Conditions: Atopic Dermatitis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 216
Healthy volunteers: no

Brief summary:
This is an up to 22-week clinical study in adult participants with moderate to severe atopic dermatitis (AD).

The purpose of the study is to test a new tablet (LEO 152020) to see if it improves AD and what the side effects are when compared with a placebo tablet with no medical ingredient.

During the study, there will be a 16-week treatment period during which the participants will be asked to take the tablets. The participants will regularly visit the clinic for tests and the study doctor will evaluate their AD. The participants will also be asked to answer questions about their AD symptoms, itch, sleep, and quality of life.

Detailed description:

Arms:
arm 1: Participants will be asked to take tablets from Week 0 to Week 16 (end of treatment). arm 2: Participants will be asked to take tablets from Week 0 to Week 16 (end of treatment). arm 3: Participants will be asked to take tablets from Week 0 to Week 16 (end of treatment). arm 4: Participants will be asked to take tablets from Week 0 to Week 16 (end of treatment).

Interventions: intervention 1: LEO 152020 tablet intervention 2: LEO 152020 placebo tablet
Intervention descriptions: intervention 1: LEO 152020 is a small drug molecule which can bind to the histamine 4 receptor (H4R) and prevent histamine from binding to the receptor. LEO 152020 is a tablet for oral administration. intervention 2: LEO 152020 placebo tablet contains the same excipients in the same concentration as LEO 152020 tablet, except that it does not contain the medical ingredient LEO 152020. LEO 152020 placebo is a tablet for oral administration.

Protocol document:
Prot_SAP_000.pdf: 
CONFIDENTIAL 
THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION AND MUST NOT BE COPIED OR MADE AVAILABLE TO ANY THIRD PARTY WITHOUT 
THE PRIOR WRITTEN CONSENT OF THE LEO PHARMA GROUP 
Clinical trial protocol 
LP0190-1488 
A phase 2 trial to evaluate the efficacy and safety of orally-administered LEO 152020 
tablets compared with placebo tablets for up to 16 weeks of treatment in adults with 
moderate to severe atopic dermatitis 
Phase 2 – Efficacy and safety 
A randomized, triple-blind, placebo-controlled, parallel-group, international trial 
This clinical trial will be conducted in compliance with the clinical trial protocol, ICH GCP, 
and the applicable regulatory requirement(s). 
LEO Pharma A/S 
Trial ID: 
LP0190-1488 
EudraCT no.: 
2020-004561-39 
NCT no.: 
NCT05117060 
Date: 
29-Mar-2022
Version: 
5.0 Global 
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Clinical trial protocol statements 
Approval statement LEO Pharma A/S 
Electronic signatures made within LEO Pharma Clinical Vault are legally binding equivalent 
of traditional handwritten signatures. The following persons have approved this clinical trial 
protocol by using electronic signatures as presented on the last page of this document: 
, MD 
 
, Medical Sciences 
 
 
 
, PhD 
 
Biostatistics lead, Medical Sciences 
 
 
 
 
 
, MD 
 
Medical lead, Medical Sciences 
 
 
 
 
 
, PhD 
 
Clinical operations lead, Global Clinical Operations 
 
 
 
 
 
, MD 
 
Signatory investigator 
 
 
 
Acknowledgement statement investigator(s) 
Each participating investigator must agree to the approved clinical trial protocol by signing a 
clinical trial protocol acknowledgement form or similar document. 
 
 
 
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Clinical trial protocol amendment summary 
Document history 
Document 
Date 
Amendment/addendum 
type 
Protocol/addendum 
version 
Amendment 5 (non-substantial) 
29-Mar-2022 
Global a 
5.0 Global 
Amendment 4 (substantial) 
30-Nov-2021 
Local (Germany b) 
4.0 DE 
Amendment 3 (substantial) 
06-Oct-2021 
Global c 
3.0 Global 
Addendum 1 to amendment 1 
05-Aug-2021 
Local (Germany d) 
1.0 DE 
Amendment 2 (non-substantial) 
07-Jul-2021 
Local (Czech Republic e) 
2.0 CZ 
Amendment 1 (non-substantial) 
30-Jun-2021 
Local (Germany f) 
2.0 DE 
Original protocol 
12-Feb-2021 
NA 
1.0 Global 
Abbreviations: BfArM = German Federal Institute for Drugs and Medical Devices; CZ = Czech Republic; 
DE = Germany; NA = not applicable. 
a This global protocol amendment includes the changes implemented in amendment 4. 
b Done at the request of the Ethics Committee of 
. This local protocol amendment took 
source in version 3.0 Global which was the latest version of the protocol submitted in Germany at the time the 
local protocol amendment was prepared. 
c This global protocol amendment included the changes implemented in amendments 1 and 2 and in addendum 1 
to amendment 1. 
d, f Done at the request of the German Federal Institute for Drugs and Medical Devices (BfArM). 
e Done at the request of the Czech State Institute for Drug Control. 
Amendment 5 (30-Mar-2022) 
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 of this protocol amendment is to: 
• Revise the response scale of the Difficulty 
 question in the eDiary 
following agreement with the FDA post final protocol. 
• Clarify the formulation of the sleep disturbance endpoints and their analysis based on 
their source data and the type of response scale. 
This global protocol amendment also includes the changes implemented in the local (German) 
protocol amendment 4 (version 4.0 DE) and will serve as global consolidated protocol for the 
trial going forward. For more detail about amendment 4, see Appendix 10. 
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The changes to the protocol are summarized in the table below. Deleted text is crossed out 
while added text is bold. Additional minor changes, not listed in the table, were implemented 
for accuracy and consistency. 
Summary of changes 
Section no. and name 
Description of change 
Brief rationale 
Section 6 Trial objectives, 
estimands, and endpoints 
(under the objective related to 
sleep disturbance and 
nocturnal 
 
Exploratory endpoints 
Based on eDiary data 
• Change in Difficulty 
 
 (weekly average) from 
baseline to at Week 
 
• Change in Frequency of 
 
 (weekly 
average) from baseline to at 
Week 
 
• 
 at Week 
 
• 
 at Week 
 
Based on actigraphy data 
• Change in 
 from 
baseline to Week 
 
• Change in 
 from baseline 
to Week 
 
• Change in number of nocturnal 
 events per hour from 
baseline to Week 
 
• Change in duration of nocturnal 
 per hour from 
baseline to Week 
 
The sleep disturbance endpoints will 
be based on data from both the 
eDiary and actigraphy devices. The 
response scales in the actigraphy 
devices are continuous while those 
in the eDiary are categorical. 
Therefore, a change from baseline 
does not have a clinically relevant 
interpretation for the eDiary data. 
The corresponding endpoints were 
therefore revised to a single 
measurement at Week 
 The 
comparison between the data at 
baseline and Week 
 will be 
described in the SAP. 
For clarity, the sleep disturbance 
endpoints were further classified 
according to the source data. 
The changes are considered 
non-substantial as related to 
exploratory endpoints with no 
impact on the primary nor secondary 
objectives of the trial. 
Section 11.5.3 Difficulty 
 (eDiary) 
Difficulty 
 is a single 
item questionnaire designed to 
assess the subject’s difficulty 
 
 because of itchy skin the past 
night. It will be assessed on an 
11-point NRS with anchors at 0 ‘not 
at all difficult’ and 10 ‘extremely 
difficult’ a 5-point categorical scale 
(‘not difficult’, ‘a little difficult’, 
‘moderately difficult’, ‘extremely 
difficult’, ‘I don’t know’). 
Following advice by the FDA post 
final protocol. The original 
numerical scale was replaced by a 
categorical scale. 
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Section no. and name 
Description of change 
Brief rationale 
Section 14.3.10 Analysis of 
exploratory endpoints 
These endpoints will be summarized 
descriptively by week and treatment 
group. Similarly, 
• Change in 
 from baseline 
to Week 
 
• Change in 
 from 
baseline to Week 
 
• Change in Difficulty 
 
weekly average) from 
baseline to Week 
 
• Change in Frequency of 
 
(weekly 
average) from baseline to 
Week 
 
will be collected using eDiary. 
These endpoints and change in 
nocturnal 
 which also is 
collected using eDiary will be 
summarized descriptively by week 
and treatment group. The weekly 
average of data collected using 
actigraphy and eDiary will be based 
on data collected over 7 days. Data 
collected after the initiation of 
rescue medication or permanent 
discontinuation of IMP will be 
excluded from the calculation of the 
weekly averages. 
 
The text deleted was revised to: 
 
The following sleep disturbance 
endpoints will be collected using 
the eDiary and summarized 
descriptively by week and 
treatment group: 
• Difficulty 
 at 
Week 
 
• Frequency of 
 
 at Week 
 
• 
 at Week 
 
• 
 at Week 
 
Consequential to change in 
Section 6 Trial objectives, 
estimands, and endpoints (see 
above). To clarify the analysis of the 
sleep disturbance endpoints based on 
eDiary data and to align the analysis 
of actigraphy data with analyses of 
other endpoints. The changes are 
considered non-substantial as related 
to exploratory endpoints with no 
impact on the primary nor secondary 
objectives of the trial. 
Appendix 4 Country-specific 
requirements (in subsection 
Japan) 
In Section 8.2 Inclusion criteria, the 
note to inclusion criterion 1 was 
revised to: 
In Japan, if the subject is less than 
20 years old prior to 01-Apr-2022, 
the legal representative must sign 
the informed consent. 
To reflect that the Japanese legal age 
of majority will change from 20 to 
18 years on 01-Apr-2022. 
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Section no. and name 
Description of change 
Brief rationale 
Appendix 10 Protocol 
amendment history 
Amendment 3 moved from Clinical 
trial protocol amendment summary 
down to Appendix 10. 
Amendment 4 added. 
Administrative change. 
Abbreviations: please refer to the list of abbreviations. 
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Table of contents 
Clinical trial protocol amendment summary ......................................................................... 3 
Table of contents ....................................................................................................................... 7 
List of panels ........................................................................................................................... 12 
List of abbreviations ............................................................................................................... 14 
1 Protocol synopsis ................................................................................................................ 19 
2 Trial identification ............................................................................................................. 23 
3 Schematic of trial design ................................................................................................... 23 
4 Schedule of trial procedures ............................................................................................. 24 
5 Introduction and trial rationale ....................................................................................... 32 
5.1 Atopic dermatitis ........................................................................................................ 32 
5.2 Experience with investigational medicinal product .................................................... 33 
5.2.1 
Nonclinical data............................................................................................. 33 
5.2.2 
Clinical data................................................................................................... 34 
5.3 Trial rationale .............................................................................................................. 34 
5.4 Ethical considerations ................................................................................................. 35 
5.5 Benefit/risk assessment ............................................................................................... 36 
6 Trial objectives, estimands, and endpoints ...................................................................... 39 
7 Trial design ......................................................................................................................... 42 
7.1 Overall trial design ..................................................................................................... 42 
7.2 Number of subjects needed ......................................................................................... 43 
7.3 End-of-trial definition ................................................................................................. 44 
8 Trial population ................................................................................................................. 45 
8.1 Subject eligibility ........................................................................................................ 45 
8.2 Inclusion criteria ......................................................................................................... 45 
8.3 Exclusion criteria ........................................................................................................ 47 
8.4 Screening and screening failures ................................................................................ 50 
9 Treatments .......................................................................................................................... 52 
9.1 Trial products description ........................................................................................... 52 
9.2 Administration of the investigational medicinal product ........................................... 52 
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9.3 Treatment assignment and blinding ............................................................................ 54 
9.3.1 
Treatment assignment .................................................................................... 54 
9.3.2 
Blinding ......................................................................................................... 55 
9.3.3 
Emergency unblinding of individual subject treatment ................................ 57 
9.4 Background treatment ................................................................................................. 57 
9.5 Rescue treatment ......................................................................................................... 58 
9.6 Concomitant medications and concurrent procedures ................................................ 59 
9.7 Prohibited medications and procedures ...................................................................... 60 
9.8 Treatment logistics and accountability ....................................................................... 61 
9.8.1 
Labelling and packaging of trial products ..................................................... 61 
9.8.2 
Shipping of trial products .............................................................................. 62 
9.8.3 
Storage of trial products ................................................................................ 62 
9.8.4 
Accountability of the investigational medicinal products ............................. 62 
9.8.5 
Treatment compliance ................................................................................... 63 
9.8.6 
Trial products destruction .............................................................................. 63 
9.9 Provision for subject care following trial completion ................................................ 64 
9.10 Reporting product complaints..................................................................................... 64 
10 Discontinuation and withdrawal ...................................................................................... 65 
10.1 General principles ....................................................................................................... 65 
10.2 Reasons for permanent discontinuation of investigational medicinal product ........... 65 
10.3 Early termination assessments .................................................................................... 66 
10.4 Continued assessment of subjects after permanent discontinuation of 
investigational medicinal product ............................................................................... 67 
10.5 Lost to follow-up ........................................................................................................ 67 
11 Trial assessments and procedures .................................................................................... 69 
11.1 Overview..................................................................................................................... 69 
11.2 Screening/baseline assessments .................................................................................. 69 
11.2.1 Demographics................................................................................................ 69 
11.2.2 Body measurements (height and weight) ...................................................... 70 
11.2.3 Medical history .............................................................................................. 70 
11.2.4 Body surface area involvement ..................................................................... 70 
11.2.5 Other screening assessments ......................................................................... 70 
11.3 Efficacy assessments .................................................................................................. 70 
11.3.1 Eczema Area and Severity Index (EASI) ...................................................... 70 
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11.3.2 Validated Investigator Global Assessment Scale for Atopic Dermatitis 
(vIGA-AD) .................................................................................................... 72 
11.3.3 Scoring Atopic Dermatitis (SCORAD) ......................................................... 73 
11.3.4 Atopic Dermatitis Symptom Diary (ADSD, eDiary) .................................... 74 
11.4 Safety assessments ...................................................................................................... 74 
11.4.1 Vital signs ...................................................................................................... 74 
11.4.2 Physical examination..................................................................................... 75 
11.4.3 Electrocardiography ...................................................................................... 75 
11.4.4 Laboratory testing ......................................................................................... 77 
11.5 Patient-reported outcomes .......................................................................................... 80 
11.5.1 Overview ....................................................................................................... 80 
11.5.2 Nocturnal 
 (eDiary) ...................................................................... 82 
11.5.3 
 (eDiary) ................................................................ 82 
11.5.4 
 (eDiary) .................................... 82 
11.5.5 
, eDiary) ............................................ 83 
11.5.6 
 (eDiary) .............................................................................. 83 
11.5.7 Patient-Oriented Eczema Measure (POEM, at trial site) .............................. 83 
11.5.8 Dermatology Life Quality Index (DLQI, at trial site) ................................... 83 
11.5.9 EuroQol 5-Dimension Health Questionnaire 5 Level (EQ-5D-5L, at trial 
site) ................................................................................................................ 84 
11.5.10 Work Productivity and Activity Impairment: Atopic Dermatitis 
(WPAI:AD, at trial site) ................................................................................ 84 
11.5.11 Hospital Anxiety and Depression Scale (HADS, at trial site) ....................... 85 
11.5.12 Patient’s Global Impression of Severity questionnaires (PGI-S, at trial 
site) ................................................................................................................ 85 
11.5.13 Patient’s Global Impression of Change questionnaires (PGI-C, at trial 
site) ................................................................................................................ 86 
11.6 Pharmacokinetic and pharmacodynamic assessments ................................................ 86 
11.6.1 Pharmacokinetic assessments ........................................................................ 86 
11.6.2 Pharmacodynamic assessments ..................................................................... 87 
11.7 Optional assessments .................................................................................................. 87 
11.7.1 Overview ....................................................................................................... 87 
11.7.2 Wristband scratch and sleep monitoring ....................................................... 87 
11.7.3 Skin biopsies ................................................................................................. 89 
11.7.4 Exit interview ................................................................................................ 90 
11.8 End of trial .................................................................................................................. 90 
11.9 Estimate of total blood volume collected ................................................................... 91 
11.10 Storage of biological samples ..................................................................................... 91 
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12 Scientific rationale for trial design and appropriateness of assessments ..................... 93 
12.1 Scientific rationale for trial design ............................................................................. 93 
12.2 Appropriateness of assessments ................................................................................. 96 
13 Adverse events ................................................................................................................... 98 
13.1 Definition and classification of adverse events .......................................................... 98 
13.2 Collection of adverse event reports ............................................................................ 98 
13.3 Reporting of adverse events........................................................................................ 99 
13.4 Reporting of serious adverse events ........................................................................... 99 
13.4.1 Investigator reporting responsibilities ........................................................... 99 
13.4.2 LEO Pharma reporting responsibilities ....................................................... 100 
13.5 Other events that require expedited reporting .......................................................... 101 
13.5.1 Pregnancy .................................................................................................... 101 
13.6 Reporting of other events.......................................................................................... 101 
13.6.1 Adverse events of special interest ............................................................... 101 
13.6.2 Medication error .......................................................................................... 104 
13.6.3 Misuse or abuse ........................................................................................... 104 
13.6.4 Aggravation of condition ............................................................................ 105 
13.7 Follow-up for final outcome of adverse events ........................................................ 105 
13.8 Handling of an urgent safety measure ...................................................................... 105 
14 Statistical methods ........................................................................................................... 107 
14.1 Sample size ............................................................................................................... 107 
14.2 Trial analysis sets ...................................................................................................... 109 
14.3 Statistical analysis ..................................................................................................... 110 
14.3.1 General principles ....................................................................................... 110 
14.3.2 Handling of missing values ......................................................................... 110 
14.3.3 Handling of intercurrent events related to the COVID-19 pandemic ......... 111 
14.3.4 Disposition of subjects ................................................................................ 113 
14.3.5 Demographics and other baseline characteristics........................................ 113 
14.3.6 Exposure and treatment compliance ........................................................... 114 
14.3.7 Testing strategy ........................................................................................... 114 
14.3.8 Analysis of primary endpoint ...................................................................... 115 
14.3.9 Analysis of secondary endpoints ................................................................. 125 
14.3.10 Analysis of exploratory endpoints .............................................................. 125 
14.3.11 Analysis of patient-reported outcomes ........................................................ 128 
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14.3.12 Analysis of pharmacodynamics .................................................................. 129 
14.3.13 Exploratory analyses ................................................................................... 129 
14.3.14 Analysis of safety ........................................................................................ 129 
14.3.15 Pharmacokinetic analysis ............................................................................ 131 
14.3.16 Interim analysis ........................................................................................... 131 
15 References ......................................................................................................................... 132 
Appendix 1: Definitions of adverse events and serious adverse events ........................... 140 
Appendix 2: Classification of adverse events ..................................................................... 142 
Appendix 3: Trial governance considerations ................................................................... 144 
Appendix 3A: Regulatory and ethical considerations ....................................................... 144 
Appendix 3B: Informed consent process........................................................................... 145 
Appendix 3C: Subject and data confidentiality ................................................................. 145 
Appendix 3D: Record keeping, quality control, and data handling .................................. 147 
Appendix 3E: Registration, reporting, and publication policy .......................................... 150 
Appendix 3F: Insurance .................................................................................................... 151 
Appendix 3G: Financial disclosure ................................................................................... 151 
Appendix 3H: Committee structure ................................................................................... 151 
Appendix 3I: Trial and trial site closure ............................................................................ 152 
Appendix 3J: Responsibilities ........................................................................................... 153 
Appendix 4: Country-specific requirements ...................................................................... 154 
Appendix 5: Short version of eligibility criteria and justification ................................... 159 
Appendix 6: Contact list ...................................................................................................... 162 
Appendix 7: Guidance to trial site before subject administers investigational medicinal 
product at site ................................................................................................................... 163 
Appendix 8: Prohibited medications (
, 
, and 
) .................... 165 
Appendix 9: COVID-19 contingency plan ......................................................................... 168 
Appendix 10: Protocol amendment history ....................................................................... 171 
 
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List of panels 
Panel 1: Trial design ................................................................................................................. 23 
Panel 2: Schedule of trial procedures ....................................................................................... 24 
Panel 3: Schedule of ECG measurements and PK blood samples in relation to fasting and 
administration of IMP ...................................................................................... 30 
Panel 4: Objectives and endpoints ........................................................................................... 39 
Panel 5: Identification of investigational medicinal products .................................................. 52 
Panel 6: Dosing schedule and treatment composition in each treatment group ....................... 55 
Panel 7: Prohibited medications and procedures ...................................................................... 60 
Panel 8: Calculation of the Eczema Area and Severity Index (EASI) ..................................... 71 
Panel 9: Eczema Area and Severity Index (EASI) severity score scale and area score scale .. 72 
Panel 10: Validated Investigator Global Assessment Scale for Atopic Dermatitis (vIGA-AD)
 .......................................................................................................................... 72 
Panel 11: Clinical laboratory tests ............................................................................................ 78 
Panel 12: Patient’s Global Impression of Severity (PGI-S) scales .......................................... 85 
Panel 13: Adverse events of special interest .......................................................................... 102 
Panel 14: Severity specifications for adverse event of electrocardiogram QT corrected interval 
prolonged a ..................................................................................................... 103 
Panel 15: Assumed response trajectories and rates of intercurrent events by treatment group, 
for subjects with baseline EASI score between [7.1, 16] ............................... 108 
Panel 16: Underlying response trajectories and rates of intercurrent events in the LP0162-
1325 and LP0162-1326 trials for subjects with a baseline EASI score between 
[16.1, 50] ........................................................................................................ 108 
Panel 17: Estimated power for the treatment contrasts of interest with respect to the primary 
endpoint .......................................................................................................... 109 
Panel 18: Primary and supplementary estimands for primary endpoint ................................ 116 
Panel 19: Handling of intercurrent events and analyses of estimands for the primary endpoint
 ........................................................................................................................ 124 
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Panel 20: a) Is the subject fasted and are there more than 6 hours since last dose of IMP? .. 163 
Panel 21: List of prohibited medications known to inhibit the 
 ................. 165 
Panel 22: List of prohibited medications known to inhibit the 
 ................... 165 
Panel 23: List of prohibited medications known to inhibit the 
 ................. 167 
 
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List of abbreviations 
AChE 
acetylcholine esterase 
AD 
atopic dermatitis 
ADSD 
Atopic Dermatitis Symptom Diary 
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 
AR(1) 
autoregressive model of order 1 
AS 
area score 
 
 
BfArM 
German Federal Institute for Drugs and Medical Devices 
BSA 
body surface area 
CCL17 
chemokine (C-C motif) ligand 17 
CDISC 
Clinical Data Interchange Standards Consortium 
CFTR 
cystic fibrosis transmembrane conductance regulator 
CI 
confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences 
Cmax 
maximum serum concentration of IMP 
CMH 
Cochran-Mantel Haenszel 
CMO 
contract manufacturing organization 
CONSORT 
Consolidated Standards of Reporting Trials 
COVID-19 
corona virus disease 2019 
CRA 
clinical research associate 
CRF 
case report form 
CRO 
contract research organization 
CTP 
clinical trial protocol 
CTR 
clinical trial report 
Ctrough 
lowest IMP concentration before next dose of IMP is administered 
CZ 
Czech Republic 
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DE 
Germany 
DLQI 
Dermatology Life Quality Index 
DMC 
data monitoring committee 
EASI 
Eczema Area and Severity Index 
EASI 50 
decrease in EASI of at least 50% from baseline 
EASI 75 
decrease in EASI of at least 75% from baseline 
EASI 90 
decrease in EASI of at least 90% from baseline 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
eDiary 
electronic diary 
EFPIA 
European Federation of Pharmaceutical Industries and Associations 
eGRF 
estimated glomerular filtration rate 
EMA 
European Medicines Agency 
ePRO 
electronic patient-reported outcome 
EQ-5D-5L 
EuroQoL 5-Dimension Health Questionnaire 5 Level 
FAS 
full analysis set 
FDA 
United States Food and Drug Administration 
FWER 
familywise error rate 
FXR 
potent farnesoid X receptor 
GCP 
Good Clinical Practice 
GPP3 
Good Publication Practice 3 
HADS 
Hospital Anxiety and Depression Scale 
HBsAg 
hepatitis B surface antigen 
HCP 
healthcare professional 
HCV 
hepatitis C virus antibody 
HDL 
high density lipoprotein 
HGM-CoA 
3-hydroxy-3-methylglutaryl-coenzyme A 
HIV 
human immunodeficiency virus 
HRQoL 
health-related quality of life 
H1R, H2R, H3R, H4R 
histamine 1, 2, 3, or 4 receptor 
ICF 
informed consent form 
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ICH 
International Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use 
ICMJE 
International Committee of Medical Journal Editors 
ID 
identification number 
IE 
intercurrent event 
IEC 
independent ethics committee 
IFN 
interferon 
IGA 
Investigator's Global Assessment 
IgE 
immunoglobulin E 
IL-13 
interleukin 13 
IL-22 
interleukin 22 
IMP 
investigational medicinal product 
IND 
investigational new drug 
IRB 
institutional review board 
IRT 
interactive response technology 
IUD 
intrauterine device 
IUS 
intrauterine hormone-releasing system 
JAK 
Janus kinase 
JM 
joint model 
LDL 
low density lipoprotein 
LEO 152020 
investigational medicinal product in this trial 
LS 
least squares 
LS-mean 
least squares mean 
MAR 
missing at random 
max 
maximum 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
multiple imputation 
min 
minimum 
MMRM 
mixed model for repeated measurements 
MNAR 
missing not at random 
N 
number of subjects 
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NA 
not applicable 
NBUVB 
narrow-band ultraviolet B 
NCT 
National Clinical Trial 
NOAEL 
no adverse-effect level 
NR 
non-response 
NRI 
non-responder imputation 
NRS 
numeric rating scale 
NSAID 
Non-steroidal anti-inflammatory drug 
PCR 
polymerase chain reaction (test) 
PD 
pharmacodynamic(s) 
PDE4i 
phosphodiesterase 4 inhibitor 
PGI-C 
Patient Global Impression of Change 
PGI-S 
Patient Global Impression of Severity 
 
 
PK 
pharmacokinetic(s) 
PMDA 
Japanese Pharmaceuticals and Medical Devices Agency 
POEM 
Patient-oriented Eczema Measure 
PRO 
patient‐reported outcome 
PUVA 
psoralen + ultraviolet A 
RADA 
Rapid Actigraphy Data Analyzer (software) 
SAE 
serious adverse event 
SARS-CoV-2 
Severe Acute Respiratory Syndrome Coronavirus 2 
SAF 
safety analysis set 
SAP 
statistical analysis plan 
SCORAD 
Scoring Atopic Dermatitis 
SD 
standard deviation 
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seq 
sequencing 
sIL-2R 
soluble interleukin 2 receptor 
SOC 
system organ class 
SS 
severity score 
SSRI 
selective serotonin reuptake inhibitor 
SUSAR 
suspected unexpected serious adverse reaction 
Syk 
spleen tyrosine kinase 
TARC 
thymus and activation-regulated chemokine 
TCI 
topical calcineurin inhibitor(s) 
TCS 
topical corticosteroid(s) 
Th2 
T helper type 2 cell 
UVA 
ultraviolet A 
UVA1 
ultraviolet A1 
UVB 
ultraviolet B 
vIGA-AD 
Validated Investigator Global Assessment Scale for Atopic Dermatitis 
 
 
WOCF 
worst observation carried forward 
WPAI:AD 
Work Productivity and Activity Impairment Questionnaire: Atopic 
Dermatitis 
 
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1 Protocol synopsis 
Trial ID 
EudraCT no.: 
NCT no.: 
IND no.: 
LP0190-1488 
2020-004561-39 
NCT05117060 
143394 
Title of trial 
A phase 2 trial to evaluate the efficacy and safety of orally-administered LEO 152020 
tablets compared with placebo tablets for up to 16 weeks of treatment in adults with 
moderate to severe atopic dermatitis 
Short title of the 
trial 
Efficacy and safety of different dose regimens of LEO 152020 tablets for the treatment 
of adults with moderate to severe atopic dermatitis up to 16 weeks 
Main objective(s) 
and endpoint(s) 
 
Objectives 
Endpoints 
Primary objective: 
To explore the exposure-response 
relationship of LEO 152020 and 
evaluate efficacy of LEO 152020 
compared with placebo for up to 
16 weeks of treatment in subjects with 
moderate to severe AD 
Primary endpoint: 
• Change in EASI a from baseline 
to Week 16. 
Secondary objective: 
To evaluate the safety of LEO 152020 
compared with placebo in subjects with 
moderate to severe AD 
Secondary endpoint: 
• Number of AEs from baseline to 
Week 16+3 days per subject. 
Abbreviations: AD = atopic dermatitis; AE = adverse event; EASI = Eczema Area 
Severity Index. 
a EASI is a validated measure used in clinical practice and clinical trials to assess the 
severity and extent of AD. EASI is a composite score ranging from 0 to 72 with higher 
scores indicating a more severe 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. 
The trial will consist of core assessments/procedures and optional components 
(wristband actigraphy, skin biopsies, and exit interviews), which are not required for 
participation in the core part of the trial and for which the subject will be asked to 
provide additional consent. 
The trial will consist of: 
• A screening period of maximum 5 weeks (at the earliest Week -5 to baseline) 
including a run-in period of 1 week (Week -1 to baseline). 
• A treatment period of 16 weeks (baseline to Week 16). 
• A safety follow-up period of 7 days (Week 16 to Week 17). 
 
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Abbreviations: AD = atopic dermatitis; N = number of subjects; SFU = safety 
follow-up. 
 
Randomization will take place at baseline. The primary endpoint will be assessed at 
Week 16. The final safety assessments will be conducted at Week 17. 
From the screening period, the subject will be asked to stop any systemic AD 
treatment. From the run-in period, the subject will be asked to stop any topical AD 
treatment with TCS, TCI, PDE4i, and/or topical JAK inhibitors and to apply an 
emollient (background treatment) at least twice daily. The subject will also be asked to 
start completing an eDiary daily. 
At baseline, the subject will be randomized to 1 of 4 oral treatments as described 
below (Number of subjects). 
In the treatment period, the subject will be asked to self-administer LEO 152020 or 
placebo tablets twice daily for 16 weeks. In this period, the subject will be asked to 
continue applying the emollient as needed and complete the eDiary. The subject will 
also be asked to visit the site for assessments and procedures. 
In the safety follow-up period, the subject will be asked to stop treatment with 
LEO 152020 or placebo tablets and the safety of the treatment will further be assessed 
at the safety follow-up visit (Week 17). 
An independent data monitoring committee will assess subject safety and overall trial 
conduct periodically. Based on their assessment, the committee will issue 
recommendations to LEO Pharma as to the pursuit of the trial. 
Main assessments 
• Eczema Area and Severity Index (EASI). 
• Adverse events. 
Main criteria for 
inclusion 
• Adult, age 18 years or older at screening. 
• Diagnosis of chronic atopic dermatitis (AD). 
• History of AD ≥1 year prior to baseline. 
• Recent (within 6 months prior to baseline) documented history of inadequate 
response to topical AD treatments or subject for whom topical AD treatments 
are medically inadvisable. 
• 7.1≤ EASI ≤50 at baseline. 
• vIGA-AD score ≥3 at baseline. 
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Main criteria for 
exclusion 
• Previous treatment with an oral H4R antagonist (including LEO 152020) within 
6 months prior to baseline. 
• Previous treatment with 3 or more systemic AD treatments prior to screening. 
• Women who are pregnant, intend to become pregnant, or are lactating. 
Investigational 
medicinal 
product(s) 
• Name of active IMP: LEO 152020 film-coated tablet. 
• Active substance: LEO 152020. 
• Dosage form: film-coated tablet. 
• Dose regimens: LEO 152020 
 LEO 152020 
 
 LEO 152020 
 
• Method of administration: oral. 
 
• Name of placebo: LEO 152020 placebo film-coated tablet. 
• Dosage form: film-coated tablet. 
• Method of administration: oral. 
Duration of trial 
participation 
Up to 22 weeks: maximum 5 weeks of screening + 16 weeks of treatment + 1 week of 
safety follow-up 
Number of subjects 
At baseline, a total of 224 subjects (including 28 Japanese subjects) will be randomized 
in a 4:3:3:4 ratio to: 
• LEO 152020 
 
• LEO 152020 
 
• LEO 152020 
 
• Placebo 
. 
Number and 
distribution of trial 
sites 
Approximately 60 sites in Europe, North America, Japan, and Australia. 
Statistical methods 
Primary and secondary endpoints: 
A primary and 2 supplementary estimands will be defined for the primary endpoint, 
change in EASI from baseline to Week 16, in order to assess different clinical questions 
of interest. 
• The primary estimand for the primary endpoint will use the hypothetical strategy 
to handle the occurrence of pre-defined intercurrent events (initiation of rescue 
treatment and permanent discontinuation of IMP). 
• A first supplementary estimand will use the treatment policy and hypothetical 
strategies to account for the occurrence of intercurrent events. 
• A second supplementary estimand will use the composite and hypothetical 
strategies to handle the occurrence of intercurrent events. 
For the main analysis of the primary estimand, data observed after the occurrence of an 
intercurrent event will be excluded from the analysis. Missing data will be assumed to 
be MAR. The primary endpoint will be analyzed using an MMRM including treatment, 
visit, visit by treatment interaction terms, and region (Japan, non-Japanese countries) as 
factors, and adjusting for the baseline EASI score as a covariate. The covariance matrix 
will be assumed to have an unstructured form and the Kenward-Rodger approximation 
will be used to estimate the denominator degrees of freedom. 
To explore the exposure-response relationship, the change in EASI score from baseline 
to Week 16 will be assessed based on an ANCOVA model including region as a factor 
and Ctrough at Week 16 and baseline EASI score as covariates. Data observed after the 
occurrence of an intercurrent event will be excluded and missing data will be assumed 
to be MAR. 
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Abbreviations: AD = atopic dermatitis; AE = adverse event; EASI = Eczema Area and Severity Index; 
EudraCT = European Union Drug Regulating Authorities Clinical Trials Database; H4R = histamine 4 
receptor; ID = identification; IMP = investigational medicinal product; IND = investigational new drug; 
JAK = Janus kinase; MAR = missing at random; MMRM = mixed model for repeated measurements; 
N = number of subjects; NCT = National Clinical Trial; PDE4i = phosphodiesterase 4 inhibitor; SFU = safety 
follow-up; TCI = topical calcineurin inhibitor(s); TCS = topical corticosteroid(s), vIGA-AD = Validated 
Investigator Global Assessment Scale for Atopic Dermatitis. 
The secondary endpoint, number of AEs from baseline to Week 16+3 days per subject, 
will be reported descriptively by treatment group. 
Signatory 
investigator 
, MD 
 
 
Hannover, Germany 
Sponsor 
LEO Pharma A/S, Industriparken 55, DK-2750 Ballerup, Denmark 
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2 Trial identification 
EudraCT number: 2020-004561-39. 
NCT number: NCT05117060. 
IND number: 143394. 
The clinical trial protocol will be registered in local registries as 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 
 
Abbreviations: AD = atopic dermatitis; N = number of subjects; SFU = safety follow-up. 
 
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4 Schedule of trial procedures 
Panel 2: Schedule of trial procedures 
 
Screening 
Screening 
run-in 
Baseline 
Start of treatment 
Treatment 
> 
> 
> 
> 
> 
> 
Treatment 
End of treatment a 
Primary endpoint 
Safety follow up a 
Early termination b 
Unscheduled visit c 
Reference 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
NA 
NA 
 
Week 
-5 
-1 
0 
1 
2 
4 
6 
8 
10 
12 
14 
16 
17 
NA 
NA 
 
Day 
-35 
-7 
1 
7 
14 
28 
42 
56 
70 
84 
98 
112 
119 
NA 
NA 
 
Visit window (days) d 
NA 
-3 
NA 
±1 
±2 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
+3 
NA 
NA 
 
Trial population and 
eligibility 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent(s) e 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix 3B 
Subject eligibility 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
8.1 to 8.3 
Screening/baseline 
assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics  
X f 
 
X f 
 
 
 
 
 
 
 
 
 
 
 
 
11.2.1 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
11.2.3 
BSA involvement g 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
11.2.4 and 
11.3.3 
Hepatitis B, C, and 
HIV 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
(X) h 
Exclusion 
criteria 7 and 
9 
Tuberculosis test per 
local standard of care 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
(X) h 
11.2.5 and 
Exclusion 
criterion 8 
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Screening 
Screening 
run-in 
Baseline 
Start of treatment 
Treatment 
> 
> 
> 
> 
> 
> 
Treatment 
End of treatment a 
Primary endpoint 
Safety follow up a 
Early termination b 
Unscheduled visit c 
Reference 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
NA 
NA 
 
Week 
-5 
-1 
0 
1 
2 
4 
6 
8 
10 
12 
14 
16 
17 
NA 
NA 
 
Day 
-35 
-7 
1 
7 
14 
28 
42 
56 
70 
84 
98 
112 
119 
NA 
NA 
 
Visit window (days) d 
NA 
-3 
NA 
±1 
±2 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
+3 
NA 
NA 
 
Body measurement 
(height and weight) 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
11.2.2 
Randomization and 
treatments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medication / 
concurrent procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(X) 
9.6 
Background treatment 
(emollient) 
 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
 
 
9.4 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
9.3.1 
Dispensing of IMP 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
(X) 
9.8.4 
Administration of IMP 
at the trial site i 
 
 
X 
X 
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) 
9.8.5 
Administration of IMP 
at the subject’s home j 
 
 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> j 
 
 
 
9.2 
Return of unused IMP 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
(X) 
9.8.4 
IMP accountability 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
(X) 
9.8.4 
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Screening 
Screening 
run-in 
Baseline 
Start of treatment 
Treatment 
> 
> 
> 
> 
> 
> 
Treatment 
End of treatment a 
Primary endpoint 
Safety follow up a 
Early termination b 
Unscheduled visit c 
Reference 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
NA 
NA 
 
Week 
-5 
-1 
0 
1 
2 
4 
6 
8 
10 
12 
14 
16 
17 
NA 
NA 
 
Day 
-35 
-7 
1 
7 
14 
28 
42 
56 
70 
84 
98 
112 
119 
NA 
NA 
 
Visit window (days) d 
NA 
-3 
NA 
±1 
±2 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
+3 
NA 
NA 
 
Subject assessments 
(eDiary) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
eDiary hand-out / 
training 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
11.5.1 
eDiary completion k 
 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
 
 
 
11.5.1 
Return of eDiary 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
(X) 
11.5.1 
 Patient reported 
outcomes (completed 
at the trial site) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
POEM 
 
 
X 
 
 
X 
 
 
 
 
 
X 
 
X 
(X) 
11.5.7 
DLQI 
 
 
X 
 
 
X 
 
 
 
 
 
X 
 
X 
(X) 
11.5.8 
EQ-5D-5L 
X 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
(X) 
11.5.9 
WPAI:AD 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
(X) 
11.5.10 
HADS 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
(X) 
11.5.11 
PGI-S l 
 
 
X 
 
 
X 
 
X 
 
X 
X 
X 
 
X 
(X) 
11.5.12 
PGI-C m 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
(X) 
11.5.13 
Efficacy assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EASI 
X 
X 
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 
 
X 
(X) 
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Screening 
Screening 
run-in 
Baseline 
Start of treatment 
Treatment 
> 
> 
> 
> 
> 
> 
Treatment 
End of treatment a 
Primary endpoint 
Safety follow up a 
Early termination b 
Unscheduled visit c 
Reference 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
NA 
NA 
 
Week 
-5 
-1 
0 
1 
2 
4 
6 
8 
10 
12 
14 
16 
17 
NA 
NA 
 
Day 
-35 
-7 
1 
7 
14 
28 
42 
56 
70 
84 
98 
112 
119 
NA 
NA 
 
Visit window (days) d 
NA 
-3 
NA 
±1 
±2 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
+3 
NA 
NA 
 
SCORAD 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
(X) 
11.3.3 
Safety assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
13 
Vital signs 
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) 
11.4.2 
ECG 
X n 
X n 
X n 
X n 
X n 
X n 
X n 
X n 
X n 
X n 
X n 
X n 
X n 
X n 
(X) 
11.4.3 
Urine dipstick 
(urinalysis) o 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
(X) 
11.4.4 
Clinical chemistry, 
hematology 
X 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
(X) 
11.4.4 
Urine pregnancy test p 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
X 
X 
(X) 
11.4.4 
Serum pregnancy test p 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
(X) 
11.4.4 
Pharmacokinetic and 
pharmacodynamic 
assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK blood sample(s) 
 
 
X n 
X n 
 
X n 
 
X n 
 
X n 
 
X n 
 
X n 
(X) 
11.6.1 
PD blood biomarkers 
 
 
X 
 
 
X 
 
X 
 
 
 
X 
 
X 
(X) 
11.6.2 
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Screening 
Screening 
run-in 
Baseline 
Start of treatment 
Treatment 
> 
> 
> 
> 
> 
> 
Treatment 
End of treatment a 
Primary endpoint 
Safety follow up a 
Early termination b 
Unscheduled visit c 
Reference 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
NA 
NA 
 
Week 
-5 
-1 
0 
1 
2 
4 
6 
8 
10 
12 
14 
16 
17 
NA 
NA 
 
Day 
-35 
-7 
1 
7 
14 
28 
42 
56 
70 
84 
98 
112 
119 
NA 
NA 
 
Visit window (days) d 
NA 
-3 
NA 
±1 
±2 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
+3 
NA 
NA 
 
Optional assessments 
q 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Wristband actigraphy 
 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
 
 
 
11.7.2 
Return of the wristband 
actigraphy devices r 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
(X) 
11.7.2 
Skin biopsies (skin 
biomarkers) s 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
(X) 
11.7.3 
Check of wound 
healing 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
(X) 
(X) 
11.7.3 
Exit interview t 
 
 
 
 
 
 
 
 
 
 
 
X  
 
 
 
11.7.4 
End of treatment/trial 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
End of treatment form 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
11.8 
End of trial form 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
11.8 
Abbreviations: AD = atopic dermatitis; ADSD = atopic dermatitis symptom diary; AE = adverse event; BSA = body surface area; CTP = clinical trial protocol; 
DLQI = Dermatology Life Quality Index; EASI = Eczema Area and Severity Index; ECG = electrocardiogram; eCRF = electronic case report form; 
eDiary = electronic diary; EQ-5D-5L = EuroQoL (Quality of Life) 5-Dimension Health Questionnaire 5 Level; HADS = Hospital Anxiety and Depression Scale; 
HIV = human immunodeficiency virus; HRQoL = health-related quality of life; IFN = interferon; IMP = investigational medicinal product; NA = not applicable; 
PD = pharmacodynamic(s), PGI-C = Patient Global Impression of Change; PGI-S = Patient Global Impression of Severity; PK = pharmacokinetic(s); 
POEM = Patient-oriented Eczema Measure; PRO = patient reported outcome; SCORAD = Scoring Atopic Dermatitis; vIGA-AD = Validated Investigator Global 
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Assessment Scale for Atopic Dermatitis; 
; WPAI:AD = Work Productivity and Activity Impairment Questionnaire: Atopic 
Dermatitis; (X) = assessment/procedure to be conducted, if applicable. 
a An end-of-treatment form and end-of-trial form must be completed in the eCRF for all randomized subjects. 
b 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. 
Discontinued/withdrawn subjects should be followed up as described in Section 10.3. 
c If necessary, (an) unscheduled visit(s) may be added to the subject’s schedule, e.g. due to an AE, a significant change in disease state, or difficulty complying with 
the CTP requirements. At an unscheduled visit, the investigator should at least collect AE data. Other assessments/procedures to be conducted will be at the 
discretion of the investigator. 
d If the date of a visit does not conform to the schedule of trial procedures, subsequent visits should be planned to maintain the visit schedule relative to 
baseline/randomization. 
e The informed consent form must be signed prior to conducting any protocol-related assessments/procedures, including but not limited to screening evaluations and 
washout of disallowed medications. Screening evaluations may start later than the date when the informed consent form was signed. 
f At screening, the demographic data listed in Section 11.2.1 will be recorded. At baseline, only age will be recorded on the randomization form. 
g BSA affected by AD will be assessed as component A of SCORAD (Section 11.3.3). 
h If the results of the hepatitis B, C, HIV, and/or tuberculosis tests are inconclusive at screening, they may be repeated at an unscheduled visit, if necessary. 
i At each visit between baseline and Week 14, the subject will self-administer the morning dose of IMP at the trial site under the supervision of the site staff. 
j Between visits from baseline to Week 16, the subject will self-administer the IMP at their home. The subject will take their last dose of IMP in the evening before 
the Week 16 visit. 
k ADSD, Nocturnal 
 Difficulty 
 Frequency of 
 During the Night, 
 and 
 will be completed in the eDiary 
daily. 
l Includes ADSD PGI-S, 
 PGI-S, Nocturnal 
 PGI-S, Difficulty 
 PGI-S, Frequency of 
During the Night PGI-S, 
 
PGI-S, and 
 PGI-S. 
m Includes ADSD PGI-C, 
 PGI-C, Nocturnal 
 PGI-C, Difficulty 
 PGI-C, Frequency of 
 During the Night PGI-C, 
 
PGI-C, and 
 PGI-C. 
n See Panel 3 for more information. 
o It will be at the discretion of the investigator if a urine sample should be sent to the central laboratory for further analysis. 
p Women of childbearing potential only. 
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q Wristband actigraphy, skin biopsies, and exit interviews are optional components of the trial for subgroups of subjects. Participation in these components is not 
required for participation in the core part of the trial and the subject will be asked to provide additional consent. 
r At the indicated visits, subjects will be asked to bring the wristband actigraphy devices back to the site and the investigator or site staff will transfer data from the 
devices. Subjects will be asked to return the devices at Week 16 or at their last visit in the trial. 
s Skin biopsies should be taken from the locations described in Section 11.7.3. 
t Exit interviews should be scheduled as described in Section 11.7.4. 
Panel 3: Schedule of ECG measurements and PK blood samples in relation to fasting and administration of IMP 
Week -5 
(screening) 
Week -1 
(run-in) 
Week 0 
(baseline) 
Week 1 
Weeks 2, 6, 10, 
and 14 
Weeks 4, 8, and 
12 
Week 16 
Week 17 
(safety 
follow-up) 
Early 
termination 
NA 
NA 
Subject is fasted c 
NA 
NA 
• 3 consecutive 
ECGs a 
• Laboratory 
assessments 
• 1 ECG b 
• Laboratory 
assessments 
• Pre-dose ECG d 
• Pre-dose PK e 
• Laboratory 
assessments 
 
 
• Pre-dose PK g 
• Laboratory 
assessments 
• 1 ECG b 
• 1 PK 
• Laboratory 
assessments 
• 1 ECG b 
• Laboratory 
assessments 
• 1 ECG b 
• 1 PK 
• Laboratory 
assessments 
NA 
NA 
Administration of IMP 
Wait 
 and proceed with 
Subject may 
break fast 
NA 
NA 
 
 
• Post-dose ECG 
• Post-dose PK f 
• Post-dose ECG  
• Post-dose PK f 
• Post-dose 
ECG 
• Post-dose 
ECG  
• Post-dose PK 
f 
 
 
 
NA 
NA 
Subject may break fast 
NA 
NA 
NA 
 
 
• Japan: post-dose 
ECG 
(4 hours±15 min 
after dosing) h 
• Japan: post-dose 
ECG 
(4 hours±15 min 
after dosing) h 
 
 
 
 
 
Abbreviations: ECG = electrocardiogram; IMP = investigational medicinal product; NA = not applicable, PK = pharmacokinetic(s). 
If at any ECG measurement, the subject presents with a 
, the ECG should be repeated. If the 
 is confirmed, a 
PK sample (if not already planned at the visit) must be taken close to the last ECG. See Section 11.4.3 for more information. 
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a In line with exclusion criterion 13. Must be measured before any blood sample collected at the same visit. 
b Must be measured before any blood sample collected at the same visit. 
c The subject will be asked to come fasted to the trial site, i.e. arrive at the site minimum 2 hours after their last meal. 
d Must be measured before any blood sample collected at the same visit and shortly before IMP administration. 
e Should be taken within 5-10 min of the pre-dose ECG measurement shortly before IMP administration. 
f Should be taken within 5-10 min of the post-dose ECG measurement, i.e. 
 after dosing. 
g Should be taken shortly before IMP administration. 
h See also Appendix 4. 
 
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5 Introduction and trial rationale 
5.1 
Atopic dermatitis 
AD is a chronic inflammatory skin disease, often referred to as eczema and characterized by 
widespread skin lesions, manifested as red, itchy, swollen, cracked, weeping lesions with 
crusting/scaling, intractable itch (pruritus), and enhanced susceptibility to bacterial and viral 
skin infections. Persistent itch that often causes sleep deprivation and disfiguration of the skin 
substantially impairs patients’ quality of life (1, 2). In a subset of patients, onset of AD 
precedes that of other conditions such as food allergies, asthma, and allergic rhinitis in a 
pattern known as the atopic march (3). AD has a worldwide lifetime prevalence of 15 to 20% 
in children (4) and up to 10% in adults (5, 6) and its prevalence has increased 2- to 3-fold 
during the past 3 decades in industrialized countries (5). Pathophysiology of AD is 
complicated and regulated by several genetic and environmental factors. However, it is 
believed to be mainly driven by Th2 cell responses (7, 8). 
Itch can be defined as an unpleasant cutaneous sensation associated with the immediate desire 
to scratch and has been attributed to increased release of various itch mediators such as 
histamine. Itch is known to be a common symptom in dermatologic and systemic diseases (9). 
Although numerous substances such as substance P, serotonin, IL-31, and tryptase are known 
to cause itch, histamine is also well known to evoke itch when applied to the skin (10, 11). 
Itch is a primary symptom of AD and can occur both during the day and at night. Nocturnal 
itch can significantly impact a patient’s sleep and quality of life (12, 13). Nocturnal scratching 
can lead to difficulties falling asleep and frequent awakening (14). The resulting fatigue and 
difficulty concentrating can prevent the patient from fully engaging in school, work, hobbies, 
and socially (15). In addition, persistent scratching can lead to secondary impacts of AD such 
as decreased skin barrier function and increased risk of infection, as well as disfigurement, 
scarring, and other complications (16, 17). 
Treatment recommendations for AD include topical treatments, mainly TCS. However, not all 
patients with moderate to severe AD are adequately treated with TCS and TCI. TCS and oral 
systemic treatments (e.g. cyclosporine, azathioprine) are all associated with toxicities when 
used in the long-term (18-20). Therefore, patients with moderate to severe AD experience a 
high unmet need for alternative AD treatments. 
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Since histamine levels are highly elevated in inflamed skin (21), it is possible that histamine is 
involved in inflammatory skin pathology. However, antagonists blocking H1R or H2Rs are 
largely ineffective in reducing chronic symptoms of AD (22, 23). H4R was discovered in the 
early 2000s and various selective H4R antagonists have allowed understanding the expression 
and function of the H4 receptor (24, 25). Research on H4R has shown that H4R antagonists 
have anti-pruritic and anti-inflammatory effects in inflammatory mouse models (26, 27) and 
in clinical trials in AD (28, 29). Therefore, H4R may present a novel therapeutic target in AD. 
5.2 
Experience with investigational medicinal product 
An overview of nonclinical and clinical data on LEO 152020 is available in the current 
edition of the investigator’s brochure (30). 
5.2.1 
Nonclinical data 
LEO 152020 binds selectively to human H4R and has been characterized as antagonist, 
inhibiting the histamine-induced effects of the H4R. 
 
 
 
In safety pharmacological studies, LEO 152020 did not have any neurobehavioral and 
respiratory effects. Oral dosing in monkeys at dose levels up to 
 mg/kg did not result in any 
changes in body temperature, blood pressure, or heart rate, and there were no clinical signs of 
AChE inhibition. ECG monitoring showed a 
 
 at doses 
 mg/kg with no biological significance in the monkey. 
Ex vivo and in vivo models have shown that LEO 152020 has 
 efficacy and 
in addition has 
 in several models of pruritus in mice. 
In a 26-week rat toxicology study, histopathological investigation showed an 
 
 in the 
 
compared with their control. 
 were also observed and 
considered secondary to the findings in the 
 These findings were observed at the highest 
dose level tested (
) and were partially reversed after a 
 recovery period. 
In this study, NOAEL was 
 mg/kg/day for 
 corresponding to a safety margin of 
 
and an exposure margin of 
 to the therapeutic dose of LEO 152020 
 
The pharmacokinetic profile of LEO 152020 was investigated in mice, rats, and monkeys. 
The main route of elimination was urinary and the unchanged parent compound was the 
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predominant component in all urine, feces, and plasma. No metabolites observed were >5% of 
the dose administered. LEO 152020 was evaluated to be non-genotoxic and with no 
phototoxic potential. Repeated-dose studies in rats and monkeys up to 16 weeks revealed a 
toxicity profile amenable to clinical monitoring and of low concern for human risk and 
provided adequate safety margins. 
5.2.2 
Clinical data 
A first-in-human clinical trial (JWP-FRC-101) in healthy Korean, Caucasian, and Japanese 
subjects (88 subjects) was completed. This trial contained single-ascending dose (
 
 mg) and multiple ascending dose (
 mg) parts. There were emerging 
 tolerability issues observed in the 
 cohort (highest 
dose tested), 
 cohort and 
 cohort. 
All of these 
 events were classified as mild, occurred rapidly after dosing, and 
the majority of events resolved within 1-3 hours. In addition, 1 SAE was observed for the 
lowest single dose (
 mg) and considered not related to LEO 152020 by the sponsor. There 
were no other SAEs reported in the other dose groups. 
Given the mild severity, fast onset, and transient nature of the 
 events, and that 
the events were primarily observed at the higher dose levels in the first-in-human trial, these 
events were not considered a safety concern and are not expected to be relevant at the 
therapeutic doses given in this trial. 
Single dose administration of LEO 152020 resulted in an 
 with the mean and 
upper bound of the 90% CI of 
 exceeding 
 at single doses of 
 and 
 mg (31). 
 effect was observed in the 
 and 
 mg multiple dose groups where the 
upper bound of the 90% CI exceeded 
 (
, respectively). The mean effect 
in the 
 and 
 mg multiple dose groups were 
 and 
, respectively. Furthermore, 
in the multiple dose but not the single dose part of the trial, a dose dependent 
 
was observed with a 
 of 
 in the 
 mg dose group. In the 
 dose group, the 
 was 
 Thus, it is unlikely 
that these findings are clinically relevant at the therapeutic doses given in this trial. 
5.3 
Trial rationale 
This trial will provide information on the efficacy and safety of LEO 152020 and on the 
exposure-response relationship of LEO 152020. This will allow identification of efficacious 
dose(s) of LEO 152020 to inform further clinical development. 
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The trial design is presented in Section 7.1 and illustrated in Section 3. The scientific rationale 
for the trial design is presented in Section 12. 
5.4 
Ethical considerations 
This trial will be conducted in accordance with the ethical principles originating from the 
Declaration of Helsinki (32) and ICH GCP (33) 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 152020 will be evaluated in adults with moderate to severe AD who may benefit from 
treatment with LEO 152020. Appropriate measures will be taken to protect the subject from 
potential risks related to treatment with LEO 152020 and to closely monitor the subject 
(Section 5.5). 
Participation in the trial is voluntary and the subject may 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 be excluded from participation in the trial. Women of childbearing potential must agree to 
use highly effective contraception to prevent pregnancy during the trial. In addition, 
pregnancy tests (urine and serum) 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 be excluded from participation in the trial. 
It will be explained to the subject that the trial will consist of core assessments/procedures and 
optional components not required for participation in the core part of the trial and for which 
the subject will be asked to provide additional consent. 
In accordance with the current version of ICH and GCP guidelines, qualified medical 
personnel employed by LEO Pharma will be readily available to advise on trial-related 
medical questions. Medical monitoring will be conducted throughout the trial to ensure 
subject safety during their participation in the trial. Safety data will be reviewed by qualified 
personnel to ensure that prompt action is taken, if needed, to protect the subject. 
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5.5 
Benefit/risk assessment 
There is a clear, unmet need for safe, long-term treatment options for subjects with moderate 
to severe AD and treatments adequately addressing itch. As a novel oral H4R antagonist, 
LEO 152020 is expected to be efficacious against both inflammation and itch caused by AD. 
Oral treatment is often considered a more convenient route of administration for the patient 
and one resulting in higher compliance than topical or subcutaneous treatments. 
The subject will be informed of the possibility and probability of receiving active or placebo 
treatment. In this trial, approximately 71% of the subjects will receive active treatment with 
LEO 152020 in dose regimens believed to have a therapeutic effect on AD (Section 12.1) and 
29% of the subjects will receive placebo (Section 9.3.1). 
All subjects will be followed-up closely by a physician during their treatment and will be able 
to monitor their own disease via the use of an electronic Diary (Section 11.5.1). Subjects will 
also be offered to participate in an optional component of the trial involving the study of 
nocturnal 
 and sleep 
 (Section 11.7.2). 
Risks to subjects will be minimized by inclusion of subjects fulfilling all eligibility criteria 
(Sections 8.1 to 8.3). In addition, close clinical monitoring (Section 4) and 
discontinuation/withdrawal criteria will ensure subject safety during the trial (Section 10.2). 
In addition to appropriate safety monitoring, an independent DMC will be established which 
will review safety data and assess overall trial conduct periodically as well as issue 
recommendations to LEO Pharma as to the pursuit of the trial (Appendix 3H). 
The subject will be informed that changes to their ongoing AD treatment may be required 
during the screening period and that their condition may as a result worsen. Therefore, 
investigators will be asked only to include subjects who are considered able to discontinue 
prohibited medications without experiencing intolerable worsening of AD. 
If medically necessary (i.e. to control intolerable worsening of AD symptoms), rescue 
treatment of AD may be provided to the subject at the discretion of the investigator 
(Section 9.5). 
Blood sampling presents the usual low risk normally associated with this procedure and will 
only be conducted by qualified medical personnel. 
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Nocturnal 
 and sleep 
 monitoring by wristband actigraphy is not 
considered to bear a risk (Section 11.7.2). A hypoallergenic bandage can be placed under each 
of the wristband actigraphy devices to prevent skin irritation on the wrists. 
Risks for subjects treated with LEO 152020 
Due to the important potential risk of 
, the dose regimens explored in this 
trial have been chosen to minimize that risk for the subjects. The highest dose regimen in the 
trial (
 is predicted to result in concentration levels below those of the 
 mg once daily dose regimen, which in the first-in-human trial resulted in a mean 
 of 
 with an upper bound of the 90% CI for 
 
(
) at 
 (Section 5.2.2). Since 
subjects with mild and moderate renal impairment may exhibit increased exposure of 
LEO 152020, ECGs will be measured at each visit (Section 4) to monitor the individual 
subjects in line with 
 for drugs for which a 
 cannot be 
excluded (Panel 2). 
To further ensure subject safety, subjects with cardiac arrhythmic risk factors, moderate and 
severe hepatic impairment, and/or severe renal impairment will be excluded from 
participation in the trial (Section 8.3). Subjects using medications for which 
 
is a known side effect and which cannot be replaced by safe alternative medication(s) will be 
excluded from participation in the trial (Section 9.7). Moreover, medications known to inhibit 
the 
 
, and/or 
 will be prohibited during the trial (Section 9.7 and 
Appendix 8). Frequent ECG monitoring will be conducted with pre- and/or post-dose ECGs 
measured and evaluated at the sites and centrally (Section 11.4.3). At selected visits, ECG and 
PK blood samples collected at the same timepoint will be used to explore the relation between 
exposure of LEO 152020 and potential 
 (Section 4). In the multiple dose part 
of the first-in-human trial, a dose-dependent 
 in heart rate was observed with a 
 
 (
) in the 
 dose group. If a subject develops 
 and 
 
, the risk of 
 may increase. To mitigate this, ECGs will be taken at 
each visit (Section 4) to monitor all subjects. 
In the first-in-human clinical trial, mild 
 adverse events were observed 
following treatment with high doses of LEO 152020. As 
 may increase 
the risk of 
, additional monitoring of 
 should be arranged, at the 
discretion of the investigator, for subjects who experience prolonged episodes of 
 
during the treatment period. 
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Risks for subjects who consent to provide skin biopsies 
Subjects who consent to provide skin biopsies may experience discomfort associated with the 
collection of the samples. To alleviate this, the subject will receive an injection of a local 
anesthetic to numb the area where the biopsy will be taken. Complications of skin biopsies 
may include bleeding, bruising and/or pain, and infection at the biopsy site. Pressure dressings 
and ice can be used to help alleviate these symptoms. Wound healing at the biopsy site will be 
checked at a subsequent visit. The subject will be informed that they may retain small scars 
after the procedure. 
Risks associated with the COVID-19 pandemic 
Participation in clinical trials may currently be associated with increased risks and challenges 
due to the COVID-19 pandemic caused by SARS-CoV-2. EMA (35), FDA, and national 
health authorities across the world have issued guidelines aiming at providing 
recommendations for conducting clinical trials during the COVID-19 pandemic. Subjects and 
sites are expected to follow the recommendations and preventive measures issued by their 
local health authorities. 
LEO Pharma has evaluated currently available safety data on LEO 152020. Based on 
nonclinical studies, LEO 152020 is considered a mild immunomodulatory compound and its 
mechanism of action is not believed to present a risk of decreased anti-viral immunity in 
subjects infected by COVID-19. In addition, LEO 152020 is not believed to increase the 
susceptibility of the subject to contract COVID-19 or other infections. 
However, adhering to the schedule of trial procedures in the context of a pandemic, entails a 
risk of increased exposure to SARS-CoV-2 by spending time in public areas (e.g. commuting 
to and from the trial site, dwelling at the hospital for the time of the visit) and having 
increased human contacts (e.g. with the site staff). Given the rapidly evolving epidemic 
situation and the potential for the pandemic to relapse, LEO Pharma will carefully monitor the 
pandemic situation and issue risk mitigation measures to protect subjects and staff involved in 
the trial while ensuring integrity of the trial data. A COVID-19 contingency plan is presented 
in Appendix 9. 
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 oral treatment option for 
AD. Therefore, the currently expected benefit/risk profile is considered in favor of conducting 
the trial. 
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6 Trial objectives, estimands, and endpoints 
Trial objectives and endpoints are presented in Panel 4. 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 4: Objectives and endpoints 
Objectives 
Endpoints 
Primary objective (continues) 
 
To explore the exposure-response 
relationship of LEO 152020 and 
evaluate efficacy of LEO 152020 
compared with placebo for up to 
16 weeks of treatment in subjects with 
moderate to severe AD (continues) 
Primary endpoint 
• 
Change in EASI from baseline to Week 16. 
Exploratory endpoints 
• 
EASI at each visit from Week 1 to Week 16. 
• 
Having a decrease in EASI of at least 50% 
(EASI 50) from baseline to Week 16. 
• 
Time from randomization to having an observed 
decrease in EASI of at least 50% (EASI 50) from 
baseline. 
• 
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. 
• 
Having a decrease in vIGA-AD of at least 2 points 
from baseline to Week 16. 
• 
SCORAD at each visit from Week 1 to Week 16. 
• 
Change in ADSD score (weekly average) from 
baseline to Week 16. 
• 
Change in each ADSD individual symptom score a 
(weekly average) from baseline to Week 16. 
• 
Having a decrease in ADSD 
 score (weekly 
average) of at least 4 points from baseline to 
Week 16 in subjects with ADSD 
 score ≥4 at 
baseline. 
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Objectives 
Endpoints 
Primary objective (continued) 
 
To explore the exposure-response 
relationship of LEO 152020 and 
evaluate efficacy of LEO 152020 
compared with placebo for up to 
16 weeks of treatment in subjects with 
moderate to severe AD (continued) 
• 
Time from randomization to having a decrease in 
ADSD 
 score (weekly average) of at least 
4 points from baseline in subjects with ADSD 
 
score ≥4 at baseline. 
Secondary objectives 
 
To evaluate the safety of LEO 152020 
compared with placebo in subjects 
with moderate to severe AD 
Secondary endpoints 
• 
Number of AEs b from baseline to Week 16+3 days 
per subject. 
Exploratory objectives (continues) 
 
To evaluate effect of treatment with 
LEO 152020 compared with placebo 
for up to 16 weeks of treatment on 
PROs in subjects with moderate to 
severe AD 
Exploratory endpoints 
• 
Change in POEM from baseline to Week 16. 
• 
Change in DLQI from baseline to Week 16. 
• 
Having a decrease in DLQI of at least 4 points from 
baseline to Week 16 in subjects with DLQI ≥4 at 
baseline. 
• 
Change in EQ-5D-5L from baseline to Week 16. 
• 
Change in HADS from baseline to Week 16. 
• 
Change in WPAI:AD (for each individual domain) 
from baseline to Week 16. 
• 
Having a decrease in POEM of at least 4 points 
from baseline to Week 16 in subjects with 
POEM ≥4 at baseline. 
Exploratory objectives (continued) 
 
To evaluate pharmacokinetic 
parameters of LEO 152020 for up to 
16 weeks of treatment in subjects with 
moderate to severe AD 
Exploratory endpoint 
• 
Ctrough of LEO 152020 at Weeks 
. 
• 
Cmax of LEO 152020 at Weeks 
. 
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Objectives 
Endpoints 
To evaluate effect of treatment with 
LEO 152020 compared with placebo 
for 
 of treatment on 
disease biomarkers and biomarkers 
related to the mechanism of action of 
LEO 152020 in subjects with 
moderate to severe AD 
Exploratory endpoints 
• 
Change in expression levels of blood biomarkers 
from baseline to 
 
• 
Change in expression levels of AD disease 
biomarkers in skin from baseline to 
 
To explore the effect of treatment with 
LEO 152020 compared with placebo 
for 
 of treatment on 
sleep disturbance and nocturnal 
 in subjects with moderate 
to severe AD 
Exploratory endpoints 
Based on eDiary data 
• 
Difficulty 
 at Week 
 
• 
Frequency of 
 During the Night at 
Week 
 
• 
 at Week 
 
• 
 at Week 
 
Based on actigraphy data 
• 
Change in 
 from baseline to 
Week 
 
• 
Change in 
 from baseline to Week 
 
• 
Change in number of nocturnal 
 events 
per hour from baseline to Week 
 
• 
Change in duration of nocturnal 
 per hour 
from baseline to Week 
 
Abbreviations: AD = atopic dermatitis; ADSD = Atopic Dermatitis Symptom Diary; AE = adverse event; 
Cmax = maximum serum concentration; Ctrough = lowest IMP concentration before the next dose of IMP is 
administered; DLQI = Dermatology Life Quality Index; EASI = Eczema Area and Severity Index; 
EASI 50 = decrease in EASI of at least 50% from baseline; EASI 75 = decrease in EASI of at least 75% from 
baseline; EASI 90 = decrease in EASI of at least 90% from baseline; ECG = electrocardiogram; EQ-5D-
5L = EuroQoL 5-Dimension Health Questionnaire 5 Level; HADS = Hospital Anxiety and Depression Scale; 
IMP = investigational medicinal product; POEM = Patient-oriented Eczema Measure; PRO = patient-reported 
outcome; 
; 
; 
; 
SCORAD = Scoring Atopic Dermatitis; vIGA-AD = Validated Investigator Global Assessment Scale for Atopic 
Dermatitis; 
; WPAI:AD = Work Productivity and Activity Impairment 
Questionnaire: Atopic Dermatitis. 
a Includes 
 
b Treatment emergent AEs (Section 14.3.14.1). 
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7 Trial design 
7.1 
Overall trial design 
Overview 
This is a phase 2 randomized, triple-blind, placebo-controlled, parallel-group, international 
trial to evaluate the efficacy and safety of orally-administered LEO 152020 tablets 
(
 
 and 
 compared with placebo 
tablets for up to 16 weeks of treatment in adults with moderate to severe AD. 
The trial will consist of: 
• A screening period of maximum 5 weeks (at the earliest Week -5 to baseline) including 
a run-in period of 1 week (Week -1 to baseline). 
• A treatment period of 16 weeks (baseline to Week 16). 
• A safety follow-up period of 7 days (Week 16 to Week 17). 
Randomization will take place at baseline. The primary endpoint will be assessed at Week 16. 
The final safety assessments will be conducted at Week 17. 
The subject’s visit schedule and the assessments/procedures to be conducted at each visit are 
presented in Section 4. The trial rationale is presented in Section 5.3 and the scientific 
rationales for trial design are presented in Section 12.1. 
Screening period 
In the screening period, eligibility of the subject to participate in the trial will be evaluated. 
From the screening visit, the subject will be asked to stop any systemic AD treatment 
(Section 8.3 and Section 9.7). 
The screening period will include a run-in period (Week -1 to baseline). From the run-in visit 
(Week -1), the subject will be asked to stop any topical AD treatment with TCS, TCI, PDE4i, 
and/or topical JAK inhibitors and to apply an emollient (background treatment, Section 9.4). 
The subject will be asked to apply the emollient at least twice daily and for at least 7 days 
prior to the planned randomization (baseline). 
At the run-in visit, the subject will receive an eDiary and training in using the device. From 
Week -1, the subject will be asked to complete the eDiary for 7 days prior to randomization 
(Section 11.5.1). 
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At the run-in visit, subjects who consented to participate in wristband actigraphy will receive 
2 actigraphy devices. From Week -1, the subjects will be asked record scratch and sleep data 
with the devices daily (Section 11.7). 
The total duration of the screening period including the run-in period will depend on the time 
needed for washout of the systemic AD treatment(s) by baseline and may last for a maximum 
of 5 weeks, as applicable. It will be recorded in the eCRF if washout was required and which 
treatment(s) were stopped. 
Re-screening of subjects is not allowed unless the screening failure was due to an 
administrative reason (Section 8.4). 
Randomization 
At baseline, the subject will be randomized to 1 of 4 oral treatments as described in 
Section 9.3.1. 
Treatment period 
In the treatment period, the subject will be asked to self-administer LEO 152020 or placebo 
tablets twice daily for 16 weeks (Section 9.2). In this period, the subject will be asked to 
continue applying the emollient as needed and complete the eDiary. If the subject has 
provided additional consent, optional assessments and procedures may apply (see 
Section 11.7). The subject will also be asked to visit the site for assessments and procedures. 
Safety follow-up period 
In the safety follow-up period, the subject will be asked to stop treatment with LEO 152020 
or placebo tablets and the safety of the treatment will further be assessed at the safety 
follow-up visit (Week 17). In this period, the subject may continue applying the emollient as 
needed. Continued treatment of the subject’s AD should at the earliest resume after the safety 
follow-up visit (or the last visit of the subject in the trial for discontinued/withdrawn 
subjects). 
7.2 
Number of subjects needed 
224 subjects (including 28 Japanese subjects) are planned to be randomized in the trial. 
Based on an anticipated screening failure rate of 30-35%, between 292 and 304 subjects 
should be screened for the trial. 
The trial will be conducted at approximately 60 sites in Europe, North America, Japan, and 
Australia. 
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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 will be considered to have completed the trial if they have completed all trial 
periods including the safety follow-up visit at Week 17 (see Section 11.8 for data to be 
recorded on the end-of-trial form). 
The end of the trial is defined as the date of last visit of 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. 
Data monitoring committee 
An independent DMC will assess subject safety and overall trial conduct periodically 
(Appendix 3H). Based on their assessment, the DMC will issue recommendations to 
LEO Pharma as to the pursuit of the trial. Depending on the DMC’s recommendations, 
LEO Pharma may decide to terminate the trial prematurely in interest of subject safety. 
Organization and operation of the DMC will be described in a separate DMC charter. Data to 
be provided to the DMC for their assessment will be described in a separate DMC statistical 
plan. 
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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 according to the schedule of trial procedures (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 
The subjects must fulfil all of the following criteria to be eligible for the trial: 
1. Signed and dated informed consent obtained prior to any protocol-related procedures. 
2. Adult, age 18 years or older at screening. 
3. Diagnosis of chronic AD as defined by the Hanifin and Rajka (1980) criteria for AD 
(36). 
4. History of AD ≥1 year prior to baseline. 
5. Recent (within 6 months prior to baseline) documented history of inadequate response 
to topical AD treatments* or subject for whom topical AD treatments are medically 
inadvisable. 
*Inadequate response to topical AD treatments is defined as failure to achieve and 
maintain remission or a low disease activity state corresponding to 
0 (clear) ≤ IGA ≤ 2 (mild) despite treatment with a daily regimen of TCS of medium 
to high 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). 
6. 7.1≤ EASI ≤50 at baseline. 
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7. vIGA-AD score ≥3 at baseline. 
8. BSA ≥5% at baseline. 
9. Subject agrees to apply an emollient to lesional and non-lesional skin at least twice 
daily for at least 7 consecutive days immediately prior to baseline. 
10. Women of childbearing potential* must use highly effective contraception** from 
randomization to the end of the trial (safety follow-up visit). 
* A woman of childbearing potential is defined as a female subject aged ≥12 years or a 
younger girl who, at the discretion of the investigator, is deemed to be of reproductive 
potential. A woman is defined as not being of childbearing potential if she is 
postmenopausal (at least 12 months with no menses without an alternative medical 
reason prior to screening), or surgically sterile (hysterectomy, bilateral salpingectomy, 
or bilateral oophorectomy). 
**A highly effective method of contraception is defined as one which results in a low 
failure rate (less than 1% per year when used correctly and consistently) such as: 
• Bilateral tubal occlusion. 
• IUD. 
• IUS. 
• Combined (estrogen- 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 lifestyle of 
the subject and not just being without a current partner). 
• Same-sex partner. 
• Vasectomized partner (given that the subject is monogamous). 
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8.3 
Exclusion criteria 
Subjects are not eligible for the trial if they violate any of the following criteria: 
1. Concurrent skin disease at baseline which may interfere with the trial assessments, at 
the discretion of the investigator. 
2. Active skin infection or any other clinically apparent infection at baseline which may 
interfere with the trial assessments, at the discretion of the investigator. 
3. Previous treatment with an oral H4R antagonist (including LEO 152020) within 
6 months prior to baseline. 
4. Previous treatment with 3 or more systemic AD treatments prior to screening. 
5. Systemic treatment including systemic corticosteroids known or suspected to have an 
effect on AD within 4 weeks or 5 half-lives prior to baseline, whichever is longer. 
6. Phototherapy within 4 weeks prior to baseline. 
7. Positive HBsAg, anti-HBs*, anti-HBc, or HCV serology at screening. 
*Subjects with positive anti-HBs are eligible provided that they have a negative 
HBsAg, negative anti-HBc (blood pattern in vaccinated subjects), and negative HCV 
serology. 
8. Current active tuberculosis based on test per local standard at screening. The screening 
for tuberculosis should be done according to guidelines for patients subject to biologic 
treatment as per local standard of care. 
9. Infection with HIV. 
10. History of lymphoproliferative disease or malignancy (except treated and recovered 
non-melanoma skin cancer or cervical carcinoma in situ) within 5 years prior to 
screening. 
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11. Subjects at risk for Torsade de Pointes based on any of the following: 
a. Uncorrected hypokalemia or hypomagnesemia at Week -1, history of cardiac 
failure, history of clinically significant/symptomatic bradycardia. 
b. 
 or family history of idiopathic sudden death. 
12. Use within 5 half-lives prior to screening of concomitant medication for which 
 
 is a known side effect and which cannot be discontinued or replaced by 
(a) safe alternative medication(s). 
13. Resting QTcF (average of a triplicate measurement) <300 ms or >450 ms (men) or 
>460 ms (women) at screening. 
14. Known history of ventricular arrhythmias. 
15. Second- or third degree- atrioventricular block. 
16. Subjects with severe renal impairment as determined by eGFR levels below 
30 mL/min at screening (37). For eGFR levels allowed in Germany and Japan, see 
Appendix 4. 
17. Subjects with medical history of chronic moderate to severe liver disease. 
18. Clinically significant abnormal finding* at screening and/or baseline which, in the 
opinion of the investigator, may: 
a. Affect subject safety and well-being or put the subject at risk because of their 
participation in the trial. 
b. Influence the assessments. 
c. Impede the subject’s ability to complete the trial. 
*Examples include clinically significant abnormal vital sign, physical examination, 
ECG (based on central ECG report), and laboratory result. 
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19. Any unstable medical, surgical, psychiatric, or additional physical disorder* at any 
time during the trial which, in the opinion of the investigator, may: 
a. Affect subject safety and well-being or put the subject at risk because of their 
participation in the trial. 
b. 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. 
20. Known or suspected hypersensitivity to any components of the IMPs or to drugs of a 
similar chemical class. 
21. Treatment with any nonmarketed drug substance (that is, an agent which has not yet 
been made available for clinical use following registration) within 4 weeks or 
5 half-lives of the drug prior to baseline, whichever is longer. 
22. Current participation in any other interventional clinical trial. 
23. Previously screened* in this trial. 
*Re-screening of subjects is not allowed unless the screening failure was due to an 
administrative reason (Section 8.4). 
24. Current or recent chronic alcohol or drug abuse within 12 months prior to screening. 
25. Subjects, who, in the opinion of the investigator, would be noncompliant or unable to 
understand the trial and give adequately informed consent. 
26. Employees of the trial site, any other individuals directly involved with the planning 
or conduct of the trial, or immediate family members of such individuals. 
27. Subjects who are legally institutionalized. 
28. Women who are pregnant, intend to become pregnant, or are lactating. 
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8.4 
Screening and screening failures 
Subject identification number 
Trial participation begins once written informed consent is obtained (Appendix 3B). Once 
informed consent is obtained, a subject ID will be assigned to the subject by a central IRT 
system. 
After a subject ID has been assigned, the screening evaluations to assess eligibility may begin. 
The date of first screening activity can be the same as when informed consent was obtained or 
a later date. The subject ID will be used to identify the subject during screening and 
throughout the trial, if applicable. Subjects who have given written informed consent to 
participate in the trial and who have been assigned a subject ID are considered ‘screened’ 
subjects. 
Investigator logs 
The investigator will maintain a log of all subjects considered for screening, whether they 
provided written informed consent or not (screening log). This log will be anonymous and 
will include the allocated subject ID and the reason(s) for not entering the trial, if applicable. 
In addition, the investigator will maintain a log of all consented subjects (subject 
identification log). This log will include each subject’s identity, date of consent, and 
corresponding subject ID, so that any subject may be identified, if required for any reason. 
The log must not be copied or retained by LEO Pharma. 
Screening failures 
Screening failures are defined as subjects who consent to participate in the trial but who are 
subsequently not randomized to treatment. A minimal set of screening failure information is 
required to ensure transparent reporting of screening failures to meet the CONSORT 
publishing requirements (38) and to respond to queries from regulatory authorities. As a 
minimum, the following data will be recorded in the eCRF for screening failures: 
• Date of informed consent(s). 
• Date of screening failure. 
• Reason for screening failure. 
a. Failure to meet eligibility criteria and which eligibility criterion(ia) was (were) not 
met. 
b. Withdrawal by subject. 
c. Lost to follow-up. 
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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 (S)AEs. 
Any SAE will require expedited reporting as described in Section 13.4. 
Re-screening of screening failures (subjects who did not meet the eligibility criteria for 
participation in the trial) is not allowed. However, 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), re-screening may be 
permitted. This will require approval by the sponsor’s medical expert after thorough review of 
data from the original screening visit in the eCRF. Subjects to be re-screened must sign a new 
ICF. Re-screened subjects will get a new subject ID. In addition, the subject ID from the 
previous screening will be recorded in the eCRF. 
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9 Treatments 
9.1 
Trial products description 
In this trial, the IMPs are (Panel 5): 
• LEO 152020 film-coated tablet 50 mg. 
• LEO 152020 placebo film-coated tablet. 
Panel 5: Identification of investigational medicinal products 
Investigational 
medicinal product 
Dosage form 
Active ingredient and concentration 
Manufacturer 
responsible for batch 
release 
LEO 152020 
film-coated tablet 
50 mg 
Film-coated 
tablet 
 
 
 
LEO Pharma 
LEO 152020 placebo 
film-coated tablet 
Film-coated 
tablet 
Not applicable 
LEO Pharma 
Composition of LEO 152020 film-coated tablet 50 mg is described in the investigator’s 
brochure. LEO 152020 placebo film-coated tablet contains the same ingredients as 
LEO 152020 film-coated tablet, except the active ingredient LEO 152020. 
9.2 
Administration of the 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. At each dispensing 
visit, the IRT system will assign any required kit number(s) to the subject. 
From baseline to Week 16, the subject will be asked to self-administer the IMP at the trial site 
or at their home. The subject will self-administer their first dose of IMP at the site and their 
last dose of IMP at home, in the evening before the Week 16 visit. At the Week 16 visit or the 
last visit in the trial, the investigator or site staff should confirm with the subject the date and 
time of last dose of IMP and record the information in the eCRF. 
Every day between baseline and Week 16, the subject will be asked to take  tablets of IMP: 
 tablets in the 
 and  tablets in the 
 (Panel 6). Administration of the IMP will 
be explained to the subject in separate instructions for use in their language. 
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Administration of the IMP at the trial site 
At the visits indicated in the schedule of trial procedures (Section 4), the subject will be asked 
to self-administer the IMP at the trial site under the supervision of the site staff. At baseline, 
the subject will self-administer the first dose of IMP at the site. At trial visits from Week 1 to 
Week 14, the subject will self-administer their morning dose of IMP at the site. The subject 
will be asked to come fasted to the trial site, i.e. arrive at the site minimum 2 hours after their 
last meal. 
Visits should be scheduled at times to make 
• Fasted state and minimum time of  hours between consecutive doses of IMP feasible 
for the subject. 
• ECG measurement(s) and PK blood sampling feasible for the site staff (see Section 4 
[Panel 2 and Panel 3], Sections 11.4.3 and 11.6.1). 
At each visit from Week 1 to Week 14 before the subject self-administers the IMP, the site 
staff should check if the subject is fasted (i.e. arrived at the trial site minimum 2 hours after 
their last meal) and when they took their last dose of IMP and follow the flowcharts provided 
in Appendix 7. 
Reporting in eCRF 
It will be recorded in the eCRF if the subject was fasted (i.e. had arrived at the trial site 
minimum 2 hours after their last meal). 
Administration of the IMP at the subject’s home 
The subject will be instructed to take 
 doses of IMP 
 hours apart and no less 
than  hours apart. 
If the subject misses a dose of IMP at home 
If the subject misses a dose of IMP at home, they will be instructed to proceed as follows: 
• If at the time the subject becomes aware of the missed dose of IMP, there are more than 
 hours to the next planned dose, the subject should take the missed dose as soon as 
they become aware. 
• If at the time the subject becomes aware of the missed dose of IMP, there are less than 
 hours to the next planned dose, the subject should skip the missed dose and wait until 
the next planned dose of IMP. 
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If the subject misses a visit or a dose of IMP at the trial site 
If the subject misses a visit or a dose of IMP at the trial site, they will be instructed to 
maintain their dosing schedule and, if possible, to take the missed dose of IMP at their home 
instead (Panel 20). 
Precautions pre- and post-dose of IMP at the trial site 
ECGs will be measured pre- and/or post-dose of IMP (Section 11.4.3). 
Provisions for overdose 
The risk of accidental overdose with a clinical consequence is considered low as it would 
involve intake of an unlikely large dose of IMP at once: 
 mg in a single dose (39). This is 
equivalent to  tablets in the LEO 152020 
 treatment group where the 
highest exposure is expected. 
To minimize the risk of accidental overdose, site staff should explain to the subject how to 
self-administer the IMP and instructions for use will be given to the subject to take home. For 
more information about medication errors, including accidental overdose, see Section 13.6.2. 
There are no available data on overdose with LEO 152020. LEO Pharma does not recommend 
any specific treatment in relation to overdose. It will be at the discretion of the investigator to 
take appropriate action to treat and follow up on any accidental overdose. 
9.3 
Treatment assignment and blinding 
9.3.1 
Treatment assignment 
Subjects who comply with all eligibility criteria (Sections 8.1 to 8.3) will be randomized to 
1 of the following oral treatments: 
• LEO 152020 
 
• LEO 152020 
 
• LEO 152020 
 
• Placebo 
. 
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Within the strata defined by baseline disease severity (EASI at baseline) and region (Japan, 
non-Japanese countries), subjects will be randomized in a 4:3:3:4 ratio, using a permuted 
block design. Approximately 30% subjects with EASI between 7.1 and 16 at baseline 
(7.1≤ EASI ≤16) and 70% subjects with EASI between 16.1 and 50 at baseline 
(16.1≤ EASI ≤50) will be randomized in the trial. 
The IRT system will be used to control randomization and to track stratification and IMP 
supply chain and expiry. 
9.3.2 
Blinding 
Triple blinding (subject, investigator, and assessor of the data/study outcome [sponsor]) from 
randomization to formal unblinding of the trial will be applied. 
Investigational medicinal product 
The packaging and labelling of the IMPs will contain no evidence of their identity. 
LEO 152020 film-coated tablets 50 mg and LEO 152020 placebo film-coated tablets have 
been designed to look alike (same size and color) and telling them apart by sensory evaluation 
is not considered possible. 
To ensure blinding across all treatment groups, subjects will be asked to take  tablets of IMP 
daily:  tablets in the 
 and  tablets in the 
 (Section 9.2) as described in 
Panel 6. 
Panel 6: Dosing schedule and treatment composition in each treatment group 
Treatment group 
 dose of IMP 
 dose of IMP 
LEO 152020 
film-coated tablet 
50 mg 
LEO 152020 
placebo 
film-coated tablet 
LEO 152020 
film-coated tablet 
50 mg 
LEO 152020 
placebo 
film-coated tablet 
LEO 152020 
 
LEO 152020 
 
LEO 152020 
 
Placebo
 
Abbreviations: IMP = investigational medicinal product. 
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To avoid medication errors in the LEO 152020 
 treatment group and to 
ensure blinding across all treatment groups, the 
 doses of IMP must 
clearly be identified on the packaging for all treatment groups. Packaging and labelling of the 
IMPs is described in more detail in Section 9.8.1. 
Safety 
During trial conduct, unblinding of an individual subject for emergency or regulatory 
purposes (SUSAR reporting) may be necessary. In such cases, unblinding will strictly be 
limited to the individual(s) needed to conduct the unblinding procedure. No unblinded safety 
data will be shared with the rest of the clinical team before DBL. For more information about 
emergency unblinding, see Section 9.3.3. 
Subject safety and overall trial conduct will be monitored by an external unblinded DMC not 
involved in trial conduct as described in a separate DMC charter (see also Appendix 3H). In 
their interactions with the sponsor, the DMC will not share unblinded data. 
Pharmacokinetics and pharmacodynamics 
PK and PD samples will be collected for all subjects as part of the general blood work in the 
trial. Skin biopsies are an optional component of the trial and will be collected for a subgroup 
of subjects randomly and without knowledge of treatment allocation (Section 11.7.3). 
PK blood samples of subjects treated with LEO 152020 will be analyzed by an external 
unblinded, specialized laboratory not involved in trial conduct. During the trial, raw PK data 
will be reviewed by an unblinded monitoring scientist at the sponsor to ensure data quality. In 
this context, unblinding means knowing the link between subject ID and treatment allocation 
only. No unblinded PK data will be shared with the clinical team at the sponsor before DBL. 
All PD blood samples and skin biopsies will be analyzed by an external unblinded, 
specialized laboratory not involved in trial conduct. No unblinded PD data will be shared with 
the sponsor clinical team before DBL. 
Data monitoring 
Until DBL, data monitoring at the sponsor will be conducted on blinded data. 
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9.3.3 
Emergency unblinding of individual subject treatment 
While safety of the subject always comes first, it is still important to carefully consider if 
unblinding is necessary to ensure subject safety. An emergency unblinding request can be 
made by the investigator, HCPs who are not members of the site staff, or authorized 
LEO Pharma personnel. 
Provisions are in place for 24-hour emergency unblinding of individual subject treatment. If 
emergency unblinding is required, the investigator can unblind a subject’s treatment via the 
unblinding IRT system or unblinding CRO. 
For a requester who is not a member of the site staff and who does not have access to the IRT 
system (e.g. a physician in an emergency room), a local contact number for the emergency 
unblinding CRO will be provided on the subject card (Appendix 3B) to be used if the 
investigator or delegated site staff cannot be reached. In such case, 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 contact 
information for the LEO Pharma 24/7 medical cover. 
9.4 
Background treatment 
The subject will be asked to apply an emollient on lesional and non-lesional skin from 
Week -1 to Week 16. 
In the run-in period (Week -1 to baseline), the subject should apply the emollient at least 
twice daily for at least 7 consecutive days immediately prior to randomization. 
In the treatment period (baseline to Week 16), the subject will be asked to apply the emollient 
as needed. 
In the safety follow-up period (Week 16 to Week 17), the subject may continue applying the 
emollient as needed. 
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The emollient should preferably be a basic, bland, additive-free emollient. The emollient 
should preferably not contain additives such as ceramide, hyaluronic acid, urea, polidocanol, 
or filaggrin. 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-moisturized in the absence of systemic and/or topical AD 
treatment(s) in the run-in period (Week -1 to baseline) and the safety follow-up period 
(Week 16 to Week 17). 
• Act as a complement to systemic treatment with the IMP (standard of care) and keep the 
subject’s skin well-moisturized in the treatment period (baseline to Week 16). 
9.5 
Rescue treatment 
If medically necessary (i.e. to control intolerable worsening of AD symptoms), rescue 
treatment of AD may be provided to the subject at the discretion of the investigator. If 
possible, the investigator should attempt to limit the first step of rescue treatment to topical 
treatment and escalate to systemic treatment if the subject does not respond adequately to 
topical rescue treatment. 
Topical rescue treatment 
In this trial, topical rescue treatment of AD consists of TCS and TCI. Subjects provided with 
topical rescue treatment between first dose of IMP and Week 16 may continue treatment with 
the IMP and remain in the trial with no change to the visit schedule nor trial 
assessments/procedures. 
Systemic rescue treatment. 
If the subject is provided with systemic rescue treatment of AD at any time during the 
treatment period, treatment with IMP will immediately and permanently be discontinued (see 
also Section 9.7 for prohibited medications). 
Before administering topical or systemic rescue treatment, the investigator may conduct 
efficacy and safety assessments (e.g. disease severity scores [EASI, vIGA-AD, and 
SCORAD], AEs, safety laboratory samples, PK blood sample, and concomitant 
medications/concurrent procedures). However, to safeguard subject safety and well-being, the 
assessments should only be conducted if the subject’s health permits. To further attend to 
subject safety and well-being, an unscheduled visit , scheduled earlier than the next planned 
visit, may be arranged to administer the topical or systemic rescue treatment. 
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If the subject is permanently discontinued from IMP due to use of systemic rescue 
medication, every effort must be done to monitor the subject as described in Section 10.3. 
9.6 
Concomitant medications 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 medication for AD. In case of rescue 
medication for AD, a specification of the reason for lack of efficacy of the IMP should 
be provided: 
o Lack of efficacy on itch. 
o Lack of efficacy on visible AD symptoms. 
o Lack of efficacy on both itch and visible AD symptoms. 
o Other (if other, a specification should be provided). 
• Indication. 
• Start and stop dates of administration (it will also be recorded if the medication is 
ongoing). 
• Dosage information, including dose per administration, unit, and frequency. 
• Route of administration: oral, cutaneous, subcutaneous, transdermal, ophthalmic, 
intramuscular, respiratory (inhalation), intralesional, intraperitoneal, nasal, vaginal, 
rectal, intravenous, or other (if other, a specification should be provided). 
Any concurrent procedure conducted within 3 months prior to screening must be recorded in 
the subject’s medical record and the eCRF with details such as: 
• Procedure name (including anatomical area, if relevant). 
• Indication. 
• Start and stop dates (it will also be recorded if the procedure is ongoing). 
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Investigators may prescribe concomitant medications or treatments to provide adequate 
supportive care, at their discretion. Concomitant medication for conditions other than AD 
(except prohibited medications) may be continued during the trial without dosage change 
whenever possible. 
9.7 
Prohibited medications and procedures 
The medications and procedures listed in Panel 7 and Appendix 8 are prohibited during the 
trial. Prohibited medications and procedures prior to and during screening are also listed 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). 
Prohibited topical medications used as rescue treatment of intolerable AD symptoms are 
allowed (Section 9.5). Such use of prohibited topical medications does not constitute a 
protocol deviation. 
Panel 7: Prohibited medications and procedures 
Medication 
Prohibited from 
Prohibited to 
Allergen immunotherapy 
Within 5 half-lives prior to baseline 
Week 17 
(safety follow-up) 
H4R antagonist (oral) 
Within 6 months prior to baseline 
(exclusion criterion 3) 
Week 17 
Immunoglobulin or blood product 
Within 5 half-lives prior to baseline 
Week 17 
Investigational agents other than 
LEO 152020 
Within 4 weeks or 5 half-lives prior 
to baseline, whichever is longer 
Week 17 
Live (attenuated) vaccine 
Baseline 
Week 17 
Medication for which 
 is a 
known side effect 
Within 5 half-lives prior to screening 
Week 17 
Medications known to inhibit the 
 
 a 
Within 5 half-lives prior to baseline 
Week 17 
Medications known to inhibit the 
 
 b 
Within 5 half-lives prior to baseline 
Week 17 
Medications known to inhibit the 
 
 c 
Within 5 half-lives prior to baseline 
Week 17 
Retinoids 
Within 4 weeks prior to baseline 
Week 17 
Systemic AD treatments 
Within 4 weeks or 5 half-lives prior 
to baseline, whichever is longer 
Week 17 
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Medication 
Prohibited from 
Prohibited to 
Systemic anti-histamines d 
Within 4 weeks or 5 half-lives prior 
to baseline, whichever is longer 
Week 17 
Systemic corticosteroids e 
Within 4 weeks or 5 half-lives prior 
to baseline, whichever is longer 
Week 17 
Systemic 
immunosuppressive/immunomodulatory 
treatment (e.g. azathioprine, cyclosporine, 
dupilumab (or other biologics), 
interferon-gamma, JAK inhibitors, 
methotrexate, mycophenolate mofetil) 
Within 4 weeks or 5 half-lives prior 
to baseline, whichever is longer 
Week 17 
TCS/TCI, except if used as rescue treatment Week -1 
Week 16 
(end of treatment) 
Other topical AD treatments 
Week -1 
Week 17 
Topical antibiotics f 
Week -1 
Week 16 
Procedure 
Prohibited from 
Prohibited to 
Bleach bath 
Within 4 weeks prior to baseline 
Week 16 
UVA, UVA1, UVB, NBUVB, PUVA 
therapy, other phototherapy, or tanning beds 
Within 4 weeks prior to baseline 
Week 17 
Abbreviations: AD = atopic dermatitis; 
; H4R = histamine receptor 4; 
JAK = Janus kinase; NBUVB = narrow-band ultraviolet B; 
; 
; PUVA = psoralen + ultraviolet A; 
; TCI = topical calcineurin inhibitor(s); 
TCS = topical corticosteroid(s); UVA = ultraviolet A; UVA1 = ultraviolet A1; UVB = ultraviolet B. 
a, b, c See Appendix 8. 
d Locally-administered anti-histamines (e.g. eye drops, nasal spray) are allowed. 
e Inhaled or intranasal steroids at doses up to 1 mg prednisone/day are allowed. 
f Except if used on small lesional areas. 
9.8 
Treatment logistics and accountability 
9.8.1 
Labelling and packaging of trial products 
The IMPs will be packaged in individually numbered kits according to the principles of 
blinding described in Section 9.3.2 (Panel 6). 
 doses of IMP must clearly 
be identified on the packaging for all treatment groups. 
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 (40), local 
regulations, and trial requirements. Label text will be translated into local languages as 
required. 
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9.8.2 
Shipping of trial products 
Initial shipment of IMPs for each trial site will be triggered by first subject screened at the 
site. 
9.8.3 
Storage of trial products 
At the trial site, 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. 
At the trial site, the IMP must be stored ≤25°C/77°F and must not be refrigerated nor frozen. 
Storage of IMP may be delegated, e.g. to a hospital pharmacy, as locally applicable and must 
be documented in the site signature and designation of responsibility log. 
Temperature of the storage facilities at the trial site should be monitored using 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 conditions 
and storage facilities should be checked at least every working day. 
Damaged IMP should be documented in the IRT system. Damaged IMP may not be dispensed 
to the subject. 
Storage of the IMP at the subject’s home will be described in separate instructions for use for 
the subject to take home. 
9.8.4 
Accountability of the investigational medicinal products 
The investigator is fully responsible for the IMPs at the trial site and for maintaining adequate 
control of the IMPs and documenting all transactions with them. 
The IMP will be dispensed to the subject using an IRT system. Dispensing of the IMP may be 
delegated, e.g. to a hospital pharmacy, as locally applicable and must be documented in the 
Site Signature and Designation of Responsibility Log. 
At each visit after baseline, the subject will be asked to return all (partly) used and unused 
IMP kits. Returned IMP need not be stored at the trial site at the storage temperature specified 
in Section 9.8.3 but must be stored separately from non-allocated IMP. 
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All returned IMP kits will fully be accounted for by the site staff in the IRT system (see 
separate trial product handling manual for more information). The IRT system will also 
maintain the inventory status of all IMP kits at the trial site (see separate IRT manual for more 
information on how to update kit status in the IRT system). 
All returned IMP tablets will fully be accounted for by the site staff. Documentation of IMP 
accountability must be kept for the IMP dispensed to each subject randomized in the trial. 
This documentation must be available during monitoring visits and will be checked by the 
CRA to verify correct dispensing of the IMPs. 
Reporting in eCRF 
It will be recorded in the eCRF how many morning doses and how many evening doses of 
IMP were taken from the dispensed kit. 
9.8.5 
Treatment compliance 
Treatment compliance for IMP taken at the site 
Treatment compliance for IMP taken at the site will be accounted for in the eCRF (see 
reporting in eCRF below). 
Treatment compliance for IMP taken at the subject’s home 
Treatment compliance for IMP taken at the subject’s home will be determined based on IMP 
accountability. At each visit between baseline and Week 16, all returned IMP tablets will fully 
be accounted for by the site staff (Section 9.8.4). In case of non-compliance with 
administration of the IMP at the subject’s home, the investigator or site staff should remind 
the subject of the importance of adhering to the dosing schedule. 
Reporting in eCRF 
It will be recorded in the eCRF if IMP was taken at the site. If not, a reason should be 
provided. Date and time of IMP administration will also be recorded. 
9.8.6 
Trial products destruction 
All IMP kits ([partially] used and unused) must be returned to the CMO for destruction 
according to approved procedures and/or local requirements. 
Empty kits, i.e. not containing any IMP (only packaging material), may be destroyed at the 
trial site. 
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9.9 
Provision for subject care following trial completion 
To ensure appropriate treatment of the subject after completion of the trial, the subject will be 
treated at the discretion of the investigator or referred to (an)other physician(s) according to 
standard practice. 
9.10 Reporting product complaints 
Any defects or issues with the IMP including use errors and inadequate labelling must be 
reported to the Quality Department via Global Safety at LEO Pharma on the trial-specific 
(paper) complaint form within 3 days of first knowledge. 
Critical complaints (defined as any defect, issue, that has or potentially could have a serious 
impact on the subject [e.g. SAE]) must be reported to the Quality Department via Global 
Safety within 24 hours of knowledge. 
Complaint forms should contain a detailed description of the defect, issue, including whether 
it led to an AE. (S)AEs which occur due to a defect or issue with the IMP will be reported by 
the investigator as described in Section 13.3 and Section 13.4. 
During the investigation of the product complaint, the IMP must be stored at labelled 
conditions unless otherwise instructed. The trial site will be notified whether the IMP needs to 
be returned for further investigation or may be destroyed. 
Global Safety, LEO Pharma contact information for reporting product complaints: 
E-mail address: drug.safety@leo-pharma.com. 
Fax number: +45 7226 3287. 
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10 Discontinuation and withdrawal 
10.1 General principles 
If the subject, the investigator, or LEO Pharma considers that it is not in the subject’s best 
interest to continue treatment with the IMP or participate in the trial altogether, a subject may 
at any time: 
• Permanently discontinue IMP (but continue to participate in trial-related activities as 
described in Section 10.3). 
• Or withdraw from the trial (and thereby stop participating in further trial-related 
activities. Subjects will be encouraged to attend safety assessments to the extent 
possible to leave the trial in all safety [Section 10.3]). 
Subjects who permanently discontinue IMP or withdraw from the trial 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 permanent discontinuation of investigational medicinal 
product 
Subjects will permanently discontinue IMP in the event of: 
• Evidence of pregnancy. 
• An AE that, in the opinion of the investigator or sponsor’s medical expert, 
contraindicates further dosing. 
• Initiation of systemic rescue treatment of AD. 
• Initiation of prohibited medication (except topical medications used as rescue treatment 
of AD) which cannot be safely replaced by other non-prohibited medications. 
• QTcF >500 ms or increase in QTcF from baseline >60 ms. 
• Other reasons, at the discretion of the investigator. If other, a specification should be 
provided. 
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Reporting in eCRF 
The primary reason for permanent discontinuation of IMP must be recorded in the subject’s 
medical record and on the end of treatment form in the eCRF where the following options are 
available: 
• Death. 
• Pregnancy. 
• Adverse event (if adverse event, a specification must be provided). 
• Lack of efficacy. If lack of efficacy, a specification of the reason for lack of efficacy of 
the IMP must be provided: 
o Lack of efficacy on itch. 
o Lack of efficacy on visible AD symptoms. 
o Lack of efficacy on both itch and visible AD symptoms. 
o Other (if other, a specification must be provided). 
• Withdrawal by subject. 
• Lost to follow-up. 
• Other (if other, a specification must 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. 
For reasons for withdrawal from the trial, see in Section 11.8, End of trial form. 
10.3 Early termination assessments 
Assessments/procedures to be conducted at the visits below are listed in the schedule of trial 
procedures (Section 4). 
Permanent discontinuation of IMP 
Subjects who permanently discontinue IMP prior to Week 16 will be asked to attend: 
• An early termination visit as soon as possible after last dose of IMP. 
• The primary endpoint visit (nominal), 16 weeks after first dose of IMP. 
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See also Section 10.4 for the continued assessment of discontinued subjects. 
Withdrawal from trial 
Subjects who withdraw from the trial prior to randomization will be considered screening 
failures 
Subjects who withdraw from trial after randomization will be asked to attend: 
• An early termination visit as soon as possible after last dose of IMP. 
• A safety follow-up visit (7 days after last dose of IMP). 
A subject, who at the earliest can come to the early termination visit 3 days after last dose of 
IMP or later, should only be asked to attend the early termination visit. 
If the subject agrees, the investigator will review any AEs which will be followed up as 
described in Section 13.7. 
10.4 Continued assessment of subjects after permanent discontinuation of 
investigational medicinal product 
Subjects who permanently discontinue IMP prior to Week 16 should be encouraged to 
continue participating in the trial and to follow their visit schedule to the extent possible. 
10.5 Lost to follow-up 
A subject will be considered lost to follow-up if they repeatedly fail to return for scheduled 
visits and if the trial site is not able to get in contact with them. 
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 remind the subject of the importance of respecting the visit schedule. 
The trial site should also ascertain whether 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). At visits with ECG measurement(s) and/or PK blood sample(s), the 
sequence of assessments presented in Panel 3 must be followed. 
Subjects will be under the careful supervision of a principal investigator who must be a 
dermatologist or allergist. Investigators must be physicians and have experience in treating 
atopic dermatitis as well as documented experience with and/or training in the assessments 
used in the trial. In the US, advanced registered nurses may be investigators (but not principal 
investigators). 
AEs must be assessed by medically qualified personnel (Section 13.2). 
11.2 Screening/baseline assessments 
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). 
• Ethnic origin (self-reported by the subject, Hispanic or Latino, not Hispanic or Latino), 
as allowed by local legislation. 
• Race: American Indian or Alaska native, Asian, Asian Japanese, Black or African 
American, native Hawaiian or other Pacific islander, White, other (if other, a 
specification should be provided). 
At baseline, only age will be recorded on the randomization form (Section 4). 
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11.2.2 
Body measurements (height and weight) 
Height and weight will be recorded according to the schedule of trial procedure (Section 4). 
The subject’s height (without shoes) and the subject’s weight (in indoor clothing and without 
shoes) will be measured. 
11.2.3 
Medical history 
Medical history will be recorded according to the schedule of trial procedures (Section 4). 
Atopy history (age at onset of AD, and previous AD treatments) as well as other relevant 
medical and surgical history, including concurrent diagnoses within 12 months prior to 
baseline, will be recorded. 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 
Body surface area involvement 
BSA affected by AD will be assessed according to the schedule of trial procedures (Section 4) 
as component A of SCORAD (see Section 11.3.3). 
11.2.5 
Other screening assessments 
Hepatitis B and C, and HIV testing will be conducted according to the schedule of trial 
procedures (Section 4). Tuberculosis testing will be per local standard of care (see exclusion 
criterion 8). If the tuberculosis test cannot be analyzed locally, it should be sent to the central 
laboratory. 
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). The assessment will be based on the condition of the disease at the time of 
evaluation and not in relation to the condition at a previous visit. 
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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 8. Briefly, the 
investigator will assess the severity of 4 AD disease characteristics (erythema, 
induration/papulation, excoriation, and lichenification) on the 4 body regions (head/neck, 
trunk, upper extremities, and lower extremities). Severity will be assessed using the severity 
score scale presented in Panel 9. For each body region, a severity sum score will be calculated 
and multiplied by an area score (Panel 9) and a weighting factor. The EASI score equals the 
sum of scores obtained for each body region (Panel 8) (41). 
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. 
Panel 8: Calculation of the Eczema Area and Severity Index (EASI) 
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 (42). 
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Panel 9: Eczema Area and Severity Index (EASI) 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-score 0.5 is not allowed. Half-scores 
1.5 and 2.5 are allowed (42). 
 
4 
50% to 69% affected area 
 
5 
70% to 89% affected area 
 
6 
90% to 100% affected area 
 
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). vIGA-AD is based on a 5-point scale ranging from 0 (clear) to 4 (severe) 
(Panel 10) (43). 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 score will be recorded in the eCRF. 
Panel 10: Validated Investigator Global Assessment Scale for Atopic Dermatitis 
(vIGA-AD) 
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, 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 and crusting may be present. 
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11.3.3 
Scoring Atopic Dermatitis (SCORAD) 
SCORAD will be assessed by the investigator according to the schedule of trial procedures 
(Section 4). The assessment will be based on the condition of the disease at the time of 
evaluation and not in relation to the condition at a previous visit. 
SCORAD scores range from 0 to 103 with higher scores indicating a more severe or more 
extensive condition. The assessment consists of 3 components: A=extent, B=intensity, and 
C=subjective symptoms (44). 
Extent (A) 
The extend of AD will be assessed by the investigator for each body region (the numbers in 
brackets indicate the highest possible score for each region): head and neck (9%), anterior 
trunk (18%), back (18%), upper limbs (18%), lower limbs (36%), and genitals (1%). The 
extend of AD is the sum of scores of all body regions and the maximum score is 100%. 
Intensity (B) 
The intensity of 6 specific symptoms of AD (erythema, edema/papulation, oozing/crusting, 
excoriation, lichenification, and dryness) will be assessed by the investigator. The first 
5 symptoms will be assessed on an average representative area using the following scale: 
• 0=None/absent. 
• 1=Mild. 
• 2=Moderate. 
• 3=Severe. 
Dryness will be assessed on non-lesional skin. 
The intensity score is the sum of intensity scores of the 6 symptoms and the maximum score 
is 18. 
Subjective symptoms (C) 
Average itch and sleeplessness over the last 3 days/nights will be assessed by the subject on a 
visual analogue scale, where 0 means no itching (or no trouble sleeping) and 10 means 
unbearable itching (or a lot of trouble sleeping). The subjective symptom score is the sum of 
the itch and sleeplessness scores and the maximum score is 20. 
SCORAD is calculated as A/5 + 7B/2 + C. 
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Reporting in eCRF 
Components A, B, and C will be recorded in the eCRF. 
11.3.4 
Atopic Dermatitis Symptom Diary (ADSD, eDiary) 
ADSD is considered a subject’s assessment of efficacy. ADSD is a 9-item sign and symptom 
diary developed by LEO Pharma. It assesses the severity of 
 
. The subject assesses 
the severity of each symptom ‘at its worst’ over the past 24 hours using an 11-point NRS, with 
anchors at 0=‘no [symptom]’ and 10=‘worst possible [symptom]’. 
From Week -1 to Week 16, ADSD will be completed by the subject on the eDiary daily. An 
overview of all PROs, including other PROs collected in the eDiary and PROs collected at the 
trial site, is presented in Section 11.5.1. 
11.4 Safety assessments 
11.4.1 
Vital signs 
Vital signs (resting blood pressure, pulse, and body temperature) will be measured according 
to the schedule of trial procedures (Section 4) 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 (abnormal) value, the second measurement should be 
considered false and the third measurement should be recorded in the eCRF. Only the last 
measurement considered true should be recorded in the eCRF. 
In case of an abnormal clinically significant vital sign at screening and/or baseline, it will be 
at the discretion of the investigator if the subject should be randomized in the trial in 
accordance with exclusion criterion 18. During the trial, if a subject presents with an 
abnormal clinically significant vital sign, the investigator must take appropriate action, at their 
discretion. 
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Reporting in eCRF 
Vital signs will be recorded in the eCRF and if not measured, a reason should be provided. 
Abnormal clinically significant vital signs at screening and baseline will be documented as 
medical history in the eCRF. At subsequent visits, any new abnormal clinically significant 
vital signs, symptoms, or illnesses, as well as any clinically significant deterioration of a 
pre-existing condition after randomization will be reported as an AE as described in 
Section 13.3. 
11.4.2 
Physical examination 
A physical examination of the subject including general appearance, regional lymph nodes, 
and dermatologic examination must be conducted according to the schedule of trial 
procedures (Section 4). If clinically indicated, ad hoc physical examination may be conducted 
at any time during the trial. 
In case of an abnormal clinically significant finding during physical examination at screening 
and/or baseline, it will be at the discretion of the investigator if the subject should be 
randomized in the trial in accordance with exclusion criterion 18. During the trial, if a subject 
presents with an abnormal clinically significant 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. 
Abnormal clinically significant findings during physical examination at screening and 
baseline except findings related to AD will be documented as medical history in the eCRF. At 
subsequent visits, any new abnormal clinically significant findings, symptoms, or illnesses, as 
well as any clinically significant deterioration of a pre-existing condition after randomization 
will be reported as an AE as described in Section 13.3. 
11.4.3 
Electrocardiography 
ECGs must be measured according to the schedule of trial procedure and special attention 
should be paid to timing of measurements (see Section 4, Panel 2 and Panel 3, for more 
information). 12-lead resting digital ECGs will be recorded after the subject has been in 
supine position for at least 5 minutes. 
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At an unscheduled visit, it will be at the discretion of the investigator if an ECG should be 
measured. 
The investigator must evaluate each ECG for immediate subject safety and date and sign their 
evaluation. In case of a suspected abnormal ECG, the investigator must take appropriate 
action, at their discretion. 
All ECG data will be transferred to a central ECG service company for central evaluation. At 
the service company, a cardiologist will analyze and interpret the ECG data and provide ECG 
evaluation reports to the trial sites. 
The investigator must review the ECG reports and evaluate all abnormal ECGs (clinically 
significant or not clinically significant). The investigator must document their review by 
signing the ECG reports at the trial site. The investigator is ultimately responsible for judging 
the clinical significance of any abnormal ECG. However, 
 >450 ms (men) and 
 >460 ms (women) are considered clinically relevant 
 and should 
therefore be reported as AEs as described in Section 13.6.1. 
If a subject presents with a severe 
, i.e. 
 >500 ms or an increase in 
 from baseline >60 ms, the ECG should be repeated. If the 
 or increase in 
 
from baseline is confirmed: 
• A PK sample (if not already planned at the visit) must be taken close to the last 
measured ECG. 
• The subject must permanently be discontinued from IMP. 
If the subject presents with a moderate 
, i.e. 480 ms< 
 ≤500 ms or 
30 ms< increase in 
 from baseline ≤60 ms, the ECG should be repeated. If the 
 or 
increase in 
 from baseline is confirmed: 
• A PK sample (if not already planned at the visit) must be taken close to the last 
measured ECG. 
• A post-dose ECG and post-dose PK sample must be taken as described in Panel 3 for 
Week 1 at every visit onwards and as long as the subject presents with the moderate QT 
prolongation. 
If the subject returns to 
 ≤480 ms (mild 
 or normal 
 interval) and 
increase in 
 from baseline ≤30 ms, the ECG and PK monitoring schedule described in 
Section 4 should be followed again. 
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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. 
It will also be recorded if the subject was fasted (i.e. had arrived at the trial site minimum 
2 hours after their last meal). The investigator’s evaluation of ECG result (normal, abnormal 
not clinically significant, abnormal clinically significant) must also be recorded. 
Before first dose of IMP, any abnormal clinically significant or clinically relevant ECG 
finding will be documented as medical history in the eCRF. After first dose of IMP, any new 
abnormal clinically significant or clinically relevant ECG finding, symptoms, or illnesses, as 
well as any clinically significant deterioration of a pre-existing condition will be reported as 
an AE as described in Section 13.3. 
11.4.4 
Laboratory testing 
11.4.4.1 Overview 
Blood and urine samples will be collected according to the schedule of trial procedures 
(Section 4) and the evaluations listed in Panel 11 will be conducted by the central laboratory. 
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Panel 11: Clinical laboratory tests 
Clinical chemistry 
Hematology 
Alanine aminotransferase 
Albumin 
Alkaline phosphatase 
Aspartate aminotransferase 
Bilirubin 
Calcium 
Cholesterol 
LDL cholesterol 
HDL cholesterol 
Creatinine 
Gamma glutamyl transferase 
Magnesium 
Potassium 
Protein 
Sodium 
Urea nitrogen 
Basophils 
Eosinophils 
Hematocrit 
Hemoglobin 
Leukocytes 
Lymphocytes 
Monocytes 
Neutrophils 
Thrombocytes 
Serology 
Tuberculosis test 
Hepatitis B virus core antibody 
Hepatitis B virus surface antibody 
Hepatitis B virus surface antigen 
Hepatitis C virus antibody 
HIV-1 antibody 
HIV-2 antibody 
Per local standard at screening (see exclusion 
criterion 8) 
Urinalysis 
Pregnancy test a 
Glucose 
Ketones 
Leukocytes 
Nitrite 
Occult blood 
Protein 
Choriogonadotropin beta 
Urine pregnancy test b 
Abbreviations: HDL = high density lipoprotein; HIV = human immunodeficiency virus; LDL = low density 
lipoprotein. 
a Women of childbearing potential only. 
b A positive urine pregnancy test must be verified with a serum pregnancy test. 
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11.4.4.2 Investigator evaluation of laboratory samples 
Laboratory samples sent to the central laboratory 
Clinical chemistry, hematology, serology, and urinalysis will be analyzed by a central 
laboratory which will provide results to the trial sites. Laboratory parameters will be classified 
as low, normal, or high, depending on whether the value is below, within, or above the 
reference range. The investigator must evaluate all results outside the reference range 
(clinically significant or not clinically significant) and sign and date their evaluation which 
will be archived in the investigator’s trial file. 
In case of an abnormal clinically significant laboratory result at screening and/or baseline, it 
will be at the discretion of the investigator if the subject should be randomized in the trial in 
accordance with exclusion criterion 18. 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 interpretation of a positive test result for 
Hepatitis B, Hepatitis C, or HIV, these will be conducted by the central laboratory. Subjects 
with a positive serology or tuberculosis test at screening should be referred to a competent 
health care structure for treatment and follow-up. 
Serum pregnancy tests for women of childbearing potential will be analyzed by a central 
laboratory which will provide results to the trial sites. 
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 conducted at the trial site 
Subjects with a positive tuberculosis test conducted at the trial site at screening should be 
referred to a competent health care structure for treatment and follow-up. 
Urine samples will be tested with a dipstick at the trial site. It will be at the discretion of the 
investigator if a urine sample should be sent to the central laboratory for further analysis. 
Urine pregnancy tests for women of childbearing potential will be conducted at the trial sites. 
A positive urine pregnancy test must be verified with a serum pregnancy test. 
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Reporting in eCRF 
It will be recorded in the eCRF if a blood sample was collected. 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. 
Abnormal clinically significant laboratory results at screening, Week -1, and baseline will be 
documented as medical history in the eCRF. At subsequent visits, any new abnormal clinically 
significant laboratory results, symptoms, or illnesses, as well as any clinically significant 
deterioration of a pre-existing condition after randomization will be reported as an AE as 
described in Section 13.3. 
11.5 Patient-reported outcomes 
11.5.1 
Overview 
During the trial, the subject will be asked to assess their perception of AD by means of PROs. 
PROs considered subject assessment of efficacy are described in Section 11.3.4. Other PROs 
used in the trial are described in the subsections below. 
At the screening visit, subject eligibility to participate in the trial must be confirmed before 
any PROs are completed. 
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At Week -1, the subject will receive an eDiary and training in using the device. From Week -1 
to Week 16, the subject will be asked to complete the eDiary twice daily once in the morning 
and once in the evening as described below. The following PROs will be completed in the 
morning: 
• Nocturnal 
 (Section 11.5.2). 
• Difficulty 
 (Section 11.5.3). 
• Frequency of 
 During the Night (Section 11.5.4). 
• 
 (Section 11.5.5). 
• 
 (Section 11.5.6). 
ADSD (all components, see Section 11.3.4) will be completed in the evening. 
Between Week -1 and Week 16, an automatic alarm will inform the investigator/site staff 
about non-compliance with eDiary completion. In case of non-compliance, the investigator 
should remind the subject of the importance of completing the eDiary daily. 
Subjects will be asked to return the eDiary at Week 16 or at their last visit in the trial. 
The subject will be asked to complete the following PROs on an electronic device at the trial 
site according to the schedule of trial procedures (Section 4): 
• POEM. 
• DLQI. 
• EQ-5D-5L. 
• WPAI:AD. 
• HADS. 
• PGI-S 
o ADSD. 
o 
 
o Nocturnal 
 
o Difficulty 
. 
o Frequency of 
 During the Night. 
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o 
 
o 
 
• PGI-C 
o ADSD. 
o 
 
o Nocturnal 
 
o Difficulty 
 
o Frequency of 
 During the Night. 
o 
 
o 
 
11.5.2 
Nocturnal 
 (eDiary) 
Nocturnal 
 is a single item questionnaire designed to assess how much the subject 
 during the past night. It will be assessed on a 6-point categorical 
scale (‘none of the night’, ‘a little of the night’, ‘some of the night’, ‘a lot of the night’, ‘all of 
the night’, ‘I don't know’). The subject will be asked to assess Nocturnal 
 in the 
eDiary daily. 
11.5.3 
Difficulty 
 (eDiary) 
Difficulty 
 is a single item questionnaire designed to assess the subject’s 
difficulty 
 the past night. It will be assessed on a 5-point 
categorical scale (‘not difficult’, ‘a little difficult’, ‘moderately difficult’, ‘extremely difficult’, 
‘I don’t know’). The subject will be asked to assess Difficulty 
 in the eDiary 
daily. 
11.5.4 
Frequency of 
 During the Night (eDiary) 
Frequency of 
 During the Night is a single item questionnaire designed to assess 
how many times the subject 
 the past night. It will be assessed 
on a 5-point categorical scale (‘not at all’, ‘
 1 time’, ‘
 2 times’, ‘
 
3 times or more’, ‘I don’t know’). The subject will be asked to assess Frequency of 
 
 During the Night in the eDiary daily. 
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11.5.5 
, eDiary) 
 is a single item questionnaire designed to assess for how long the subject was 
 
. It will be assessed on a 7-point categorical scale (‘I did 
not 
’, ‘30 minutes or less’, ‘more than 30 min but less than 
1 hour’, ‘more than 1 hour but less 2 hours’, ‘more than 2 hours but less than 3 hours’, 
‘3 hours or more’, ‘I don't know’). The subject will be asked to assess 
 in the eDiary 
daily. 
11.5.6 
 (eDiary) 
 is a single item questionnaire designed to assess how much of the 
 
. It will be assessed on 6-point categorical scale (‘none of the 
 ‘a little 
of the 
 ‘some of the 
 ‘a lot of the 
 ‘all of the 
 ‘I don't know’). The 
subject will be asked to assess 
 in the eDiary daily. 
11.5.7 
Patient-Oriented Eczema Measure (POEM, at trial site) 
POEM consists of 7 items, each addressing a specific symptom (itching, sleep, bleeding, 
weeping, cracking, flaking, and dryness). The subject will be asked to score how often they 
experienced each symptom over the past week on a 5-point categorical scale (0=‘no days’, 
1=‘1 to 2 days’, 2=‘3 to 4 days’, 3=‘5 to 6 days’, 4=‘every day’). The total score (0 to 28) is 
the sum of the 7 items and reflects disease-related morbidity with higher scores indicating 
more severe symptoms (45). The subject will be asked to complete POEM on an electronic 
device at the trial site according to the schedule of trial procedures (Section 4). 
11.5.8 
Dermatology Life Quality Index (DLQI, at trial site) 
DLQI consists of 10 items addressing the subject’s perception of the impact of their skin 
disease on different aspects of their quality of life over the past week such as 
dermatology-related symptoms and feelings, daily activities, leisure, work or school, personal 
relationships, and the treatment. Each item will be scored on a 4-point Likert scale (0=‘not at 
all/not relevant’, 1=‘a little’, 2=‘a lot’, 3=‘very much’). The total score (0 to 30) is the sum of 
the 10 items with higher scores indicating a poorer quality of life (46). The subject will be 
asked to complete DLQI on an electronic device at the trial site according to the schedule of 
trial procedures (Section 4). 
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11.5.9 
EuroQol 5-Dimension Health Questionnaire 5 Level (EQ-5D-5L, 
at trial site) 
 EQ-5D-5L is a self-administered questionnaire used to assess health status ‘today’ and is 
divided into 2 sections. The first section includes 5 dimensions (mobility, self-care, usual 
activity, pain/discomfort, and anxiety/depression). Each dimension is assessed using a 5-point 
categorical scale (‘no problems’, ‘slight problems’, ‘moderate problems’, ‘severe problems’, 
and ‘extreme problems’). The second section consists of a vertical visual analogue scale 
anchored at 0 (‘the worst health you can imagine’) and 100 (‘the best health you can 
imagine’) (47). The subject will be asked to complete EQ-5D-5L on an electronic device at 
the trial site according to the schedule of trial procedures (Section 4). 
11.5.10 
Work Productivity and Activity Impairment: Atopic Dermatitis 
(WPAI:AD, at trial site) 
WPAI:AD consists of 6 items and scores can be calculated for 4 domains, each reflecting the 
percentage impairment due to AD during the past week, with higher scores indicating a 
greater impairment and lesser productivity (48): 
• Absenteeism: percentage work time missed due to AD for those who were employed the 
past week. 
• Presenteeism: percentage impairment while working due to AD for those who were 
employed and actually worked the past week. 
• Work productivity loss: percentage overall work impairment due to AD for those who 
were employed the past week. 
• Activity impairment: percentage activity impairment due to AD for all respondents. 
The subject will be asked to complete WPAI:AD on an electronic device at the trial site 
according to the schedule of trial procedures (Section 4). 
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11.5.11 
Hospital Anxiety and Depression Scale (HADS, at trial site) 
HADS is a 14-item questionnaire with scores ranging from 0 to 21 for anxiety and 0 to 21 for 
depression. Each of the 14 items will be evaluated on a Likert scale. Scores are considered 
normal from 0 to 7 and abnormal from 11 to 21 and are categorized as: normal (0 to 7), mild 
(8 to 10), moderate (11 to 14), and severe (15 to 21) (49). The subject will be asked to 
complete HADS on an electronic device at the trial site according to the schedule of trial 
procedures (Section 4). If the subject presents with symptoms of clinical depression and/or 
anxiety, the investigator should take appropriate action at their discretion. 
11.5.12 
Patient’s Global Impression of Severity questionnaires (PGI-S, 
at trial site) 
PGI-S is a single item questionnaire designed to assess the subject’s overall perception of 
severity. In this trial the severity of signs and symptoms of AD, 
 nocturnal 
 
difficulty 
, frequency of 
 during the night, 
 and 
 
 over the past week will be evaluated. The subject will be asked to choose 1 option 
from a 4-point categorical scale as described in Panel 12 (50). The subject will be asked to 
complete the PGI-S questionnaires (ADSD PGI-S, 
 PGI-S, Nocturnal 
 PGI-S, 
Difficulty 
 PGI-S, Frequency of 
During the Night PGI-S, 
 
PGI-S, 
 PGI-S) on an electronic device at the trial site according to the 
schedule of trial procedures (Section 4). 
Panel 12: Patient’s Global Impression of Severity (PGI-S) scales 
Patient reported outcome 
Scale 
ADSD PGI-S 
 PGI-S 
Nocturnal 
 PGI-S 
Difficulty 
 PGI-S 
‘None’, ‘mild’, ‘moderate’, ‘severe’ 
Frequency of 
 During the Night PGI-S 
‘Never’, ‘sometimes’, ‘often’, ‘very often’ 
 PGI-S 
‘None’, ‘a little’, ‘some’, ‘a lot’ 
 PGI-S 
‘Poor’, ‘fair’, ‘good’, ‘excellent’ 
Abbreviations: ADSD = atopic dermatitis symptom diary; PGI-S = Patient’s Global Impression of Severity; 
. 
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11.5.13 
Patient’s Global Impression of Change questionnaires (PGI-C, 
at trial site) 
PGI-C is a single item questionnaire designed to assess the subject’s overall impression of 
change. In this trial the change in signs and symptoms of AD, 
 nocturnal 
 
difficulty 
 frequency of 
 during the night, 
 and 
 
 since the subject started treatment will be evaluated. The subject will be asked to 
choose 1 option from a 5-point categorical scale (‘much better’, ‘a little better’, ‘no change’, 
‘a little worse’, ‘much worse’) (50). The subject will be asked to complete the PGI-C 
questionnaires (ADSD PGI-C, 
 PGI-C, Nocturnal 
 PGI-C, Difficulty 
 
 PGI-C, Frequency of 
 During the Night PGI-C, 
 PGI-C, 
 
 PGI-C) on an electronic device at the trial site according to the schedule of trial 
procedures (Section 4). 
11.6 Pharmacokinetic and pharmacodynamic assessments 
11.6.1 
Pharmacokinetic assessments 
Blood samples for the measurement of LEO 152020 plasma concentration (Ctrough and Cmax) 
will be collected according to the schedule of trial procedures and special attention should be 
paid to timing of collection (see Section 4, Panel 2 and Panel 3, for more information). 
Pre- and post-dose PK blood samples should be collected within 5-10 min after the pre- and 
post-dose ECGs, respectively (see also Section 11.4.3 for more information about timing for 
the ECG measurements). 
Given the time window for post-dose ECG measurements (1 hour±15 min after dosing), the 
time window for a post-dose PK blood sample is 
 after dosing. 
Instructions for collection, handling, and shipment of PK samples will be provided in a 
separate laboratory manual. 
PK samples of subjects treated with LEO 152020 will be analyzed by an external laboratory 
using a validated bioanalytical method. The method used to analyze the samples will be 
described in a separate bioanalytical report appended to the CTR. 
Reporting in eCRF 
It will be recorded in the eCRF if PK blood samples were collected. If not, a reason should be 
provided. 
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11.6.2 
Pharmacodynamic assessments 
Blood biomarkers 
Serum samples for biomarker analysis will be collected according to the schedule of trial 
procedures (Section 4). 
If no efficacy of treatment is observed (no superiority of LEO 152020 vs. placebo), analysis 
of blood biomarkers may not be carried out since effects of LEO 152020 on molecular 
markers would in this case not be expected. 
Collection, handling, and shipment instructions for serum samples will be provided in a 
separate laboratory manual. 
The biomarker assessments are exploratory in nature and their results will be reported in a 
separate report appended to the CTR. 
Reporting in eCRF 
It will be recorded in the eCRF if PD blood biomarker samples were collected. If not, a reason 
should be provided. 
For skin biomarkers, see Section 11.7.3. 
11.7 Optional assessments 
11.7.1 
Overview 
Optional assessments are listed in the schedule of trial procedures (Section 4) and described in 
the subsections below. Participation in these optional components of the trial is not required 
for participation in the core part of the trial and the subject will be asked to provide additional 
consent. 
The optional assessments are exploratory in nature and their results will be presented in a 
separate addendum to the CTR. 
11.7.2 
Wristband scratch and sleep monitoring 
Subjects participating in this optional component of the trial will be the first approximately 
100 subjects who provide additional consent for this assessment. 
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At Week -1, the subject will receive 2 wristband actigraphy devices (
, 
) together with instructions for use. From Week -1 to Week 16, the subject 
will be asked to wear 1 device on each wrist daily and without interruption. If this is too 
inconvenient, the device worn on the subject’s dominant wrist should at least be worn at 
nighttime during the subject’s standard sleep period. If necessary, a hypoallergenic bandage 
can be placed under each device to prevent skin irritation. The devices are water resistant and 
do not need to be removed for showering or bathing but should be removed when spending an 
extended time in the water (e.g. when swimming). 
At each visit between Week -1 and Week 16, the subject will be asked to bring the devices 
back to the site for data transfer using the 
 software. The devices can record 
30 days of data at a time. Therefore, the time between consecutives visit should not exceed 
30 days and special attention should be paid in case of missed visits. 
The wristband actigraphy devices contain a tri-axial accelerometer sampling motion (in units 
of acceleration, g) at a rate of 20 Hz. Actigraphy data will be processed in Rapid Actigraphy 
Data Analyzer software 
). First, the segmentation 
algorithm (51) will be applied which objectively differentiates active, major rest, minor rest, 
and missing data periods (during which the device was not worn). Within the major rest 
periods, which represent time for the main sleep period, the 
 algorithm (52) and 
sleep/wake algorithm (53) will be applied. The 
 algorithm will quantify individual 
 events used to generate 
 endpoints including the number of events per 
hour and the duration (in seconds) of events per hour. The 
algorithm uses 
movement to estimate 
 versus 
 and will be used generate 
 endpoints 
including 
 (percentage of the major rest period spent 
 
 (in 
minutes), and nocturnal 
 
Reporting in eCRF 
At the run-in visit, it will be recorded in the eCRF which hand is the subject’s dominant hand 
and the ID numbers of the wristband actigraphy devices provided to the subject. At each visit 
between baseline and Week 16, it will be recorded: 
• If the subject wore the device as instructed. If not, a reason should be provided. 
• If data was transferred from the devices. If not, a reason should be provided. 
• If new devices were provided to the subject along with their device ID numbers. 
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11.7.3 
Skin biopsies 
Subjects, who have lesions at a location suitable for a biopsy (i.e. ventral arm, ventral 
forearm, dorsal arm, dorsal forearm, antecubital fossa, trunk, lower limb) will be asked if they 
agree to provide skin biopsies. Skin biopsies will be collected according to the schedule of 
trial procedures (Section 4). 
Subjects participating in this optional component of the trial will be the first approximately up 
to 40% of randomized subjects who provide additional consent for this assessment. 
A total of 3 skin biopsies (3-mm punch biopsies) will be collected according to the schedule 
of trial procedures (Section 4): 
• 2 at baseline (1 biopsy from lesional skin and 1 biopsy from non-lesional skin). 
• 1 at Week 16 (end of treatment) from the same area as where the baseline lesional skin 
biopsy was taken or from a nearby area. 
To minimize discomfort, a local anesthetic should be injected to numb the area where the 
biopsy will be taken. Subjects who previously have had reactions to anesthetic medication 
must be excluded from participation in this component of the trial (but may be included in the 
core part of the trial, provided that they meet all eligibility criteria). A check of wound healing 
at the biopsy site including removal of sutures, if applicable, will be conducted at the next 
trial visit according to the schedule of trial procedures (Section 4). 
Further instructions for collection, handling, and shipment of skin biopsy samples will be 
provided in a separate laboratory manual. 
Reporting in eCRF 
It will be recorded in the eCRF if a biopsy was collected, from which body location it was 
collected (ventral arm, ventral forearm, dorsal arm, dorsal forearm, antecubital fossa, trunk, 
lower limb, other [if other, a specification should be provided]), and if it was collected from 
lesional or non-lesional skin. If a biopsy was not taken, a reason should be provided. 
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11.7.4 
Exit interview 
Native English-/German-speaking subjects at selected trial sites in Canada, Germany, and US 
will be invited to participate in an exit interview. The purpose of the exit interview is to learn 
about the subject’s experience of AD, the treatment, perception of change in the aspects 
addressed by specific PROs (including whether the changes were perceived as meaningful), 
wristband actigraphy (if applicable), and overall experience of participating in the trial. The 
exit interview will be conducted in English/German by a CRO. Participants in the exit 
interviews will be the first approximately 50 subjects at the selected trial sites who agree to 
take part in an interview. 
Exit interviews will be conducted as video conferences or over the telephone at a date and 
time agreed with the subject between the Week 12 and Week 14 visits. Exit interviews will be 
scheduled to occur as soon as possible after Week 16 and at the latest 24 hours before the 
safety follow-up visit (Week 17). 
The exit interviews will be qualitative, semi-structured interviews conducted by experienced 
interviewers. Each interview is expected to last approximately 60 minutes. Interviewers will 
use the semi-structured interview guide to drive the discussion. Interviews will be 
audio-recorded and transcribed to accurately capture the subject’s experience. Qualitative 
analysis of the transcripts will be conducted using thematic analysis in Atlas.ti software. The 
interviewers will be trained in capturing potential AEs and will report any potential AEs to the 
trial site as described in Section 13.2. 
11.8 End of trial 
End-of-treatment form 
An end-of-treatment form will be completed in the eCRF for all subjects after their last dose 
of IMP. For subjects who completed treatment, this will be done at the Week 16 visit. For 
subjects who were permanently discontinued from IMP/withdrawn from the trial, this will be 
done at the early termination visit. 
Reporting in eCRF 
It will be recorded on the end-of-treatment form in the eCRF if the subject completed 
treatment. It will be recorded if the reason was due to the COVID-19 pandemic. Date and 
time of last dose of IMP will also be recorded. 
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End-of-trial form 
At their last visit in the trial, an end-of-trial form must be completed in the eCRF for all 
randomized subjects. The following data will be recorded: 
• If the subject completed 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 withdrawing from the trial (death, pregnancy, adverse event, lack of 
efficacy (lack of efficacy on itch, lack of efficacy on visible AD symptoms, lack of 
efficacy on both itch and visible AD symptoms, other [if other, a specification should be 
provided]), withdrawal by subject, lost to follow-up, or other [if other, a specification 
should be provided]). In case of withdrawal by the subject, it will be recorded if the 
subject withdrew consent and, if yes, the date of consent withdrawal. 
• If the subject attended the (nominal) primary endpoint visit (Week 16 or 16 weeks after 
first dose of IMP). If not, the primary reason for not attending the visit should be 
provided (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 17). If not, the primary reason 
for not attending the visit (death, pregnancy, adverse event, withdrawal by subject, lost 
to follow-up, safety follow-up information collected at early termination visit [see 
Section 10.3], or other [if other, a specification should be provided]). 
11.9 Estimate of total blood volume collected 
Blood samples will be collected for clinical chemistry, hematology, serology, PK, PD, and 
safety assessments. The maximum total volume of blood to be collected during the trial will 
be under 200 mL. If additional blood samples are needed, the total volume of blood collected 
may be more than this value. However, the maximum total volume of blood will be less than 
that collected during a blood donation (approximately 500 mL). 
11.10 Storage of biological samples 
The blood and urine samples for laboratory testing (clinical chemistry, hematology, serology, 
and urinalysis) will be collected to monitor and ensure subject safety during the trial and will 
only be stored until analysis is completed by the central laboratory. 
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PK blood samples will be retained for as long as the quality of the material permits evaluation 
but for no longer than 12 months after completion of the CTR. Any remaining PK samples 
may be used for semi-quantitative metabolite identification. 
PD blood samples and skin biopsies will be retained for as long as the quality of the material 
permits evaluation but for no longer than 12 months after completion of the CTR. If the 
subject provides additional consent for this, the residual material from PD blood samples and 
skin biopsies will be transferred to a biobank established by LEO Pharma and hosted by 
 (Germany). The residual samples will be used for future 
research conducted by LEO Pharma. The samples will be labelled with the trial ID, subject 
ID, and sample date to protect subject privacy and allow for continued blinding in future 
analyses. The samples will be stored in the biobank for as long as the quality of the material 
permits evaluation 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 has been designed to explore the exposure-response relationship of LEO 152020 and 
evaluate the efficacy and safety of orally-administered LEO 152020 compared with placebo 
for up to 16 weeks of treatment in adults with moderate to severe AD (Section 6, primary 
objective). 
Population 
The target patient population consists of adults with chronic moderate to severe AD not 
adequately controlled with topical AD treatment (or for whom topical AD treatment is not 
indicated). 
Therefore, the most important inclusion criterion for participation in the trial is an established 
diagnosis of AD, as defined by the Hanifin and Rajka 1980 criteria for AD (36) to ensure 
correct diagnosis and rule out differential diagnosis, and a history of AD of at least 1 year 
prior to baseline (inclusion criterion 4). 
In addition, another prerequisite for participation in the trial is a recent (within 6 months prior 
to baseline) documented history of inadequate response to topical AD treatments or being a 
patient for whom topical treatment is medically inadvisable, to ensure that the subject is 
candidate for oral treatment with LEO 152020 (inclusion criterion 5). Subjects with less than 
3 previous documented systemic AD treatments are also eligible to participate in the trial after 
appropriate washout (exclusion criterion 4). 
Due to the potential important risk of 
, exclusion criteria have been defined to 
exclude subjects with 
 from participation in the trial (see 
Section 8.3 for the exclusion criteria and Section 5.5 for mitigation of the risk of QT 
prolongation). 
The other eligibility criteria have been chosen to ensure inclusion of the targeted patient 
population, ensure subject safety, and minimize factors which could interfere with the trial 
assessments and procedures (Section 8.2 and Section 8.3). 
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Approximately 30% subjects with EASI between 7.1 and 16 at baseline (7.1≤ EASI ≤16) and 
70% subjects with EASI between 16.1 and 50 at baseline (16.1≤ EASI ≤50) will be 
randomized in the trial to ensure a trial population representative of the target patient 
population. 
Treatment groups 
Based on PK, PD, and safety results of the first-in-human trial with LEO 152020 (39), 
population PK simulations, 
 analysis, and published data of other 
H4R compounds (28), the currently identified dosing bracket to proceed with for development 
of LEO 152020 is between 
 and 
 To inform phase 3 
dose selection, the dose regimens LEO 152020 
 LEO 152020 
 
 and LEO 152020 
 were therefore selected for investigation in this 
trial. 
The treatment groups will be conducted in parallel as all selected dose regimens were 
demonstrated well tolerated in the first-in-human trial with LEO 152020 (39). The 
LEO 152020 
 treatment group has been included to explore whether a 
 dose of LEO 152020 could be efficacious to treat AD. 
The placebo treatment group will serve as control to evaluate the efficacy and safety of 
LEO 152020. 
Trial periods 
The maximum duration of the screening period was set to 5 weeks in total to ensure that the 
general medical condition of the subject, as established by the examinations and laboratory 
assessments conducted at the screening visit, has not significantly changed by baseline while 
allowing enough time for complete washout of any disallowed AD treatment (Section 7.1). 
The 1-week run-in period is to ensure washout of any topical AD treatment and establish a 
baseline for AD symptoms (ADSD, Section 11.3.4) as well as nocturnal 
 and 
 
data (Section 11.7.2). The subject will be asked to apply a background treatment (emollient) 
on lesional and non-lesional skin at least twice daily for at least 7 consecutive days to keep 
their skin well-moisturized and mitigate the absence of systemic and/or topical AD 
treatment(s). 
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AD is a chronic condition and based on published data of another H4R antagonist (28) the 
16-week treatment duration is to ensure that LEO 152020 will reach maximum effect. During 
the treatment period, the subject will be asked to continue applying the emollient as needed, 
in complement to treatment with LEO 152020 (standard of care). 
After the last dose of IMP, the 7-day safety follow-up period has a duration superior to 
 half-lives of LEO 152020 and is to allow complete washout of LEO 152020 before the last 
safety assessments are conducted. 
Mitigation of bias 
Triple blinding (subject, investigator, and assessor of the data/study [sponsor]) will minimize 
ascertainment bias (Section 9.3.2). 
The combination of randomization and blinding will minimize the likelihood of allocation 
bias. The risk of allocation bias will further be reduced through the use of central 
randomization, i.e. the randomization will not be stratified by site nor will complete blocks be 
allocated to sites. The use of randomization will also ensure that baseline factors are not 
confounded with treatment. The use of a permuted block randomization within the strata 
defined by baseline disease severity (EASI at baseline) and region (Japan and non-Japanese 
countries) will limit any potential imbalance in the allocation of subjects across these factors 
(Section 7.1). 
Endpoints and estimands 
The endpoints have been selected to evaluate the efficacy of LEO 152020 in improving the 
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 152020 
(54). 
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The primary estimand addressing the primary endpoint will use the hypothetical strategy to 
handle the occurrence of intercurrent events (initiation of rescue treatment or permanent 
discontinuation of IMP). The estimand addresses the clinical question, what would the effect 
of treatment be, if subjects adhered to the specified treatment regimen, i.e. did not 
permanently discontinue IMP and did not receive rescue treatment. The estimated treatment 
effect can be interpreted as the expected benefit of treatment if subjects adhered to the 
treatment regimen. 
12.2 Appropriateness of assessments 
All trial assessments and procedures are listed in the schedule of trial procedures (Section 4). 
Efficacy assessments 
EASI, vIGA-AD, and SCORAD are validated measures used in clinical practice and/or 
clinical trials by investigators to assess the severity and extend of AD (Sections 11.3.1 to 
11.3.3). SCORAD additionally assesses subjective symptoms. 
ADSD is a validated diary developed by LEO Pharma for subjects to assess the severity of 
9 key signs and symptoms of AD (Section 11.3.4). 
PROs 
A range of validated PROs will be used to assess subject perception of AD. The PROs have 
been selected to cover key signs and symptoms of AD (including 
 as well as 
health-related quality of life (including 
 quality and impact of 
 on sleep quality), 
mental health, and work productivity (Sections 11.5.7 to 11.5.13). The PROs are scheduled in 
a combination to balance the time spent by the subject on these questionnaires at the trial site 
and daily in the eDiary. 
Safety assessments 
Standard clinical methods of subject evaluations, such as AE monitoring (Section 13), vital 
signs, physical examinations, ECG, laboratory testing including pregnancy testing 
(Section 11.4) will be used to assess subject safety. 
Due to the important potential risk of 
, subjects’ ECGs will be monitored as 
described in Section 11.4.3 and the ECG endpoints will be used to assess effect of treatment 
on 
. 
An independent DMC will review all safety data and monitor the overall conduct of the trial 
periodically (Appendix 3H). 
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Pharmacokinetic assessments 
Plasma concentration of LEO 152020 (Ctrough and Cmax) will be measured pre- and/or 
post-dose of IMP and PK parameters will be derived to explore the exposure-response 
relationship of LEO 152020 (Section 11.6). 
Based on data from the first-in-human trial with LEO 152020 (39), Cmax is expected to occur 
at 
 Therefore, post-dose PK blood samples will be collected shortly after the 
post-dose ECG measurement (see Panel 3 for more information). 
Pharmacodynamics assessments 
H4R is expressed on many types of immune cells including dendritic cells, mast cells, 
eosinophils and Th2 cells. Inhibition of H4R signaling has been demonstrated to reduce 
migration of immune cells to the skin site of inflammation and reduce levels of cytokines and 
other proinflammatory mediators in mouse skin (mouse skin inflammation models) (55-59). 
In humans, inhibition of H4R signaling is expected to reduce inflammation in AD lesional 
skin, leading to improvement of AD symptoms. 
The purpose of including biomarker assessments is to investigate the effect of LEO 152020 
on systemic molecular markers of AD (Section 11.6.2) and on markers of AD in skin lesions 
(see Section 11.7.3). Inflammatory markers (cytokines and chemokines) associated with AD 
(e.g. CCL17, sIL-2R, IL-13, IL-22, IgE) will be measured in serum over time to determine 
AD burden. Skin biopsies will be analyzed for the expression of genes involved in the 
pathogenesis of AD including inflammatory genes, genes involved in immune function, and 
genes involved in skin differentiation and barrier function. The purpose is to show disease 
resolution at the molecular level. In addition, transcriptome profiling of skin biopsies will be 
used to identify any markers or combination of markers that predict treatment response, thus 
allowing for a precision medicine approach, should such markers be identified. 
Nocturnal 
 and sleep monitoring 
Wristband actigraphy is considered relevant for evaluating the effects of treatment on 
nocturnal 
 and sleep 
 as motion data can be captured in a safe, 
non-invasive, and objective manner (Section 11.7.2). 
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13 Adverse events 
13.1 Definition and classification of adverse events 
Adverse events (AEs) and serious adverse events (SAEs) are defined in Appendix 1. 
Classification of AEs in terms of severity, causality, and outcome is defined in Appendix 2. 
13.2 Collection of adverse event reports 
AE data must be collected from time of first trial-related activity after the subject has signed 
the informed consent form (ICF) until subject’s completion of the clinical trial (all trial 
periods including safety follow-up visit at Week 17, see Section 7.3). 
AEs must be assessed by medically qualified personnel. 
At all visits, the subject will be asked a non-leading question by the investigator about AEs, 
e.g.: “How have you felt since I saw you last?” No specific symptoms should be asked for. It 
is important that the investigator also observes the subject for any changes not reported by the 
subject and records these changes. 
Any potential AE reported by the subjects during an exit interview must be collected by the 
interviewer on the Potential Adverse Event Collection Form. The interviewer must forward 
the completed form to the investigator within 24 hours of the interview. The investigator must 
evaluate if the potential AEs are indeed to be considered as AEs and whether they were 
already recorded in the eCRF and date and sign their evaluation within 24 hours of receipt of 
the form. Interviewer and investigator should confirm to each other receipt of the form by the 
investigator within those 24 hours. If the confirmed AEs were not recorded in the eCRF, or if 
the investigator is in doubt, they must record the AEs in the eCRF. If considered relevant, the 
investigator should follow up on the AEs with the subject no later than at the safety follow-up 
visit. If a potential AE qualifies as an SAE, the SAE must be reported within 24 hours of 
receipt by the site/investigator as described in Section 13.4.1. 
Principles for data recording in the eCRF are described in Sections 11.4.1 to 11.4.4. 
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13.3 Reporting of adverse events 
AEs reported by the subject or observed by the investigator must be recorded on the AE form 
of the eCRF and should be described in the following manner: 
The AE term must be in precise English medical terminology (that is, not necessarily the 
exact words used by the subject). Whenever possible, a specific diagnosis should be stated 
(e.g. ‘allergic contact dermatitis’). 
The duration of the AE must be reported by the start date and stop date of the event unless the 
event is ongoing. If the event is ongoing, it will be marked as ongoing. In addition, it will be 
recorded if the AE started prior to first administration of IMP. 
AEs must be classified in terms of severity, causality, and outcome according to the 
definitions in Appendix 2. 
Action taken with IMP: any action taken with IMP as a consequence of the AE must be 
recorded in the eCRF (dose not changed, drug interrupted, drug withdrawn, not applicable, 
unknown). 
Other action taken: any other action taken as a result of the AE must be recorded in the eCRF 
(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. For timing of SAE reporting in Germany, see Appendix 4. This report should 
contain amongst others an assessment of available information on seriousness, severity, causal 
relationship to the IMP or trial procedure, the action taken, the outcome to date, and a 
narrative description of the course of the event. For more details regarding reporting of any 
SAE, please see the guidance text on the SAE form. 
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By signing and dating the SAE form, the investigator acknowledges that he/she is aware of 
the SAE and has assessed the causal relationship of the IMP(s) and any of the other 
medications to the SAE. 
The actual reporter, if not the investigator, should also sign and date the SAE form. 
The completed SAE form must be faxed or scanned and e-mailed to Global Safety at 
LEO Pharma using the e-mail address or fax number below: 
Global Safety at LEO Pharma 
E-mail address: drug.safety@leo-pharma.com. 
Fax number: +45 7226 3287. 
If relevant, the investigator will enclose other information with the SAE form, such as 
anonymized reports of diagnostic procedures, hospital records, autopsy reports, etc. 
Additionally, Global Safety at LEO Pharma may request further information in order to fully 
assess the SAE. The investigator must forward such information to LEO Pharma upon request 
by fax or e-mail (see contact details above). 
The investigator must notify the local IRB(s)/IEC(s) of SAEs, as required by current 
applicable legislation for the concerned country. 
SAEs occurring after the completion of the clinical trial should not be routinely sought or 
recorded. 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 an SAE is expected. The 
relevant reference safety information document for this clinical trial is the investigator’s 
brochure edition 3.0 Section 7.2 and subsequent updates. 
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. 
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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 (33), and 
which are unexpected (suspected, unexpected serious adverse reactions [SUSARs]), are 
subject to expedited reporting to regulatory authorities, IEC(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. 
In US, the following reporting requirements apply: all SAEs which are assessed as causally 
related to the IMP(s) by LEO Pharma (60, 61) and which are unexpected (serious and 
unexpected suspected adverse reactions [IND safety report]) are subject to expedited reporting 
to regulatory authorities, IRB(s). Investigators will be notified of the evolving safety profile 
of the IMP on an ongoing basis. 
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 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 (Section 10.2 and Section 10.3). 
13.6 Reporting of other events 
13.6.1 
Adverse events of special interest 
The events listed in Panel 13 are considered AESIs in this trial and will require additional data 
to be recorded in the eCRF. LEO Pharma may request that the investigator forwards 
additional test results, as appropriate. An AESI may be serious or non-serious. Serious AESIs 
require expedited reporting via the SAE form as described in Section 13.4. AESIs will be 
reviewed by the DMC (Appendix 3H). 
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Panel 13: Adverse events of special interest 
Adverse event of 
special interest 
Rationale 
Additional data to be recorded 
Data 
collection 
method 
Eczema herpeticum 
Eczema herpeticum is a 
well-known severe skin 
infection in patients with AD 
which occurs in lesional skin. 
The additional information will 
be collected to better understand 
the pathogenic nature of the 
eczema. 
Skin findings: 
• Lesion type (papules, 
vesicles, crusts, eroded pits, 
other [if other, a specification 
should be provided]). 
• Disseminated / localized. 
• Location (face, scalp, back, 
chest, upper limb, lower 
limb, genitals). 
• Present in an area with 
visible eczema / no visible 
eczema / present in areas 
with and without eczema. 
• Monomorphic / polymorphic. 
• Confirmation of herpes 
simplex virus (PCR, viral 
culture, Tzanck test, other [if 
other, a specification should 
be provided], not confirmed). 
eCRF 
Skin infection 
requiring systemic 
treatment 
Patients with AD are 
predisposed to develop skin 
infections due to impaired skin 
barrier and modified cutaneous 
immune response. 
Bacterial and viral infections 
represent the most common 
complications of AD. 
The additional information will 
be collected to better understand 
the pathogenic nature and 
localization of the skin 
infection. 
• Location (face, scalp, back, 
chest, upper limb, lower 
limb, genitals). 
• Outcome of pathogenic swab 
(positive [staphylococcus 
aureus, streptococcus, 
candida, other, if other, a 
specification should be 
provided], negative, not 
performed). 
eCRF 
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Adverse event of 
special interest 
Rationale 
Additional data to be recorded 
Data 
collection 
method 
Electrocardiogram 
 
 
This AESI was defined based 
on data from the first-in-human 
trial with LEO 152020 (39) 
• ECG (measured according to 
the schedule of trial 
procedures [Section 4]). 
• Severity of the 
 
 (mild, 
moderate, severe, see QTcF 
severity criteria in Panel 14). 
• Symptoms believed to be 
related to the 
 
and duration of 
the symptoms. 
eCRF 
Abbreviations: AD = atopic dermatitis; AESI = adverse event of special interest; ECG = electrocardiogram; 
eCRF = electronic case report form; PCR = polymerase chain reaction (test); 
 
 
 
AESIs of electrocardiogram QT corrected interval prolonged 
QTcF >450 ms (men) and QTcF >460 ms (women) are considered clinically relevant QT 
prolongations and must be reported as AEs. QTcF severity of the AE must be recorded in the 
eCRF (see Panel 14 for guidance). For guidance on handling events of QT prolongation, see 
Section 11.4.3. 
Panel 14: Severity specifications for adverse event of electrocardiogram 
 
 a 
Mild 
Moderate 
Severe 
Men: 450 ms< average 
 ≤480 ms 
Women: 460 ms< average 
 ≤480 ms 
480 ms< average 
 ≤500 ms 
or 
30 ms < increase in 
 from 
baseline ≤60 ms 
Average QTcF >500 ms 
or 
Increase in QTcF from baseline 
>60 ms 
Abbreviations: 
 
 
a Modified from (62) in line with the 
 guideline on clinical evaluation of 
 (34). 
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13.6.2 
Medication error 
Medication error refers to any unintentional error in the dispensing or administration of an 
IMP. Medication errors include accidental overdose or underdose, inappropriate schedule of 
product administration (
 doses of IMP taken less than  hours apart), incorrect 
route of product administration, wrong product administered, expired product administered. 
At each visit between Week 0 and Week 16, the investigator will ask the subject if they took 
any consecutive doses of IMP less than  hours apart. If this happened, the investigator will 
report each incidence as a medication error in the eCRF. 
Reporting in eCRF 
Medication errors must be recorded in the eCRF, on the AE form. For accidental overdose or 
underdose, only cases for which a clinical consequence occurred or could have occurred 
based on the investigator’s judgement should be recorded in the eCRF. 
In addition, any clinical consequence of the medication error must be recorded as a separate 
AE on the AE form. If the AE originating from the medication error qualifies as an SAE, 
expedited reporting will be required (Section 13.4). 
13.6.3 
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 CTP. 
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 the 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 
consequence of misuse or abuse must be recorded as a separate AE on the AE form. If the AE 
originating from the misuse or abuse qualifies as an SAE, expedited reporting will be required 
(Section 13.4). 
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13.6.4 
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 Section 13.3 and Section 13.4. 
As AD is a fluctuating disease, an AE should only be reported if the 
aggravation/exacerbation/worsening exceeds normal disease fluctuation or if lesions start 
appearing in a body area which is normally not affected by AD. 
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). The investigator should follow up on the outcome of all non-serious AEs classified as 
possibly or probably related to the IMP until the safety follow-up visit or until the final 
outcome is determined, whichever comes first. Non-serious AEs classified as not related to 
the IMP do not need to be followed up for the final outcome after the subject has left the trial. 
All SAEs must be followed up until a final outcome has been established, that is, the 
follow-up may continue beyond the end of the clinical trial. For SAEs which have stabilized 
and from which the subject cannot be expected to recover during the trial or the safety 
follow-up periods, e.g. chronic or stabilized conditions, the final outcome at the discretion of 
the investigator should be reported as ‘recovering/resolving’ or ‘not recovered/not resolved’. 
In addition, a statement detailing why the subject cannot be expected to recover during the 
trial, e.g. that the SAE has stabilized 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 (63). 
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. 
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The investigator must immediately inform LEO Pharma – by contacting the clinical project 
manager or medical expert – of this change in a clinical trial procedure or of the temporary 
halt; the investigator will provide full details of the information and the decision-making 
process leading to the implementation of the urgent safety measure. 
LEO Pharma must act immediately upon receipt of the urgent safety measure notification in 
accordance with internal procedures and local legislation. 
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14 Statistical methods 
14.1 Sample size 
A total of 224 subjects, including 28 Japanese subjects will be randomised in a 4:3:3:4 ratio to 
the following treatment groups: 
• LEO 152020 
 
• LEO 152020 
 
• LEO 152020 
 
• Placebo 
 
The sample size is chosen, based on the results of a simulation, to approximately provide 90% 
power to reject the null hypothesis that the difference in the mean change in EASI score from 
baseline to Week 16 between the 
 and placebo 
 groups is greater than or 
equal to 0. The underlying assumptions for the simulation are presented below. 
To approximate the power, 1,000 data sets with 224 subjects were generated based on the 
specified randomization scheme in Section 7.1. Each data set was analyzed based on the main 
analysis of the primary estimand specified in Section 14.3.8.1. The FWER for the analysis of 
each simulated data set was controlled based on the procedure specified in Section 14.3.7. The 
simulation made separate assumptions for the EASI response trajectory and rate of 
intercurrent events depending on baseline disease severity. For a given level of baseline 
disease severity, the assumed EASI response trajectory and rate of intercurrent events for the 
active arms, 
 
 and 
 are assumed to be 
the same. 
For subjects with a baseline EASI score between 
 the assumed response trajectory, in 
terms of the mean change in EASI score from baseline through Week 16, and the rate of 
intercurrent events, used to inform the simulation, are provided in Panel 15. The correlation 
matrix was assumed to have an AR(1) structure, with a correlation parameter equal to 0.65 
and a residual variance assumed to be 18.9. 
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Panel 15: Assumed response trajectories and rates of intercurrent events by treatment 
group, for subjects with baseline EASI score between [
] 
 
Week 2 
Week 4 
Week 6 
Week 8 
Week 10 
Week 12 
Week 14 
Week 16 
Mean change from baseline to Week 16 in EASI score 
LEO 152020 
Placebo 
Proportion of subjects experiencing intercurrent event from the trial (%) 
LEO 152020 
Placebo 
Abbreviation: EASI = Eczema Area and Severity Index. 
For subjects with a baseline EASI score between [
], data was resampled from a 
previous phase 3 development program in AD conducted in a similar patient population (64, 
65). The observed mean change in EASI score from baseline to Week 16 and the rate of 
intercurrent events from the data used as the basis for resampling are provided in Panel 16. 
Panel 16: Underlying response trajectories and rates of intercurrent events in the 
LP0162-1325 and LP0162-1326 trials for subjects with a baseline EASI score between 
[
 
 
Week 2 
Week 4 
Week 6 
Week 8 
Week 10 
Week 12 
Week 14 
Week 16 
Mean change from baseline to Week 16 in EASI score 
LEO 152020 
Placebo 
Proportion of subjects experiencing an intercurrent event (%) 
LEO 152020 
Placebo 
Abbreviation: EASI = Eczema Area and Severity Index. 
The estimated power for the treatment contrasts of interest based on the simulation are 
provided in Panel 17. 
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Panel 17: Estimated power for the treatment contrasts of interest with respect to the 
primary endpoint 
Treatment contrast (difference in the mean 
change in EASI from baseline to Week 16) 
Estimated marginal 
power 
Estimated power 
(Hochberg) a 
LEO 152020 
 vs. placebo
 
 
90.8% 
90.8% 
LEO 152020 
 vs. placebo
 
 
85.3% 
79.4% 
LEO 152020 
 vs. placebo
 
 
85.3% 
79.4% 
Abbreviations: EASI = Eczema Area Severity Index; FWER = familywise error rate. 
a The Hochberg gatekeeping procedure that is to be implemented in order to control the FWER is described in 
Section 14.3.7. 
14.2 Trial analysis sets 
All screened subjects will be accounted for in the CTR. 
All subjects randomized and exposed to IMP will be included in the full analysis set and will 
be analyzed for efficacy based on the planned (randomized) treatment allocation. Exclusions 
from the full analysis set can be considered in special cases as described in ICH E9, 
Section 5.2.1, Full Analysis Set. If it is decided to exclude a subject from the full analysis set, 
a justification addressing ICH E9 will be given. 
A safety analysis set will be defined as all subjects who were exposed to IMP and will be 
analyzed according to the actual treatment received. 
A PK analysis set will be defined as all subjects who were exposed to active IMP and 
provided at least one sample for measuring LEO 152020 plasma concentration. 
Additionally, a FASactigraphy analysis set will be defined as the subset of subjects in the FAS 
who have signed the informed consents for the actigraphy devices. 
The decisions regarding inclusion/exclusion of subjects or subject data from the trial analysis 
sets will be documented in the analysis set definition document before breaking the 
randomization code. 
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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 SAF. 
If not mentioned otherwise, endpoints will be summarized descriptively at each relevant visit 
by treatment group. For endpoints evaluated over time, plots will be made to explore the 
trajectory with time. 
An observed-cases approach will be used for tabulations of data by visit (i.e. involving only 
those subjects for whom data was collected at each specific visit). The number of subjects for 
whom data was not collected at each specific visit will also be provided. 
Categorical data will be summarized by treatment group, using the number and percentage of 
subjects in each category. Continuous data will be summarized using the mean, median, SD, 
1st quartile, 3rd quartile, minimum and maximum values. Additionally, the geometric mean 
and coefficient of variation (CV) will be provided for PK endpoints. 
In general, for endpoints evaluated as the change from baseline and/or where a baseline 
adjustment is applied, baseline is defined as the assessment conducted at the randomization 
visit (Visit 3) if not otherwise stated. 
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 finalized before breaking the 
randomization code. 
Any changes from the statistical analyses planned in this CTP 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 missing values for the primary endpoint are described in 
Section 14.3.8. 
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For other continuous endpoints for which MMRM analysis will be used, it will be assumed 
that missing data is missing at random. Under the MAR assumption, the estimator for a 
likelihood-based analysis, e.g. maximum likelihood estimation of an MMRM, is unbiased. 
For dichotomized endpoints, missing data will be considered as non-response and imputed 
using NRI. 
14.3.3 
Handling of intercurrent events related to the COVID-19 
pandemic 
As the COVID-19 pandemic might, extraordinarily, influence trial events and data in manners 
not foreseen by the protocol, this section introduces statistical considerations for handling of 
intercurrent events related to the pandemic for the primary endpoint. 
Interruption of IMP during the treatment period is not considered as an intercurrent event as 
LEO Pharma, in the context of a pandemic and provided local ECG monitoring is possible, 
will ensure continued IMP supply to the subject. Therefore, the intercurrent event, initiation of 
rescue medication will also be considered independent of the pandemic (see Appendix 9). 
The causal relationship of permanent discontinuation of IMP related to the pandemic will be 
recorded in the eCRF (see also Section 10.2). 
The hypothetical strategy will be used to handle the occurrence of intercurrent events related 
to the COVID-19 pandemic. The strategy aims to assess the effect of treatment in the 
hypothetical scenario, in which intercurrent events do not occur. Specifically, in the context of 
the pandemic, interest lies in assessing the treatment effect, if the trial were to be conducted in 
a setting unaffected by the COVID-19 pandemic. 
The above envisioned hypothetical scenario can be formalized through the use of the potential 
outcome framework introduced by Rubin (66). A simplified scenario presented in Parra et al. 
(67), where pandemic related intercurrent events can only occur at a single timepoint will be 
considered. Let, 
• Y represent the outcome, e.g. change in EASI from baseline to Week 16. 
• A0 represent the randomly assigned treatment. 
• A1 represent the event status for pandemic related intercurrent events. 
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In the potential outcome framework, it will be assumed that it is possible, through some 
means, to intervene on the event status for pandemic related intercurrent events. In other 
words, subjects can be arbitrarily assigned to experience or not experience a pandemic related 
intercurrent event. Based on the above specified hypothetical scenario, interest lies in the 
potential outcomes, 
 
which refer to the outcomes had treatment, A0=a0, been assigned and pandemic related 
intercurrent events were not allowed to occur. In this simplified scenario, the population level 
summary specified in Panel 18 can be expressed in terms of the potential outcomes as, 
 
Here, the expectations refer to the mean change in EASI score from baseline to Week 16, if all 
subjects had been randomized to the specified treatment group, e.g. 
 group, 
in a setting in which pandemic related intercurrent events do not occur (A1=0). Under the 
consistency assumption, the observed outcome is assumed to be equal to the corresponding 
potential outcome. For example, the observed value for a subject randomized to treatment 
A0=1 and who did not experience a pandemic related intercurrent event, would be equal to 
their potential outcome, 
 
For subjects experiencing a pandemic related intercurrent event, the value of the potential 
outcome, 
 
is not observed. In order to completely specify the hypothetical scenario of interest, one must 
specify how the values of the unobserved potential outcomes, i.e. the outcomes that would be 
observed had subjects not experienced pandemic related intercurrent events, relate to the 
observed data. From a missing data standpoint, this can be achieved through explicit 
assumptions, such as MAR or through the specification of a plausible imputation model. 
𝑌𝐴0=𝑎0,𝐴1=0 
𝐸 𝑌𝐴0=1,𝐴1=0 −𝐸 𝑌𝐴0=0,𝐴1=0  
𝑌𝐴0=1,𝐴1=0 
𝑌𝐴0=𝑎0,𝐴1=0 
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If, under the hypothetical scenario, subjects are at risk for additional intercurrent events, e.g. 
non-pandemic related intercurrent events, imputation-based inference may need to account for 
the likelihood of subjects experiencing such events and subsequently handle their occurrence 
accordingly. 
In Section 14.3.8.1, the hypothetical strategy will be used to handle the occurrence of all 
intercurrent events, regardless of the relation to the pandemic. In this section, the potential 
outcomes of interest are with respect to the outcomes that would be observed if all 
intercurrent events were not allowed to occur. 
These assumptions will be described in general terms in Section 14.3.8 and elucidated upon in 
the SAP. 
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. 
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 Panel 19 for the main analysis of 
each estimand. Details of the analyses are described in Section 14.3.8. 
14.3.4 
Disposition of subjects 
The reasons for permanent discontinuation of IMP or withdrawal from trial will be presented 
for all randomized subjects by last visit attended and by treatment group. 
A subject disposition summary table will be made including information on the number of 
subjects screened, randomized, exposed, completed trial, permanently discontinued IMP, and 
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 randomized subjects and by treatment group. Presentations of age, sex, ethnicity, race, and 
baseline EASI score by treatment group will also be given by region and baseline disease 
severity (EASI score at baseline ≤16 and ≥16.1). 
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Other baseline characteristics include height, weight, body mass index, duration of AD, 
concurrent diagnoses (from medical history), concomitant medication (including indication), 
and previous AD treatments. 
14.3.6 
Exposure and treatment compliance 
The duration of exposure to treatment in a specific week interval will be calculated as the 
number of days from date of first dose of IMP in that period to the date of last dose of IMP in 
that period, both days included. 
Exposure to treatment will be presented for the safety analysis set as days of exposure per 
treatment group. 
The average number of weekly doses of IMP and the average total number of doses of IMP 
administered will be presented for the SAF by treatment group for week of treatment intervals 
and for the whole treatment period, respectively. 
Treatment compliance will be presented for the SAF for each treatment group as the 
percentage of missed doses of IMP. 
14.3.7 
Testing strategy 
This is a phase 2 trial with the primary objective to explore the exposure-response relationship 
of LEO 152020 and evaluate efficacy of LEO 152020 compared with placebo. The 
investigation of exposure-response relationship is regarded as an exploratory analysis 
supporting the understanding of the dependency from exposure on efficacy achieved. A 
gatekeeping procedure will be applied to control the overall type 1 error rate in the strong 
sense. 
The gatekeeping procedure will first test the null hypothesis comparing the mean change in 
EASI score from baseline to Week 16 between the LEO 152020 
 and 
placebo 
 groups. If this null hypothesis is rejected, the procedure will go on to test 
the null hypotheses associated with the following treatment contrasts: 
• Change in EASI from baseline to Week 16 between LEO 152020 
 
and placebo 
 
• Change in EASI from baseline to Week 16 between LEO 152020 
 
and placebo 
 
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Otherwise testing will stop. When testing the remaining 2 hypotheses, the Hochberg 
procedure will be used to control the overall type I error rate in the strong sense. The 
Hochberg procedure is a step-up procedure that first assesses whether the maximum of the 2 
p-values is less than 0.05. If so, both hypotheses are rejected. If the maximum p-value is 
greater than 0.05, the procedure will move on to test the hypothesis associated with the 
minimum p-value at the 2.5% significance level. If the minimum p-value is less than 0.025, 
then the corresponding hypothesis is rejected. Hypothesis testing will be based on the main 
analysis of the primary estimand. 
14.3.8 
Analysis of primary endpoint 
The primary endpoint will be analyzed differently to address the 2 aspects of the primary 
objective: efficacy evaluation and exploration of the exposure-response relationship. 
The primary analysis will evaluate the efficacy of LEO 152020 compared with placebo. A 
primary and 2 supplementary estimands have been specified in order to address clinical 
questions of interest. 
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Panel 18: Primary and supplementary estimands for primary endpoint 
Objective 
Estimands 
Endpoint 
 
Estimand type 
(Primary/ 
supplementary) 
Interpretation of the estimand 
Comparison 
groups 
Intercurrent 
events (strategy) 
Population 
level 
summary 
 
Primary objective 
To evaluate efficacy 
of LEO 152020 
compared with 
placebo for up to 
16 weeks of 
treatment in subjects 
with moderate to 
severe AD 
Primary 
Assesses the effect of treatment if 
subjects adhered to the treatment 
regimen, i.e. they did not permanently 
discontinue IMP and did not initiate 
the use of rescue medication prior to 
Week 16 (Section 14.3.8.1). 
 
Under this hypothetical scenario, the 
occurrence of IEs is assumed not to 
affect the change in EASI score from 
baseline to Week 16, i.e. the potential 
outcomes for subjects experiencing IEs 
are assumed to follow the same 
distribution as the outcomes for 
subjects in the same treatment group, 
who did not experience IEs. 
Dose regimens of 
LEO 152020 
 
 
 
vs. placebo
 
 
Permanent 
discontinuation of 
IMP due to 
pandemic related 
factors 
(hypothetical) 
 
Permanent 
discontinuation of 
IMP due to non-
pandemic related 
factors 
(hypothetical) 
 
Initiation of rescue 
medication 
(hypothetical) 
Difference in 
mean change 
in EASI from 
baseline to 
Week 16 
Primary 
endpoint 
Change in 
EASI from 
baseline to 
Week 16 
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Objective 
Estimands 
Endpoint 
 
Estimand type 
(Primary/ 
supplementary) 
Interpretation of the estimand 
Comparison 
groups 
Intercurrent 
events (strategy) 
Population 
level 
summary 
 
First 
supplementary 
Assesses the effect of treatment in the 
hypothetical scenario in which the 
COVID-19 pandemic did not occur, 
regardless of the occurrence of non-
pandemic related IEs 
(Section 14.3.8.2). 
 
Under this hypothetical scenario, the 
potential outcomes for subjects 
experiencing a pandemic related IE are 
assumed to follow the distribution 
describing the outcomes for subjects in 
the same treatment group who did not 
experience a pandemic related 
intercurrent event and ignoring the 
occurrence of non-pandemic 
intercurrent events. 
Dose regimens of 
LEO 152020 
 
 
 
vs. placebo
 
 
Permanent 
discontinuation of 
IMP due to 
pandemic related 
factors 
(hypothetical) 
 
Permanent 
discontinuation of 
IMP due to non-
pandemic related 
factors (treatment 
policy) 
 
Initiation of rescue 
medication 
(treatment policy) 
Difference in 
mean change 
in EASI from 
baseline to 
Week 16 
Primary 
endpoint 
Change in 
EASI from 
baseline to 
Week 16 
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Objective 
Estimands 
Endpoint 
 
Estimand type 
(Primary/ 
supplementary) 
Interpretation of the estimand 
Comparison 
groups 
Intercurrent 
events (strategy) 
Population 
level 
summary 
 
Second 
supplementary 
Assesses the effect of treatment in the 
hypothetical scenario, in which the 
COVID-19 pandemic did not occur and 
where the occurrence of non-pandemic 
related IEs indicates subsequent non-
response (Section 14.3.8.3). 
 
Under this hypothetical scenario, the 
potential outcomes for subjects 
experiencing a pandemic related 
intercurrent event are assumed to 
follow the distribution describing the 
outcomes for subjects in the same 
treatment group who did not 
experience a pandemic related 
intercurrent event. 
Dose regimens of 
LEO 152020 
 
 
 
vs. placebo
 
 
Permanent 
discontinuation of 
IMP due to 
pandemic related 
factors 
(hypothetical) 
 
Permanent 
discontinuation of 
IMP due to non-
pandemic related 
factors (composite) 
 
Initiation of rescue 
medication 
(composite) 
Difference in 
mean change 
in EASI from 
baseline to 
Week 16 
Primary 
endpoint 
Change in 
EASI from 
baseline to 
Week 16 
Abbreviations: AD = atopic dermatitis; ; COVID-19 = corona virus disease 2019; EASI = Eczema Area and Severity Index; IE = intercurrent events; 
IMP = investigational medicinal product.
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For the evaluation of efficacy, the following intercurrent events are considered to affect the 
interpretation of the measurements of the endpoint/variable: 
Non-pandemic related intercurrent events 
• Initiation of rescue treatment: This event occurs when a subject initiates rescue 
treatment. This event can occur at the discretion of the investigator. The timing of the 
event is defined 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. 
• Permanent discontinuation of IMP independently 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, or at the discretion of the 
investigator or the sponsor. The timing of the event is defined as the date of permanent 
discontinuation of IMP recorded in the eCRF. 
Pandemic related intercurrent events 
• 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 and is not attributed to lack of efficacy or randomized 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 the hypothetical strategy to handle the occurrence of 
intercurrent events. The estimand attempts to quantify the effect of treatment, in the 
hypothetical scenario, where subjects do not permanently discontinue IMP for any reason and 
where rescue medication is not made available prior to Week 16. 
For subjects observed to experience an intercurrent event, the potential outcomes under the 
envisioned hypothetical scenario, are assumed to follow the outcome distribution for subjects 
in the same treatment group, who did not experience an intercurrent event. 
The primary estimand assesses the expected benefit of the treatment when adhering to the 
treatment regimen in the context of the specified hypothetical scenario. 
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Main analysis 
Data collected after permanent discontinuation of IMP, regardless of reason, or the initiation 
of rescue treatment will be excluded from the analysis and "treated as missing". 
The endpoint will be analyzed using a MMRM. The model will include treatment, visit, visit 
by treatment interactions, and region (Japan, non-Japanese countries) as factors and be 
adjusted for the baseline EASI score as a covariate. The covariance matrix will be assumed to 
have an unstructured form and the Kenward-Roger approximation will be used to estimate the 
denominator degrees of freedom. Missing data, including data excluded due to the occurrence 
of an intercurrent event, is assumed to be MAR. The estimated LS-mean treatment 
differences, based on the observed margins, will be presented with 95% CIs and nominal 
p-values at each visit. The primary comparison is the treatment difference at Week 16, 
between the 
 and placebo groups. 
Sensitivity analysis 
The following sensitivity analyses will assess the robustness of the results of the main 
analysis with respect to the underlying statistical assumptions. The impact of the missing data 
assumptions on data excluded after the occurrence of an intercurrent event/due to the 
pandemic will not be considered in the sensitivity analyses, as the MAR assumption is aligned 
with the envisioned hypothetical scenario. 
• Sensitivity analysis 1: Exclusion of subjects with monotone missing data at Week 1 
Subjects with monotone missing data from Week 1 onwards are automatically excluded 
from the analysis. Although under the MAR assumption, the estimator of the treatment 
effect based on a likelihood analysis of a MMRM is unbiased, such exclusions run 
contrary to the intent of the FAS. 
This sensitivity analysis will assess the robustness of the results of the main analysis 
with regards to the exclusion of subjects with no observed post-baseline EASI 
assessments. The analysis will include all randomized subjects regardless of whether a 
subject has observed post-baseline EASI score assessments. To assess the impact of 
excluding subjects with no post-baseline EASI score assessments from the analysis, the 
LS-mean treatment contrasts for the MMRM specified in the main analysis, will be 
estimated using the mean baseline EASI score and the proportion of subjects from each 
region based on the FAS. 
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• Sensitivity analysis 2: Functional form of the baseline EASI score covariate 
This sensitivity analysis will assess the robustness of the results of the main analysis 
with respect to the assumed linear relationship between the mean change in EASI score 
from baseline to Weeks 1-16 and the baseline EASI score. Additional details for each 
sensitivity analysis will be specified in the SAP. 
14.3.8.2 First supplementary estimand 
The first supplementary estimand will use a combination of the treatment policy and 
hypothetical strategies, to handle the occurrence of non-pandemic and pandemic related 
intercurrent events, respectively. The treatment policy strategy  attempts to quantify the effect 
of the decision to treat subjects with the randomized treatment and therefore ignores the 
occurrence of non-pandemic related intercurrent events. 
This supplementary estimand will evaluate the treatment difference in the change in EASI 
score from baseline to Week 16 in the hypothetical scenario in which the COVID-19 
pandemic did not occur and regardless of the occurrence of non-pandemic related intercurrent 
events.  Under this hypothetical scenario, the potential outcomes for subjects experiencing a 
pandemic related intercurrent event are assumed to follow the observed outcome distribution, 
irrespective of the occurrence of non-pandemic related intercurrent events, among subjects in 
the same treatment group. 
Main analysis 
Data collected after the occurrence of a non-pandemic related intercurrent event will be 
included in the analysis. Whereas data collected after a pandemic related intercurrent event 
will be excluded from the analysis and ‘treated as missing’. 
Intermittent missing data will be imputed based on a Markov Chain Monte Carlo method, in 
order to obtain 1,000 copies of the data set with a monotone missing data pattern. Missing 
data, including data 'treated as missing' after the occurrence of a pandemic related intercurrent 
event,  will be imputed assuming the data is MAR within each treatment group. For a given 
treatment group, the imputation model will be based on all data observed prior to the 
occurrence of pandemic related intercurrent events. In particular, data observed after the 
occurrence of non-pandemic related intercurrent events will be included in the imputation 
model, in line with the specified treatment policy approach for handling non-pandemic related 
intercurrent events. 
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For each of the 1,000 complete datasets, the change in EASI score from baseline to Week 16 
will be analyzed using an ANCOVA model including treatment, and region (Japan, 
non-Japanese countries) as factors, and baseline EASI score as a covariate. The pooled 
estimates of the difference in the LS-mean change from baseline to Week 16, based on the 
observed margins, along with the associated 95% CIs and nominal p-values will be presented. 
Pooled inference will be based on applying Rubin’s rules to the estimates and standard errors 
from the ANCOVA analysis of the imputed datasets. 
Sensitivity analysis 
A tipping point analysis will be performed based on implementing a delta-adjusted multiple 
imputation approach. The delta-adjusted imputation approach allows for missing data to be 
imputed under the MNAR assumption. Heuristically, the imputation strategy, adjusts/shifts the 
parameters of the MAR distribution based on the value of a numeric offset term, denoted by 
delta. The tipping point analysis will adjust the values of the parameters in the MAR 
distribution representing the mean change in EASI score from baseline to Weeks 1-16. The 
analysis will assess how robust the results of the main analysis are to varying departures from 
the MAR assumption within each active treatment group. 
14.3.8.3 Second supplementary estimand 
A second supplementary estimand will use a combination of the composite and hypothetical  
strategies to handle the occurrence of non-pandemic and pandemic related intercurrent events, 
respectively. In the context of this trial, the composite strategy  attempts to quantify the effect 
of treatment, assuming that the occurrence of a non-pandemic related intercurrent event is 
indicative of subsequent treatment failure. For the primary endpoint, treatment failure will be 
defined as failing to obtain a decrease in EASI of at least 50% from baseline to Week 16. 
This supplementary estimand evaluates the treatment difference in the change in EASI score 
from baseline to Week 16 in the hypothetical scenario in which the COVID-19 pandemic did 
not occur and assuming that the occurrence of non-pandemic related intercurrent events is 
indicative of subsequent treatment failure. 
Main analysis 
Data observed after the occurrence of an intercurrent event will be excluded from the analysis 
and "treated as missing". Intermittent missing data will be imputed using a Markov Chain 
Monte Carlo method, in order to obtain 1,000 copies of the data set with a monotone missing 
data pattern. 
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Monotone missing data that is not due to the pandemic and data "treated as missing" due to 
the occurrence of a non-pandemic related intercurrent event will be imputed under the MAR 
assumption, with the additional stipulation that the imputation model will be truncated in 
order to align with the assumption that 
 
The additional stipulation ensures that these subjects will be considered as non-responders 
based on the imputed Week 16 EASI score. 
For subjects experiencing a pandemic related intercurrent event or with monotone missing 
data due to the pandemic, the imputation model needs to account for the possibility of 
experiencing a subsequent non-pandemic related intercurrent under the envisioned 
hypothetical scenario. Missing data will therefore be imputed from the joint distribution 
describing the time to experiencing a non-pandemic related intercurrent event and the 
longitudinal EASI score assessments under a MAR assumption. If the imputed time to first 
non-pandemic related intercurrent event is less than 16 weeks, all subsequent EASI scores for 
that subject will be imputed based on the above imputation model for non-pandemic related 
intercurrent events. 
For each of the 1,000 complete datasets, the change in EASI score from baseline to Week 16 
will be analyzed using an ANCOVA model including treatment and region (Japan, 
non-Japanese countries) as factors, and baseline EASI score as a covariate. The pooled 
estimates of the difference in the LS-mean change in EASI score from baseline to Week 16, 
based on the observed margins, along with the associated 95% CIs and nominal p-values will 
be presented. Pooled inference will be based on applying Rubin’s rules to the estimates and 
standard errors from the ANCOVA analysis of the imputed datasets. 
Panel 19 presents an overview of how observed and missing data will be handled according to 
the intercurrent events for the analyses of estimands. 
 
𝑌𝐸𝐴𝑆𝐼,𝑊𝑒𝑒𝑘 16 > 𝑌𝐸𝐴𝑆𝐼,𝐵𝑎𝑠𝑒𝑙𝑖𝑛𝑒
2
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Panel 19: Handling of intercurrent events and analyses of estimands for the primary endpoint 
Events 
Data observed or missing 
Estimand strategy 
Primary  
estimand 
First supplementary 
estimand  
Second supplementary 
estimand 
Initiation of rescue treatment a 
Observed 
Treated as 
missing/Not used 
Used 
Treated as missing, MI (MAR 
ensuring NR) 
Missing 
Not used 
MI (MAR) 
MI (MAR ensuring NR) 
Permanent discontinuation of IMP 
independently of the COVID-19 pandemic 
Observed 
Treated as 
missing/Not used 
Used 
Treated as missing, MI (MAR 
ensuring NR) 
Missing 
Not used 
MI (MAR) 
MI (MAR ensuring NR) 
Permanent discontinuation of IMP due to 
the COVID-19 pandemic 
Observed 
Treated as 
missing/Not used 
Treated as missing, MI 
(MAR) 
Treated as missing, MI 
(JM/MAR ensuring NR)  
Missing 
Not used 
MI (MAR) 
MI (JM/MAR ensuring NR) 
No intercurrent events 
Observed 
Used 
Used 
Used 
Missing independently of the 
COVID-19 pandemic 
Not used 
MI (MAR) 
MI (MAR ensuring NR) 
Missing due to the COVID-19 
pandemic 
Not used 
MI (MAR) 
MI (JM/MAR ensuring NR) 
Abbreviations: COVID-19 = coronavirus disease 2019; IMP = investigational medicinal product; JM = joint model; MAR = missing at random; MI = multiple 
imputation; NR = non-response. 
a Initiation of rescue treatment is considered an intercurrent event regardless of the relatedness to the COVID-19 pandemic. 
 
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14.3.8.4 Exposure-response modeling of LEO 152020 
To explore the exposure-response relationship of LEO 152020, the change in EASI score 
from baseline to Week 16 will be assessed based on an ANCOVA model, including the Ctrough 
values at Week 16 and the baseline EASI score as covariates and region (Japan, non-Japanese 
countries) as a factor. Data observed after the occurrence of an intercurrent event, will be 
excluded from the analysis and "treated as missing". Week 16 data, that is either missing or 
"treated as missing" due to the occurrence of an intercurrent event, will be assumed to be 
missing at random. The difference in the LS-mean change in EASI score from baseline to 
Week 16, based on the observed margins, along with the associated 95% CIs and nominal p-
values will be presented. In case a linear relationship between change in EASI from baseline 
to Week 16 and Ctrough cannot be shown, alternative models such as non-sigmoidal (with a hill 
coefficient =1) Emax or sigmoidal Emax will be considered. Further details regarding the 
goodness of fit criteria and  the non-linear model will be described in the SAP. 
14.3.9 
Analysis of secondary endpoints 
Analysis of secondary endpoints 
• Number of AEs from baseline to Week 16+3 days per subject. 
is described in detail in Section 14.3.14.1. 
14.3.10 
Analysis of exploratory endpoints 
Continuous endpoints 
• EASI at each visit from Week 1 to Week 16. 
• SCORAD at each visit from Week 1 to Week 16. 
• Change in ADSD score (weekly average) from baseline to Week 16. 
• Change in each ADSD individual symptom score (weekly average) from baseline to 
Week 16. 
will be summarized descriptively at each visit by treatment group and will be analyzed using 
an MMRM. The model will include treatment, visit, visit by treatment interaction terms, 
region (Japan, non-Japanese countries), and baseline disease severity (EASI score at 
baseline ≤16 and ≥16.1) as factors and adjust for the baseline value of the endpoint of interest 
as a covariate. For the analysis of the EASI score at each visit, the baseline disease severity 
factor will be excluded from the MMRM in order to avoid introducing a discontinuity in the 
relationship between the post-baseline EASI scores and the baseline EASI score. The model 
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will use an unstructured covariance matrix, and the Kenward-Roger approximation to 
estimate the denominator degrees of freedom. The SAP will specify alternative structures for 
the covariance matrix, to be used in case of non-convergence. For these endpoints, data 
collected after permanent discontinuation of IMP or after initiation of rescue medication will 
be excluded from the analysis and ‘treated as missing’. Missing data will be assumed to be 
MAR. The estimates will be presented with 95% CIs and nominal p-values at each visit. 
Binary 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. 
• Having a decrease in vIGA-AD of at least 2 points from baseline to Week 16. 
• Having a decrease in ADSD 
 score (weekly average) of at least 4 points from 
baseline to Week 16 in subjects with ADSD 
 score ≥4 at baseline. 
will be summarized descriptively at each visit by treatment group and will be analyzed based 
on a logistic regression model, including region (Japan, non-Japanese countries) and baseline 
disease severity (EASI score at baseline ≤16 and ≥16.1) as factors and adjusting for the 
baseline value of the endpoint as a covariate. The logistic regression model will be used to 
estimate the risk difference and associated 95% confidence interval based on the standardized 
estimator presented in Ge et al. (68). For the analysis of the EASI responder endpoints, 
baseline disease severity will not be included as a factor in the logistic regression model. 
Subjects who prior to the Week 16 visit received rescue treatment or permanently 
discontinued IMP or have missing data will be considered as non-responders. 
Time-to-event endpoint 
• Time from randomization to having an observed decrease in EASI of at least 50% 
(EASI 50) from baseline. 
• Time from randomization to having a decrease in ADSD 
 score (weekly average) 
of at least 4 points from baseline in subjects with ADSD 
 score ≥ 4 at baseline. 
will be analyzed according to Gray’s test, stratified by region (Japan, non-Japanese countries) 
and baseline disease severity (EASI score at baseline ≤16 and ≥16.1). Gray’s test accounts for 
the occurrence of the competing risks, permanent discontinuation of IMP and initiation of 
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rescue medication. Inference will be based on the estimated cumulative incidence functions 
derived from the Aalen-Johansen estimator. The estimated cumulative incidence functions 
will be presented by treatment group along with pointwise 95% confidence intervals. In 
addition, the estimated sub-distributional hazard ratio from a Fine and Gray model, stratified 
by region (Japan, non-Japanese countries) and baseline disease severity (EASI score at 
baseline ≤16 and ≥16.1) and adjusted for the baseline value of the endpoint of interest, will be 
presented along with the corresponding 95% CI. 
The following sleep 
 and nocturnal 
 endpoints will be collected using 
actigraphy: 
• Change in 
 from baseline to Week 16. The endpoint is measured in minutes and 
weekly averages will be reported. 
• Change in number of nocturnal 
 events per hour from baseline to Week 16. 
The endpoint will be assessed daily and the weekly averages will be reported. 
• Change in duration of nocturnal 
 events per hour from baseline to Week 16. 
The endpoint will be assessed daily and the weekly averages will be reported. 
• Change in 
 from baseline to Week 
 
 is calculated 
as the proportion of time spent 
 versus total time 
, expressed as a 
percentage. This will be assessed daily and weekly averages will be reported. 
These endpoints will be summarized descriptively by week and treatment group. The weekly 
average of data collected using actigraphy will be based on data collected over 7 days. Data 
collected after the initiation of rescue medication or permanent discontinuation of IMP will be 
excluded from the calculation of the weekly averages. In order to calculate the weekly 
average, a minimum of 4 out of the 7 planned measurements will be required. 
The following sleep disturbance endpoints will be collected using the eDiary and summarized 
descriptively by week and treatment group: 
• Difficulty 
 at Week 
 
• Frequency of 
 During the Night at Week 
 
• 
 at Week 
 
• 
 at Week 
 
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14.3.11 
Analysis of patient-reported outcomes 
Continuous endpoints 
• Change in POEM from baseline to Week 16. 
• Change in DLQI from baseline to Week 16. 
• Change in EQ-5D-5L from baseline to Week 16. 
will be summarized descriptively by week and treatment group and will be analyzed using the 
same MMRM model described in Section 14.3.10 for continuous endpoints. 
The following endpoints 
• Change in HADS from baseline to Week 16. 
• Change in WPAI:AD (for each individual domain) from baseline to Week 16. 
will be analyzed using an ANCOVA model including treatment, region (Japan, non-Japanese 
countries), and baseline disease severity (EASI score at baseline ≤16 and ≥16.1) as factors 
and adjusted for the baseline score as covariate. Data collected after the occurrence of an 
intercurrent event will be excluded from the analysis and "treated as missing". Missing data 
will be assumed to be MAR. 
Binary endpoints 
• Having a decrease in DLQI of at least 4 points from baseline to Week 16 in subjects 
with DLQI ≥4 at baseline. 
• Having a decrease in POEM of at least 4 points from baseline at Week 16 in subjects 
with POEM≥4 at baseline. 
will be summarized descriptively at each visit by treatment group and will be analyzed using 
the same logistic regression model described in Section 14.3.10 for binary endpoints. 
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14.3.12 
Analysis of pharmacodynamics 
Exploratory analyses for the following endpoints will be conducted for the total population as 
well as by baseline disease severity (EASI score at baseline ≤16 and ≥16.1) 
• Change in expression levels of blood biomarkers from baseline to Week 
 
• Change in expression levels of AD disease biomarkers in skin from baseline to 
Week 
 
The biomarker results will be reported in an addendum to the CTR. If biopsies are collected 
from less than 10% of the randomized subjects in a specific treatment group, analysis may not 
be carried out for that treatment group as the number of biopsies may be too low to allow for 
a meaningful analysis. 
14.3.13 
Exploratory analyses 
Additional exploratory analyses will be described in the SAP and will be conducted 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 trial according to MedDRA. AEs will be presented by preferred 
term and primary SOC. 
Treatment-emergent AEs will be summarized; however, all AEs recorded during 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 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 started 3 days after the last 
dose of IMP. The tabulations described below will only include the treatment-emergent AEs. 
In each of the tabulations, AEs are defined by MedDRA preferred terms within primary SOC. 
AEs will be summarized in terms of the number of subjects with at least 1 event, the 
percentage of subjects with at least 1 event, the number of events, and the event rate per 
100 patient years of observation time. 
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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 by treatment group for all AEs, 
SAEs, related AEs, AESIs, and AEs leading to permanent discontinuation of IMP and/or 
withdrawal from trial. 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 AE (as described in the 
paragraph above) will be tabulated by treatment group from baseline to Week 16+3 days. 
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 
administration of IMP. No narratives will be given. 
14.3.14.2 Vital signs and physical examination 
The change in vital signs (resting blood pressure, pulse, and body temperature) from baseline 
to each relevant visit will be summarized by treatment group as mean, standard deviation 
(SD), median, minimum and maximum values for the safety analysis set. 
Subjects with abnormal, clinically significant physical findings will be listed. Furthermore, a 
shift table for physical findings showing the change from baseline to Week 16 in clinical 
assessments (normal; abnormal, not clinically significant; abnormal, clinically significant) 
will be performed. 
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14.3.14.3 Electrocardiography 
Absolute values and change in ECG parameters (
) from baseline to each 
relevant visit will be summarized by treatment group as mean, SD, median, minimum and 
maximum values for the safety analysis set. 
Subjects with abnormal clinically significant ECG parameters will be listed. Furthermore, a 
shift table showing the change in clinical assessments (normal, abnormal not clinically 
significant, abnormal clinically significant) for the ECG parameters from baseline to Week 16 
will be provided. 
14.3.14.4 Clinical laboratory evaluation 
The change in each of the laboratory parameters from baseline to each relevant visit will be 
summarized 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. 
14.3.15 
Pharmacokinetic analysis 
The PK endpoint 
• Ctrough of LEO 152020 at Weeks 
 
• Cmax of LEO 152020 at Weeks 
. 
will be summarized for subjects in the PK analysis set and with PK assessments at the 
relevant visits using geometric mean, coefficient of variation (derived based on a log-normal 
distribution assumption), median, 1st quartile, 3rd quartile, minimum and maximum values. 
14.3.16 
Interim analysis 
No interim analysis is planned. 
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49. 
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FDA. Food and Drug Administration. Patient-Focused Drug Development Guidance 
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Moreau A, Anderer P, Ross M, Cerny A, Almazan TH, Peterson B, Moreau A, Anderer 
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adhesion molecule upregulation. Br J Pharmacol. 2004;142(1):161-171. 
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67. 
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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 unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with 
the use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product (69). 
This definition includes: 
• Accidental injuries. 
• Events related to trial procedures. 
• Reasons for any unfavorable and unplanned change in medication (drug and/or dose). 
• Clinically significant worsening of pre-existing conditions. 
• Reasons for admission to hospital or surgical procedures*. 
• AEs commonly observed and AEs anticipated based on the pharmacological effect of 
the IMP. 
• Any laboratory abnormality assessed as clinically significant by the investigator (see 
Section 11.4.4.2). 
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 hospitalization or prolongation of existing hospitalization*. 
• 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 hospitalization but may jeopardize 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 hospitalization, 
development of drug dependency, or drug abuse. 
Additionally, all malignancies, including skin malignancies, should be reported as SAEs. 
*Hospitalization for procedures or treatments planned prior to the subject consented to trial 
participation does not constitute an AE and should therefore not be reported as AE or SAE. 
Hospitalization for elective treatment of a pre-existing condition which did not worsen from 
the subject consented to trial participation is not considered an AE and should therefore not be 
reported as AE or SAE, even if not planned before consent to trial participation. 
Hospitalization 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. 
Hospitalization for administrative purpose does not constitute an AE and should therefore not 
be reported as AE or SAE. 
Complications that occur during hospitalization are AEs. If a complication prolongs 
hospitalization, the event is an SAE. 
When in doubt as to whether hospitalization occurred, the AE should be considered serious. 
Adverse events of special interest definition 
An AESI (serious or non-serious) is an event type of scientific and medical concerns specific 
to the product or development program, for which additional monitoring may be appropriate. 
Such an event may warrant further investigation in order to characterize 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) may also be warranted. 
AEs considered AESIs in this trial are described in Section 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 AE worsens in severity, the new severity including date of worsening should be 
recorded. However, if an AE with onset prior to IMP initiation worsens after first dose of IMP, 
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. 
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 an 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. 
In summary, the definitions used by LEO Pharma are more conservative than those used by 
CDISC. 
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Appendix 3: Trial governance considerations 
Appendix 3A: Regulatory and ethical considerations 
This trial will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines including the current 
version of the Declaration of Helsinki (32) and Council for International Organizations 
of Medical Sciences (CIOMS) International Ethical Guidelines (70). 
• Current version of applicable International Council for Harmonization Good Clinical 
Practice (ICH GCP) Guidelines (33). 
• EU General Data Protection Regulation 2016/679 of 27 April 2016. 
• Applicable laws and regulations. 
The appropriate regulatory authorities 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, subject information sheet, and 
informed consent forms, or advertisements) will be submitted to the IRB/IEC. These 
documents must be reviewed and approved by the IRB/IEC before the trial is initiated. 
Any amendments to the protocol must be approved by/receive favorable opinion from 
relevant regulatory authorities and IRBs/IECs, as required, prior to implementation. 
The principal investigator will be responsible for the following, if required by local 
legislation: 
• Providing written summaries of the status of the trial to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC. 
• Notifying the local IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures. 
• 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 emphasize that participation in the clinical trial is voluntary and that the 
subject may withdraw from the clinical trial at any time and for any reason. All subjects will 
be given an opportunity to ask questions and will be given sufficient time to consider before 
consenting. 
The subject’s signed and dated informed consent to participate in the clinical trial will be 
obtained prior to any clinical trial-related procedure being carried out in accordance with 
ICH GCP and all applicable laws and regulations. The authorized person obtaining the 
informed consent must also sign the ICF. 
Subjects will be re-consented to the most current version of the ICF(s) during their 
participation in the trial, if required. 
A copy of the ICF(s) must be provided to the subject. 
Subject card 
At screening, subjects will be provided with a card stating that they are participating in a 
clinical trial and which will contain contact address(es) and telephone number(s) of relevant 
trial site staff including the number for the investigator in case of an emergency. The subject 
card will also include a local telephone number for the emergency unblinding CRO to be used 
if the investigator or delegated site staff cannot be reached at the time of emergency 
unblinding request or if unblinding in the IRT system cannot be conducted. 
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 authorized personnel appointed by LEO Pharma, 
by appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
Trial subjects must be informed that LEO Pharma might keep their trial-related data for as 
long as they are useful for developing treatments for the disease or other diseases and future 
research. 
Processing of personal data 
This protocol specifies the personal data on trial subjects (e.g. race, ethnicity [if collection is 
allowed by local legislation], age, sex, health condition, medical history, test results, etc.) 
which shall be collected as part of the clinical trial and processed during and after trial 
completion. 
Personal data collected as part of the clinical trial will be transferred to/from the 
institution/investigator, LEO Pharma, and third parties acting on behalf of LEO Pharma. 
Processing of personal data on behalf of LEO Pharma requires a written agreement between 
LEO Pharma and the relevant party which covers collection, processing, and transfer of 
personal data in the clinical trial. In certain cases, an agreement on transfer of personal data 
may also be required. 
Investigators and LEO Pharma must ensure that collection, processing, and transfer of 
personal data are in compliance with applicable legislation on data protection and privacy, 
including but not limited to the EU General Data Privacy Regulation. 
Subjects must be asked to consent to the collection, processing, and transfer of their personal 
data to EU and non-EU countries for the purpose of conducting the clinical trial, research and 
development of new or existing products/services, improving existing products/services, 
applying for marketing authorizations for products/services, marketing of products/services, 
and other related activities. 
LEO Pharma has obtained the necessary authorizations for the processing of personal data 
collected in the trial. 
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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. 
The date and time of sampling must be recorded on the laboratory requisition form. 
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. 
• Randomization code number. 
• The fact that the subject is participating in a clinical trial in atopic dermatitis including 
treatment with LEO 152020 for 16 weeks. 
• Other relevant medical information. 
Trial monitoring 
The trial will be monitored on an ongoing basis to verify that (i) the rights and well-being of 
the trial subjects is protected; (ii) the reported trial data are accurate, complete, and verifiable 
from source documents; and (iii) the conduct of the trial is in compliance with the currently 
approved protocol/amendment(s), ICH GCP, and all applicable regulatory requirement(s). 
The monitoring will be performed in a systematic, prioritized, risk-based approach, and as a 
combination of on site, remote, and centralized monitoring. For more details, please refer to 
the trial-specific monitoring guideline and data review plan. 
In order to perform their role effectively, CRAs and persons involved in quality assurance and 
inspections will need direct access to source data, e.g. medical records, laboratory reports, 
appointment books, etc. If the electronic medical record does not have a visible audit trail, the 
investigator must provide the CRA with signed and dated printouts. In addition, relevant site 
staff should be available for discussions at monitoring visits and between monitoring visits 
(e.g. by telephone). 
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Protocol compliance 
Protocol deviations will be documented and notified to the investigator. Protocol deviations 
will be assessed by LEO Pharma and major protocol deviations described in the CTR. 
Sponsor audits, IRB/IEC review, and regulatory agency inspections 
The clinical trial will be subject to audits conducted by LEO Pharma or inspections from 
domestic or foreign regulatory authorities or from IRBs/IECs. Audits and inspections may 
take place during or after the trial. The investigator and the site staff as well as LEO Pharma 
staff have an obligation to cooperate and assist in audits and inspections. This includes giving 
auditors and inspectors direct access to all source documents and other documents at the trial 
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 authorized by the 
investigator will enter subject data into an electronic CRF (eCRF). Data recorded in the eCRF 
will be accessible to the trial site and LEO Pharma personnel immediately after entry. The 
eCRF must be maintained in an up-to-date state by the trial site at all times. 
The investigator must verify the correctness of the data entered by the site by electronically 
dating and signing the eCRF. This signature information will be kept in the audit trail and 
cannot be altered. Any correction(s) made by the investigator or authorized site staff to the 
eCRF after original entry will be documented in the audit trail. Changes to data already 
approved will require re-signature by the investigator. The person making the change to the 
data, and the date, time, and reason for the change will be identified in the audit trail. 
Subject data should be entered into the eCRF no later than 5 working days after each visit 
unless a different deadline is stated in the clinical trial agreement. Queries for discrepant data 
will be generated automatically by the system upon entry or manually by the CRA, sponsor’s 
medical expert, or the data manager. All queries will be raised electronically within the 
electronic data capture system. This systematic validation will ensure that a clean and 
consistent database is provided for the statistical analysis. 
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An electronic PRO (ePRO) solution will be used to capture patient-reported data (eDiary data 
and data from questionnaires completed at the trial site). This solution allows data to be 
available immediately after entry to site staff, including the investigator, and CRAs 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. 
Statistical programming standards 
CDISC controlled terminology version 30-Mar-2018 or newer was used for definition of 
controlled terminology 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 (33). Essential trial documents must be stored 
until LEO Pharma informs the investigator that the documents are no longer to be retained, or 
longer if required by local regulations. 
In addition, the investigator is responsible for the archiving of all relevant source documents 
so that the trial data can be compared against source data after the completion of the trial (e.g. 
in case of an inspection from regulatory authorities). 
The investigator is required to ensure the continued storage of the documents even if the 
investigator leaves the trial site or retires before the end of the required storage period. 
No documents may be destroyed during the retention period without the written approval of 
LEO Pharma. No documents may be transferred to another location or party without written 
acceptance from LEO Pharma. 
The destruction process must ensure confidentiality of data and must be done in accordance 
with local regulatory requirements. 
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For archiving purposes, each investigator will be supplied with an electronic copy of the 
eCRFs, ePRO, and eDiary data for all screened subjects at the trial site. This is done after 
completion of the trial and before access to the eCRF/ePRO/eDiary data is revoked. Audit 
trail information will be included. eCRFs and ePRO/eDiary data must be available for 
inspection by authorized 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 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 fulfill 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 
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. 
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LEO Pharma may give researchers outside LEO Pharma access to anonymized data from this 
trial for further research according to the principles outlined by the European Federation of 
Pharmaceutical Industries and Associations (EFPIA) (71). 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 and update this information, should any 
relevant change occur, during the course of the clinical trial and for 1 year after completion of 
the clinical trial, or for a longer period of time if required by local legislation. 
Appendix 3H: Committee structure 
Subject safety will carefully be assessed by an independent DMC. All members of the DMC 
will be independent of the trial (i.e. they will not be investigators or employees at 
participating sites) and of LEO Pharma (i.e. they will not be LEO Pharma employees). The 
DMC members will be experienced with clinical trial conduct and have expertise from 
different scientific areas relevant to the trial. The DMC will be responsible for evaluating 
subject safety through assessment of the safety of the treatment regimens during the trial and 
through monitoring of the overall conduct of the trial. 
The DMC will review accumulated data on a regular basis. Additional meetings may also be 
called for on an ad hoc basis, as requested by the DMC or LEO Pharma. All data collected at 
the time of data cut-off/scheduled meetings will be included in the summaries for the DMC, 
including data from subjects still ongoing in the trial. The DMC will examine summaries and 
listings of AEs, specific laboratory parameters, and subject disposition data as described in 
the DMC charter. Details of the analyses to be presented to the DMC will be specified in a 
separate DMC statistical analysis plan which will be made available to the DMC. 
The DMC will have an independent statistician and an independent administrator who will 
remain independent of the trial management team. 
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The chairman of the DMC will, in conjunction with the other members, communicate their 
recommendations to relevant representatives from the clinical trial team at LEO Pharma A/S 
in an open wrap-up session after each meeting. After each meeting, the chairman of the DMC 
will provide LEO Pharma with a signed (by the DMC Chair) written DMC recommendation 
regarding safety concerns and trial continuation. Details on all aspects related to the DMC 
will be provided in the DMC charter. 
Appendix 3I: Trial and trial site closure 
Premature termination of trial or trial site 
LEO Pharma, the investigator, the IRBs/IECs, or competent authorities may decide to stop the 
clinical trial, part of the trial, or a trial site at any time, but agreement on procedures to be 
followed must be obtained. 
If a clinical trial is suspended or prematurely terminated, the investigator must inform the 
subjects promptly and ensure appropriate therapy and follow-up. As specified by applicable 
regulatory requirements, the investigator or LEO Pharma must promptly inform IRBs/IECs 
and provide a detailed written explanation. Relevant competent authorities must be informed. 
The trial must be terminated if the perception of the benefit/risk ratio (judged from clinical 
signs and symptoms, [S]AEs, and/or remarkable safety laboratory changes) becomes 
unfavorable for the continuation of the trial. 
Reasons for the premature closure of a trial site by LEO Pharma or investigator may include 
but are not limited to: 
• Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, LEO Pharma procedures, or GCP guidelines. 
• Inadequate recruitment 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. 
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When the randomization code has been broken, the investigators will receive information 
about treatment allocation for the subjects randomized 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 clinical trial report 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 related 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: Country-specific requirements 
This appendix describes country-specific requirements and procedures. For each item below, 
the original protocol text is in regular font and the country-specific changes crossed out 
(deleted text) or bold (text applicable in the country in question). 
GERMANY 
Section 5.5 Benefit/risk assessment 
In Germany, the following edited text will apply: 
To further ensure subject safety, subjects with cardiac arrhythmic risk factors, moderate or 
severe hepatic impairment, and/or severe renal impairment will be excluded from 
participation in the trial (Section 8.3). 
Section 8.3 Exclusion criteria 
In Germany, exclusion criterion 16 will be: 
Subjects with severe renal impairment as determined by eGFR levels below 3090 mL/min 
at screening. 
Section 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. 
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. 
In Germany, the following text will apply: 
Any SAE must be reported to LEO Pharma on the (paper) SAE form immediately 
without undue delay. 
SAEs occurring after the completion of the clinical trial should not be routinely sought 
or recorded. However, such events should be reported immediately without undue 
delay to Global Safety at LEO Pharma (see contact details above) if the investigator 
becomes aware of them. 
 
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JAPAN 
Section 5.5 Benefit/risk assessment 
To further ensure subject safety, subjects with cardiac arrhythmic risk factors, moderate or 
severe hepatic impairment, and/or severe renal impairment will be excluded from 
participation in the trial (Section 8.3). 
In Japan, subjects with renal impairment will not be included in the trial: 
To further ensure subject safety, subjects with cardiac arrhythmic risk factors, 
moderate or severe hepatic impairment and/or renal impairment will be excluded 
from participation in the trial (Section 8.3). 
Section 8.2 Inclusion criteria 
Inclusion criterion 1 
Signed and dated informed consent obtained prior to any protocol-related procedures. 
In Japan, if the subject is less than 20 years old prior to 01-Apr-2022, the legal 
representative must sign the informed consent. 
Inclusion criterion 2 
Adult, age 18 years or older at screening. 
In Japan, inclusion criterion 2 will be: Japanese adults, age 18 years or older at 
screening. 
Inclusion criterion 5 
Recent (within 6 months prior to baseline) documented history of inadequate response to 
topical AD treatments* or subject for whom topical AD treatments are medically 
inadvisable. 
*Inadequate response to topical AD treatments is defined as failure to achieve and maintain 
remission or a low disease activity state corresponding to 0 (clear) ≤ IGA ≤ 2 (mild) despite 
treatment with a daily regimen of TCS of medium to high 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). 
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In Japan, a list of TCS medications which are considered medium to high in potency 
will be provided as a separate document to the investigators to aid eligibility 
assessment. 
Exclusion criterion 16 
Subjects with severe renal impairment as determined by eGFR levels below 30 mL/min at 
screening. 
In Japan, subjects with renal impairment will not be included in the trial. Exclusion 
criterion 16 will be: 
Subjects with renal impairment as determined by eGFR levels below 90 mL/min at 
screening. 
Section 9.8.4 Accountability of the investigational medicinal products 
The investigator is fully responsible for the IMPs at the trial site and for maintaining 
adequate control of the IMPs and documenting all transactions with them. 
In Japan, the Head of Institute will be responsible for the IMPs at the trial site. 
Section 9.10 Reporting product complaints 
Global Safety, LEO Pharma contact information for reporting product complaints: 
E-mail address: drug.safety@leo-pharma.com. 
Fax number: +45 7226 3287. 
In Japan, product complaints must be reported to Pharmacovigilance, LEO Pharma 
K.K. using the contact information below: 
E-mail address: clinical_trial_jp@leo-pharma.com. 
Fax number: +81 3 4243 3311. 
Note: Reports sent to the above email address and fax number will be manually 
forwarded to Global Safety, LEO Pharma. 
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Section 11.1 Overview 
Subjects participating in the trial will be under the careful supervision of a principal 
investigator who must be a dermatologist or allergist. Investigators must be physicians and 
have experience in treating atopic dermatitis as well as documented experience with and/or 
training in the assessments used in the trial. 
In Japan, investigators must be board-certified dermatologists. 
Section 11.4.3 Electrocardiography 
Between baseline and Week 16, at the visits indicated in Section 4, pre-dose ECGs must be 
measured shortly before dosing and post-dose ECGs must be measured 
 after 
dosing. 
In Japan at the request of PMDA, 1 additional ECG will be measured at baseline and 
Week 1, 
 after dosing. 
Section 11.7.2 Wristband scratch and sleep monitoring 
In Japan, the optional wristband actigraphy component of the trial will not be 
available. 
Section 13.4.1 Investigator reporting responsibilities 
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 7226 3287. 
In Japan, SAEs must be reported to Pharmacovigilance, LEO Pharma K.K. using the 
contact information below: 
E-mail address: clinical_trial_jp@leo-pharma.com. 
Fax number: +81 3 4243 3311. 
Note: Reports sent to the above email address and fax number will be manually 
forwarded to Global Safety, LEO Pharma. 
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Section 13.4.2 LEO Pharma reporting responsibilities 
Global Safety at LEO Pharma will notify the regulatory authorities and concerned 
investigators of SAEs according to the current applicable legislation for the concerned 
countries. 
In Japan, Pharmacovigilance, LEO Pharma K.K. will notify the regulatory authorities 
and concerned investigators of SAEs. 
Section 13.5.1 Pregnancy 
The completed pregnancy forms must be faxed or scanned and e-mailed to Global Safety at 
LEO Pharma. Contact details are given in Section 13.4.1. 
In Japan, any pregnancy must be reported to Pharmacovigilance, LEO Pharma K.K. 
using the contact information below: 
E-mail address: clinical_trial_jp@leo-pharma.com. 
Fax number: +81 3 4243 3311. 
Note: Reports sent to the above email address and fax number will be manually 
forwarded to Global Safety, LEO Pharma. 
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Appendix 5: Short version of eligibility criteria and justification 
Inclusion criteria 
No. 
Short version 
Justification 
1 
Signed and dated informed consent obtained 
prior to any protocol related procedures 
GCP requirement 
2 
Adult, age 18 years or older at screening 
The trial will be conducted in adults only. 
3 
Diagnosis of chronic AD as defined by the 
Hanifin and Rajka (1980) criteria for AD 
To ensure correct diagnosis of AD and rule out 
differential diagnosis 
4 
History of AD ≥1 year prior to baseline 
To ensure inclusion of subjects with chronic AD 
which is the target population for this trial 
5 
Recent (within 6 months prior to baseline) 
documented history of inadequate response to 
topical AD treatments or subject for whom 
topical AD treatments are medically 
inadvisable 
To ensure that the subject is candidate for systemic 
AD treatment 
6 
7.1≤ EASI ≤50 at baseline 
To ensure inclusion of subjects within the entire 
range of moderate to severe AD but exclude 
subjects with a very severe disease as there is a 
high risk that treatment of this population with 
placebo would not be tolerated 
7 
vIGA-AD score ≥3 at baseline 
To ensure inclusion of subjects with moderate to 
severe AD and that the subject has a disease 
severity allowing assessment of improvement 
8 
BSA ≥5% at baseline 
To ensure that the subject has sufficient lesional 
skin area to assess AD severity 
9 
Subject agrees to apply an emollient to lesional 
and non-lesional skin at least twice daily for at 
least 7 consecutive days immediately prior to 
baseline. 
To keep the subject’s skin well-moisturized in the 
absence of systemic and/or topical AD treatment(s) 
10 
Women of childbearing potential must use 
highly effective contraception from 
randomization to the end of the trial (safety 
follow-up visit). 
To avoid exposing an embryo to LEO 152020 as 
only nonclinical data on effect of LEO 152020 on 
reproduction are currently available 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Exclusion criteria  
No. 
Short version 
Justification 
1 
Concurrent skin disease at baseline which may 
interfere with the trial assessments, at the 
discretion of the investigator 
To avoid interference with the trial assessments 
2 
Active skin infection or any other clinically 
apparent infection at baseline which may 
interfere with the trial assessments, at the 
discretion of the investigator 
To avoid interference with the trial assessments 
3 
Previous treatment with an oral H4R 
antagonist (including LEO 152020) 
The trial will evaluate the effect of LEO 152020 in 
subjects who have never been exposed to a drug 
with the same mode of action 
4 
Previous treatment with 3 or more systemic 
AD treatments prior to screening 
The primary objective of the study is to investigate 
the exposure-response of LEO 152020. Subjects 
who have been treated with 3 or more systemic AD 
treatments could be resistant to any systemic AD 
treatment. Therefore, these subjects may not 
benefit from treatment with LEO 152020 and their 
data may not inform the primary objective of the 
trial. 
5 
Systemic treatment including systemic 
corticosteroids known or suspected to have an 
effect on AD within 4 weeks or 5 half-lives 
prior to baseline, whichever is longer 
To ensure that previous AD treatments are washed 
out and do not interfere with trial assessments at 
baseline 
6 
Phototherapy within 4 weeks prior to baseline 
To ensure that residual effect of phototherapy is 
avoided and does not interfere with trial 
assessments at baseline 
7 
Positive HBsAg, anti-HBs, anti-HBc, or HCV 
serology at screening 
To ensure subject safety by avoiding inclusion of 
subjects with immune-compromised state and/or 
latent infections 
8 
Current active tuberculosis based on test per 
local standard at screening. 
To ensure subject safety by avoiding inclusion of 
subjects with immune-compromised state and/or 
latent infections 
9 
Infection with HIV 
To ensure subject safety by avoiding inclusion of 
subjects with immune-compromised state and/or 
latent infections 
10 
History of lymphoproliferative disease or 
malignancy (except treated and recovered 
non-melanoma skin cancer or cervical 
carcinoma in situ) within 5 years prior to 
screening 
To ensure subject safety by avoiding inclusion of 
subjects with immune-compromised state 
11 
Subjects at risk for Torsade de Pointes 
To ensure subject safety by avoiding inclusion of 
subjects with cardiac arrhythmic risk factors. 
12 
Use within 5 half-lives prior to screening of 
concomitant medication for which QT 
prolongation is a known side effect and which 
cannot be discontinued or replaced by (a) safe 
alternative medication(s) 
To ensure subject safety by minimizing possible 
risk of QT prolongation 
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13 
Resting QTcF (average of a triplicate 
measurement) < 300 ms or >450 ms (men) or 
>460 ms (women) at screening 
To ensure subject safety by avoiding inclusion of 
subjects with prolonged QT interval 
14 
Known history of ventricular arrhythmias 
To ensure subject safety by avoiding inclusion of 
subjects at risk of experiencing cardiac side effects 
15 
Second- or third degree- atrioventricular block 
To ensure subject safety by avoiding inclusion of 
subjects at risk of experiencing cardiac side effects 
16 
Subjects with severe renal impairment as 
determined by eGFR levels below 30 mL/min 
at screening 
To ensure subject safety by excluding the most 
fragile subgroup of subjects with severe renal 
impairment 
17 
Subjects with medical history of chronic 
moderate to severe liver disease 
To ensure subject safety by excluding subjects 
with potential impaired ability to excrete 
LEO 152020 
18 
Clinically significant abnormal finding at 
screening and/or baseline 
To ensure subject safety 
19 
Any unstable medical, surgical, psychiatric, or 
additional physical disorder at any time during 
the trial 
To ensure subject safety 
20 
Known or suspected hypersensitivity to any 
components of the IMPs or to drugs of a 
similar chemical class 
To avoid allergic reactions to LEO 152020 
21 
Treatment with any non-marketed drug 
substance within 4 weeks or 5 half-lives of the 
drug prior to baseline, whichever is longer 
To ensure subject safety and avoid interference 
with the trial assessments 
22 
Current participation in any other 
interventional clinical trial 
To ensure subject safety and avoid interference 
with the trial assessments 
23 
Previously screened in this trial 
To ensure the integrity of the trial. However, 
rescreening is allowed in case the reason for the 
screening failure was administrative (Section 8.4) 
24 
Current or recent chronic alcohol or drug abuse 
within 12 months prior to screening 
To ensure subject safety and avoid inclusion of 
subjects anticipated to have a challenge completing 
the trial 
25 
Subjects, who, in the opinion of the 
investigator, would be noncompliant or unable 
to understand the trial and give adequately 
informed consent 
To exclude potentially noncompliant subjects and 
subjects not able to provide adequately informed 
consent 
26 
Employees of the trial site, any other 
individuals directly involved with the planning 
or conduct of the trial, or immediate family 
members of such individuals 
GCP requirement 
27 
Subjects who are legally institutionalized 
To avoid inclusion of subjects not able to provide 
fully informed consent 
28 
Women who are pregnant, intend to become 
pregnant, or are lactating 
To avoid exposing an embryo/newborn to 
LEO 152020 as only nonclinical data on effect of 
LEO 152020 on fetal development/lactation in are 
currently available 
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Appendix 6: Contact list 
Contact details for the clinical project manager, appointed CRA, and sponsor’s medical expert 
are provided to the trial sites as a separate contact list. 
Sponsor 
ULEO Pharma A/SU (referred to as ‘LEO Pharma’ or ‘the sponsor’ in this clinical trial protocol) 
is the sponsor of the clinical trial: 
LEO Pharma A/S 
Industriparken 55 
DK-2750 Ballerup 
Denmark 
Coordinating investigator 
, MD 
 
 
 
 
 Hannover 
Germany 
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Appendix 7: Guidance to trial site before subject administers 
investigational medicinal product at site 
Panel 20: a) Is the subject fasted and are there more than  hours since last dose of 
IMP? 
 
b) If the subject took a morning dose of IMP in error before the visit 
 
Abbreviations: ECG = electrocardiogram; IMP = investigational medicinal product; PK = pharmacokinetic(s). 
a Last meal taken more than 2 hours prior to arrival at trial site. 
b Last dose of IMP taken more than  hours prior to the dose of IMP at trial site. 
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c See Section 9.2, If the subject misses a visit or a dose of IMP at the trial site. The subject may take the IMP at 
home and a note of this should be recorded in the subject’s record. 
d If the subject took a morning dose of IMP in error before the visit, efforts should be made to measure the ECG 
within 
 of IMP intake. 
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Appendix 8: Prohibited medications (
, 
, and 
) 
Panel 21: List of prohibited medications known to inhibit the 
 
Medication 
Therapeutic class 
 
Antianginal 
 
FXR agonist 
 
Angiotensin II inhibitor (angiotensin receptor 
blocker) 
 
Other immunomodulator 
Abbreviations: 
; FXR = potent farnesoid X receptor. 
Panel 22: List of prohibited medications known to inhibit the 
 
Medication 
Therapeutic class 
Antiarrhythmic 
Calcium channel blocker 
 
HMG-CoA reductase inhibitor (statin) 
Antibiotic 
l 
Antiviral 
Antipsychotic 
Sodium-dependent glucose cotransporter 2 inhibitor 
Alpha/beta adrenergic antagonist 
Antibiotic 
H1 receptor antagonist 
Antibiotic 
Calcium channel blocker 
Antiarrhythmic 
Gonadotropin-releasing hormone receptor antagonist 
Antibiotic 
Central nervous system agent 
SSRI 
Syk-inhibitor 
Antifungal 
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Medication 
Therapeutic class 
Other antiparkinsonian 
Antifungal 
Other respiratory system products 
Antifungal 
Antiviral 
Opioid 
Beta3-adrenergic agonist 
NSAID 
Serotonin modulator 
Antifungal 
Proton pump inhibitor 
Proton pump inhibitor 
SSRI 
Antiarrhythmic 
Antifungal 
Antiparasitic 
Antiarrhythmic 
Antiarrhythmic 
Antianginal 
Antibiotic 
Antipsychotic 
Antiemetic 
Antibiotic 
Hypnotic (sedative) 
Alpha/beta adrenergic antagonist 
Antibiotic 
CFTR potentiator 
Anticoagulant and antiplatelet 
Vasopressin antagonist 
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Medication 
Therapeutic class 
Central nervous system agent 
Calcium channel blocker 
Anticoagulants and antiplatelet 
Antifungal 
Abbreviations: CFTR = cystic fibrosis transmembrane conductance regulator; H1 = histamine 1; 
HMG-CoA = 3-hydroxy-3-methylglutaryl-coenzyme A; NSAID = non-steroidal anti-inflammatory drug; 
; SSRI = selective serotonin reuptake inhibitor; Syk = spleen tyrosine kinase. 
Panel 23: List of prohibited medications known to inhibit the 
 
Medication 
Therapeutic class 
Antiandrogen 
NSAID 
Fibric acid derivative 
NSAID 
HMG-CoA reductase inhibitor (statin) 
Uricosuric 
Antibiotics 
Abbreviations: HMG-CoA = 3-hydroxy-3-methylglutaryl-coenzyme A; NSAID = non-steroidal anti-
inflammatory drug; 
 
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Appendix 9: COVID-19 contingency plan 
Without compromising subject and site staff safety, it is expected that all efforts will be made 
to ensure subject attendance to trial visits to conduct important efficacy and safety 
assessments. 
As protective/preventive measures can differ across countries and regions, no general 
instructions from the sponsor can be provided and the investigators will be trusted to take 
appropriate actions. This includes but is not limited to complying with local regulations and 
recommendations, increasing protective safety and hygiene measures (e.g. social distancing, 
wearing mask, disinfecting hands) for both subject and site staff, and frequently monitoring 
the subject’s health. 
To minimize exposure to COVID-19 in public transportation, 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, the site should postpone screening and randomization of 
subjects until on-site visits can be conducted again. For subjects already randomized in the 
trial, safety monitoring is an obligation of LEO Pharma and an on-site visit can be converted 
into a remote visit by means of a video consultation/telephone call for the primary purpose of 
safety monitoring. To ensure subject privacy, both investigator and subject should confirm 
their identity at the start of the remote visit. The date of the remote visit should be 
documented in the subject’s record. 
At a remote visit, the following safety data must be collected: 
• AEs. 
• Concomitant medication and concurrent procedures, including use of rescue medication 
by the subject. 
• If applicable, result of the urine pregnancy test*. 
*If needed, women of childbearing potential will be provided with urine pregnancy 
tests. They will be asked to take the test prior to the remote visit and inform the 
investigator of the result at the remote visit. A woman with a positive urine pregnancy 
test 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 at a 
local laboratory. 
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If applicable, the subject will receive a link to complete PROs, which should have been 
assessed at the trial site, in a web browser (Section 11.5.1). The pandemic is not expected to 
affect subjects’ ability to complete PROs in the eDiary daily (Section 11.5.1). The remote visit 
must not be used for conducting any investigator’s assessments of efficacy. 
Continued treatment with the IMP may be allowed if, in addition to the safety assessments 
listed above, ECG monitoring by a cardiologist and safety laboratory testing can be arranged 
locally and the results shared with the investigator in time for the nominal safety assessments. 
If the above can be arranged, IMP will be shipped to the subject’s home and LEO Pharma will 
provide a shipment solution for return of all (partly) used and unused IMP to the trial site for 
the purpose of IMP accountability. 
If the above cannot be arranged, the investigator or site representative should contact their 
local monitor and discuss each individual subject case. 
If local restrictions preventing the subject from visiting the site are introduced between 
2 visits, the subject may continue treatment with the IMP until the scheduled visit as the 
measures may change favorably prior to that visit. If the measures are still effective at the 
scheduled visit, the procedures described above should be followed to decide whether the 
subject may continue dosing with the IMP. 
If due to local restrictions, an early termination visit cannot be conducted, a remote safety 
follow-up visit should be conducted instead. During this visit, AEs, concomitant medications, 
and concurrent procedures (including use of rescue medication) must be collected. It will be at 
the discretion of the investigator to conduct other assessments based their local COVID-19 
situation. 
If at any time during the trial, a subject gets infected with SARS-CoV-2, they should seek 
appropriate care and inform the investigator or site staff as soon as possible. The infection 
should be reported as AE. Based on sponsor’s evaluation, LEO 152020 is not believed to 
increase susceptibility of treated subjects to contract COVID-19 and is not expected to 
decreased anti-viral immunity in infected subjects (Section 5.5). However, decision to 
continue treatment with IMP of an infected subject should be based on careful evaluation of 
the subject’s condition and will be at the discretion of the investigator. If in doubt or in case of 
questions, the investigator should contact the sponsor’s medical expert. 
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In general in the context of the COVID-19 pandemic, more frequent telephone contacts 
between site staff and subjects should be arranged to closely monitor subject safety, treatment 
compliance, status of subject participation in the trial, and to provide guidance to the subject 
as to what they will be asked to do in a remote setting to maximize data quality and integrity. 
Reporting in eCRF 
It will be recorded in the eCRF if a visit or unscheduled visit was conducted remotely. If a 
trial site visit was not conducted, it will be recorded if this was due to the COVID-19 
pandemic. If an unscheduled visit at the trial site is needed due to the COVID-19 pandemic, 
the reason should be recorded in the eCRF. 
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Appendix 10: Protocol amendment history 
The current protocol amendment (amendment 5) is described before the table of content. 
Amendment 4 (30-Nov-2021, local Germany) 
This amendment was 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 local protocol amendment was to exclude all subjects with renal 
impairment from participation in the trial in Germany. This was done at the request of the 
Ethics Committee of 
 (Ethikkommission der 
 
). 
Summary of changes for amendment 4 
Section no. and name 
Description of change 
Brief rationale 
Section 8.3 Exclusion criteria 
Exclusion criterion 16 
Subjects with severe renal 
impairment as determined by eGFR 
levels below 30 mL/min at screening 
(37). For eGFR levels allowed in 
Germany and Japan, see 
Appendix 4. 
At the request of the Ethics 
Committee of 
 
, subjects with renal 
impairment will not be included in 
the trial. This change is to refer to 
the applicable exclusion criterion 16 
in Germany. 
Appendix 4 Country-specific 
requirements 
Following items added in subsection 
‘Germany’: 
In Section 5.5 Benefit/risk 
assessment, the following edited text 
will apply in Germany: 
• To further ensure subject safety, 
subjects with cardiac arrhythmic 
risk factors, moderate or severe 
hepatic impairment, and/or 
severe renal impairment will be 
excluded from participation in 
the trial (Section 8.3). 
 
In Section 8.3 Exclusion criteria, the 
following edited exclusion criterion 
will apply in Germany: 
• Subjects with severe renal 
impairment as determined by 
eGFR levels below 3090 mL/min 
at screening. 
To exclude subject with renal 
impairment in Germany. 
Abbreviations: please refer to the list of abbreviations. 
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Amendment 3 (06-Oct-2021, global) 
This amendment was 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 of the protocol amendment was to: 
• Allow data collection after the occurrence of intercurrent events (initiation of rescue 
treatment and permanent discontinuation of IMP) and incorporate the data when 
applying the treatment policy strategy to handle these events. The collection of data 
described is in line with ICH E9 (R1) addendum. Consequently, sections related to 
rescue treatment, permanent discontinuation of IMP / withdrawal from trial, estimand 
strategy, and statistical analysis methods were revised. 
• Include subjects with mild and moderate renal impairment in the trial. 
• Increase monitoring to safeguard subject safety and well-being. 
• Update of the contraception requirements for men and women. 
 
 
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Summary of changes for amendment 3 
Section no. and name 
Description of change 
Brief rationale 
 
 
 
Section 4 Schedule of trial 
procedures (Panel 2) 
Urine pregnancy test added at the 
early termination visit. 
To ensure women of childbearing 
potential are tested for pregnancy 
prior to withdrawing from the trial in 
case early termination and safety 
follow-up visits are replaced by a 
single early termination visit (see 
also changes in Section 10.3 Early 
termination assessments). 
 
Footnotes related to PK blood 
samples edited and/or merged to 
refer to Panel 3. 
 
To clarify the order of assessments. 
In footnote starting with ‘At the 
indicated visits, subjects will be 
asked to bring the wristband 
actigraphy devices…’: 
The devices can record 30 days of 
data at a time. Therefore, the time 
between consecutives visit should 
not exceed 30 days and special 
attention should be paid in case of 
missed visits. 
Deleted because this will be 
explained in the actigraphy device 
manual. 
Section 5.2.1 Nonclinical data 
Section updated with: 
• Results from in vitro safety 
pharmacology screen showing 
inhibition of acetylcholinesterase 
by LEO 152020 as well as 
information about other relevant 
nonclinical investigations in 
monkeys showing clinical signs 
of cholinergic activation. 
• Results of 26-week rat 
toxicology study showing 
 
 
partially reversible after  
 
 compared to the 
highest dosing regimen tested in 
this trial). 
To align with updates in the 
investigator’s brochure and provide 
additional nonclinical context for the 
new information. 
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Section no. and name 
Description of change 
Brief rationale 
Section 5.2.2 Clinical data 
There were emerging 
 
 
 
 
 
 
events were classified as mild, 
occurred rapidly after dosing, and 
the majority of events resolved 
within 
 hours. 
(…) 
To align with updates in the 
investigator’s brochure. 
Given the mild severity, fast onset, 
and transient nature of the 
 events, and that 
the events were primarily 
observed at the 
 
, these 
events were not considered a 
safety concern and are not 
expected to be relevant at the 
therapeutic doses given in this 
trial. 
(…) 
 
The mean effect in the 
 and 
 mg multiple dose groups were 
 and 
, respectively. 
Furthermore, in the multiple dose 
but not the single dose part of the 
trial, a dose dependent 
 in 
heart rate was observed with a 
 decrease of 
 in 
the 
 mg dose group. In the 
 dose group, the 
heart rate 
 was 
 
(
). Thus, it is unlikely that 
these findings are clinically 
relevant at the therapeutic doses 
given in this trial. 
To align with updates in the 
investigator’s brochure. 
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Section no. and name 
Description of change 
Brief rationale 
Section 5.5 Benefit/risk 
assessment (Risks for subjects 
treated with LEO 152020) 
 
(Continues) 
Due to the important potential risk 
of QT prolongation, the dose 
regimens explored in this trial have 
been chosen so that at the highest 
expected exposure (Cmax), the 
potential resulting QT prolongation, 
i.e. the upper bound of the 90% CI 
for 
 
), is 
below 
 (34). Due to the 
 
 the dose regimens 
explored in this trial have been 
chosen to minimize that risk for 
the subjects. The highest dose 
regimen in the trial (
 
 is predicted to result in 
concentration levels below those of 
the 
 mg once daily dose 
regimen, which in the 
first-in-human trial resulted in a 
mean 
 of 
 
with an upper bound of the 90% 
CI for 
 
 
 at 
 
(Section 5.2.2). Since subjects with 
mild and moderate renal 
impairment may exhibit increased 
exposure of LEO 152020, ECGs 
will be measured at each visit 
(Section 4) to monitor the 
individual subjects in line with 
 for drugs for which 
a 
 cannot 
be excluded (Panel 2). 
To update mitigation of the 
 
 as subjects with mild 
and moderate renal impairment will 
be included in the trial (see also 
changes to exclusion criterion 16), 
except in Japan (see Appendix 4 
Country-specific requirements). This 
is considered acceptable since 
subjects will be monitored with 
ECGs taken at every visit. 
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Section no. and name 
Description of change 
Brief rationale 
Section 5.5 Benefit/risk 
assessment (Risks for subjects 
treated with LEO 152020) 
 
(Continued) 
To further ensure subject safety, 
subjects with cardiac arrhythmic risk 
factors, moderate and severe 
hepatic impairment, and/or severe 
renal impairment will be excluded 
from participation in the trial 
(Section 8.3). 
 
To align with exclusion criterion 17. 
At selected visits, ECG and PK 
blood samples collected at the same 
timepoint will be used to explore the 
relation between exposure of 
LEO 152020 and potential 
 
 (Section 4). In the 
multiple dose part of the 
first-in-human trial, a 
dose-dependent 
 in heart 
rate was observed with a 
 
) in the 
 
dose group. If a subject develops 
 and 
, 
the risk of 
 may 
increase. To mitigate this, ECGs 
will be taken at each visit 
(Section 4) to monitor all subjects. 
 
To align with updates in the 
investigator’s brochure and provide 
further guidance to the investigator. 
 
In the first-in-human clinical trial, 
mild 
 adverse 
events were observed following 
treatment with 
 
LEO 152020. As 
 
 may increase the risk 
of 
, additional 
monitoring of 
 should 
be arranged, at the discretion of 
the investigator, for subjects who 
experience 
 
 during the 
treatment period. 
To align with updates in the 
investigator’s brochure and provide 
further guidance to the investigator. 
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Section no. and name 
Description of change 
Brief rationale 
Section 6 Trial objectives, 
estimands, and endpoints 
 
Section 14.3.10 Analysis of 
exploratory endpoints 
 
Section 14.3.11 Analysis of 
patient-reported outcomes 
 
Section 14.3.15 
Pharmacokinetic analysis 
 
(Continues) 
• EASI at each visit from baseline 
Week 1 to Week 16. 
• SCORAD at each visit from 
baseline Week 1 to Week 16. 
 
‘Baseline’ replaced by ‘Week 1’ 
because baseline measures are meant 
to characterize the subject 
population and act as reference 
values for assessing within-subject 
changes during the trial. 
 
• Time from randomization to 
having an observed decrease in 
EASI of at least 50% (EASI 50) 
from baseline. 
• Time from randomization to 
having a decrease in ADSD 
 
score (weekly average) of at least 
4 points from baseline in subjects 
with ADSD 
 score ≥ 4 at 
baseline. 
 
To clarify the reference time point 
for an observed decrease in EASI 
and ADSD 
 score. 
 
• Change in vIGA-AD from 
baseline to Week 16. 
• 
VIGA-AD at each visit from 
baseline to Week 16. 
 
Deleted because it is considered 
sufficient to include: 
• Having vIGA-AD of 0 (clear) or 
1 (almost clear) at Week 16. 
• Having a decrease in vIGA-AD 
of at least 2 points from baseline 
to Week 16. 
to support the primary objective. 
 
• Change in ECG parameters 
 
 from baseline to 
Week 12. 
• ECG parameters 
 
 at baseline, Weeks 1, 4, 
and 12. 
 
Deleted as endpoint (but not 
assessments) for this trial because a 
thorough 
 clinical trial with 
LEO 152020 is planned to be 
conducted. 
 
• PGI-C (each individual 
component) at Weeks 8, 12, 
and 16. 
• PGI-S (each individual 
component) at baseline and 
Weeks 4, 8, 12, 14, and 16. 
 
Deleted as endpoints (but not 
assessments) for this trial because 
those will be used to qualify other 
PROs. The PROs listed under the 
objective related to sleep disturbance 
and nocturnal 
 are 
considered sufficient to support the 
objective. 
 
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Section no. and name 
Description of change 
Brief rationale 
Section 6 Trial objectives, 
estimands, and endpoints 
 
Section 14.3.10 Analysis of 
exploratory endpoints 
 
Section 14.3.11 Analysis of 
patient-reported outcomes 
 
Section 14.3.15 
Pharmacokinetic analysis 
 
(Continued) 
• Ctrough of LEO 152020 at 
baseline, Weeks 
 
 
 
Deleted ‘baseline’ because there can 
be no Ctrough at baseline (the subject 
has not received IMP). 
• Cmax of LEO 152020 at 
baseline, Weeks 
 
 
‘Baseline replaced by ‘Week ’ 
because baseline values are meant to 
characterize the subject population 
and Cmax will be measured 
approximately 
 after IMP 
intake at Week . 
Section 7.1 Overall trial 
design, subsection 
‘Randomization’ 
Subsection shortened. 
 
To avoid repetition with 
Section 9.3.1 Treatment assignment. 
 
Section 7.2 Number of 
subjects needed 
 
Section 1 Protocol synopsis 
(Trial design [in the figure], 
Number of subjects) 
 
Section 3 Schematic of trial 
design (Panel 1) 
Number (N) of subjects in each 
treatment group deleted. 
 
The randomization scheme does not 
ensure that subjects will be allocated 
in the proportion that was initially 
specified. However, within each 
stratum, subjects will still be 
randomized in a 4:3:3:4 ratio based 
on a permuted block design. 
 
Section 7.2 Number of 
subjects needed 
Based on an anticipated attrition rate 
of 15% in all treatment groups, this 
will provide a total of 192 subjects 
for analysis. 
 
Deleted because all subjects 
included in the full analysis set, i.e. 
randomized and exposed to IMP will 
be included in the analysis. 
 
A block size of 14 will be used for 
randomization ensuring a balanced 
distribution of subjects across the 
sites. 
Deleted because this information 
will be specified in the 
randomization form to minimize the 
chance of allocation bias. 
Section 7.3 End-of-trial 
definition 
Depending on the DMC’s 
recommendations, LEO Pharma may 
decide to terminate the trial 
prematurely in interest of subject 
safety. In such case, the end of the 
trial would be defined as the date of 
trial termination. 
Because in case of premature trial 
termination, the trial end is still 
defined as the date of last visit of the 
last subject in the trial globally. 
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Section no. and name 
Description of change 
Brief rationale 
Section 8.2 Inclusion criteria 
 
Section 1 Protocol synopsis 
(Main criteria for inclusion) 
 
Appendix 4 Country-specific 
requirements 
 
Appendix 5 Short version of 
eligibility criteria and 
justification 
Inclusion criterion 2: 
Adult, age 18 years or older at 
baseline screening. 
To ensure that subjects will at least 
be 18 years at screening when they 
provide informed consent. 
Section 8.2 Inclusion criteria, 
criteria 10 and 11. 
 
Section 5.4 Ethical 
considerations 
 
Appendix 5 Short version of 
eligibility criteria and 
justification 
Contraception reduced to 1 highly 
effective contraception method for 
women of childbearing potential and 
contraception deleted for male 
subjects with a partner of 
childbearing potential. 
 
To reflect the recommendations 
about contraception of the Clinical 
Trials Facilitation and Coordination 
Group (CTFG) guidance v1.1 for 
IMPs with unlikely human 
teratogenicity, fetotoxicity, or 
genotoxicity (see also the 
investigator’s brochure). 
 
Section 8.3 Exclusion criteria, 
criteria 1 and 2 
 
Appendix 5 Short version of 
eligibility criteria and 
justification 
Concurrent skin disease at baseline 
which may interfere with the trial 
assessments, at the discretion of 
the investigator. 
 
Active skin infection or any other 
clinically apparent infection at 
baseline which may interfere with 
the trial assessments, at the 
discretion of the investigator. 
To clarify that these 2 eligibility 
assessments will be left at the 
discretion of the investigator. 
Section 8.3 Exclusion criteria, 
criterion 8 
 
Section 4 Schedule of trial 
procedures (Panel 2) 
 
Section 11.2.5 Other screening 
assessments 
 
Section 11.4.4 Laboratory 
testing (Panel 11) 
 
Appendix 5 Short version of 
eligibility criteria and 
justification 
Current active tuberculosis based on 
mycobacterium tuberculosis IFN 
gamma response test at screening 
test per local standard of care at 
screening. The screening for 
tuberculosis should be done 
according to guidelines for 
patients subject to biologic 
treatment as per local standard of 
care. 
To take into account local 
differences in standard of care. The 
new approach is considered equally 
safe. 
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Section no. and name 
Description of change 
Brief rationale 
Section 8.3 Exclusion criteria, 
criterion 11 
 
Section 4 Schedule of trial 
procedures (Panel 2) 
Uncorrected hypokalemia or 
hypomagnesemia at screening 
and/or baseline Week -1, history of 
cardiac failure, history of clinically 
significant/symptomatic 
bradycardia. 
 
Clinical chemistry and hematology 
blood sample added at Week -1 to 
reflect the above. 
To allow for timely results prior to 
randomization. 
Section 8.3 Exclusion criteria, 
criterion 16 
 
Appendix 5 Short version of 
eligibility criteria and 
justification 
Subjects with signs of severe renal 
impairment as determined by eGRF 
levels below 90 30 mL/min at 
screening and/or baseline. 
To allow the inclusion of a broader 
patient population in the trial, except 
in Japan (see Appendix 4 
Country-specific requirements). The 
inclusion of subjects with mild to 
moderate renal impairment is 
considered safe and will be further 
safeguarded by increasing ECG 
monitoring to each visit in line with 
 (see also changes to 
Section 11.4.3 Electrocardiography). 
Section 8.3 Exclusion criteria, 
criteria 24 and 25 
 
Appendix 5 Short version of 
eligibility criteria and 
justification 
Exclusion criterion 25 added: 
Subjects, who, in the opinion of 
the investigator, would be 
noncompliant or unable to 
understand the trial and give 
adequately informed consent. 
 
To exclude potentially noncompliant 
subjects and subjects not able to 
provide adequately informed 
consent. 
Current or recent chronic alcohol or 
drug abuse, or any other condition 
associated with poor compliance as 
judged by the investigator within 
12 months prior to screening. 
To avoid redundancy with added 
criterion 25 
Section 8.3 Exclusion criteria, 
criterion 28 
 
Appendix 5 Short version of 
eligibility criteria and 
justification 
Women who are pregnant, intend to 
become pregnant, or are lactating. 
To clarify and avoid pregnancy 
during the trial. 
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Section no. and name 
Description of change 
Brief rationale 
Section 9.3.1 Treatment 
assignment 
Subjects who comply with all 
eligibility criteria (Sections 8.1 to 
8.3) will be randomized at baseline 
to 1 of the following oral treatments 
in a 4:3:3:4 ratio stratified by 
baseline disease severity (EASI at 
baseline) and region (Japan and non-
Japanese countries): 
 
Within the strata defined by 
baseline disease severity (EASI at 
baseline) and region (Japan, non-
Japanese countries), subjects will 
be randomized in a 4:3:3:4 ratio, 
using a permuted block design. 
To clarify randomization and 
stratification. 
Section 9.3.2 Blinding 
 
Section 12.1 Scientific 
rationale for trial design 
Triple blinding (subject, assessor 
investigator, and assessor of the 
data/study outcome [sponsor]) 
from randomization to formal 
unblinding of the trial will be 
applied. 
To clarify the extent of blinding. 
Section 9.5 Rescue treatment 
 
Section 5.5 Benefit/risk 
assessment 
Subjects will be allowed to receive 
topical rescue treatment during the 
treatment period with no permanent 
discontinuation of IMP (nor 
withdrawal from the trial). 
 
The duration of topical rescue 
treatment and decision to escalate to 
systemic rescue treatment and when 
to escalate will be left at the 
discretion of the investigator. 
 
Discontinued subjects due to the use 
of systemic rescue treatment will no 
longer be withdrawn from the trial. 
To allow subjects who initiates 
topical rescue treatment prior to 
Week 4 to continue treatment with 
IMP and remain in the trial. Further, 
to allow collection of data after 
initiation of rescue treatment and 
discontinuation of IMP. 
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Section no. and name 
Description of change 
Brief rationale 
Section 9.5 Rescue treatment 
Immediately b Before administering 
a topical or systemic rescue 
treatment, the investigator should 
make every attempt to may conduct 
efficacy and safety assessments (e.g. 
disease severity scores [EASI, vIGA 
AD, and SCORAD], AEs, safety 
laboratory samples, PK blood 
sample, and concomitant 
medications/concurrent procedures). 
If necessary However, to safeguard 
subject safety and well-being, the 
assessments should only be 
conducted if the subject’s health 
permits. To further attend to 
subject safety and well-being, an 
unscheduled visit should, scheduled 
earlier than the next planned visit, 
may be arranged for this purpose to 
administer the topical or systemic 
rescue treatment. 
 
To clarify conditions for conducting 
assessments before administering 
rescue treatment and that an 
unscheduled visit may be used to 
provide diligent attention to the 
subject. 
If the subject is withdrawn from the 
trial permanently discontinued 
from IMP due to use of systemic 
rescue medication, the subject 
should be followed up every effort 
must be done to monitor the 
subject as described in Section 10.3. 
To align with other changes in 
Section 9.5 Rescue treatment (see 
entry above) and clarify follow up of 
discontinued subjects. 
Section 9.6 Concomitant 
medications and concurrent 
procedures 
 
Section 10.2 Reasons for 
permanent discontinuation of 
investigational medicinal 
product (Reporting in eCRF) 
 
Section 11.8 End of trial (End-
of-trial form) 
Specifications of the reasons for lack 
of efficacy of the IMP added: 
• Lack of efficacy on itch. 
• Lack of efficacy on visible AD 
symptoms. 
• Lack of efficacy on both itch 
and visible AD symptoms. 
• Other (if other, a specification 
should be provided). 
To gain knowledge of whether the 
lack of efficacy is related to lack of 
effect of the IMP on itch and/or 
visible AD symptoms. 
Section 9.6 Concomitant 
medications and concurrent 
procedures 
Investigators may prescribe 
concomitant medications or 
treatments to provide adequate 
supportive care, at their discretion. 
(…) Any questions about 
concomitant or prior therapy should 
be addressed to the sponsor’s 
medical expert. 
While some decisions will be left at 
the discretion of the investigator, it 
is implicit that they are welcome to 
consult the sponsor's medical expert, 
if needed. 
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Section no. and name 
Description of change 
Brief rationale 
Section 9.7 Prohibited 
medications and procedures 
(Panel 7) 
Footnote to systemic anti-histamines 
added: 
Locally-administered 
anti-histamines (e.g. eye drops, 
nasal spray) are allowed. 
 
To clarify that locally-administered 
anti-histamines will be allowed 
during the trial. 
Footnote to topical antibiotics 
added: 
Except if used on small lesional 
areas 
To clarify that topical antibiotics 
may be used to small lesional areas 
Section 9.8.3 Storage of trial 
products 
At the subject’s home, the IMP 
should be stored below 40°C/104°F 
and should not be stored in the 
fridge or freezer. Storage of the IMP 
at the subject’s home will be 
described in separate instructions for 
use for the subject to take home. 
Deleted as the storage of the IMP at 
the subject’s home will be described 
in the IMP instruction for use. 
Section 9.8.5 Treatment 
compliance 
For IMP taken at the site, date and 
time of IMP intake will be recorded 
in the eCRF. 
It will be recorded in the eCRF if 
IMP was taken at the site. If not, a 
reason should be provided. If yes, 
date and time of IMP 
administration will also be 
recorded. 
To clarify what data will be 
collected to evaluate treatment 
compliance. 
Section 10 Discontinuation 
and withdrawal 
 
Section 4 Schedule of trial 
procedures (Panel 2, 
footnotes) 
 
Section 5.5 Benefit/risk 
assessment 
 
Section 11.4.3 
Electrocardiography 
The difference between permanent 
discontinuation of IMP and 
withdrawal from the trial was 
clarified. 
 
Permanent discontinuation of IMP 
and withdrawal from trial will be 
2 separate events and subjects who 
permanently discontinue IMP will 
no longer automatically be 
withdrawn from the trial. 
 
Subjects who permanently 
discontinue IMP will be asked to 
attend an early termination visit as 
soon as possible after last dose of 
IMP and the nominal primary 
endpoint visit 16 weeks after first 
dose of IMP. 
Subjects who withdraw from the 
trial will be asked to attend an early 
termination visit and a safety follow-
up visit 7 days after last dose of 
IMP. 
To clarify the difference between 
permanent discontinuation of IMP 
and withdrawal from trial and allow 
collection of post-discontinuation 
data in line with ICH E9 (R1) 
addendum. 
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Section no. and name 
Description of change 
Brief rationale 
Section 10.4 Continued 
assessment of subjects after 
permanent discontinuation of 
investigational medicinal 
product 
Section added. 
Subjects who permanently 
discontinue IMP prior to Week 16 
should be encouraged to continue 
participating in the trial and to 
follow their visit schedule to the 
extent possible. 
To allow collection of 
post-discontinuation data in line 
with ICH E9 (R1) addendum. 
Section 11.4.3 
Electrocardiography 
 
Section 4 Schedule of trial 
procedures (Panel 2 and 
Panel 3) 
 
(Continues) 
ECG monitoring increased to be 
conducted at all visits (optional at an 
unscheduled visit) and footnotes to 
schedule of trial procedures edited 
and/or merged to reflect the new 
monitoring setup. 
To safeguard safety of all subjects, 
including subjects with mild and 
moderate renal impairment (see also 
changes to exclusion criterion 16) in 
line with 
. 
 
 
 
 
 
 
 
 
 
At the screening visit, 3 consecutive 
ECGs must be measured. 
Between baseline and Week 16, at 
the visits indicated in Section 4, pre 
dose ECGs must be measured 
shortly before dosing and post dose 
ECGs must be measured 
 after dosing. In Japan 
at the request of PMDA, 1 additional 
ECG will be measured at baseline 
and Week 1, 
 after 
dosing. 
 
Deleted to avoid redundancy with 
Panel 3. 
The collection of a PK sample was 
added in case a moderate or severe 
 is detected at visits: 
A PK sample (if not already 
planned at the visit) must be taken 
close to the last measured ECG. 
 
Added to study the potential 
relationship between exposure and 
QT prolongation. 
If the subject returns to 
 
≤480 ms (mild 
 or 
normal 
) and increase 
in 
from baseline ≤30 ms, the 
ECG and PK monitoring schedule 
described in Section 4 may should 
be followed again. 
 
To clarify that moderate 
 
 is defined as either 
480 ms< 
 ≤500 ms OR 
30 ms< increase in 
 from 
baseline ≤60 ms. 
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Section no. and name 
Description of change 
Brief rationale 
Section 11.4.3 
Electrocardiography 
 
Section 4 Schedule of trial 
procedures (Panel 2 and 
Panel 3) 
 
(Continued) 
During the trial Before first dose of 
IMP, any abnormal clinically 
significant or clinically relevant 
ECG finding will be documented as 
medical history in the eCRF. After 
first dose of IMP, any new 
abnormal clinically significant or 
clinically relevant ECG finding, 
symptoms, or illnesses, as well as 
any clinically significant 
deterioration of a pre-existing 
condition after randomization will 
be reported as an AE as described in 
Section 13.3. 
To clarify how ECG findings will be 
reported in relation to first dose of 
IMP. 
Section 11.4.3 
Electrocardiography 
 
Section 10.2 Reasons for 
permanent discontinuation of 
investigational medicinal 
product 
 
Section 13.6.1 Adverse events 
of special interest (Panel 14 
and footnote) 
(…) change increase in 
 from 
baseline (…). 
To clarify that only increases in 
 from baseline constitute 
 
 
Section 11.4.4.2 Investigator 
evaluation of laboratory 
samples (Laboratory tests 
conducted at the trial site) 
 
Section 11.2.5 Other screening 
assessments 
Tuberculosis testing will be 
conducted as per local standard. 
Added the following in 
Section 11.4.4.2 and 11.2.5, 
respectively: 
 
Subjects with a positive 
tuberculosis test conducted at the 
trial site at screening should be 
referred to a competent health 
care structure for treatment and 
follow up. 
 
Tuberculosis testing will be per 
local standard of care (see 
exclusion criterion 8). If the 
tuberculosis test cannot be 
analyzed locally, it should be sent 
to the central laboratory. 
To clarify operational considerations 
regarding tuberculosis testing. 
Section 11.6.2 
Pharmacodynamic 
assessments (Blood 
biomarkers) 
8 mL of blood will be collected into 
Vacutainer® tubes to obtain 4 mL of 
serum which will be stored at 
<-20°C until shipment to the central 
laboratory for further processing. 
Deleted because this will be 
described in a separate laboratory 
manual. 
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Section no. and name 
Description of change 
Brief rationale 
Section 11.7.2 Wristband 
scratch and sleep monitoring 
At each visit between baseline and 
Week 16, it will be recorded: 
• If the subject wore the device 
as instructed. If not, a reason 
should be provided. 
To clarify what data will be recorded 
in the eCRF. 
Section 11.7.3 Skin biopsies 
The biopsies will be transferred to 
RNAlaterTM solution (for RNA 
stabilization) immediately after 
collection and stored at 2 8°C for 16 
30 hours. The sample will then be 
transferred to a clean tube and stored 
at < 20°C until shipment to the 
central laboratory for further 
processing. 
Deleted as the method for handling 
skin biopsy samples will be 
described in a separate laboratory 
manual. 
Section 11.8 End of trial (End-
of-trial form) 
Data to collect in the eCRF added: 
If the subject attended the 
(nominal) primary endpoint visit 
(Week 16 or 16 weeks after first 
dose of IMP). If not, the primary 
reason for not attending the visit 
should be provided (death, 
pregnancy, adverse event, lack of 
efficacy, withdrawal by subject, 
lost to follow up, or other [if other, 
a specification should be 
provided]). 
To clarify collection of data on the 
end-of-trial form as permanently 
discontinued subjects will no longer 
be automatically withdrawn from 
trial and asked to come to a nominal 
primary endpoint visit. 
Section 11.9 Estimate of total 
blood volume collected 
Maximum total volume of blood to 
be collected during the trial updated. 
To reflect the samples added in 
Section 4 Schedule of trial 
procedures and take into account 
possible extra PK samples in case 
the subject experiences a 
 
 
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Section no. and name 
Description of change 
Brief rationale 
Section 12.1 Scientific 
rationale for trial design 
Mitigation of bias 
Stratified randomization according 
to baseline disease severity (EASI at 
baseline) will ensure balanced 
allocation of subjects with 
≤ EASI ≤
 and subjects with 
≤ EASI ≤
 at baseline between 
the treatment groups, thereby 
minimizing allocation bias and 
baseline confounding. Stratification 
by region (Japan and non-Japanese 
countries) will ensure balanced 
allocation of subjects in each region 
(Section 7.1). 
The combination of 
randomization and blinding 
minimizes the likelihood of 
allocation bias. The risk of 
allocation bias is further reduced 
through the use of central 
randomization, i.e. the 
randomization will not be 
stratified by site nor will complete 
blocks be allocated to sites. The 
use of randomization also ensures 
that baseline factors will not be 
confounded with treatment. The 
use of a permuted block 
randomization within the strata 
defined by baseline disease 
severity (EASI at baseline) and 
region (Japan and non-Japanese 
countries) will limit any potential 
imbalance in the allocation of 
subjects across these factors 
(Section 7.1). 
To clarify the mitigation of bias. 
Section 12.2 Appropriateness 
of assessments 
Inflammatory markers (cytokines 
and chemokines) associated with 
AD (e.g. CCL17, CCL18, sIL-2R, 
IL-13, IL-22, PBMC, RN6A seq, 
IgE, IgG4) will be measured in 
serum over time to determine AD 
burden. 
To clarify the biomarkers which 
may be evaluated in this trial. 
Section 14.1 Sample size 
 
Section 14.3.7 Testing 
strategy 
Sample size justification revised. 
To reflect the changes in 
Section 14.3.8 Analysis of primary 
endpoint. 
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Section no. and name 
Description of change 
Brief rationale 
Section 14.3.8 Analysis of 
primary endpoint 
 
Section 1 Protocol synopsis 
(Statistical methods) 
 
Section 12.1 Scientific 
rationale for trial design 
(Endpoints and estimands) 
 
Section 14.3.3 Handling of 
intercurrent events related to 
the COVID-19 pandemic 
Estimand strategy revised. 
To include data collected after 
occurrence of intercurrent events 
(initiation of rescue treatment and 
permanent discontinuation of IMP) 
in the analysis in line with ICH E9 
(R1) addendum. 
 
The original primary estimand 
(composite) was exchanged with 
1 of the original supplementary 
estimands (hypothetical) to improve 
the interpretability of the primary 
estimand. 
Based on feedback from health 
authorities. Improving the 
interpretability of the primary 
estimand will aid dose-selection for 
phase 3 clinical development. 
Section 14.3.8 Analysis of 
primary endpoint 
 
Section 14.3.10 Analysis of 
exploratory endpoints 
Analysis methods clarified. 
To improve the interpretability of 
the results of the data analysis. 
Section 14.3.10 Analysis of 
exploratory endpoints 
 
Section 14.3.2 Handling of 
missing values 
 
Section 14.3.11 Analysis of 
patient-reported outcomes 
Analysis method of binary endpoints 
changed from CMH test to logistic 
regression. 
To avoid potential invalidity of the 
analysis method due potential small 
strata sizes. 
Section 14.3.14.3 
Electrocardiography 
Section added. 
Absolute values and change in 
ECG parameters 
 
 from baseline to each 
relevant visit will be summarized 
by treatment group as mean, SD, 
median, minimum and maximum 
values for the safety analysis set. 
Subjects with abnormal clinically 
significant ECG parameters will 
be listed. Furthermore, a shift 
table showing the change in 
clinical assessments (normal, 
abnormal not clinically significant, 
abnormal clinically significant) for 
the ECG parameters from 
baseline to Week 16 will be 
provided. 
To clarify presentation of the ECG 
data. 
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Section no. and name 
Description of change 
Brief rationale 
Appendix 2 Classification of 
adverse events 
If the severity of an AE worsens, a 
new AE should be recorded. If the 
AE worsens in severity, the new 
severity including date of 
worsening should be recorded. 
However, if an AE with onset 
prior to IMP initiation worsens 
after first dose of IMP, a new AE 
should be recorded. 
To collect more accurate 
information on worsening of AE 
severity and to ease reporting for the 
investigator. 
Appendix 4 Country-specific 
requirements 
For Germany, text in Section 13.4 
Reporting of serious adverse events 
will read: 
Any SAE must be reported to 
LEO Pharma on the (paper) SAE 
form within 24 hours of first 
knowledge immediately without 
undue delay. 
 
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) 
immediately without undue delay 
if the investigator becomes aware of 
them. 
 
Rephrased at the request of BfArM 
to abide by German law for timing 
of SAE reporting in Germany. 
For Japan, text in Section 5.5 
Benefit/risk assessment will read: 
To further ensure subject safety, 
subjects with cardiac arrhythmic risk 
factors, moderate or severe hepatic 
impairment, and/or severe renal 
impairment will be excluded from 
participation in the trial (Section 
8.3). 
 
For Japan, text in Section 8.3 
Exclusion criteria, exclusion 
criterion 16 will read: 
Subjects with signs of severe renal 
impairment as determined by eGFR 
levels below 3090 mL/min at 
screening. 
In Japan, subject with renal 
impairment will not be included in 
the trial. 
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Section no. and name 
Description of change 
Brief rationale 
Appendix 7 Guidance to trial 
site before subject administers 
investigational medicinal 
product at site 
In Panel 20 a) and b), box ECG/PK 
planned at visits replaced by PK 
planned at visit. 
 
Footnote to Panel 20 b) added: 
If the subject took a 
 dose 
of IMP in error before the visit, 
efforts should be made to measure 
the ECG within 
 of 
IMP intake. 
To update and provide further 
guidance to the investigator. 
Appendix 10 Protocol 
amendment history 
Section added. 
To list the local protocol 
amendments and local addendum to 
amendment preceding this global 
amendment. 
Abbreviations: please refer to the list of abbreviations. 
___________________________________________________________________________ 
 
The global protocol amendment (v3.0) of 06-Oct-2021 includes the changes implemented for 
Germany (local amendment 1 and addendum 1 to amendment 1) and Czech Republic (local 
amendment 2). Therefore, the corresponding summary of changes tables for these protocol 
amendments are not reproduced below (see summary of changes table for amendment 3 
above). 
___________________________________________________________________________ 
 
Addendum 1 to amendment 1 (05-Aug-2021, local Germany) 
Overall rationale for the addendum 
This addendum to amended protocol v2.0 DE (30-Jun-2021) was to address comments from 
the German Federal Institute for Drugs and Medical Devices (BfArM). The purpose of the 
addendum was to have the timing for reporting of serious adverse events (SAEs) to comply 
with current German law. 
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Amendment 2 (07-Jul-2021, local Czech Republic) 
This amendment was 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 impacted the safety or 
physical/mental integrity of subjects nor the scientific value of the trial. 
Overall rationale for the amendment 
This protocol amendment was to address comments from the Czech State Institute for Drug 
Control to v1.0 of the global protocol. The purpose of the amendment was mainly to clarify 
aspects related to rescue treatment and prior and concomitant medications. 
___________________________________________________________________________ 
 
Amendment 1 (30-Jun-2021, local Germany) 
This amendment was 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 impacted the safety or 
physical/mental integrity of subjects nor the scientific value of the trial. 
Overall rationale for the amendment 
This protocol amendment was to address comments from the German Federal Institute for 
Drugs and Medical Devices (BfArM) to v1.0 of the global protocol. The purpose of the 
amendment was mainly to clarify aspects related to rescue treatment and timing for reporting 
SAEs. 
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