the subject has experienced a non-pandemic-related intercurrent event. Within a 
given treatment group, observed data from subjects not experiencing an intercurrent event 
will be used to impute missing data for subjects who experience an intercurrent event. 
Missing data or data ‘treated as missing’ at Week 16 due to the pandemic will be imputed 
using MI assuming MAR within treatment group using data from subjects who have not 
experienced an intercurrent event.   
For each of the 100 complete datasets, the change in EASI score from baseline to Week 16 
will be analysed using an ANCOVA model adjusted for treatment, region, baseline EASI 
score, and baseline disease severity. The pooled estimate of the difference in the LS-mean 
change from baseline, along with the associated 95% CIs and nominal p-values will be 
presented based on applying Rubin’s rules to the estimates and standard errors from the 
ANCOVA analysis of the imputed datasets. 
14.3.8.1.1 Sensitivity analysis for primary estimand 
The primary estimand will be analysed using a MMRM on the post-baseline responses up to 
Week 16 including treatment, visit, interaction between treatment and visit, region and 
baseline disease severity as factors and adjusting for baseline EASI score as covariate. The 
model will use an unstructured covariance matrix, Kenward-Roger approximation to estimate 
denominator degrees of freedom. This model assumes that data is missing at random within 
each treatment group and the model will be used to predict missing data. The estimates will be 
presented with nominal p-values and 95% CI at each visit. 
14.3.8.2 First supplementary estimand 
A first supplementary estimand will use composite strategy to handle intercurrent events. A 
composite strategy accounts for the occurrence of intercurrent events, through the definition 
of a suitable composite endpoint, whose components include the aforementioned intercurrent 
events, as well as the endpoint of interest.  
The first supplementary estimand for the primary endpoint is the treatment difference in 
change in EASI score from baseline to Week 16 as if initiation of rescue treatment or 
permanent discontinuation of IMP did not happen. For subjects who received rescue treatment 
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or who have permanently discontinued IMP prior to the endpoint of interest, observed data 
after the intercurrent events will be considered non-response by using LOCF. Similarly, 
missing data for subjects who do not attend the visit for the endpoint of interest and do not 
experience an intercurrent event prior to this visit will be imputed as LOCF. 
The change in EASI score from baseline to Week 16 will be analysed using an ANCOVA 
model adjusted for treatment, region, baseline EASI score, and baseline disease severity. The 
difference in the LS-mean change from baseline between the treatment groups will be 
presented along with the corresponding 95% CI and nominal p-value. 
14.3.8.2.1 Sensitivity analysis for the first supplementary estimand 
For subjects who received rescue treatment or who have permanently discontinued IMP prior 
to the endpoint of interest, observed data after the intercurrent events will be considered 
non-response by using WOCF including the baseline value. Similarly, missing data for 
subjects who do not attend the visit for the endpoint of interest and do not experience an 
intercurrent event prior to this visit will be imputed as WOCF. The same ANCOVA model 
described for the primary analysis of the primary estimand will be used. 
14.3.8.3  Second supplementary estimand 
A second supplementary estimand will use a pandemic-modified composite strategy. The 
strategy follows a composite strategy for intercurrent events independent of the COVID-19 
pandemic.  
The second supplementary estimand for the primary endpoint is the treatment difference in 
change in EASI score from baseline to Week 16 without initiation of rescue treatment or 
permanent discontinuation of IMP and as if the COVID-19 pandemic did not happen. For 
subjects who experience non pandemic-related intercurrent events prior to the endpoint of 
interest, observed data after the intercurrent events will be considered non-response by using 
LOCF. For subjects who experience a pandemic-related intercurrent event prior to the 
endpoint of interest, observed data after the event will be ‘treated as missing’ and imputed 
assuming MAR. 
For imputation purposes, data available from all subjects will be used, but excluding 
individual subject data captured after the intercurrent events. 
The procedure for imputing values will be implemented in a 2-step procedure, where all 
missing or ‘treated as missing’ data related to pandemic will be imputed using MI (100 
iterations) assuming MAR within treatment groups. Once the 100 complete data sets have 
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been generated by MI, LOCF imputation of relevant data points not affected by the pandemic 
will be applied according to the rules described above. 
For each of the 100 complete datasets, the change in EASI score from baseline to Week 16 
will be analysed using an ANCOVA model including treatment, region, and baseline disease 
severity as factors and adjusting for baseline EASI score as covariate. The pooled estimate of 
the difference in the LS-mean change from baseline, along with the associated 95% CIs and 
nominal p-values will be presented based on applying Rubin’s rules to the estimates and 
standard errors from the aforementioned ANCOVA analysis of the imputed datasets.  
14.3.8.4 Third supplementary estimand 
A third supplementary estimand will use a treatment policy strategy which attempts to 
quantify the effect of the decision to treat subjects with the randomised treatment, thus 
ignoring the occurrence of intercurrent events. Data collected for the primary endpoint are 
used regardless of whether an intercurrent event (independent of the pandemic) occurred. 
Data collected after an event related to the pandemic will be ‘treated as missing’ and imputed 
assuming MAR. 
This supplementary estimand will evaluate the treatment difference in change in EASI score 
from baseline to Week 16 regardless of permanent discontinuation of IMP or initiation of 
rescue treatment and as if the COVID-19 pandemic did not happen. Observed data will be 
used in the analysis, including the data observed after the occurrence of non-pandemic-related 
intercurrent events. For subjects who experience a pandemic-related intercurrent event prior 
to Week 16, observed data at Week 16 will be ‘treated as missing’ and imputed assuming 
MAR. 
If data is missing at Week 16 due to a non-pandemic-related intercurrent event, the data will 
be imputed using MI (100 iterations) assuming MAR within each treatment group and 
whether the subject has experienced a non-pandemic-related intercurrent event. Within a 
given treatment group, observed data from subjects not experiencing an intercurrent event 
will be used to impute missing data for subjects who experience an intercurrent event. 
Missing data or data ‘treated as missing’ at Week 16 due to the pandemic will be imputed 
using MI assuming MAR within treatment group using data from subjects who have not 
experienced an intercurrent event.   
For each of the 100 complete datasets, the change in EASI score from baseline to Week 16 
will be analysed using an ANCOVA model adjusted for treatment, region, baseline EASI 
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score, and baseline disease severity. The pooled estimate of the difference in the LS-mean 
change from baseline, along with the associated 95% CIs and nominal p-values will be 
presented based on applying Rubin’s rules to the estimates and standard errors from the 
ANCOVA analysis of the imputed datasets. 
Panel 13 presents an overview of how observed and missing data will be handled according to 
the intercurrent events for the analyses of estimands. 
 
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Panel 13: Handling of intercurrent events and analyses of estimands for the primary endpoint  
Events  
Data observed or 
missing 
Estimand strategy 
Primary:  
‘Hypothetical’  
 
First supplementary: 
‘Composite’ 
Second supplementary: 
‘Pandemic modified 
composite’  
Third supplementary: 
‘Treatment policy’  
Initiation of rescue 
treatmenta 
Observed 
MI (MAR) 
LOCF 
LOCF 
Used 
Missing  
MI (MAR) 
LOCF 
LOCF 
MI (MAR) 
Permanent 
discontinuation of IMP 
independent of the 
pandemic 
Observed 
MI (MAR) 
LOCF 
LOCF 
Used 
Missing 
MI (MAR) 
LOCF 
LOCF 
MI (MAR) 
Permanent 
discontinuation of IMP 
related to the pandemic 
Observed 
Treated as missing, 
MI (MAR) 
LOCF 
Treated as missing,  
MI (MAR) 
Treated as missing,  
MI (MAR) 
Missing 
MI (MAR) 
LOCF 
MI (MAR) 
MI (MAR) 
No intercurrent events 
Observed 
Used 
Used 
Used 
Used 
Missing 
independent of 
the pandemic 
MI (MAR) 
LOCF 
LOCF 
MI (MAR) 
Missing related 
to the pandemic 
MI (MAR) 
LOCF 
MI (MAR) 
MI (MAR) 
Abbreviations: COVID-19 = coronavirus disease 2019; IMP = investigational medicinal product; LOCF= last observation carried forward;  
MAR = missing at random; MI = multiple imputation. 
a Initiation of rescue treatment is considered an intercurrent event regardless of the relatedness to the COVID-19 pandemic.
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14.3.9 Analysis of secondary endpoint 
Analysis of the secondary endpoint 
• Number of treatment-emergent adverse events from baseline to Week 16 per subject. 
is described in Section 14.3.14.1 in details. 
14.3.10 
Analysis of exploratory efficacy endpoints 
Binary endpoints 
The following endpoints; 
• Having a decrease in EASI of at least 50% (EASI 50) from baseline to Week 16. 
• Having a decrease in EASI of at least 75% (EASI 75) from baseline to Week 16. 
• Having a decrease in EASI of at least 90% (EASI 90) from baseline to Week 16. 
• Having vIGA-AD of 0 (clear) or 1 (almost clear) at Week 16.  
will be analysed using CMH test stratified by region and baseline disease severity. Subjects 
who received rescue treatment prior to the Week 16 visit or permanently discontinued IMP or 
have missing data will be considered as non-responders. Additionally, responder rates will be 
summarised descriptively at each visit by treatment group. 
Time-to-event endpoints  
The endpoints; 
• Time to having a decrease in EASI of at least 50% (EASI 50) between baseline and 
Week 16. 
• Time to having a decrease in EASI of at least 75% (EASI 75) between baseline and 
Week 16. 
• Time to having a decrease in EASI of at least 90% (EASI 90) between baseline and 
Week 16. 
• Time to initiation of TCI or TCS rescue treatment between baseline and Week 16. 
will be analysed according to Gray’s test, stratified by region and baseline disease severity. 
Gray’s test accounts for the occurrence of the competing risks, permanent discontinuation of 
IMP and initiation of rescue treatment. Inference will be based on the estimated cumulative 
incidence of achieving the endpoint derived from the Aalen-Johansen estimator. The 
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estimated cumulative incidence functions will be presented by treatment group along with 
95% confidence bands.  
14.3.11 
Analysis of patient-reported outcomes 
Continuous endpoints  
The following endpoints; 
• Change in Worst Daily Pruritus NRS (weekly average) from baseline to Weeks 1, 2, 4, 8, 
12, and 16. 
• Change in POEM score from baseline to Week 16. 
• Change in DLQI from baseline to Week 16.  
will be summarised descriptively at each visit by treatment group and will be analysed using a 
MMRM model including treatment, visit, interaction between treatment and visit, region and 
baseline disease severity as factors and adjusting for baseline value for the endpoint of interest 
as covariate. The model will use an unstructured covariance matrix, Kenward Roger 
approximation to estimate denominator degrees of freedom. For these endpoints, data 
collected after permanent discontinuation of IMP or after initiation of rescue treatment will 
not be included in the analysis but will be ‘treated as missing’. This model assumes that data 
is missing at random within each treatment group. The estimates will be presented with 
nominal p-values and 95% CI at each visit. 
Binary endpoints 
The following endpoints; 
• Having a decrease in Worst Daily Pruritus NRS (weekly average) of ≥3 points from 
baseline at Weeks 1, 2, 4, 8, 12, and 16, assessed separately. 
• Having a decrease in Worst Daily Pruritus NRS (weekly average) of ≥4 points from 
baseline at Weeks 1, 2, 4, 8, 12, and 16, assessed separately, among subjects with a 
baseline Worst Daily Pruritus NRS ≥4 points. 
will be summarised descriptively at each visit by treatment group and will be analysed using 
the same CHM test described in Section 14.3.10 for binary endpoints. 
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Time-to-event endpoints  
The endpoints; 
• Time to reduction of Worst Daily Pruritus NRS (weekly average) of ≥3 points between 
baseline and Week 16. 
• Time to reduction of Worst Daily Pruritus NRS (weekly average) of ≥4 points between 
baseline and Week 16 among subjects with a baseline Worst Daily Pruritus NRS ≥4 
points. 
will be summarised descriptively at each visit by treatment group and will be analysed using 
the same analysis method described in Section 14.3.10 for time-to-event endpoints.  
14.3.12 
Analysis of pharmacodynamics 
For the following endpoints; 
• Change in expression of AD disease biomarkers in serum from baseline to Week 16. 
• Change in expression of AD disease biomarkers in skin from baseline to Week 16. 
explorative analyses will be performed for the total population as well as by baseline disease 
severity. 
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. 
14.3.13 
Exploratory analyses 
Descriptive statistics of BSA score (absolute and change from baseline) will be summarised at 
each visit by treatment group. Additional exploratory analyses will be described in the SAP 
and will be performed if deemed necessary.   
14.3.14 
Analysis of safety 
The analysis of safety will be based on the safety analysis set. 
14.3.14.1 Adverse events 
AEs will be coded during the course of the trial according to the MedDRA. AEs will be 
presented by preferred term and primary SOC. 
Treatment-emergent AEs will be summarised; however, all AEs recorded during the course of 
the trial will be included in subject data listings. Treatment-emergent and non-treatment-
emergent AEs will be listed separately. An event will be considered treatment-emergent if 
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started after the first dose of IMP or if started before the first dose of IMP and worsened in 
severity after first dose of IMP. An event will not be considered treatment-emergent if starting 
18 weeks after the last dose of IMP. The tabulations described in the following will only 
include the treatment-emergent events. 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, AESIs, 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. 
Tabulations by SOC and preferred term will be presented for all AEs, SAEs, related AEs, 
AESIs, and AEs leading to withdrawal from trial and/or permanent discontinuation of IMP. In 
addition, all AEs will be presented by severity and causal relationship to IMP, respectively. 
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.  
SAEs will be evaluated separately and a narrative will be given. AESIs will be tabulated and 
listed by treatment group, no narratives will be given except if these are serious.  
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. 
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14.3.14.2 Vital signs and physical examination 
The change in vital signs (blood pressure, pulse, and body temperature) from baseline to each 
relevant visit will be summarised 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. 
14.3.14.3 ECG 
The change in ECG from baseline to each visit will be summarised 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. 
14.3.14.4 Clinical laboratory evaluation 
The change in each of the laboratory parameters from baseline to each visit will be 
summarised by treatment group as mean, SD, median, minimum and maximum values for the 
safety analysis set. 
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. 
14.3.14.5 Anti-drug antibodies 
For the endpoint 
• Having a positive ADA response at Weeks 0, 4, 8, 12, 16, 32, assessed separately. 
the ADA status (positive vs. negative) at each assessment time point will be summarised by 
treatment group. If considered relevant, descriptive statistics including number of subjects, 
mean, SD, median, and range of the actual ADA titres by treatment group and visit will be 
provided. The ADA status across the trial for each subject (positive vs. negative) will also be 
classified and summarised by treatment group.  
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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. 
14.3.15 
Analysis of pharmacokinetics  
The endpoint 
• Serum concentration of LEO 138559 at Weeks 0, 1, 2, 4, 6, 8, 10, 12, 14, 16, 32, 
assessed separately. 
will be evaluated based on the PK analysis set. LEO 138559 serum concentrations will be 
listed and summarised by visit. 
14.3.16 
Interim analysis 
The trial will be unblinded once all randomised subjects have completed the Week 16 visit. 
All pre-specified analyses will be based on the data lock point date of the last subject’s 
Week 16 visit. The CTR will include all data from the trial including data from the safety 
follow-up period.  
A written plan (trial blinding plan) detailing the blinded/unblinded staff for the interim 
analysis will be prepared before FSFV. 
 
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15 References 
1. 
Eichenfield LF. Consensus guidelines in diagnosis and treatment of atopic dermatitis. 
Allergy. 2004;59 Suppl 78:86-92. 
 
2. 
Weidinger S, Beck LA, Bieber T, Kabashima K, Irvine AD. Atopic dermatitis. Nat Rev 
Dis Primers. 2018;4(1):1-20. 
 
3. 
Dalgard FJ, Gieler U, Tomas-Aragones L, Lien L, Poot F, Jemec GBE, Misery L, 
Szabo C, Linder D, Sampogna F, et al. The psychological burden of skin diseases: a 
cross-sectional multicenter study among dermatological out-patients in 13 European 
countries. J Invest Dermatol. 2015;135(4):984-991. 
 
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Kiebert G, Sorensen SV, Revicki D, Fagan SC, Doyle JJ, Cohen J, Fivenson D. Atopic 
dermatitis is associated with a decrement in health-related quality of life. Int J 
Dermatol. 2002;41(3):151-158. 
 
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Deckers IA, McLean S, Linssen S, Mommers M, van Schayck CP, Sheikh A. 
Investigating international time trends in the incidence and prevalence of atopic 
eczema 1990-2010: a systematic review of epidemiological studies. PLoS One. 
2012;7(7):e39803. 
 
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Abuabara K, Yu AM, Okhovat JP, Allen IE, Langan SM. The prevalence of atopic 
dermatitis beyond childhood: A systematic review and meta-analysis of longitudinal 
studies. Allergy. 2018;73(3):696-704. 
 
7. 
Silverberg JI, Hanifin JM. Adult eczema prevalence and associations with asthma and 
other health and demographic factors: a US population-based study. J Allergy Clin 
Immunol. 2013;132(5):1132-1138. 
 
8. 
Salimi M, Barlow JL, Saunders SP, Xue L, Gutowska-Owsiak D, Wang X, Huang LC, 
Johnson D, Scanlon ST, McKenzie AN, et al. A role for IL-25 and IL-33-driven type-2 
innate lymphoid cells in atopic dermatitis. J Exp Med. 2013;210(13):2939-2950. 
 
9. 
Soumelis V, Reche PA, Kanzler H, Yuan W, Edward G, Homey B, Gilliet M, Ho S, 
Antonenko S, Lauerma A, et al. Human epithelial cells trigger dendritic cell mediated 
allergic inflammation by producing TSLP. Nat Immunol. 2002;3(7):673-680. 
 
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Patients With Moderate-to-Severe Atopic Dermatitis: A Randomized Clinical Trial. 
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King BA, Thyssen JP, Silverberg JI, Bieber T, et al. Baricitinib in patients with 
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Thijs JL, Strickland I, Bruijnzeel-Koomen C, Nierkens S, Giovannone B, Csomor E, 
Sellman BR, Mustelin T, Sleeman MA, de Bruin-Weller MS, et al. Moving toward 
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Bieber T, D'Erme AM, Akdis CA, Traidl-Hoffmann C, Lauener R, Schäppi G, Schmid-
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Kotenko SV, Izotova LS, Mirochnitchenko OV, Esterova E, Dickensheets H, Donnelly 
RP, Pestka S. Identification, cloning, and characterization of a novel soluble receptor 
that binds IL-22 and neutralizes its activity. J Immunol. 2001;166(12):7096-7103. 
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35. 
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LP0145 (edition 4.0). 2021. 
 
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Guttman-Yassky E, Khattri S, Brunner P, Neumann A, Malik K, Fuentes-Duculan J, 
Garcet S, Suarez-Farinas M, Lebwohl M, Krueger J. 313 A pathogenic role for 
Th22/IL-22 in atopic dermatitis is established by a placebo-controlled trial with an anti 
IL-22/ILV-094 mAb. Journal of Investigative Dermatology. 2017;137(5):S53. 
 
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Pfizer INC. Protocol (3199K1-2001 (B1981001)); A Randomized, Parallel, Double-
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WMA. World Medical Association. Declaration of Helsinki – ethical principles for 
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ICH. International Council for Harmonisation of Technical Requirements for 
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EMA. European Medicines Agency. Guidance on the Management of Clinical Trials 
during the COVID-19 (Coronavirus) Pandemic. Version 3. 2020. 
 
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FDA. FDA Guidance on Conduct of Clinical Trials of Medical Products during 
COVID-19 Public Health Emergency. 2020. 
 
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Prevention. 2020. 
 
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Schulz KF, Altman DG, Moher D. CONSORT 2010 Statement: updated guidelines for 
reporting parallel group randomised trials. BMC Med. 2010;8:18. 
 
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Johansson SG, Bieber T, Dahl R, Friedmann PS, Lanier BQ, Lockey RF, Motala C, 
Ortega Martell JA, Platts-Mills TA, Ring J, 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):832-836. 
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45. 
Sampson HA, Muñoz-Furlong A, Campbell RL, Adkinson NF, Bock SA, Branum A, 
Brown SG, Camargo CA, Cydulka R, Galli SJ, et al. Second symposium on the 
definition and management of anaphylaxis: summary report--Second National Institute 
of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. 
J Allergy Clin Immunol. 2006;117(2):391-397. 
 
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European Union. Guidelines for good manufacturing practices for medicinal products 
for human and veterinary use. 2010;Volume 4. 
 
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Eli Lilly and Company. Validated Investigator Global Assessment scale for Atopic 
Dermatitis. vIGA-AD™. 2017. 
 
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Charman CR, Venn AJ, Williams HC. The patient-oriented eczema measure: 
development and initial validation of a new tool for measuring atopic eczema severity 
from the patients' perspective. Arch Dermatol. 2004;140(12):1513-1519. 
 
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Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI)--a simple practical 
measure for routine clinical use. Clin Exp Dermatol. 1994;19(3):210-216. 
 
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Hanifin JM, Rajka G. Diagnostic features of atopic dermatitis. Acta Derm Venereol. 
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Barbier N, Paul C, Luger T, Allen R, De Prost Y, Papp K, Eichenfield LF, Cherill R, 
Hanifin J. Validation of the Eczema Area and Severity Index for atopic dermatitis in a 
cohort of 1550 patients from the pimecrolimus cream 1% randomized controlled 
clinical trials programme. Br J Dermatol. 2004;150(1):96-102. 
 
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54. 
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Pharmaceuticals for Human Use. Integrated addendum to ICH E6(R1): Guideline for 
good clinical practice E6(R2). 2016. 
 
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FDA. The Food and Drug Administration. Guidance for Industry and Investigators. 
Safety Reporting Requirements for INDs and BA/BE Studies. 2012. 
 
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FDA. The Food and Drug Administration. Guidance for Clinical Investigators, 
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Szepietowski JC, Sofen H, et al. Efficacy and safety of dupilumab in adults with 
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Ge M, Durham LK, Meyer RD, Xie W, Thomas N. Covariate-Adjusted Difference in 
Proportions from Clinical Trials Using Logistic Regression and Weighted Risk 
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ICH. International Council for Harmonisation of Technical Requirements for 
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Principles for Responsible Clinical Trial Data Sharing. 2013. 
 
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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. (60) 
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. 
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• 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. 
*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 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 AE or SAE, even if not planned before consent to trial participation. 
Hospitalisation for routine scheduled treatment or monitoring not associated with any 
aggravation of the condition does not constitute an AE and should therefore not be reported as 
AE or SAE. 
Hospitalisation for administrative purpose does not constitute an AE and should therefore not 
be reported as AE or SAE. 
Complications that occur during hospitalisation are AEs. If a complication prolongs 
hospitalisation, the event is an SAE. 
When in doubt as to whether hospitalisation occurred, the AE should be considered serious. 
Definition of adverse events of special interest 
An AESI (serious or non-serious) is one of scientific and medical concerns specific to the 
sponsor's product or programme, for which ongoing monitoring may be appropriate. Such an 
event might warrant further investigation in order to characterise and understand it. 
Depending on the nature of the event rapid communication by the investigator to the sponsor 
and/or from the sponsor to other parties (e.g., regulators) might also be warranted.  
AESIs are described in Sections 13.6.1. 
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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. 
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. 
If the severity of an AE worsens, a new AE should be recorded. 
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. 
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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. 
Recovered/ 
resolved 
The event has stopped. The stop date of the event must be recorded. 
Recovering/ 
resolving 
The subject is clearly recovering from an event. The event is not yet 
completely resolved.  
Not 
recovered/ 
not resolved 
Event is still ongoing.  
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 a SAE, the sequelae 
should be specified. 
Fatal 
The subject has died as a consequence of the event. Date of death is recorded 
as stop date for the AE. 
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. 
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In summary, the definitions used by LEO Pharma are more conservative than those used by 
CDISC. 
Serious adverse events  
For SAEs which have stabilised and from which the subject cannot be expected to recover 
during the trial or the safety follow-up periods, for example chronic illnesses, the final 
outcome should be reported as ‘recovering’ or ‘not recovered’ as per the investigators 
discretion; in addition, a statement that the SAE has stabilised or is chronic should be added 
to the narrative description of the SAE on the SAE form.  
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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 (38) and Council for International 
Organisations of Medical Sciences (CIOMS) International Ethical Guidelines (61). 
• Current version of applicable International Council for Harmonisation Good Clinical 
Practice (ICH GCP) Guidelines (54). 
• 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. 
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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. 
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 screening, subjects will be provided with a card stating that they are participating in a 
clinical trial and which contains contact address(es) and telephone number(s) of relevant trial 
site staff including the number for the investigator in case of emergency situations. The 
subject card also includes a local telephone number for the emergency unblinding CRO to be 
used if the investigator or delegated site staff cannot be reached or if unblinding in the IRT 
cannot be performed. 
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.  
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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. 
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 (for example race, ethnicity, age, 
gender, health condition, medical history, test results, etc.) which shall be collected as part of 
the clinical trial and processed during and after trial completion. 
Personal data collected as part of the clinical trial will be transferred to/from the 
institution/investigator, LEO Pharma, and third parties acting on behalf of LEO Pharma. 
Processing of personal data on behalf of LEO Pharma requires a written agreement between 
LEO Pharma and the relevant party which covers collection, processing, and transfer of 
personal data in the clinical trial as well as reporting obligations in the event of any data 
breach. In certain cases, an agreement on transfer of personal data may also be required. 
Investigators and LEO Pharma must ensure that collection, processing, and transfer of 
personal data are in compliance with applicable legislation on data protection and privacy, 
including but not limited to the EU General Data Privacy Regulation. 
Subjects will 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. 
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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. Clinical 
assessments/safety evaluations must be signed and dated by medically qualified investigators. 
If the worksheet does not become part of the subject’s medical record, the following should as 
a minimum be added to the subject’s medical record: 
• Subject ID. 
• A statement from the investigator to verify that each of the eligibility criteria were met 
and documented. 
• Randomisation code number. 
• The fact that the subject is participating in a clinical trial in AD including treatment with 
LEO 138559 or placebo for 16 weeks. 
• Other relevant medical information. 
Trial monitoring 
During the course of the trial, CRA(s) (blinded and unblinded) will visit the trial site. These 
visits have the following objectives: (i) to continually verify source data to confirm that data 
entered into the eCRF by authorised site personnel are accurate, complete, and verifiable from 
source documents; (ii) to confirm that the safety and rights of subjects are being protected; 
and (iii) to confirm that the trial is being conducted in accordance with the currently approved 
protocol and any other trial agreements, ICH GCP, and all applicable regulatory requirements. 
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 addition to on-site monitoring, pre-specified trial data will undergo central monitoring as 
specified in the trial’s data review plan. 
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In order to perform their role effectively, CRAs (blinded or unblinded) and persons involved 
in quality assurance and inspections will need direct access to source data, for example, 
medical records, laboratory reports, appointment books, etc. based on the assignment. If the 
electronic medical record does not have a visible audit trail, the investigator must provide the 
applicable CRA (blinded or unblinded) 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 major 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 
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 eCRFs. 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. 
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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 applicable CRA 
(blinded or unblinded), 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. 
An ePRO solution will be used to capture patient-reported data (data from questionnaires 
completed at the trial site and eDiary data). By the use of an ePRO, data will be available 
immediately after data entry and available for the blinded CRAs and site personnel, including 
the investigator, with reader access only. The ePRO system is a separate application from the 
eCRF and data captured from the eCRF and the ePRO will be stored on different servers 
during data capture. Data from both systems will be included in the final trial database. 
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.  
Software used 
CDISC controlled terminology version 06‑Nov‑2020 or newer was used throughout this 
protocol. Standard data tabulation model (SDTM) version 1.4 will be used for data 
tabulations. 
Archiving of trial documentation 
The investigator at each trial site must make arrangements to store the essential trial 
documents, including the investigator trial file (54). 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 (for 
example 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. 
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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 and ePRO data for all screened subjects at the trial site. This is done after completion 
of the trial and before access to the eCRF/ePRO is revoked. Audit trail information will be 
included. eCRFs and ePRO data 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 on leopharmatrials.com in accordance with our 
Position on Public Access to Clinical Trial Information within approximately 12 months of 
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.   
Publications 
A publication can be a journal manuscript, an abstract, a poster/presentation for a congress, or 
any openly accessible material. 
A primary publication including the primary results of the trial (i.e. the results of the primary 
endpoint[s]) may be submitted for peer-reviewed publication within 12 months of database 
lock. In such case, LEO Pharma would be responsible for this publication. All authors (trial 
responsible employees and/or applicable investigators and advisors) must fulfil the criteria for 
authorship from the International Committee of Medical Journal Editors (ICMJE). 
The investigators may reach out to LEO Pharma to publish results that are not included in the 
primary publication. The investigator and LEO Pharma should agree on terms for data sharing 
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and collaboration on such publications, as well as timing for release of the publication(s). In 
all cases, LEO Pharma retains the right to review and comment on the draft publication in due 
time before submission, but the investigator is not required to revise the draft accordingly, 
unless it discloses company confidential information or protected personal information, or 
may compromise intellectual property rights of LEO Pharma. 
LEO Pharma may give researchers outside LEO Pharma access to anonymised data from this 
trial for further research according to the principles outlined by the European Federation of 
Pharmaceutical Industries and Associations (EFPIA) (62). In that case, the researchers are 
obliged to attempt publication of the results obtained from their analyses. 
LEO Pharma follows Good Publication Practice (GPP3) standards and the recommendations 
from ICMJE. 
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. 
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 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 IRB/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 
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regulatory requirements, the investigator or LEO Pharma must promptly inform IRB/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 early 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. 
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. 
The national coordinating investigators are responsible for national issues relating to the 
clinical trial as agreed to in a national coordinating 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: AAD Consensus Criteria for the diagnosis of AD 
From Eichenfield, L. F. (2004). "Consensus guidelines in diagnosis and treatment of atopic 
dermatitis." Allergy 59(s78): 86-92. 
AD is best viewed as a syndrome. Clinical findings that define this syndrome and clinical 
criteria of AD include the following: 
A. Essential features (must be present): 
1. Pruritus 
2. Eczema (acute, subacute, chronic) 
a) Typical morphology and age-specific patterns* 
b) Chronic or relapsing history 
*Patterns include: (i) facial, neck, and extensor involvement in infants and children; (ii) 
current or prior flexural lesions in any age group; (iii) sparing of groin and axillary regions. 
B. Important features (seen in most cases, adding support to the diagnosis) 
1. Early age at onset 
2. Atopy 
a. Personal and/or family history 
b. IgE reactivity 
3. Xerosis 
C. Associated features (these clinical associations help to suggest the diagnosis of AD but 
are too nonspecific to be used for defining or detecting AD for research or 
epidemiologic studies): 
1. Atypical vascular responses (e.g., facial pallor, white dermographism, delayed 
blanch response) 
2. Keratosis pilaris/hyperlinear palms/ichthyosis 
3. Ocular/periorbital changes 
4. Other regional findings (e.g., perioral changes/periauricular lesions) 
5. Perifollicular accentuation/lichenification/prurigo lesions 
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Exclusionary conditions: It should be noted that a diagnosis of AD depends on excluding 
conditions such as scabies, seborrheic dermatitis, allergic contact dermatitis, ichthyoses, 
cutaneous lymphoma, psoriasis, and immune deficiency diseases. 
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Appendix 5: Guidance for anaphylaxis diagnosis 
From Sampson HA, Muñoz-Furlong A, Campbell RL, Adkinson FN Jr, Bock SA, Branum A, 
et al. Second symposium on the definition and management of anaphylaxis: Summary report -
- Second National Institute of Allergy and Infectious Diseases/Food Allergy and Anaphylaxis 
Network symposium. J Allergy Clin Immunol. 2006;117(2):391-397. 
The National Institute of Allergy and Infectious Diseases (NIAID) and Food Allergy and 
Anaphylaxis Network Guidance for Anaphylaxis Diagnosis (FAAN) define anaphylaxis as a 
serious allergic reaction that is rapid in onset and may cause death. They recognise 
3 categories of anaphylaxis, with criteria designated to capture from 80% of cases 
(category 1) to >95% of all cases of anaphylaxis (for all 3 categories).  
Clinical criteria for diagnosing anaphylaxis 
Anaphylaxis is highly likely when any one of the following 3 criteria are fulfilled: 
1) Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue, or both (e.g., generalised hives, pruritus or flushing, swollen lips-
tongue-uvula) 
AND AT LEAST ONE OF THE FOLLOWING: 
• Respiratory compromise (e.g., dyspnoea, wheeze-bronchospasm, stridor, 
reduced peak expiratory flow [PEF], hypoxemia). 
• Reduced blood pressure (BP) or associated symptoms of end-organ 
dysfunction (e.g., hypotonia [collapse], syncope, incontinence). 
2) Two or more of the following that occur rapidly after exposure to a likely allergen for 
that patient (minutes to several hours): 
• Involvement of the skin-mucosal tissue (e.g., generalised hives, itch-flush, 
swollen lips-tongue-uvula). 
• Respiratory compromise (e.g., dyspnoea, wheeze-bronchospasm, stridor, 
reduced PEF, hypoxemia). 
• Reduced BP or associated symptoms (e.g., hypotonia [collapse], syncope, 
incontinence). 
• Persistent gastrointestinal symptoms (e.g., crampy abdominal pain, vomiting). 
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3) Reduced BP after exposure to known allergen for that patient (minutes to several 
hours): 
• Infants and children: low systolic BP (age specific) or greater than 30% 
decrease in systolic BP. 
• Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from 
that person’s baseline. 
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Appendix 6: Country-specific requirements  
Not applicable  
 
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Appendix 7: 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 (38) 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 [as defined by the AAD Consensus Criteria (1) 
and Appendix 4] 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 baseline 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 unborn/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 unborn/newborn child. 
 
 
 
Exclusion criteria  
No. 
Short version  
Justification 
1 
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. 
2 
Previously randomised in this clinical trial. 
To ensure integrity and validity of the trial data due to the possibility of 
duplicate subject entries. 
3 
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). 
4 
Treatment with systemic immunosuppressive/immunomodulating 
medication, immunoglobulin/blood products, or phototherapy 
within 4 weeks or 5 half-lives prior to randomisation, whichever is 
longer. 
To not interfere with efficacy assessments. 
5 
Treatment with biologics within 5 half-lives (if known) or 
16 weeks prior to randomisation, whichever is longer. 
To not interfere with efficacy assessments. 
6 
Treatment with TCS, TCI, topical PDE-4 inhibitor, or other 
topical prescription treatments within 1 week prior to 
randomisation. 
To not interfere with efficacy assessments. 
7 
Treatment with a live (attenuated) vaccine within 12 weeks prior 
to randomisation. 
As LEO 138559 could potentially interact with this. 
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8 
History of malignancy within 5 years prior to randomisation, 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. 
9 
Clinically significant active chronic or acute infection requiring 
systemic treatment within 4 weeks prior to randomisation that 
may compromise the safety of the subject. 
To ensure safety of subjects given the potential increased risk of 
infections of the skin with LEO 138559. 
10 
Skin infection within 1 week prior to randomisation. 
To ensure safety of subjects given the potential increased risk of 
infections of the skin with LEO 138559. 
11 
Current or recent (within 2 years prior to randomisation) 
gastrointestinal ulcers. 
To ensure safety of subjects given the potential increased risk of 
impaired wound healing of the intestine with LEO 138559. 
12 
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. 
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 138559. 
13 
Known or suspected hypersensitivity to any component(s) of the 
IMP. 
To ensure safety of subjects. 
14 
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 given the potential increased risk of 
infections with LEO 138559. 
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15 
History of human immunodeficiency virus (HIV) infection or 
positive HIV serology at screening. 
To ensure safety of subjects given the potential increased risk of 
infections with LEO 138559. 
16 
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. 
 
17 
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. 
18 
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. 
19 
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. 
20 
Moderate to severe asthma [as defined by GINA guidelines (42)]. 
To ensure safety of subjects by decreasing the risk of enrolling subjects 
who may be at increased risk of severe COVID-19 infection. 
21 
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. 
22 
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. 
23 
Subject is pregnant or lactating. 
For the safety of the unborn/newborn child. 
24 
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. 
25 
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. 
26 
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. 
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27 
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. 
28 
Treatment with any non-marketed drug substance within the last 4 
weeks or 5 half-lives prior to randomisation, whichever is longer. 
To ensure safety of subjects and ensure lack of confounding of 
measurements (e.g., efficacy, PK, and PD). 
29 
Subjects who are legally institutionalised. 
To ensure compliance with Declaration of Helsinki (38). 
30 
Positive SARS-CoV-2 PCR test at screening.  
To ensure safety of subjects and trial site staff. 
 
 
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Appendix 8: Contact list 
Contact details for the CPM, National Lead CRAs, CRAs (blinded and unblinded), and 
sponsor’s medical expert are provided to the trial sites as a separate contact list. 
Sponsor 
LEO Pharma A/S (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 
  
  
 
 
 Germany 
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Appendix 9: COVID-19 pandemic contingency plan 
Without compromising subject and site staff safety as well as trial integrity, it is expected that 
all efforts will be made to ensure subject attendance to the planned trial visits and thereby 
ensure the conduct of important safety and efficacy assessments. 
As protective/preventive measures to be taken in the context of the COVID-19 pandemic can 
differ across countries and regions, no general instructions from the sponsor can be provided 
and the investigators will be trusted to take appropriate action. This includes but is not limited 
to complying with recommendations and regulations issued by their local health authorities, 
the increase of protective safety and hygiene measures (e.g., wearing mask, disinfecting 
hands, social distancing) for both subject and site staff, and the frequent monitoring of the 
subject’s health. 
To minimise subject exposure to COVID-19 in public transportation and public areas, 
LEO Pharma will reimburse travel cost of subjects using taxis or their own vehicle (including 
parking fees) to commute to and from the trial site. 
If on-site visits are not possible due to preventive measures issued by local health 
authority(ies) or site obligations, the affected site(s) will postpone screening and 
randomisation of subjects until on-site visits can be conducted again. 
Safety monitoring is an obligation of LEO Pharma and in case the subject, due to local 
restrictions, is prevented from coming to the trial site, the investigator can convert on-site 
visits into phone visits for the primary purpose of safety monitoring. At a phone visit, the 
following data may be collected:  
• AEs. 
• Concomitant medication and concurrent procedures. 
• Urine pregnancy test. Women of childbearing potential will be provided with urine 
pregnancy tests, if needed. The subject will take the test at home and inform the 
investigator about the result over the phone. 
• POEM and DLQI collected on the web-based solution by remote transfer to the vendor. 
The phone visits must not be used for conducting the investigator’s assessments of efficacy. 
If on-site visits are not possible, it will be at the discretion of the investigator if clinical 
laboratory samples or a serum pregnancy test are necessary to ensure subject safety. 
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A subject testing positive for COVID-19 (test taken at their own initiative) between screening 
(at the earliest Week -4) and washout (Week -1) may be rescreened once if the screening 
period does not exceed 28 days in total (see Section 8.4). A subject testing positive during the 
washout period (Week -1 to Week 0) must be withdrawn from the trial. A subject testing 
positive for COVID-19 after randomisation may be temporarily discontinued from IMP. IMP 
treatment may be reinstituted at the investigator’s discretion. 
In general, in the context of the COVID-19 pandemic, in case site visits will not be possible, 
more frequent telephone contacts between site staff and subjects should take place to closely 
monitor subject safety and the status of subject participation in the trial and to provide 
guidance to the subject as to what they are required to do in a remote setting to maximise data 
integrity and quality. 
Reporting in eCRF 
It will be recorded in the eCRF if a visit or an assessment was conducted remotely or if it was 
not conducted. If it was not conducted, it will be recorded if this was due to the COVID-19 
pandemic. Telephone contacts and occurrence of unscheduled visits if allowed to take place 
during the pandemic will also be recorded. It will be recorded if the telephone contact or 
unscheduled visits were due to the pandemic. 
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Appendix 10: Protocol amendment history 
The protocol amendment summary of changes table for the current amendment is located 
directly before the table of contents. 
Amendment 2 (17-Nov-2021) 
This amendment is considered to be non-substantial based on the criteria set forth in Article 
10(a) of Directive 2001/20/EC of the European Parliament and the Council of the European 
Union or subsequent regulation because it neither significantly impacts the safety or 
physical/mental integrity of subjects nor the scientific value of the trial. 
Overall rationale for the amendment 
The main purpose for this protocol amendment is to remove the capping specified for each 
AD disease severity group (moderate defined as EASI <21 and severe defined as EASI ≥21) 
in Sections 7.1 and 12.1.  
In the protocol a capping was introduced to ensure enrolment of enough subjects with a high 
unmet need (defined as severe subjects with a baseline EASI score ≥21). This was originally 
described in the protocol in Section 12.1: ’The minimum limit for inclusion of 50% of 
subjects with ‘stratum B’ at baseline has been chosen to ensure inclusion of a suitable 
proportion of subjects representative of the target population that experiences a high unmet 
need for AD treatments.’ This capping was further addressed in the protocol in Section 7.1 
stating that each stratum (‘stratum A’ defined as having EASI <21 and ‘stratum B’ defined as 
having EASI ≥21) will comprise exactly 26 subjects randomised, equivalent to 50% of the 
total sample size.  
During trial conduct it has become clear that the screening process of trying to reach the exact 
distribution as original stated in Section 7.1 is more complex than anticipated. However, it has 
also become clear that severe subjects with a baseline EASI score ≥21 represent more than 
50% of subjects fulfilling the eligibility criteria, and therefore the initial aim to include 
sufficient subjects with an unmet need is no longer of concern. 
Removing the capped enrolment does not affect the total number of subjects, statistical 
analysis methods or interpretation of the trial results, and has no impact on patient safety, thus 
no impact on the scientific value or integrity of the trial.  
All changes to the protocol are presented in the summary of changes table below except for a 
few minor editorial changes (e.g., spelling errors). 
 
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Summary of changes 
Section no. and name 
Description of change 
Brief rationale 
Section 1 Protocol 
synopsis, Section 2 
Trial identification 
under EudraCT number 
NCT number added. 
Pre-IND 
 
Editorial. 
Section 1 Protocol 
synopsis, Section 8.3 
Exclusion criteria, 
no. 10 and Appendix 7 
Short version and 
justification for 
eligibility criteria 
Skin infection within 1 week prior to 
the baseline visit randomisation. 
To be more specific and consistent. 
 
 
Section 4 Schedule of 
trial procedures, 
footnote o) 
o) Relevant concomitant medications 
/ concurrent procedures should be 
included from 3 months prior to 
baseline (Day 1) screening until end 
of trial (Week 32). 
To align with Section 9.6. 
Section 7.1 Overall 
trial design  
Randomisation will be stratified by 
baseline disease severity. One 
stratum, ‘stratum A’, will be defined 
as having EASI <21 and the other 
stratum, ‘stratum B’, will be defined 
as having EASI ≥21. Each stratum 
will comprise exactly 26 subjects 
randomised, equivalent to 50% of 
total sample size. IRT will be used to 
control randomisation and 
stratification factors. 
To remove the capping for both strata. 
However, stratified randomisation to 
assure that treatment groups are balanced 
will be maintained. 
Section 9.3 Treatment 
assignment 
Subjects eligible on 
inclusion/exclusion criteria at 
baseline may be prevented from 
being randomised into the trial due to 
the applied capping limitation in 
baseline severity (as described in 
Section 8.2). 
This has been deleted as the capping for 
both strata is removed (see above). 
Section 9.5 Rescue 
treatment 
If a subject receives rescue treatment 
with any TCS/TCI before Week 4, 
super potent TCS (e.g., clobetasol 
propionate 0.05% cream) between 
Week -1 and Week 16, or systemic 
rescue treatment (besides systemic 
antihistamines and/or anti-infectives) 
at any point during the trial between 
Week -4 (or 5 half-lives, whichever is 
longer) and Week 32, treatment with 
IMP will be discontinued, and the 
subject will be withdrawn from the 
trial. 
For readability and to align Section 9.5 
with Section 10.1. 
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Section no. and name 
Description of change 
Brief rationale 
However, treatment with IMP will 
be discontinued if a subject 
receives the following treatment: 
Rescue treatment with any 
TCS/TCI before Week 4. 
Super potent TCS (e.g., clobetasol 
propionate 0.05% cream) 
between Week -1 and Week 16. 
Systemic rescue treatment (besides 
systemic antihistamines and/or 
anti-infectives) at any point 
during the trial between Week 
-4 (or from 5 half-lives of Week 
0, whichever is longer) and 
Week 16. 
Section 10.2.1 Reasons 
for permanent 
discontinuation of IMP 
In the Reporting in eCRF subsection, 
‘Death’ has been deleted.  
Death is captured as an SAE and to align 
with the eCRF. 
Section 11.1 Overview 
AEs must be assessed by medically 
qualified personnel a physician 
(Section 13.2). 
Editorial.  
Section 11.4.4 ECG 
At each visit, the individual 
measurements as well as the average 
of 3 consecutive 12-lead resting 
digital ECG measurements will be 
recorded after the subject has been in 
supine position for at least 5 minutes. 
ECG must be measured before any 
blood samples scheduled at the same 
visit. 
In alignment with Section 11.1, the ECG 
measurements can be done at any time, 
and not in any pre-specified order. 
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Section no. and name 
Description of change 
Brief rationale 
Section 12.1 Scientific 
rationale for trial 
design 
The combination of randomisation 
and blinding (Section 9.3.1) 
minimises the likelihood of 
allocation bias. The risk of 
allocation bias is further reduced 
through the use of central 
randomisation. The use of 
randomisation also ensures that 
baseline factors will not be 
confounded with treatment. 
Randomisation within the strata 
defined by baseline disease severity 
(‘stratum A’ [EASI <21] or 
‘stratum B’ [EASI ≥21]) will limit 
any potential imbalance in the 
allocation of subjects across 
baseline disease severity. Stratified 
randomisation according to baseline 
disease severity (“stratum A” [EASI 
<21] or “stratum B” [EASI ≥21]) will 
minimise allocation bias and ensure 
balanced allocation of subjects with 
“stratum A” vs. “stratum B” at 
baseline between the treatment 
groups, thereby minimising baseline 
confounding. The minimum limit for 
inclusion of 50% subjects with 
“stratum B” at baseline has been 
chosen to ensure inclusion of a 
suitable proportion of subjects 
representative of the target 
population who experiences a high 
unmet need for AD treatments.   
The rational for randomisation and 
blinding has been updated to clarify and be 
more specific on how to avoid imbalance 
of allocation of subjects across baseline 
disease severity and treatment arms. 
 
 
 
 
 
 
 
 
 
 
 
 
The capping for both strata has been 
removed (Please refer to change in 
Section 7.1). However, stratified 
randomisation to assure that treatment 
groups are balanced will be maintained. 
Section 13.2 Collection 
of adverse event 
reports 
AEs must be assessed by medically 
qualified personnel a physician. In 
the US only, certain AE 
assessments can be delegated to 
investigators with other 
qualifications. However, the 
diagnosis, seriousness, and 
causality of the AEs must be 
assessed by a physician. 
Clarification. 
Appendix 1 Definitions 
of adverse events and 
serious adverse events 
Additionally, all malignancies, 
including skin malignancies, should 
be reported as SAEs. 
Editorial. 
Appendix 10 Protocol 
amendment history 
Protocol amendment 1, Summary of 
changes table moved to Appendix 10. 
Editorial 
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Section no. and name 
Description of change 
Brief rationale 
Appendix 10 Protocol 
amendment history 
Addition of a provision to allow 
rescreening of subjects testing 
positive for COVID 19 or with an 
indeterminate tuberculosis test at 
screening and conditions for 
rescreening. 
Correction to Amendment 1 Summary of 
changes table. 
Abbreviations: please refer to the list of abbreviations. 
Amendment 1 (07-May-2021) 
This amendment is considered to be 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 purpose of this protocol amendment is to allow for the clarification and addition of 
eligibility criteria and the inclusion of additional safety assessments. The most important 
changes to the protocol are summarised in the table below. Additional minor changes, not 
listed in the table, were included for clarity and consistency. 
Summary of changes 
Section no. and 
name 
Description of change 
Brief rationale 
Section 1 Protocol 
synopsis 
 
Section 8.2 
Inclusion criteria 
or Section 8.3 
Exclusion criteria 
 
Appendix 7 Short 
version and 
justification for 
eligibility criteria 
Changes to eligibility criteria: 
• Inclusion criterion no. 2: 18-64 years 
old (both included) at baseline 
screening. 
 
To ensure that subjects are at 
least 18 years at screening when they 
provide informed consent. 
• Exclusion criterion no. 8: History of 
malignancy within 5 years prior to 
randomisation, apart from adequately 
treated nonmetastatic basal cell 
carcinoma, squamous cell carcinoma of 
the skin, or cervical carcinoma in-situ, 
considered cured by the standard of 
care. 
To ensure that only subjects considered 
cured from nonmetastatic basal cell 
carcinoma, squamous cell carcinoma of 
the skin, or cervical carcinoma in-situ by 
the standard of care will be included in the 
trial. 
• Exclusion criterion no. 16: 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 that only subjects with a 
negative tuberculosis test at screening will 
be included in the trial. 
Addition of eligibility criterion: 
• Exclusion criterion no. 30: Positive 
SARS-CoV-2 PCR test at screening. 
 
To increase subject and trial site staff 
safety. 
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Section no. and 
name 
Description of change 
Brief rationale 
Section 4 
Schedule of trial 
procedures 
 
Section 11.2.4 
Other assessments 
 
Section 11.4.5.1 
Overview 
 
Section 11.4.5.2 
Investigator 
evaluation of 
laboratory 
samples 
Addition of a SARS-CoV-2 PCR test at 
screening. 
To increase subject and trial site staff 
safety. 
Section 8.4 
Screening and 
screening failures 
Addition of a provision to allow 
rescreening of subjects testing positive for 
COVID-19 at screening and conditions for 
rescreening. 
Rescreening may be allowed after 
evaluation by the sponsor’s medical expert 
and provided that the screening period 
does not exceed 28 days in total. 
To mitigate potential issues with subject 
recruitment. 
Appendix 9 
COVID-19 
pandemic 
contingency plan 
Addition of text to clarify actions in case 
subjects test positive for COVID-19 (test 
taken at their own initiative) during the 
screening period. 
Subjects testing positive between Week -4 
and Week -1 may be rescreened under the 
conditions described in Section 8.4. 
Subject testing positive between Week -1 
and Week 0 will be withdrawn from the 
trial. 
To provide guidance to the investigator 
and mitigate potential issues with subject 
recruitment. 
Section 4 
Schedule of trial 
procedures 
Addition of a clinical 
chemistry/haematology blood sample at 
Week 2. 
To increase subject safety. 
Addition of a separate line for IgE 
analysis. 
To clarify that hepatitis B, C, and HIV 
testing will be conducted at screening only 
and that IgE analysis will be conducted 
from baseline at the visits indicated in the 
schedule of trial procedures. 
Section 11.1 
Overview 
Panel 6: Sequence 
of assessments 
 
Grouping of safety and laboratory 
assessments, PK blood samples, and 
pharmacodynamics in 1 unique box in the 
panel and addition of a footnote to explain 
this.  
Because the order in which safety and 
laboratory assessments, PK blood 
sampling and pharmacodynamics are 
conducted does not matter as long as all of 
the above assessments are conducted after 
the investigator assessments and before 
administration of IMP.  
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Section no. and 
name 
Description of change 
Brief rationale 
Section 11.4.5.1 
Overview 
Addition of analytes tested: lactate 
dehydrogenase and C-reactive protein. 
To increase understanding of systemic 
inflammation. 
Section 12.1 
Scientific 
rationale for trial 
design 
Addition of a rationale for the additional 
dose of IMP given at Week 1. 
Weekly dosing from Week 0 to Week 2 
will allow 75% of the expected steady 
state exposure to be safely reached already 
after 3 weeks of treatment. 
To clarify the reason for supplementing 
the Q2W dosing schedule with a dose of 
IMP at Week 1. 
Appendix 3D 
Record keeping, 
quality control, 
and data handling 
Change in the trial monitoring subsection 
and update of the monitoring method. 
The monitoring will be performed in a 
systematic, prioritised, risk-based 
approach, and as a combination of on-site, 
remote, and centralised monitoring. 
To clarify how monitoring will be 
conducted. 
Abbreviations: please refer to the list of abbreviations. 
 
 
 
 
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