Conditions: Atopic Dermatitis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 251
Healthy volunteers: no

Brief summary:
This is a double-blind, multi-centre, randomised, 5-arm, vehicle-controlled, parallel-group trial. The trial is designed to establish a dose-response signal and investigate the efficacy and safety of delgocitinib cream in the treatment of adult subjects with mild to severe atopic dermatitis (AD).

Detailed description:

Arms:
arm 1: Delgocitinib cream applied twice daily for 8 weeks arm 2: Delgocitinib cream applied twice daily for 8 weeks arm 3: Delgocitinib cream applied twice daily for 8 weeks arm 4: Delgocitinib cream applied twice daily for 8 weeks arm 5: Delgocitinib cream vehicle applied twice daily for 8 weeks

Interventions: intervention 1: Delgocitinib cream intervention 2: Delgocitinib cream vehicle
Intervention descriptions: intervention 1: Cream for topical application intervention 2: The cream vehicle is similar to the delgocitinib cream except that it does not contain any active ingredient.

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
 
 
 
 
Cover Page 
 
 
Official title: A phase 2b, double-blind, randomised, 5-arm, vehicle-controlled, dose-ranging trial to evaluate the efficacy and 
safety of twice daily topical applications of delgocitinib cream 1, 3, 8, 20 mg/g for 8 weeks in adult subjects with mild to severe 
atopic dermatitis 
LEO Pharma number: LP0133-1275 
NCT number: NCT03725722 
Date: 22-Aug-2019 
 


 
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 GROUP 
Updated Clinical Trial Protocol 
LP0133-1275 
Phase 2b dose-ranging trial to evaluate delgocitinib cream 1, 3, 8, and 20 mg/g compared to 
delgocitinib cream vehicle over an 8-week treatment period in adult subjects with atopic 
dermatitis 
Phase 2b – dose-ranging trial 
A phase 2b, double-blind, randomised, 5-arm, vehicle-controlled, dose-ranging trial to 
evaluate the efficacy and safety of twice daily topical applications of delgocitinib cream 
1, 3, 8, 20 mg/g for 8 weeks in adult subjects with mild to severe atopic dermatitis 
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: 
LP0133-1275 
Date: 
22-Aug-2019
EudraCT no: 
Not applicable 
Version: 
3.0 


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Trial ID: LP0133-1275 
Date: 22-Aug-2019 
Version: 3.0 
Page 3 of 125 
 
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 GROUP 
 
Protocol amendment summary of changes tables 
Document 
Protocol version 
Date 
Type of protocol amendment 
Amendment 2 
(substantial) 
3.0 
22-Aug-2019 
Global 
Amendment 1 
(substantial) 
2.0 
09-Jan-2019 
Global 
Original protocol 
1.0 
22-Jun-2018 
Not applicable 
 
A protocol amendment summary of changes table for the previous amendment is provided in 
Appendix 7. 
Amendment 2 (22-Aug-2019) 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union 
or subsequent regulation. 
Overall rationale for the amendment 
The main reason for the amendment is to remove the recruitment cap for the number of 
subjects within each disease severity group due to slow recruitment of subjects with severe 
atopic dermatitis. Miscellaneous other changes/updates have also been implemented. 
The table below summarises changes made in each section and a brief rationale for each 
change.  
Section no. and name Description of change 
Brief rationale 
Section 1 
Protocol synopsis 
Section 7.1 
Overall trial design 
Section 7.2 
Recruitment cap removed for the 
number of subjects within each 
disease severity group. 
Capping removed due to 
slow recruitment of subjects 
with severe atopic 
dermatitis. Capping for 
subjects with mild disease 
severity was therefore 
considered superfluous, 


Trial ID: LP0133-1275 
Date: 22-Aug-2019 
Version: 3.0 
Page 4 of 125 
 
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 GROUP 
 
Number of subjects 
needed 
Section 8.4 
Screening and 
screening failures 
Section 9.3 
Treatment assignment 
Section 12 
Scientific rationale for 
trial design and 
appropriateness of 
assessments 
Appendix 3D 
Record keeping, 
quality control, and 
data handling 
which resulted in the 
removal of the limit of the 
number of subjects with 
moderate disease severity. 
Section 14.2 
Trial analysis sets 
All subjects exposed to IMP will 
be included in the full analysis set. 
Per protocol analysis set and safety 
analysis set updated to reflect the 
change in the full analysis set. 
Randomised subjects not 
exposed to IMP will not be 
included in the full analysis 
set. No bias is introduced by 
excluding subjects, as this is 
a blinded trial. 
Throughout 
Minor editorial and document 
formatting revisions. 
Minor, therefore not 
summarised. 
 
 


Trial ID: LP0133-1275 
Date: 22-Aug-2019 
Version: 3.0 
Page 5 of 125 
 
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 GROUP 
 
Table of contents 
Table of contents ....................................................................................................................... 5 
List of panels ............................................................................................................................. 9 
List of abbreviations ............................................................................................................... 10 
1 Protocol synopsis ................................................................................................................ 13 
2 Trial identification ............................................................................................................. 19 
3 Schematic of trial design ................................................................................................... 19 
4 Schedule of trial procedures ............................................................................................. 20 
5 Introduction and trial rationale ....................................................................................... 26 
5.1 
Atopic dermatitis ..................................................................................................... 26 
5.2 
Experience with investigational medicinal product ................................................. 26 
5.3 
Trial rationale ........................................................................................................... 27 
5.4 
Justification for dose ................................................................................................ 28 
5.5 
Ethical considerations .............................................................................................. 29 
5.6 
Benefit/risk assessment ............................................................................................ 29 
6 Trial objectives and endpoints .......................................................................................... 31 
7 Trial design ......................................................................................................................... 33 
7.1 
Overall trial design .................................................................................................. 33 
7.2 
Number of subjects needed ...................................................................................... 34 
7.3 
End of trial definition ............................................................................................... 34 
7.4 
Software ................................................................................................................... 35 
8 Trial population ................................................................................................................. 36 
8.1 
Subject eligibility ..................................................................................................... 36 
8.2 
Inclusion criteria ...................................................................................................... 36 
8.3 
Exclusion criteria ..................................................................................................... 37 
8.4 
Screening and screening failures ............................................................................. 40 
9 Treatments .......................................................................................................................... 42 
9.1 
Trial product description .......................................................................................... 42 
9.2 
Administration of IMP ............................................................................................. 42 
9.3 
Treatment assignment .............................................................................................. 43 


Trial ID: LP0133-1275 
Date: 22-Aug-2019 
Version: 3.0 
Page 6 of 125 
 
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 GROUP 
 
9.3.1 
Blinding ......................................................................................................... 43 
9.3.2 
Emergency unblinding of individual subject treatment ................................ 43 
9.4 
Background treatment (emollients) ......................................................................... 44 
9.5 
Rescue treatment ...................................................................................................... 44 
9.6 
Concomitant medication and concurrent procedures .............................................. 44 
9.7 
Prohibited medication and procedures ..................................................................... 45 
9.8 
Treatment logistics and accountability .................................................................... 46 
9.8.1 
Labelling and packaging of trial products ..................................................... 46 
9.8.2 
Storage of trial products ................................................................................ 47 
9.8.3 
Drug accountability ....................................................................................... 47 
9.8.4 
Treatment compliance ................................................................................... 48 
9.8.5 
Trial product destruction ............................................................................... 48 
9.9 
Provision for subject care following trial completion ............................................. 49 
9.10 
Reporting product complaints .................................................................................. 49 
10 Discontinuation and withdrawal ...................................................................................... 49 
10.1 
General principles .................................................................................................... 49 
10.2 
IMP discontinuation rules ........................................................................................ 50 
10.2.1 Reasons for discontinuation of IMP .............................................................. 50 
10.3 
Early termination assessments ................................................................................. 51 
10.4 
Lost to follow-up ..................................................................................................... 51 
11 Trial assessments and procedures .................................................................................... 53 
11.1 
Overview .................................................................................................................. 53 
11.2 
Assessments performed only at screening/baseline ................................................. 54 
11.2.1 Demographics................................................................................................ 54 
11.2.2 Fitzpatrick skin type ...................................................................................... 55 
11.2.3 Medical history .............................................................................................. 55 
11.2.4 Height and weight ......................................................................................... 56 
11.2.5 Body surface area involvement ..................................................................... 56 
11.3 
Efficacy assessments................................................................................................ 56 
11.3.1 Eczema Area and Severity Index (EASI) ...................................................... 56 
11.3.2 Validated Investigator Global Assessment scale for Atopic Dermatitis 
(vIGA-AD) .................................................................................................... 58 
11.3.3 Scoring Atopic Dermatitis (SCORAD) ......................................................... 58 
11.4 
Safety assessments ................................................................................................... 60 
11.4.1 Vital signs ...................................................................................................... 60 


Trial ID: LP0133-1275 
Date: 22-Aug-2019 
Version: 3.0 
Page 7 of 125 
 
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THE PRIOR WRITTEN CONSENT OF THE LEO GROUP 
 
11.4.2 Physical examination..................................................................................... 60 
11.4.3 ECG ............................................................................................................... 61 
11.4.4 Laboratory testing ......................................................................................... 62 
11.4.5 Subject assessment of local tolerability ........................................................ 64 
11.5 
Pharmacokinetic assessments .................................................................................. 65 
11.5.1 Blood sampling for analysis of systemic concentration of delgocitinib ....... 65 
11.6 
Pharmacodynamics and pharmacogenomics ........................................................... 65 
11.6.1 Overview ....................................................................................................... 65 
11.6.2 Skin swabs ..................................................................................................... 66 
11.6.3 Skin biopsies and photographs (all sites, but optional) ................................. 66 
11.7 
Other assessments .................................................................................................... 68 
11.7.1 Patient-reported outcomes (PROs) ................................................................ 68 
11.7.2 Atopic dermatitis lesions on scalp ................................................................. 72 
11.8 
Estimate of total blood volume collected ................................................................ 72 
11.9 
End of trial ............................................................................................................... 72 
11.10 Storage of biological samples .................................................................................. 72 
12 Scientific rationale for trial design and appropriateness of assessments ..................... 74 
13 Adverse events ................................................................................................................... 76 
13.1 
Definition and classification of adverse events ....................................................... 76 
13.2 
Collection of adverse event reports ......................................................................... 76 
13.3 
Reporting of adverse events ..................................................................................... 76 
13.4 
Reporting of serious adverse events ........................................................................ 77 
13.4.1 Investigator reporting responsibilities ........................................................... 77 
13.4.2 LEO reporting responsibilities ...................................................................... 78 
13.5 
Other events that require expedited reporting ......................................................... 79 
13.5.1 Pregnancy ...................................................................................................... 79 
13.6 
Reporting of other events ......................................................................................... 79 
13.6.1 Adverse events of special interest ................................................................. 79 
13.6.2 Overdose........................................................................................................ 80 
13.6.3 Medication error ............................................................................................ 80 
13.6.4 Misuse ........................................................................................................... 80 
13.6.5 Abuse ............................................................................................................. 80 
13.6.6 Aggravation of condition .............................................................................. 81 
13.7 
Follow-up for final outcome of adverse events ....................................................... 81 
13.8 
Handling of an urgent safety measure ..................................................................... 81 


Trial ID: LP0133-1275 
Date: 22-Aug-2019 
Version: 3.0 
Page 8 of 125 
 
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 GROUP 
 
14 Statistical methods ............................................................................................................. 82 
14.1 
Sample size .............................................................................................................. 82 
14.2 
Trial analysis sets ..................................................................................................... 82 
14.3 
Statistical analysis .................................................................................................... 83 
14.3.1 Disposition of subjects .................................................................................. 83 
14.3.2 Demographics and other baseline characteristics.......................................... 83 
14.3.3 Exposure and treatment compliance ............................................................. 83 
14.3.4 Testing strategy ............................................................................................. 84 
14.3.5 Analysis of primary efficacy endpoint .......................................................... 84 
14.3.6 Analysis of secondary efficacy endpoints ..................................................... 85 
14.3.7 Analysis of other endpoints ........................................................................... 86 
14.3.8 Analysis of pharmacodynamics and pharmacogenomics.............................. 88 
14.3.9 Analysis of safety .......................................................................................... 89 
14.3.10 Pharmacokinetics .......................................................................................... 90 
14.3.11 Interim analysis ............................................................................................. 90 
14.3.12 General principles ......................................................................................... 90 
14.3.13 Handling of missing values ........................................................................... 91 
15 References ........................................................................................................................... 92 
Appendix 1: Definitions of adverse events and serious adverse events ............................. 96 
Appendix 2: Classification of adverse events ....................................................................... 98 
Appendix 3: Trial governance considerations ................................................................... 101 
Appendix 3A: Regulatory and ethical considerations .............................................. 101 
Appendix 3B: Informed consent process ................................................................. 101 
Appendix 3C: Subject and data confidentiality ....................................................... 102 
Appendix 3D: Record keeping, quality control, and data handling ......................... 103 
Appendix 3E: Registration, reporting and publication policy ................................. 108 
Appendix 3F: Insurance ........................................................................................... 109 
Appendix 3G: Financial disclosure .......................................................................... 109 
Appendix 3H: Trial and site closure ........................................................................ 110 
Appendix 3I: Responsibilities .................................................................................. 111 
Appendix 4: Short version of eligibility criteria ................................................................ 112 
Appendix 5: Contact list ...................................................................................................... 114 
Appendix 6: Hanifin and Rajka (1980) diagnostic criteria for AD .................................. 115 
Appendix 7: Protocol amendment history ......................................................................... 116 


Trial ID: LP0133-1275 
Date: 22-Aug-2019 
Version: 3.0 
Page 9 of 125 
 
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 GROUP 
 
List of panels 
Panel 1: Trial design ................................................................................................................. 19 
Panel 2: Schedule of trial procedures ....................................................................................... 20 
Panel 3: Objectives and endpoints ........................................................................................... 31 
Panel 4: Identification of IMPs ................................................................................................ 42 
Panel 5: Prohibited medication and procedures ....................................................................... 46 
Panel 6: Sequence of assessments ............................................................................................ 53 
Panel 7: Fitzpatrick skin classification ..................................................................................... 55 
Panel 8: Calculation of the Eczema Area and Severity Index .................................................. 57 
Panel 9: EASI severity score scale and area score scale .......................................................... 57 
Panel 10: Validated Investigator Global Assessment scale for Atopic Dermatitis ................... 58 
Panel 11: Clinical laboratory tests ............................................................................................ 63 
Panel 12: Subject assessment of local tolerability after IMP application ................................ 64 
Panel 13: Adverse events of special interest ............................................................................ 79 
Panel 14: Transmission of electronic data .............................................................................. 107 
 


Trial ID: LP0133-1275 
Date: 22-Aug-2019 
Version: 3.0 
Page 10 of 125 
 
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 GROUP 
 
List of abbreviations 
AD 
Atopic dermatitis 
ADSD 
Atopic dermatitis symptom diary 
AE 
Adverse event 
AS 
Area score 
AUC 
Area under the curve 
b.i.d. 
Twice daily 
BSA 
Body surface area 
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
Confidence interval 
CMO 
Contract manufacturing organisation 
CONSORT 
Consolidated Standards of Reporting Trials 
CRA 
Clinical research associate 
CRO 
Contract research organisation 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTR 
Clinical trial report 
D 
Day 
DLQI 
Dermatology Life Quality Index 
EASI 
Eczema Area and Severity Index 
EASI50 
At least 50% reduction in EASI score 
EASI75 
At least 75% reduction in EASI score 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
eDiary 
Electronic diary 
EMA 
European Medicines Agency 
ePRO 
Electronic patient-reported outcome 
EQ-5D-5L 
EuroQoL 5-Dimension Health Questionnaire 5 Level 
FDA 
Unites States Food and Drug Administration 
GCP 
Good Clinical Practice 
HBcAb 
Hepatitis B core antibody 
HBsAB 
Hepatitis B surface antibody 
HBsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 


Trial ID: LP0133-1275 
Date: 22-Aug-2019 
Version: 3.0 
Page 11 of 125 
 
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 GROUP 
 
HDL 
High density lipoprotein 
HIV 
Human immunodeficiency virus 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IC50 
Half maximum inhibitory concentration 
ID 
Identification number 
IEC 
Independent ethics committee 
IgE 
Immunoglobulin E 
IL 
Interleukin 
IMP 
Investigational medicinal product 
IND 
Investigational new drug 
INN 
International non-proprietary name 
IRB 
Institutional review board 
IRT 
Interactive response technology 
JAK 
Janus kinase 
LDL 
Low density lipoprotein 
LEO 
LEO Pharma A/S 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed model for repeated measurements 
NBUVB 
Narrow band ultraviolet B 
NRS 
Numeric rating scale 
PDE-4 
Phosphodiesterase-4 
PGI-C 
Patient Global Impression of Change 
PGI-S 
Patient Global Impression of Severity 
PK 
Pharmacokinetics 
POEM 
Patient-Oriented Eczema Measure 
PRO 
Patient-reported outcome 
PT 
Preferred term 
PUVA 
Psoralen and ultraviolet A 
S. aureus 
Staphylococcus aureus 
SAE 
Serious adverse event 
SCORAD 
Scoring Atopic Dermatitis  


Trial ID: LP0133-1275 
Date: 22-Aug-2019 
Version: 3.0 
Page 12 of 125 
 
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 GROUP 
 
 
SCORAD50 
At least 50% reduction in SCORAD 
SCORAD75 
At least 75% reduction in SCORAD 
SDTM 
Study data tabulation model 
SF-36 
36-item Short Form Health Survey 
SOC 
System organ class 
SUSAR 
Serious and unexpected suspected adverse reaction 
SS 
Severity score 
STAT 
Signal transducer and activator 
TCI 
Topical calcineurin inhibitor 
TCS 
Topical corticosteroid 
Th 
T helper cell 
TSQM 
Treatment Satisfaction Questionnaire for Medication 
ULN 
Upper limit of normal range 
UV 
Ultraviolet 
UVA 
Ultraviolet A 
UVB 
Ultraviolet B 
vIGA-AD™ 
Validated Investigator Global Assessment scale for Atopic Dermatitis 
(termed vIGA-AD in this protocol) 
vIGA-AD TS 
vIGA-AD treatment success, i.e. a vIGA-AD score of 0 (clear) or 1 (almost 
clear) with at least a 2-step improvement 
W 
Week 
WHO 
World Health Organization 
WLQ 
Work Limitation Questionnaire 


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Trial ID: LP0133-1275 
Date: 22-Aug-2019 
Version: 3.0 
Page 14 of 125 
 
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 GROUP 
 
 
 
Screening period 
The screening period has a minimum duration of 2 weeks and a maximum 
duration of 4 weeks. At the screening visit, the subjects’ eligibility to enter the 
trial will be checked. The subjects will receive training in completion of an 
electronic diary (eDiary). Furthermore, the subjects will be asked to fill out 
patient-reported outcome measures (PROs).  
Treatment period 
At baseline (Day 1), subjects’ eligibility to enter the trial will be confirmed and, 
if still eligible, the subjects will be randomised to 1 of the 5 treatment groups. 
The randomisation will be stratified by the severity of AD according to vIGA-
AD (mild, moderate, and severe) and region (North America and Australia).    
The first application of the investigational medicinal product (IMP) will occur 
at the trial site at baseline (Day 1). The subsequent IMP applications will be 
performed by the subjects at home twice daily for 8 weeks. During the 
treatment period, the subjects will be required to return to the trial site for the 
visits scheduled at Weeks 1, 2, 4, 6 and 8. The last IMP application will occur 
before the subjects attend the visit scheduled at Week 8.  
Follow-up period  
All subjects will attend a follow-up visit approximately 2 weeks after the last 
IMP application for assessment of safety.  
 
 
Main assessments 
Investigator efficacy assessments: 


Trial ID: LP0133-1275 
Date: 22-Aug-2019 
Version: 3.0 
Page 15 of 125 
 
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 GROUP 
 
 EASI for assessment of severity and extent of AD. 
 vIGA-AD for assessment of the subject’s global disease severity.   
 Scoring Atopic Dermatitis (SCORAD) for evaluation of the extent and 
severity of AD lesions, along with subjective symptoms. 
Subject assessments of efficacy and health-related quality of life; PROs: 
 Atopic Dermatitis Symptom Diary (ADSD).  
 Eczema-related Sleep Numeric Rating Scale (Eczema-related Sleep NRS). 
 Patient-Oriented Eczema Measure (POEM). 
 Dermatology Life Quality Index (DLQI). 
 Patient Global Impression of Severity (PGI-S). 
 Patient Global Impression of Change (PGI-C). 
 36-item Short Form Health Survey (SF-36). 
 EuroQoL 5-Dimension Health Questionnaire 5 Level (EQ-5D-5L). 
 Work Limitation Questionnaire (WLQ). 
 Treatment Satisfaction Questionnaire for Medicine (TSQM). 
Safety assessments: 
 
Vital signs, physical examination, electrocardiograms, laboratory testing, 
subject assessment of local tolerability, and adverse events reporting. 
Main criteria for 
inclusion 
 Age 18 years and above. 
 Diagnosis of AD as defined by the Hanifin and Rajka 1980 criteria for 
AD.  
 History of AD for ≥1 year. 
 AD involvement of 5–50% treatable body surface area at screening and at 
baseline (excluding scalp). 
 Disease severity graded as mild to severe according to vIGA-AD (i.e. 
vIGA-AD ≥2) at screening and baseline. 
 Able and willing to follow trial procedures including application of IMP to 
all AD lesions.  
Main criteria for 
exclusion 
 AD lesion(s) on scalp at screening and/or baseline. 
 Active dermatologic conditions that may confound the diagnosis of AD or 
would interfere with assessment of treatment, such as scabies, cutaneous 
lymphoma, rosacea, urticaria, or psoriasis. 
 Known active allergic or irritant contact dermatitis that is likely to 
interfere with the assessment of severity of AD. 
 Use of tanning beds or phototherapy (narrow band ultraviolet B 
(NBUVB), ultraviolet B (UVB), ultraviolet A1 (UVA1), psoralen and 
ultraviolet A (PUVA)) within 4 weeks prior to baseline. 
 Treatment with the following medications within 4 weeks prior to 
baseline: 
o Systemic immunosuppressive/immunomodulating drugs (e.g. 
methotrexate, cyclosporine, azathioprine, mycophenolate-mofetil, 
Janus kinase inhibitors, retinoids). 


Trial ID: LP0133-1275 
Date: 22-Aug-2019 
Version: 3.0 
Page 16 of 125 
 
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 GROUP 
 
o Systemic corticosteroid use (excludes inhaled or intranasal 
delivery). 
o Three or more bleach baths during any week within the 4 weeks. 
 Treatment with the following medications within 2 weeks prior to baseline 
o Topical corticosteroids (TCSs). 
o Topical calcineurin inhibitors (TCIs). 
o Topical phosphodiesterase-4 (PDE-4) inhibitors. 
o Oral antibiotics. 
 Change in systemic antihistamine therapy within 2 weeks prior to baseline 
i.e. the subjects must not start antihistamine treatment or change the 
current dosage regime within 2 weeks prior to baseline. 
 Receipt of live attenuated vaccines 30 days prior to baseline and during 
the trial including the safety follow-up period. 
 Receipt of blood products within 4 weeks prior to screening.  
 Treatment with any marketed biological therapy or investigational 
biologic agents (including immunoglobulin, anti-IgE or dupilumab). 
o Any cell-depleting agents including but not limited to rituximab: 
within 6 months prior to baseline, or until lymphocyte count returns 
to normal, whichever is longer. 
o Other biologics: within 3 months or 5 half-lives, whichever is 
longer, prior to baseline. 
 History of any active skin infection within 1 week prior to baseline. 
 A helminth parasitic infection within 6 months prior to screening that has 
not been treated with, or has failed to respond to, standard of care therapy. 
 Clinically significant infection within 4 weeks prior to baseline which, in 
the opinion of the investigator, may compromise the safety of the subject 
in the trial, interfere with evaluation of the IMP, or reduce the subject’s 
ability to participate in the trial. Clinically significant infections are 
defined as:  
o A systemic infection. 
o A serious skin infection requiring parenteral (intravenous or 
intramuscular) antibiotics, antiviral, or antifungal medication. 
 Tuberculosis requiring treatment within the 12 months prior to screening  
and/or subjects with a positive blood test for tuberculosis at screening*. 
* Subjects with high risk of latent tuberculosis (e.g. prior residence in or 
travel to countries with high prevalence of tuberculosis, close contact with 
a person with active tuberculosis, or a history of active or latent 
tuberculosis where an adequate course of treatment cannot be confirmed) 
must be tested.  
 History of any known primary immunodeficiency disorder including a 
positive human immunodeficiency virus (HIV) test at screening, or the 


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Trial ID: LP0133-1275 
Date: 22-Aug-2019 
Version: 3.0 
Page 18 of 125 
 
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 GROUP 
 
Northwestern University, Department of Dermatology, Chicago, Illinois, USA 
(until 30-Sep-2019). 
George Washington University, Department of Dermatology, Washington DC, 
USA (from 01-Oct-2019). 
Sponsor 
LEO Pharma A/S, Industriparken 55, DK-2750 Ballerup, Denmark. 


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Trial ID: LP0133-1275 
Date: 22-Aug-2019 
Version: 3.0 
Page 24 of 125 
 
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 GROUP 
 
c) 
A visit at the trial site is not required on Day 4, a member of trial site personnel will call the subjects 
d) 
End of treatment assessments will be conducted at Week 8. Early termination: subjects, who discontinue IMP treatment prior to Week 8 or withdraw from trial will be asked 
to return to the trial site for end of treatment assessments at an early termination visit as soon as possible after the last IMP application for completion of all trial procedures 
scheduled for the visit at Week 8 (except for the skin biopsy, if the subject has consented to have skin biopsies obtained), and they will also be asked to return to the trial 
site 2 weeks after the last IMP application for a follow-up visit and at Week 8 for a primary endpoint visit 
e) 
All subjects will be asked to return to the trial site approximately 2 weeks after the last IMP application for assessment of safety at a follow-up visit 
f) 
Subjects who discontinue IMP treatment prior to Week 8 will be asked to return to the trial site at Week 8 for a primary endpoint visit 
g) 
Unscheduled visits may occur if subjects need to make a visit in between the scheduled visit dates due to an AE, difficulty complying with the trial protocol requirements, 
or a significant change in their disease state 
h) 
The informed consent form(s) must be signed prior to performing any protocol related procedures, including but not limited to screening evaluations and alteration of 
ongoing treatments unless medically justified 
i) 
All returned IMP tubes will be weighed by the CMO 
j) 
Relevant prior/concomitant medication should be included from 6 months prior to Day 1 (baseline) until end of trial 
k) 
Relevant medical history must be recorded from the subject’s birth. In case medical history is incomplete at screening visit, missing data will be retrieved at Day 1 
(baseline) 
l) 
BSA is assessed as a part of SCORAD 
m) Completion of the eDiary will be initiated at the latest 1 week prior to Day 1 (baseline). Compliance with the eDiary completion will be reviewed by the trial site staff 
throughout the trial. 
n) 
 Only for subjects with a paid job. 
o) 
Subjects do not have to be fasting for safety laboratory samples 
p) 
Subjects with high risk of latent tuberculosis (e.g. prior residence in or travel to countries with high prevalence of tuberculosis, close contact with a person with active 
tuberculosis, or a history of active or latent tuberculosis where an adequate course of treatment cannot be confirmed) must be tested 
q) 
For women of childbearing potential, a serum pregnancy test must be performed at the screening visit, and a urine pregnancy test at Day 1 (baseline), Weeks 4 and 8 (end of 
treatment) 
r) 
If a subject reports an AE, it is up to the investigator’s discretion to perform an unscheduled visit 
s) 
Collection of 1 PK plasma sample 2–6 hours after the morning application of IMP. Plasma sample should be collected from a non-treated area. 
t) 
The skin biopsy sampling and the recommended photography scheduled at Day 1 (baseline) must be obtained prior to the first IMP application. This should be done both on 
lesional and corresponding non-lesional skin if possible 
u) 
The skin biopsy sampling scheduled at Week 1 and Week 8 should be done on lesional skin only 
v) 
The skin biopsy scheduled at Week 8 will be obtained 2–12 hours after the last IMP application. If a subject discontinues IMP treatment prematurely or withdraws from the 
trial, the skin biopsy scheduled at Week 8 does not have to be obtained 


Trial ID: LP0133-1275 
Date: 22-Aug-2019 
Version: 3.0 
Page 25 of 125 
 
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 GROUP 
 
w) An end of trial form must be completed for all subjects, including subjects who discontinue IMP treatment prematurely or withdraw from the trial, at their last trial visit (the 
early termination visit, the safety follow-up visit, or the primary endpoint visit, whichever comes last) 
Abbreviations: ADSD, atopic dermatitis symptom diary; AE, adverse event; CMO, contract manufacturing organisation; DLQI, Dermatology Life Quality Index; ECG, 
electrocardiogram; EASI, Eczema Area and Severity Index; eDiary, electronic diary; EQ-5D-5L, EuroQoL 5 Dimension Health Questionnaire 5-Level; IgE, immunoglobulin E; IMP, 
investigational medicinal product; NRS, numeric rating scale; PGI-C, Patient Global Impression of Change; PGI-S, Patient Global Impression of Severity; PK, pharmacokinetics; 
POEM, Patient-Oriented Eczema Measure; SAE, serious adverse event; SCORAD, SCORing Atopic Dermatitis; SF-36: 36-item Short Form Health Survey;  TSQM: Treatment 
Satisfaction Questionnaire for Medication; vIGA-AD, Validated Investigator Global Assessment scale for Atopic Dermatitis; WLQ, Work Limitation Questionnaire 


Trial ID: LP0133-1275 
Date: 22-Aug-2019 
Version: 3.0 
Page 26 of 125 
 
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 GROUP 
 
5 Introduction and trial rationale 
5.1 Atopic dermatitis 
AD is a chronic inflammatory skin disease that may affect up to 20% of children and up to 
10% of adults. AD is characterised by widespread, red, swollen, cracked and weeping lesions 
with crusting and scaling, and is associated with pruritus and susceptibility to bacterial and 
viral skin infections (Silverberg & Hanifin 2013, Hanifin & Reed 2007, Bieber 2008, 
Weidinger & Novak 2016). AD is also associated with a substantial patient burden that 
typically includes poor quality of life, sleep disturbance and reduction in work productivity 
(Kiebert et al. 2002). 
AD is characterised by an activated Th2 pathway in the skin (Bieber 2008, Bao et al. 2013) 
and increased expression of Th2 cytokines such as IL-4, IL-5, IL-13, IL-2, IL-31, IL-33, and 
thymic stromal lymphopoietin (Brunner et al. 2017; Czarnowicki et al. 2017; Ong 2014).  
In the immune milieu of AD, the enhancement of Th2 cell proliferation and their release of 
various cytokines via the JAK-STAT pathway is likely the critical factor for the inflammatory 
responses in AD. This Th2 immune milieu triggers epidermal cells to release various 
chemokines, pro-inflammatory cytokines, and angiogenic factors that participate in AD 
pathophysiology. Similarly, this Th2 immune upregulation could then lead to B cell 
maturation and plasma cell differentiation, resulting in hypersecretion of IgE. IgE binding to 
skin mast cells causes histamine release, which further exacerbates AD. Moreover, IL-5 
released from this Th2 milieu could activate eosinophils that are attracted to the skin by the 
eotaxin subfamily, potentially worsening the AD condition. In addition, by means of IL-31, an 
inducer of pruritus, AD becomes increasingly intensified (Bao et al. 2013).  
5.2 Experience with investigational medicinal product 
Delgocitinib, recently assigned as the international non-proprietary name (INN) for LEO 
124249, is a pan-JAK inhibitor, which blocks various cytokine signalling pathways, and 
widely suppresses the activation of immune and inflammatory cells such as T cells, B cells, 
mast cells, and monocytes activated by these cytokines.  
JAK is a family of intracellular tyrosine kinases consisting of 4 members, JAK1, JAK2, 
JAK3, and Tyk2, which can associate directly to the intracellular part of various cytokine 
receptors in various combinations (Pesu et al. 2005, Murray 2007). After a cytokine binds to 
its cognate receptor, the relevant JAK members are autophosphorylated, which allows them to 
phosphorylate one or more STAT protein (STAT1, STAT2, STAT3, STAT4, STAT5A/B, and 
STAT6). The phosphorylated STAT proteins are in turn translocated to the nucleus where they 


Trial ID: LP0133-1275 
Date: 22-Aug-2019 
Version: 3.0 
Page 27 of 125 
 
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 GROUP 
 
initiate transcription leading to promotion of growth and activation of a variety of cells. The 
JAK family is thus essential for cytokines involved in the pathogenesis of various diseases 
with an immune-inflammatory component to exhibit their physiological activity. The immune 
mechanisms in AD are mostly driven by T cells, and JAK inhibitors inhibit signal 
transduction of many T cell-released cytokines. 
In non-clinical studies, delgocitinib blocked JAK family members with IC50 values ranging 
from 2–60 nM in biochemical assays and inhibited activation of T cells, B cells, mast cells, 
and monocytes induced by various JAK cytokines in cellular assays. Topically administered 
delgocitinib inhibited inflammation in rat and mouse models of contact dermatitis, where 
T cells activated by various JAK-dependent cytokines were involved in the pathogenesis. 
Furthermore, delgocitinib improved the impaired skin barrier function, and reduced IL-31-
induced scratching in mice. In a study by Amano et al., it was shown that IL-4 and IL-13 
downregulated genes involved in keratinocyte differentiation, that STAT3 and STAT6 are 
involved in keratinocyte differentiation and chemokine production, respectively, and that 
topical application of delgocitinib suppressed STAT3 activation and improved skin barrier 
function (Amano et al. 2015). 
So far, the clinical development programme for delgocitinib has been based on an ointment 
formulation. No clinical trials with the cream formulation have been conducted to date. 
A total of 7 clinical trials covering different patient populations/indications have been 
conducted with delgocitinib ointment: Three phase 1 trials in healthy adult subjects and adult 
subjects with AD and four phase 2 trials in adult subjects with AD, chronic hand eczema, 
inverse psoriasis and alopecia areata.  
A phase 2b trial in subjects with moderate to severe AD demonstrated a statistically 
significant and dose-dependent treatment effect of delgocitinib, formulated as an ointment, 
compared to delgocitinib ointment vehicle in terms of the percent change in the modified 
EASI score (excluding head/neck region) from baseline to end of the 4-week treatment 
period. Delgocitinib ointment was well-tolerated with no apparent dose-dependent trends in 
AEs. No SAEs were reported.  
5.3 Trial rationale 
This phase 2b trial will be the first clinical trial to investigate the cream formulation in 
subjects with AD. 


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of potential strengths. The formulation strengths are distributed equidistantly on the natural 
logarithmic scale (rounded to whole numbers 1, 3, 8, and 20 mg/g). 
5.5 Ethical considerations  
This trial will be conducted in accordance with the ethical principles that have their origins in 
the Declaration of Helsinki, the ICH-GCP guidelines, in compliance with the approved 
protocol, and applicable regulatory requirements. 
Risks associated with treatment in this clinical trial (risks of experiencing significant adverse 
reactions associated with dermal or systemic exposure to delgocitinib) are considered 
minimal.  
The trial design chosen for this efficacy and safety trial with delgocitinib cream is regarded as 
ethically justified and adherent with ethical requirements. The efficacy and safety of 
delgocitinib cream will be evaluated in adults suffering from mild to severe AD who may 
benefit from treatment in the trial. Pregnant or breastfeeding women and women trying to 
become pregnant will not be enrolled in the trial. Women of childbearing potential must agree 
to use a highly effective method of contraception to prevent pregnancy during the trial. 
Trial subjects will be informed at the screening visit that trial procedures prior to baseline 
(Day 1) may warrant an alteration of their ongoing concomitant treatments. As applicable for 
the entire trial, the subjects will be instructed to contact the investigator if their AD worsens 
significantly. 
In accordance with the current version of the ICH-GCP guidelines, qualified medical 
personnel employed by LEO will be readily available to advise on trial-related medical 
questions. Medical monitoring will be performed throughout the trial. Safety data will be 
reviewed regularly by Global Pharmacovigilance at LEO to ensure routine signal detection. 
5.6 Benefit/risk assessment 
There is an unmet medical need for new topical treatments for use in patients with mild to 
severe AD as the majority of the current treatment options have associated limitations in 
terms of efficacy and/or safety. 
No important identified risks have been documented during the overall non-clinical and 
clinical development of delgocitinib to date. A detailed overview of non-clinical and clinical 
data on delgocitinib is available in the current Investigator’s Brochure. 


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The risk to subjects in this trial will be minimised by fulfilment of all eligibility criteria and 
by close clinical monitoring. As stopping current AD treatment during the trial treatment 
period carries an inherent risk of worsening AD symptoms during the screening period, the 
subjects will be instructed to contact the investigator if their AD symptoms worsens 
significantly during this period. 
To ensure the safety and well-being of subjects participating in this trial, safety monitoring 
will be evaluated as described in Section 11.4. The risks associated with the following 
invasive trial procedures are considered minimal. Blood samples can be considered a low risk 
procedure. Skin biopsies are optional to the subject. The size of the skin biopsies should not 
necessitate suturing, but suturing can be performed at the investigator’s discretion. The risk 
associated with a skin biopsy, including secondary infection, is considered low.  
Altogether, the risks associated with participating in this clinical trial are considered very low 
and outweighed by the benefit of a potential future treatment option for AD. There is an 
opportunity for a positive treatment effect for the subjects participating in this clinical trial 
based on the currently available clinical data. 
 
 




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Objectives 
Endpoints 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
To evaluate the effect of delgocitinib 
on S. aureus colonisation of the skin, 
skin microbiome, and skin 
inflammation. 
 Change in SF-36 from baseline to Week 8. 
 
Efficacy over time 
 vIGA-AD TS at each scheduled assessment until Week 
6. 
 EASI75 at each scheduled assessment until Week 6. 
 Change in SCORAD from baseline to each scheduled 
assessment until Week 6. 
 Change from baseline to each week from Week 1 to 
Week 7 in ADSD (weekly average for each individual 
symptom). 
o Reduction of worst pruritus (weekly average) of ≥4 
points from baseline to each week from Week 1 to 
Week 7 among subjects with baseline worst pruritus 
(weekly average) ≥4.  
 Change from baseline to each week from Week 1 to 
Week 7 in Eczema-related Sleep NRS (weekly 
average). 
 Change in DLQI score from baseline to each scheduled 
assessment until Week 6. 
 Reduction in DLQI of ≥4 points from baseline to each 
scheduled assessment until Week 6 among subjects 
with baseline DLQI ≥4. 
 
 
Biomarkers 
 Change in S. aureus colonisation from baseline to 
Week 8. 
 Change in microbiome composition from baseline to 
Week 8. 
 Change in expression of genes involved in AD 
pathogenesis in skin biopsies from baseline to Week 
1. 
 Change in expression of genes involved in AD 
pathogenesis in skin biopsies from baseline to Week 
8. 
Abbreviations: ADSD, atopic dermatitis symptom diary; AE, adverse event; DLQI, Dermatology Life Quality Index; EASI, 
Eczema Area and Severity Index; EQ-5D-5L, EuroQoL 5 Dimension Health Questionnaire 5-Level; NRS, numeric rating 
scale; POEM, Patient-Oriented Eczema Measure; SAE, serious adverse event; SCORAD, SCORing Atopic Dermatitis; SF-
36: 36-item Short Form Health Survey;  TSQM: Treatment Satisfaction Questionnaire for Medication; vIGA-AD, Validated 
Investigator Global Assessment scale for Atopic Dermatitis; WLQ, Work Limitation Questionnaire 


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7 Trial design 
7.1 Overall trial design  
This is a phase 2b double-blind, multi-centre, randomised, 5-arm, vehicle-controlled, parallel- 
group trial. The trial is designed to establish a dose-response signal and to investigate the 
efficacy and safety of delgocitinib cream in the treatment of adult subjects with mild to severe 
AD. The trial design is illustrated in Panel 1.  
The trial consists of a screening period, a treatment period and a follow-up period. 
Screening period - between 2 and 4 weeks prior to baseline visit (Day 1) 
The screening period has a minimum duration of 2 weeks and a maximum duration of 4 
weeks. 
At the screening visit, the subjects’ eligibility to enter the trial will be checked. Trial-specific 
measurements will be performed as outlined in Section 11. 
The subjects will receive training in completion of an eDiary at the screening visit and will be 
given an electronic device to record certain PROs. Furthermore, to complete training of the 
eDiary and as an opportunity to fill out PROs before the treatment period, subjects will be 
asked to complete PROs at the screening visit. Completion of the eDiary will be initiated at 
the latest 1 week prior to the baseline visit (Day 1). 
All subjects must use an emollient twice daily (or more, as needed) for at least 14 days before 
Day 1; this background treatment should preferably be an additive free, basic bland emollient. 
After randomisation on Day 1, emollients must not be used concomitantly with delgocitinib 
cream or delgocitinib cream vehicle on lesional skin. Subjects may however continue to use 
their background emollient treatment on non-lesional skin throughout the trial (including 
safety follow-up). 
Treatment period - 8 weeks 
At baseline (Day 1), subjects’ eligibility to enter the trial will be confirmed and, if still 
eligible, subjects can be randomised 1:1:1:1:1 to one of the following 5 treatment groups in a 
1:1:1:1:1 ratio: delgocitinib cream 1, 3, 8, 20 mg/g or delgocitinib cream vehicle. 
The subjects will apply the IMP (delgocitinib cream 1, 3, 8, or 20 mg/g or delgocitinib cream 
vehicle) twice daily for 8 weeks. The first application of the IMP will occur at the trial site on 


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Day 1 after all baseline assessments have been carried out. The subsequent IMP applications 
will be performed by the subjects at home.  
During the 8-week treatment period, the subjects will return to the trial sites for the visits 
scheduled at Weeks 1, 2, 4, 6, and 8. On Day 4, a member of trial site personnel will call the 
subjects to ask them a non-leading question about AEs e.g. “How have you felt since I saw 
you last?”, and to inquire about compliance with treatment and eDiary completion. The last 
IMP application will occur at the subjects’ home before the subjects attend the visit scheduled 
at Week 8. Efficacy and safety assessments during the treatment period will be performed as 
described in Section 11. 
Follow-up period - 2 weeks 
All randomised subjects will attend a follow-up visit approximately 2 weeks after the last IMP 
application for assessment of safety. This visit will mark the end of trial participation for 
subjects who have completed the entire trial. For subjects who discontinue trial treatment 
prematurely or withdraw from the trial, please refer to Section 10.3. 
7.2 Number of subjects needed 
This trial will be conducted at approximately 25 sites in North America and Australia. The 
anticipated minimum number of randomised subjects per trial site is 6 and the maximum 
number of subjects per trial site is 30.  
Assuming a screening failure rate of approximately 25%, approximately 334 subjects will be 
screened and approximately 250 subjects will be randomly assigned to trial treatment (50 
subjects in each of the 5 treatment groups: delgocitinib cream 1, 3, 8, and 20 mg/g and 
delgocitinib cream vehicle). The statistical power considerations for this sample size are 
described in Section 14.1. 
The randomisation is stratified by the severity of AD according to vIGA-AD (vIGA-AD score 
of 2 (mild), 3 (moderate), or 4 (severe)) and region (North America and Australia).  
7.3 End of trial definition 
A subject is considered to have completed the trial if they have completed all periods of the 
trial (i.e. screening, treatment and the safety follow-up). 
The end of the trial is defined as the date of the last visit of the last subject in the trial 
globally. 


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Final collection of data for the primary endpoint occurs at Week 8. 
7.4 Software 
CDISC controlled terminology version 30-Mar-2018 or newer was used for definition of 
controlled terminology used throughout this protocol and will be used for statistical 
programming and output. SDTM version 1.4 will be used for data tabulations and SDTM 
Implementation Guide version 3.2 will be adhered to. 
Dose-response modelling will be done using the package DoseFinding implemented in R 
statistical software version 3.5.0. All other analysis will be performed using SAS® statistical 
software version 9.4. 
 
 


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8 Trial population  
8.1 Subject eligibility 
The investigator should only include subjects who meet all eligibility criteria, are not put at 
undue risk by participating in the trial and can be expected to comply with the protocol.  
The subject’s eligibility for the clinical trial must be verified according to the inclusion and 
exclusion criteria at visits specified in Panel 2. It will be recorded in the eCRF if the subject 
has met all the inclusion criteria and none of the exclusion criteria. 
Any implementation of national requirements/law for the subject’s participation in the clinical 
trial will be ensured and described in submission documentation to regulatory authorities and 
IRBs/IECs, as applicable.  
8.2 Inclusion criteria 
For inclusion into this trial, subjects must fulfil all of the following criteria: 
1. Signed and dated informed consent has been obtained prior to any protocol-related 
procedures. 
2. Age 18 years and above. 
3. Diagnosis of AD as defined by the Hanifin and Rajka criteria for AD (Hanifin & Rajka 
1980, Appendix 6). 
4. History of AD for ≥1 year. 
5. AD involvement of 5–50% treatable body surface area at screening and at baseline 
(excluding scalp). 
6. Disease severity graded as mild to severe according to vIGA-AD (i.e. vIGA-AD ≥2) at 
screening and baseline. 
7. Able and willing to follow trial procedures including application of IMP to all AD 
lesions. 
8. A woman of childbearing potential* must use a highly effective** form of birth 
control throughout the trial and at least for 2 weeks after last application of IMP. 
* A woman is defined as not being of childbearing potential if she is postmenopausal 
(at least 12 months with no menses without an alternative medical cause prior to 


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screening), or surgically sterile (hysterectomy, bilateral salpingectomy, or bilateral 
oophorectomy). 
**A highly effective method of birth control is defined as one which results in a low 
failure rate (less than 1% per year) such as bilateral tubal occlusion, intrauterine 
device, intrauterine hormone-releasing system, combined (oestrogen and progestogen 
containing) hormonal contraception associated with inhibition of ovulation (oral, 
intravaginal, transdermal), progestogen-only hormonal contraception associated with 
inhibition of ovulation (oral, injectable, implantable), sexual abstinence (when this is 
in line with the preferred and usual life style of the subject), vasectomised partner 
(given that the subject is monogamous). 
8.3 Exclusion criteria 
Subjects must not enter the trial if any of the following exclusion criteria are fulfilled:  
1. AD lesion(s) on scalp at screening and/or baseline. 
2. Active dermatologic conditions that may confound the diagnosis of AD or would 
interfere with assessment of treatment, such as scabies, cutaneous lymphoma, rosacea, 
urticaria, or psoriasis. 
3. Known active allergic or irritant contact dermatitis that is likely to interfere with the 
assessment of severity of AD. 
4. Use of tanning beds or phototherapy (NBUVB, UVB, UVA1, PUVA) within 4 weeks 
prior to baseline. 
5. Treatment with the following medications within 4 weeks prior to baseline: 
 Systemic immunosuppressive/immunomodulating drugs (e.g. methotrexate, 
cyclosporine, azathioprine, mycophenolate-mofetil, Janus kinase inhibitors, 
retinoids). 
 Systemic corticosteroids (excludes inhaled or intranasal delivery). 
 Three or more bleach baths during any week within the 4 weeks. 
6. Treatment with the following medications within 2 weeks prior to baseline: 
 TCSs. 
 TCIs. 
 Topical PDE-4 inhibitors. 


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 Oral antibiotics. 
7. Change in systemic antihistamine therapy within 2 weeks prior to baseline i.e. the 
subjects must not start antihistamine treatment or change the current dosage regime 
within 2 weeks prior to baseline. 
8. Receipt of live attenuated vaccines 4 weeks prior to baseline.  
9. Receipt of blood products within 4 weeks prior to screening.  
10. Treatment with any marketed biological therapy or investigational biologic agents 
(including immunoglobulin, anti-IgE or dupilumab). 
 Any cell-depleting agents including but not limited to rituximab: within 
6 months prior to baseline, or until lymphocyte count returns to normal, 
whichever is longer. 
 Other biologics: within 3 months or 5 half-lives, whichever is longer, prior to 
baseline. 
11. Treatment with any non-marketed drug substance (that is, an agent which has not yet 
been made available for clinical use following registration) within the last 4 weeks 
prior to baseline or 5 half-lives, whichever is longer. 
12. History of any active skin infection within 1 week prior to baseline. 
13. A helminth parasitic infection within 6 months prior to screening that has not been 
treated with, or has failed to respond to, standard of care therapy. 
14. Clinically significant infection within 4 weeks prior to baseline which, in the opinion 
of the investigator, may compromise the safety of the subject in the trial, interfere with 
evaluation of the IMP, or reduce the subject’s ability to participate in the trial. 
Clinically significant infections are defined as:  
 A systemic infection. 
 A serious skin infection requiring parenteral (intravenous or intramuscular) 
antibiotics, antiviral, or antifungal medication. 
15. Tuberculosis requiring treatment within the 12 months prior to screening and/or 
subjects with a positive blood test for tuberculosis at screening*. 
* Subjects with high risk of latent tuberculosis (e.g. prior residence in or travel to 
countries with high prevalence of tuberculosis, close contact with a person with active 
tuberculosis, or a history of active or latent tuberculosis where an adequate course of 
treatment cannot be confirmed) must be tested. 


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16. History of any known primary immunodeficiency disorder including a positive HIV 
test at screening, or the subject taking antiretroviral medications as determined by 
medical history and/or subject’s verbal report. 
17. Major surgery within 8 weeks prior to screening, or planned in-patient surgery or 
hospitalisation during the trial period. 
18. History of cancer:  
 Subjects who have had basal cell carcinoma, localised squamous cell 
carcinoma of the skin or in situ carcinoma of the cervix are eligible provided 
that the subject is in remission and curative therapy was completed at least 
12 months prior to screening. 
 Subjects who have had other malignancies are eligible provided that the 
subject is in remission and curative therapy was completed at least 5 years 
prior to screening. 
19. Any disorder, including but not limited to, cardiovascular, gastrointestinal, hepatic, 
renal, neurological, musculoskeletal, infectious, endocrine, metabolic, haematological, 
immunological, psychiatric, or major physical impairment that is not stable, in the 
opinion of the investigator, and could: 
 Affect the safety of the subject throughout the trial. 
 Influence the findings of the trial or their interpretations. 
 Impede the subject’s ability to complete the entire duration of trial. 
20. Any abnormal finding which may: 
 Put the subject at risk because of his/her participation in the trial. 
 Influence the results of the trial. 
 Influence the subject’s ability to complete entire duration of the trial. 
The abnormal finding must be clinically significant and observed during the screening 
period. Examples include abnormal findings in physical examination, vital signs, 
ECG, haematology, clinical chemistry, or urinalysis. 
21. Positive HBsAg, HBsAb, HBcAb or anti-HCV serology at screening. Subjects with 
positive HBsAb may be randomised provided they are hepatitis B vaccinated and have 
negative HBsAg and HBcAb. 


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22. Alanine aminotransferase or aspartate aminotransferase level ≥2.0 times the upper 
limit of normal range at screening. 
23. Known or suspected hypersensitivity to any component(s) of the IMP. 
24. Current participation in any other interventional clinical trial. 
25. Previous randomisation in this clinical trial. 
26. History of chronic alcohol or drug abuse within 12 months prior to screening, or any 
condition associated with poor compliance as judged by the investigator. 
27. Employed at the trial site or directly involved with the planning or conduct of the trial, 
or immediate family members of such individuals. 
28. Legally institutionalised. 
29. Pregnant or lactating. 
8.4 Screening and screening failures 
Subject identification number 
Trial participation begins once written informed consent is obtained. Refer to Appendix 3B 
for details on the informed consent process. Once informed consent is obtained, a subject 
identification number (subject ID) will be assigned by a central IRT system and the screening 
evaluations to assess eligibility criteria may begin. The subject ID will be used to identify the 
subject during the screening process and throughout trial participation, if applicable. Subjects 
who have given written informed consent to participate in the trial and who have been 
assigned a subject ID are considered ‘screened’ subjects. 
The investigator will maintain a log of all consented subjects at the trial site (subject 
identification list). 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. In addition, the investigator will maintain a log of 
all subjects considered for screening, whether they have provided written informed consent or 
not (screening log). This log will be anonymous and will include the reason(s) for not entering 
the trial, if applicable, or the allocated subject ID. 
Screening failures 
Screening failures are defined as subjects who consent to participate in the trial but are not 
subsequently randomly assigned to trial treatment. A minimal set of screening failure 
information is required to ensure transparent reporting of screening failure subjects to meet 
the CONSORT publishing requirements (Schulz et al. 2010) and to respond to queries from 


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regulatory authorities. Individuals who do not meet the criteria for participation in the trial 
(screening failures) may not be re-screened. However, if the reason for screening failure is 
administrative e.g. delayed test results and not due to the subject failing to meet the eligibility 
criteria, re-screening may be permitted. Individuals who are re-screened will get a new subject 
ID. 
The following data will be collected in the eCRF for screening failures: 
 Date of informed consent(s). 
 Demographics (date of birth, age, sex, ethnicity, race). 
 Reason for screening failure: 
o Failure to meet eligibility criteria (specify which).  
o Withdrawal by subject. 
o Other (specification is required). 
 Date of screening failure. 
 Any AEs and SAEs. 
 
In case of any SAEs, these must be followed-up as described in Section 13.7. 
 
 


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Trial ID: LP0133-1275 
Date: 22-Aug-2019 
Version: 3.0 
Page 43 of 125 
 
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 GROUP 
 
initially untreated area(s) of the skin, these new lesions will be treated with IMP as well 
except if they occur on scalp. Subjects should be advised to contact the investigator before 
initiating treatment of new lesions. 
The IMP application on initially affected areas and new lesions will continue until Week 8 
regardless of clearance status.  
The last IMP application will occur at the subject’s home before the subject attends the visit 
scheduled at Week 8.      
The IMP will be dispensed by the investigational staff at the visits scheduled in Section 4. The 
IRT will assign the required kit number(s) for each subject at each dispensing visit. 
The investigator will use clinical judgement to treat any symptoms connected with an 
overdose. 
9.3 Treatment assignment  
Subjects who have been found to meet all the inclusion criteria and not to fulfil any of the 
exclusion criteria will be randomised centrally at baseline (Day 1) to receive treatment with 
either delgocitinib cream (1, 3, 8, or 20 mg/g) or delgocitinib cream vehicle. The treatment 
assignment will occur on the basis of a computer-generated randomisation scheme in a 
1:1:1:1:1 ratio.  
The IRT will be used to control randomisation and stratification factors, along with IMP 
supply chain and expiry tracking.  
9.3.1 Blinding  
The packaging and labelling of the IMPs will contain no evidence of their identity. It will not 
be possible to differentiate between the IMPs solely by sensory evaluation. 
9.3.2 Emergency unblinding of individual subject treatment 
While the safety of a subject always comes first, it is still important to carefully consider if 
unblinding is necessary to ensure a subject’s safety. In many cases, IMP discontinuation and 
knowledge of the possible treatment assignment are sufficient to treat a trial subject who 
presents with an emergency condition. An emergency unblinding request can be made by the 
investigators, health care professionals who are not members of the trial staff, or authorised 
LEO personnel. 


Trial ID: LP0133-1275 
Date: 22-Aug-2019 
Version: 3.0 
Page 44 of 125 
 
THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION AND MUST NOT BE COPIED OR MADE AVAILABLE TO ANY THIRD PARTY WITHOUT 
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Provisions are in place for 24-hour emergency unblinding of individual subject treatment. If 
emergency unblinding is required, the investigator can unblind a subject’s treatment in the 
IRT. For a requester who is not a member of the trial staff and who does not have access to the 
IRT (e.g. a physician at an emergency room), a local contact number for the emergency 
unblinding CRO is provided on the subject card (see Appendix 3B) to be used if the 
investigator or delegated site staff cannot be reached. The requester will provide the trial ID 
and subject ID to the emergency unblinding CRO who will immediately reveal the subject’s 
treatment allocation. 
The emergency unblinding CRO will clarify that the requester requires immediate unblinding 
without further medical consultation. Should the requester wish to discuss whether unblinding 
is necessary, the emergency unblinding CRO will provide the requester with the LEO 24/7 
contact which will be diverted to the medical cover. 
9.4 Background treatment (emollients) 
All subjects must use an emollient twice daily (or more, as needed) for at least 14 days before 
randomisation; the background treatment should preferably be an additive free, basic bland 
emollient. After randomisation emollients must not be used concomitantly with IMP on 
lesional skin. Subjects are however allowed to continue their background emollient treatment 
on non-lesional skin throughout the trial (including safety follow-up). 
9.5 Rescue treatment 
If medically necessary (i.e. to control intolerable AD symptoms), rescue medication for AD 
may be provided to trial subjects at the discretion of the investigator. The investigators should 
make every attempt to conduct efficacy and safety assessments (for example disease severity 
scores, safety laboratory assessments) immediately before administering any rescue treatment. 
If rescue medication is initiated, the subject must stop treatment with IMP immediately and 
must not restart treatment with IMP. It must be stated in the eCRF that the subject receives 
rescue medication.  
9.6 Concomitant medication and concurrent procedures 
Any medication or vaccine that the subject receives from 6 months prior to baseline (if 
relevant) through the safety follow-up period must be recorded in the subject’s medical record 
and the eCRF along with details such as: 
 Medication name. 


Trial ID: LP0133-1275 
Date: 22-Aug-2019 
Version: 3.0 
Page 45 of 125 
 
THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION AND MUST NOT BE COPIED OR MADE AVAILABLE TO ANY THIRD PARTY WITHOUT 
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 Indication. 
 Start and stop date of administration (it will also be recorded if the medication 
is ongoing). 
 Dosage information, including dose, unit, and frequency. 
 Route of administration. 
 For topical treatment, the body location must be recorded: it must be recorded 
if the treatment is within 5 cm (approximately 2 inches) of the treatment area. 
Similarly, any concurrent procedure must also be recorded in the subject’s medical record and 
the eCRF. The following details will be recorded:  
 Procedure. 
 Body location.   
 Diagnosis. 
 Start and stop date (it will also be recorded if the procedure is ongoing).  
 For topical treatments, it must also be recorded if the procedure is inside the 
treatment area. 
Investigators may prescribe concomitant medications or treatments to provide adequate 
supportive care as deemed necessary, except for medications listed in Section 9.7. Use of 
emollients is described in Section 9.4. 
No concomitant medication is allowed on lesional skin. On non-lesional skin, background 
treatment, preferably an additive free basic bland emollient, is allowed. 
9.7 Prohibited medication and procedures 
The medications and procedures listed in Panel 5 are prohibited during the trial. In case any 
prohibited treatments are used during the trial, they must be recorded as concomitant 
medication. Any medication prescribed with the intent to treat AD will be regarded as rescue 
medication. If rescue medication is initiated, the subject must stop treatment with IMP 
immediately (see Section 9.5). 


Trial ID: LP0133-1275 
Date: 22-Aug-2019 
Version: 3.0 
Page 46 of 125 
 
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 GROUP 
 
Panel 5: Prohibited medication and procedures 
Medication 
Prohibited from 
Prohibited to 
Systemic treatment with immunosuppressive 
drugs (e.g. methotrexate, cyclosporine, 
mycophenolate-mofetil, azathioprine), 
immunomodulating drugs (e.g. JAK 
inhibitors), retinoids (e.g. alitretinoin) or 
corticosteroids (inhaled or intra-nasal steroids 
corresponding to up to 1 mg prednisone for 
asthma or rhinitis may be used) 
4 weeks prior to baseline 
End of trial 
Use of tanning beds, phototherapy (e.g. PUVA 
or UVB therapy) or bleach baths 
4 weeks prior to baseline 
End of trial 
Live attenuated vaccines 
4 weeks prior to baseline 
End of trial 
 
TCSs, TCIs or topical PDE-4 inhibitors 
2 weeks prior to baseline 
End of trial 
Change in systemic antihistamine therapy 
2 weeks prior to baseline 
End of trial 
Blood products 
4 weeks prior to screening 
End of trial 
Any marketed biological therapy or 
investigational biologic agents (including 
immunoglobulin, anti-IgE, or dupilumab): 
 
 
 
 
 
Any cell-depleting agents including 
but not limited to rituximab 
 
6 months prior to baseline or 
until lymphocyte count returns 
to normal, whichever is 
longer. 
End of trial 
 
Other biologics 
3 months or 5 half-lives, 
whichever is longer, prior to 
baseline 
End of trial 
Any non-marketed drug substance (i.e. an 
agent which has not yet been made available 
for clinical use following registration). 
4 weeks prior to baseline or 
5 half-lives whichever is the 
longest 
End of trial 
Topical treatment (e.g. drug, non-drug, wet 
wraps) on lesional skin other than the use of 
IMP. 
Baseline 
End of trial 
 
9.8 Treatment logistics and accountability  
9.8.1 Labelling and packaging of trial products 
The IMPs will be packaged in individually numbered kits. 
Primary and secondary packaging materials will be individually labelled. 


Trial ID: LP0133-1275 
Date: 22-Aug-2019 
Version: 3.0 
Page 47 of 125 
 
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 GROUP 
 
The labelling of IMPs will be in accordance with Annex 13, local regulations and trial 
requirements. Label text will be translated into local languages, as required.  
9.8.2 Storage of trial products  
All LEO supplied IMPs must be stored in a secure and restricted area under the conditions 
specified on the label and remain in the original container until dispensed. 
The IMP must be stored at 2–8°C (36–46°F) at the trial site. Do not freeze. The temperature 
during storage should be monitored by a calibrated, stationary, and continuously electronic 
recording system with alarm and back-up of data. If no alarm is triggered, a log must be 
printed, reviewed, signed and dated each month. If the alarm is triggered, the log must be 
immediately printed, reviewed, signed and dated, and appropriate follow up action will be 
taken in accordance with the trial product handling manual.  
A temperature log from the recording system must be kept at the trial site to document the 
storage within the right temperature interval. Storage facilities should be checked at least 
every working day. 
Storage of the IMPs may be delegated, e.g. to a hospital pharmacy, as locally applicable. 
In the situations listed below, site staff should not use the affected IMPs and should 
immediately contact their CRA for further guidance: 
 Temperature excursion upon receipt or during storage at the trial site. 
 Damaged kit upon receipt. 
Damaged IMP should be documented in the IRT and reported as a product complaint to 
Global Pharmacovigilance, LEO (see Section 9.10). Damaged IMP may not be used.  
Further details regarding storage (including handling of temperature excursions upon receipt 
or during storage at the trial site) and handling of damaged IMPs (including kits damaged 
upon receipt) are provided in the trial product handling manual. 
9.8.3 Drug accountability 
IMP accountability 
The investigator is fully responsible for the IMPs at the trial site and for maintaining adequate 
control of the IMPs and for documenting all transactions with them. 
Dispensing of IMPs may be delegated, e.g. to a hospital pharmacy, as locally applicable. 


Trial ID: LP0133-1275 
Date: 22-Aug-2019 
Version: 3.0 
Page 48 of 125 
 
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 GROUP 
 
An individual drug accountability form must be kept of the IMP administered to and returned 
by each subject randomised in the trial. This individual drug accountability form must be 
available during monitoring visits and will be checked by the CRA to verify correct 
dispensing of the IMP. Drug accountability information will be entered in the IRT, where also 
inventory status of all IMP at the trial site will be maintained. 
The subjects will return used, and unused IMP (including packaging material) at the visits 
specified in the schedule of trial procedures (Section 4). 
Returned trial products (used, and unused IMP [including packaging material]) can be stored 
at room temperature and must be stored separately from non-allocated trial products. 
All IMPs (including packing material) supplied by the CMO on behalf of LEO will be 
returned to the CMO on an ongoing basis. Prior to return, the IMP must be fully accounted for 
by the CRA with the help of site staff responsible for dispensing the IMPs.  
All tubes returned to the CMO will be weighed to determine the amount of IMP used. 
Reporting in eCRF 
The kit/tube number, date of IMP dispensation and return, and number of tubes dispensed and 
returned will be recorded in the eCRF. 
9.8.4 Treatment compliance 
The first application of IMP will occur at the trial site with clear instructions from the site 
staff on which areas of the skin the IMP must be applied and what amount of IMP to be used 
per application.      
At the phone call scheduled on Day 4 and at each visit scheduled in the treatment period (see 
Section 4), the subject will be asked if they have used the IMP as prescribed. If a subject is 
found to be non-compliant, the investigator must remind the subject of the importance of 
following the instructions given, including applying the IMP as prescribed. Compliance or 
non-compliance, i.e. number of missed IMP applications and the reason for it, must be 
recorded in the eCRF. 
9.8.5 Trial product destruction 
Used and unused IMPs will be destroyed by the CMO according to approved procedures 
and/or local requirements. 


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Trial ID: LP0133-1275 
Date: 22-Aug-2019 
Version: 3.0 
Page 50 of 125 
 
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 GROUP 
 
If a subject withdraws from the trial, he/she may request destruction of any samples taken and 
not tested, and the investigator must document this in the subject’s source documentation. 
Subjects who withdraw from the trial and subjects who discontinue trial treatment will not be 
replaced. 
Data to be recorded in the eCRF 
The primary reason for withdrawal from the trial and discontinuation of IMP must be 
recorded in the medical records and on the end of trial form in the eCRF where the following 
options are available: 
 Lack of efficacy. 
 Adverse event. 
 Withdrawal by subject. 
 Lost to follow-up. 
 Pregnancy. 
 Death. 
 Other. 
If ‘adverse event’ or ‘other’ is selected, a specification must be provided in the eCRF with a 
clear link to the specific AE if applicable. 
10.2 IMP discontinuation rules 
10.2.1 Reasons for discontinuation of IMP 
Subjects will discontinue IMP in the event of: 
 An AE that, in the opinion of the investigator or sponsor’s medical expert, 
contraindicates further dosing. 
 Evidence of pregnancy. 
 Initiation of rescue medication. 
 Clinically important laboratory abnormalities: 
o Alanine aminotransferase and/or aspartate aminotransferase 
values >3×ULN with total bilirubin >2×ULN (unless elevated 
bilirubin is related to Gilbert-Meulengracht Syndrome). 


Trial ID: LP0133-1275 
Date: 22-Aug-2019 
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o Confirmed aspartate aminotransferase and/or alanine 
aminotransferase >5×ULN (for more than 2 weeks). 
 Any infection that is opportunistic, such as active tuberculosis and other 
infections whose nature or course may suggest an immuno-compromised 
status. 
 Lymphopenia (lymphocytes <0.5x109/l; grade 3 according to CTCAE v5.0) 
confirmed by repeated measurement within 7 days. 
 
It is not allowed to restart IMP treatment after discontinuation of IMP. 
10.3 Early termination assessments 
An end of trial form must be completed for all subjects, including subjects who withdraw 
from the trial or discontinue IMP treatment, at their last trial visit (the early termination visit, 
the safety follow-up visit, or the primary endpoint visit, whichever comes last). 
Withdrawal from trial 
Subjects who withdraw from the trial must attend an early termination visit as soon as 
possible after last administration of IMP (see the schedule of trial procedures [Section 4] for 
data to be collected at an early termination visit). The investigator will review any AEs which 
will be followed-up according to Section 13.7, if the subject agrees. 
Discontinuation of IMP 
Subjects who discontinue IMP for any reason prior to Week 8 will be asked to attend an early 
termination visit as soon as possible after last application of IMP and return to the trial site for 
2 additional visits as indicated below. See the schedule of trial procedures (Section 4) for data 
to be collected at these visits.  
Subjects who discontinue IMP prior to Week 8 will be asked to attend: 
 Early termination visit (as soon as possible after the last IMP application). 
 Safety follow-up visit (2 weeks after last application of IMP). 
 Primary endpoint visit (8 weeks after the first IMP application). 
10.4 Lost to follow-up 
A subject will be considered lost to follow-up if he/she repeatedly fails to return for scheduled 
visits and if the trial site is not able to get in contact with the subject. 


Trial ID: LP0133-1275 
Date: 22-Aug-2019 
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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 to retrieve eDiary and unused IMP and counsel the 
subject on the importance of maintaining the assigned visit schedule and 
ascertain whether or not the subject wishes to continue in the trial. 
 Before a subject is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the subject. 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. 


Trial ID: LP0133-1275 
Date: 22-Aug-2019 
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THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION AND MUST NOT BE COPIED OR MADE AVAILABLE TO ANY THIRD PARTY WITHOUT 
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11 Trial assessments and procedures 
11.1 Overview 
Evaluations to be done at each visit are shown in the schedule of trial procedures in Section 4. 
Refer to Section 7.1 for further details on the trial design. 
Assessments and procedures at each trial visit should be performed in the following order as 
shown in Panel 6: 
Panel 6: Sequence of assessments 
 
* Blood sampling for PK, skin swabs, skin biopsies (optional) and photography of biopsied 
areas (recommended). 
Subjects participating in the trial will be under careful supervision of a principal investigator 
who must be a dermatologist or allergist. Investigators must be experienced in treating AD 
and have documented experience and/or training in use of the assessments required by the 
Patient-reported outcomes
At the screening visit, subject's eligibility to enter the trial has to be 
confirmed before the PROs can be completed 
Efficacy assessments by the investigator
Safety assessments by the investigator
Subject assessment of local tolerability
Laboratory and other assessments*


Trial ID: LP0133-1275 
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protocol and must be either a physician, certified physician’s assistant, or advanced registered 
nurse practitioner. 
Whenever possible, the same investigator should perform all the evaluations for a given 
subject throughout the entire trial period to reduce inter-rater variability. 
AEs must be assessed by medically qualified personnel (i.e. adequately trained medical 
doctors) (Section 13.2). 
11.2 Assessments performed only at screening/baseline 
11.2.1 Demographics  
The following demographic data will be recorded: 
 Date of birth. If full date of birth is not allowed to be recorded, month and year 
of birth should be collected together with the subject’s age.  
 Sex: female, male. 
 Race: American Indian or Alaska native, Asian, black or African American, 
native Hawaiian or other Pacific islander, white, other (requires a specification 
to be provided). 
 Ethnic origin (self-reported by the subjects): Hispanic or Latino, not Hispanic 
or Latino. 


Trial ID: LP0133-1275 
Date: 22-Aug-2019 
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11.2.2 Fitzpatrick skin type 
The subject’s skin type will be recorded using the Fitzpatrick skin classification (Panel 7).  
Panel 7: Fitzpatrick skin classification 
Skin type 
Description 
I 
Individuals who never tan and always sunburn if exposed to any appreciable amount 
of sunlight, primarily red-headed individuals and lightly complected blondes. 
II 
Individuals who frequently burn but are able to tan to a small degree after extended 
sun exposure. 
III 
Individuals who burn infrequently and tan readily. 
IV 
Individuals who rarely burn and tan heavily with moderate sun exposures, 
especially individuals of Asian, American Indian, Mediterranean and Latin 
American descent. 
V 
Individuals who have dark constitutive pigmentation but become noticeably darker 
with sun exposure, especially light complected black individuals, those of Indian 
descent. 
VI 
Individuals who have the heaviest constitutive pigmentation, especially dark 
skinned black individuals. 
 
11.2.3 Medical history 
Relevant medical history from the subject’s birth must be recorded.  
 Skin disease history: all past and current skin disease history including:  
o Alopecia.  
o Vitiligo. 
o Herpes simplex. 
 Atopy history: 
o Onset of AD disease. 
o Previous treatments for AD.  
o Asthma. 
o Food allergy. 
o Hay fever. 


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o Allergic conjunctivitis. 
o Atopic keratoconjunctivitis. 
o Cataract. 
o Glaucoma. 
o Eczema herpeticum. 
 Other medical and surgical history including concurrent diagnoses within the 
previous 12 months. For each condition, diagnosis or surgical procedure, the 
start date and stop date or whether it is ongoing will be recorded. 
11.2.4 Height and weight 
The subject’s height (without shoes) will be measured; the subject’s weight (in indoor 
clothing and without shoes) will be measured. 
11.2.5 Body surface area involvement 
The total BSA affected by AD will be assessed by the investigator for each section of the body 
component A of SCORAD (see Section 11.3.3) and will be reported as a percentage of all 
major body sections combined. The following body regions will be assessed (with the highest 
possible score for each region in brackets): head and neck (9%), anterior trunk (18%), back 
(18%), upper limbs (18%), lower limbs (36%) and genitals (1%). 
The total BSA score will be assessed according to the schedule of procedures (Panel 2). 
11.3 Efficacy assessments 
11.3.1 Eczema Area and Severity Index (EASI) 
The EASI is a validated measure used in clinical practice and clinical trials to assess the 
severity and extent of AD (Hanifin et al. 2001, Tofte et al. 1998). The EASI score will be 
assessed according to the schedule of trial procedures (Section 4). The assessment will be 
based on the condition of the disease at the time of evaluation and not in relation to the 
condition at a previous visit. 
The EASI is a composite index with scores ranging from 0 to 72, with higher values 
indicating more severe or more extensive condition. The index will be calculated as shown in 
Panel 8. Briefly, the investigator will assess the severity of 4 AD disease characteristics 
(erythema, induration/papulation, excoriation, and lichenification) on the 4 body regions 
(head/neck, trunk, upper extremities, lower extremities); severity will be assessed according 


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to the scale shown in Panel 9. For each body region, a severity sum score will be calculated 
which will be multiplied by an area score (Panel 9) and by a weighting factor. The EASI score 
equals the sum of the scores obtained for each body region (Panel 8). The EASI score will be 
calculated automatically. 
Panel 8: Calculation of the Eczema Area and Severity Index 
Body region 
Erythema 
Induration/ 
papulation 
Excoriation 
Lichenification 
Area score 
Weighting factor 
Score 
Head/neck 
( SS   + 
   SS   + 
   SS   + 
   SS ) 
x  AS 
x 0.1 
 
Trunk 
( SS   + 
   SS   + 
   SS   + 
   SS ) 
x  AS 
x 0.3 
 
Upper extremities 
( SS   + 
   SS   + 
   SS   + 
   SS ) 
x  AS 
x 0.2 
 
Lower extremities 
( SS   + 
   SS   + 
   SS   + 
   SS ) 
x  AS 
x 0.4 
 
The EASI score is the sum of the 4 body region scores 
 
(range 0–72) 
AS, area score; EASI, Eczema Area and Severity Index; SS, severity score. Modified from (HOME website). 
Panel 9: EASI severity score scale and area score scale 
Severity score scale 
 
Area score scale 
0 
None/absent 
 
0 
0% affected area 
1 
Mild 
 
1 
1% to 9% affected area 
2 
Moderate 
 
2 
10% to 29% affected area 
3 
Severe 
 
3 
30% to 49% affected area 
Note: half-steps (0.5, 1.5, 2.5) are 
allowed. 
 
4 
50% to 69% affected area 
 
5 
70% to 89% affected area 
 
6 
90% to 100% affected area 
EASI, Eczema Area and Severity Index 


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11.3.2 Validated Investigator Global Assessment scale for Atopic Dermatitis 
(vIGA-AD) 
The vIGA-AD is an instrument used in clinical trials to assess the subject’s global disease 
severity and is based on a 5-point scale ranging from 0 (clear) to 4 (severe) (Panel 10). The 
vIGA-AD score will be assessed at time points 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. New lesions that occurred on 
previously untreated areas will be included in the assessment. 
The vIGA-AD score is selected using the descriptors in Panel 10 that best describe the overall 
appearance of the lesions at a given time point. It is not necessary that all characteristics under 
morphological description be present. 
Panel 10: Validated Investigator Global Assessment scale for Atopic Dermatitis 
Score 
Morphological description 
0 - Clear 
No inflammatory signs of atopic dermatitis (no erythema, 
no induration/papulation, no lichenification, no 
oozing/crusting). Post-inflammatory hyperpigmentation 
and/or hypopigmentation may be present. 
1 - Almost clear 
Barely perceptible erythema, and barely perceptible 
induration/papulation, and/or minimal lichenification. No 
oozing or crusting. 
2 - Mild 
Slight but definite erythema (pink), slight but definite 
induration/papulation, and/or slight but definite 
lichenification. No oozing or crusting. 
3 - Moderate 
Clearly perceptible erythema (dull red), clearly perceptible 
induration/papulation, and/or clearly perceptible 
lichenification. Oozing and crusting may be present. 
4 - Severe 
Marked erythema (deep or bright red), marked 
induration/papulation, and/or marked lichenification. 
Disease is widespread in extent. Oozing or crusting may be 
present. 
Reference: Eli Lilly and Company 2017 
11.3.3 Scoring Atopic Dermatitis (SCORAD) 
The SCORAD is a validated tool to evaluate the extent and severity of AD lesions, along with 
subjective symptoms (European Task Force on Atopic Dermatitis 1993). The maximum total 
score is 103, with higher values indicating more severe disease. SCORAD will be assessed 
according to the schedule of trial procedures (Section 4). 


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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. Whenever possible, SCORAD should be 
assessed by the same investigator at each visit to reduce inter-rater variability. 
The assessment consists of 3 components: A = extent, B = intensity, and C = subjective 
symptoms. 
Extent (A) 
The extent of AD is assessed as a percentage of each defined body area and reported as the 
sum of all areas (maximum score = 100%). 
Intensity (B) 
The intensity of 6 specific symptoms of AD (erythema, edema/papulation, oozing/crusting, 
excoriation, lichenification, and dryness) is assessed by the investigator on an average 
representative area using the following scale: 
0 
= 
None/absent 
1 
= 
Mild 
2 
= 
Moderate 
3 
= 
Severe 
Note: dryness is evaluated on uninvolved areas. 
The sum of intensity score of the 6 symptoms will be reported (maximum score = 18). 
Subjective symptoms (C) 
A subjective assessment of the average itch and sleeplessness over the last 3 days/nights is 
recorded for each symptom by the subject on a visual analogue scale, where 0 is no itching (or 
no trouble sleeping) and 10 is unbearable itching (a lot of trouble sleeping), with a maximum 
possible score of 20. The subjective assessment will be completed by the subjects together 
with the PROs using the electronic device. 
The SCORAD is calculated as: A/5+7B/2+C. The SCORAD will be calculated automatically. 


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11.4 Safety assessments 
11.4.1 Vital signs 
Vital signs (resting blood pressure, pulse, and body temperature) will be assessed according to 
the schedule of trial procedures (Section 4). Vital signs will be measured in a supine position 
following at least 5 minutes of rest. 
If an abnormal vital sign at screening is considered to be clinically significant by the 
investigator, it will be at the discretion of the investigator if the subject should be randomised 
into the trial (respecting exclusion criterion no. 20). 
In case of abnormal findings, the vital sign measurement can be repeated approximately 
15 minutes later with subjects resting in a supine position 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. If the third measurement confirms the first measurement 
(abnormal), the second measurement will be considered false. Only the last value measured 
and considered correct will be recorded in the eCRF. 
Reporting in eCRF 
Vital signs will be recorded in the eCRF. Clinically significant abnormal vital signs at the 
screening visit will be documented as medical history in the eCRF. At subsequent visits, any 
clinically significant deterioration of a pre-existing condition as well as any new clinically 
significant sign, symptom or illness will be reported as an AE in accordance with 
Section 13.3. 
11.4.2 Physical examination 
A thorough physical examination of the subject including whole body inspection of the skin 
and auscultation of heart, lungs and abdomen; palpitation of the abdominal organs and basic 
neurological status must be performed according to the schedule of trial procedures 
(Section 4). The investigator should perform the same examinations as in clinical practice as a 
minimum. 
If the screening physical examination results in a finding, which is abnormal and of clinical 
significance, it will be at the investigator’s discretion to decide if the subject should be 
randomised into the trial (respecting exclusion criterion no. 20). 


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Reporting in eCRF 
It will be recorded in the eCRF if a physical examination was performed and the 
investigator’s evaluation (‘normal’, ‘abnormal, not clinically significant’, ‘abnormal, 
clinically significant’); if a physical examination was not performed, a reason must be given. 
Clinically significant abnormal findings at the screening visit will be documented as medical 
history in the eCRF. At subsequent visits, any clinically significant deterioration of a pre-
existing condition as well as any new clinically significant sign, symptom or illness will be 
reported as an AE in accordance with Section 13.3. 
11.4.3 ECG 
A single 12-lead resting digital ECG will be recorded after the subject has been supine for at 
least 5 minutes at the visits indicated in the schedule of trial procedures (Section 4). 
A preliminary evaluation of the ECGs will be performed by the investigators to evaluate 
immediate subject safety. As a minimum, the date of ECG collection will be recorded in the 
source documents. 
The ECG data will be transferred to a central ECG service company for central evaluation. A 
cardiologist at the ECG service company will analyse and interpret the ECG data. The ECG 
service company will provide ECG evaluation reports to the trial sites. 
The investigator must evaluate all abnormal ECG results (‘clinically significant’ or ‘not 
clinically significant’) and sign and date. The investigator has the final decision on the clinical 
significance of ECG abnormalities. 
If the screening ECG results in a finding, which is abnormal and of clinical significance, it 
will be at the investigator’s discretion to decide if the subject should be randomised into the 
trial (respecting exclusion criterion no. 20).  
The collection and transmission of ECG data will be described in a separate ECG manual. 
Test dummy transmissions will be undertaken prior to the trial conduct to ensure that 
transmissions can be made, and that date and time settings are correctly set. 
Reporting in eCRF 
It will be recorded in the eCRF if an ECG was performed and the investigator’s assessment of 
ECG results (‘normal’, ‘abnormal, not clinically significant’, ‘abnormal, clinically 
significant’); if an ECG was not performed, a reason must be given. 


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Clinically significant abnormal findings at the screening visit will be documented as medical 
history in the eCRF. At subsequent visits, any clinically significant deterioration of a 
pre-existing condition as well as any new clinically significant sign, symptom or illness will 
be reported as an AE in accordance with Section 13.3. 
11.4.4 Laboratory testing 
Blood and urine samples will be collected according to the schedule of trial procedures 
(Section 4). See Panel 11 for an overview of the individual clinical laboratory parameters to 
be assessed in this trial. 
Central laboratory 
Chemistry, haematology, urinalysis (if applicable), serology, and serum pregnancy tests will 
be analysed by a central laboratory which will provide results to the trial sites. The 
investigator must evaluate all results outside the reference range (‘clinically significant’ or 
‘not clinically significant’) and sign and date. The signed and dated version will be filed with 
the investigator’s trial documentation. Clinically significant abnormal tests must be repeated 
to confirm the abnormality. 
If a screening laboratory result is abnormal and of clinical significance, it will be at the 
investigator’s discretion to decide if the subject should be randomised into the trial 
(respecting exclusion criteria no. 16, 20, 21, 22, and 29).  
A laboratory manual will be provided to the trial sites specifying the procedures for 
collection, processing, storage, and shipment of samples, as well as laboratory contact 
information specific to this trial. 
Tests performed at the trial site 
Urine samples will be tested at the trial site with a dipstick; if abnormal, a urine sample will 
be sent to the central laboratory for further analysis. 
Women of childbearing potential will have a urine pregnancy test performed at the trial site at 
visits indicated in the schedule of trial procedures in Section 4.  
 




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Reporting in eCRF 
The site staff will record in the eCRF if a sample was taken and the investigator’s assessment 
of the results (‘normal’, ‘abnormal, not clinically significant’, ‘abnormal, clinically 
significant’). 
The date and the outcome of the urine pregnancy test will be recorded in the eCRF (‘positive’, 
‘negative’). 
Clinically significant abnormal laboratory results at the screening visit will be documented as 
medical history in the eCRF. At subsequent visits, any clinically significant deterioration of a 
pre-existing condition as well as any new clinically significant sign, symptom or illness will 
be reported as an AE in accordance with Section 13.3. 
11.4.5 Subject assessment of local tolerability 
Subjects will provide an assessment of local tolerability according to the schedule of trial 
procedures (Section 4).  
The subject will retrospectively be asked by the investigator to assess stinging/burning in 
connection with the IMP applications since their last visit. The highest (worst) skin reaction 
score across treatment area(s) will be recorded in the eCRF by use of the 4-point scale shown 
in Panel 12. 
Panel 12: Subject assessment of local tolerability after IMP application 
Grade 
Stinging/burning 
0 (none) 
No stinging or burning 
1 (mild) 
Slight warm, tingling sensation, not really 
bothersome 
2 (moderate) 
Definitive warm, tingling sensation, that is 
somewhat bothersome 
3 (severe) 
Hot, tingling/stinging sensation that has 
caused definite discomfort 
 
Subject assessment of local tolerability will be performed after safety assessments by the 
investigator (Panel 6). Local tolerability reactions are not reported as AEs; however, if they 
qualify as an SAE, they will be reported as described in Section 13.4.1. 


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11.5 Pharmacokinetic assessments 
11.5.1  Blood sampling for analysis of systemic concentration of delgocitinib 
A single blood sample for PK assessment will be collected for each subject after 2–6 hours 
after the morning application of IMP as specified in the schedule of trial procedures 
(Section 4). The PK blood sample should be collected from a non-treated area. 
It will be recorded in the eCRF if the PK blood sample was taken; if not, a reason will be 
provided. The date and time of the last IMP application prior to the PK sample being taken 
must be recorded in the eCRF. 
Collection, handling and shipment instructions for PK blood samples are provided in a 
laboratory manual. 
Plasma samples for determination of delgocitinib concentration will be analysed by a 
laboratory using a validated bioanalytical method. Details of the analytical method used will 
be described in the bioanalytical report. 
Samples from delgocitinib cream vehicle-treated subjects will not be analysed. Written 
procedures are in place to avoid unblinding of the trial and any trial subjects in relation to 
analysis of the PK samples. 
11.6 Pharmacodynamics and pharmacogenomics 
11.6.1 Overview 
Normal skin is colonised by a wide variety of microorganisms, including fungi, viruses, and 
bacteria. The skin microbiome is complex and diverse and varies between individuals and 
anatomical sites (Costello et al. 2009). It has been known for years that some skin diseases are 
associated with dysbiosis of the skinbiome. AD has long been associated with increased skin 
colonisation with S. aureus. Indeed, S. aureus colonisation has been proposed to play an 
important role in AD pathophysiology via bacterial production of specific virulence factors 
(Cardona et al. 2006). Increased colonisation with S. aureus in AD is accompanied by 
decreased colonisation with many commensal bacterial species, resulting in overall decrease 
in bacterial diversity (Kong et al. 2012). Resolution of active-disease in AD in response to 
therapy correlates with reduction of S. aureus colonisation and increase in microbiome 
diversity (Kong et al. 2012). 
The present trial will use sequencing to identify specific strains of bacteria present on the skin 
and thus characterise treatment effects on the skin microbiome in AD subjects. 


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A summary of the results will be included in the CTR if they are available in time for this. 
The full pharmacodynamics/biomarker results will be reported in an addendum report to the 
CTR. 
11.6.2 Skin swabs 
A total of 4 skin swabs for microbiome and S. aureus measurements will be taken at the time 
points specified in the schedule of trial procedures (Section 4). 
At baseline (Day 1), 2 skin swabs are to be taken:  
 1 skin swab from a representative lesional area. The location should be 
selected so that a similar non-lesional body location can be identified. 
 1 skin swab from a non-lesional area at an anatomically similar site to the 
lesional skin swab. 
At Week 8 (end of treatment), 2 skin swabs will be taken at the same locations as the baseline 
skin swabs. 
If biopsies are to be taken (see Section 11.6.3), the baseline biopsies will be taken from the 
same area as the skin swabs, so the sites selected for skin swabs must then also be appropriate 
for biopsying.  
It will be recorded in the eCRF if the skin swabs were taken and from which location (volar 
arm, lower limbs, trunk, other); if skin swabs were not taken, a comment will be provided. 
Subjects will be instructed not to shower or wash their body for at least 10 hours prior to the 
baseline visit and Week 8 visit. 
Further instructions for collection, handling and shipment for skin swabs are provided in a 
laboratory manual. 
11.6.3 Skin biopsies and photographs (all sites, but optional) 
Subjects who have lesions at a location suitable for biopsying (i.e. volar arm, lower limbs, 
trunk, other) will be asked to participate in an exploratory component involving skin biopsies. 
Participation in this component of the trial requires that the subject provides additional 
informed consent and is not mandatory for participation in the trial. Biopsies will not be taken 
if the investigator considers the procedure unsuitable for the subject (e.g. subjects receiving 
anticoagulant therapy).  


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It is expected that approximately half of the eligible subjects will accept to participate in this 
exploratory component of the trial. If biopsies are obtained from less than 10% of subjects, 
analysis may not be carried out as the number of biopsies may be to too low to allow for a 
meaningful analysis. A final decision will be made after unblinding.  
The skin biopsies will be used to analyse 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. If deemed relevant transcriptome profiling of some 
or all of the biopsies may be done. The purpose is to assess if changes in gene expression 
precedes the clinical effect of JAK inhibition and to show disease resolution also at the 
molecular level. 
A total of four skin biopsies (2 mm) will be taken at the timepoints specified in the schedule 
of trial procedures (Section 4): at baseline (lesional and non-lesional skin), after 1 week of 
treatment (lesional only) and at end of treatment (lesional only).  
Skin biopsies will be taken from the same body location as the skin swabs. It will be recorded 
in the eCRF if the biopsy was taken and from which body location (volar arm, lower limbs, 
trunk, other); if not, a comment should be provided. All four biopsies will be from an 
anatomically similar body location to the extent possible.  
A check of skin biopsy wound healing including removal of suture, if applicable, will be 
performed at the next trial visit as specified in the schedule of trial procedures (Section 4). 
The biopsies will be transferred to RNAlater (RNA stabilisation) solution immediately after 
being collected and placed at 2–8°C for 16–30 hours. The sample will then be transferred to a 
clean tube and stored at <-20°C in suitable rack and kept until shipment to the central 
laboratory for further processing. Further instructions for collection, handling, and shipment 
for skin biopsy samples are provided in a laboratory manual. 
It is recommended to document the biopsied areas with photographs taken before biopsying 
and immediately after, both at baseline, after 1 week of treatment and at the end of treatment, 
using digital photography assessments. This will serve both as a documentation of the biopsy 
site and to show disease progression over time. The photography component for the skin 
biopsies is recommended and not mandatory. 
The trial sites participating in this photography component will be expected to use their own 
equipment to take the photographs. Instructions and specifications for photography will be 
provided in a photography manual. 


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The photographs will have no other subject identifier than the subject ID and visit number and 
will be transmitted electronically using a secure file transfer protocol. Features that could 
potentially be used to identify the subject e.g. tattoos or jewelry will be removed from the 
photographs before they are transferred to LEO. 
Printed copies of the photographs must be included as part of the individual subject source 
documentation. 
LEO may at its discretion use the photographs in publications, posters, and similar types of 
information material or media targeting patients and health care professionals. The 
photographs may also be part of training material used for training and educational purposes. 
Steps will be taken to ensure that the identity of the subject is protected to the extent possible. 
11.7 Other assessments 
11.7.1 Patient-reported outcomes (PROs) 
Each subject must make individual assessments relating to their perception of their disease 
and quality of life. These will be performed prior to the investigator performing his/her 
efficacy assessments. At the screening visit, the subject’s eligibility needs to be established 
before the PROs can be completed. 
The subjects will receive an eDiary device and eDiary training, as well as complete all of the 
PROs (except TSQM), at the screening visit. Completion of the eDiary will be initiated at the 
latest 1 week prior to the baseline visit (Day 1). 
Two PROs will be assessed daily using an eDiary: 
 ADSD. 
 Eczema-related Sleep NRS. 
The subjects must complete the eDiary each day in the evening, and compliance with the 
eDiary completion will be reviewed by the trial site staff throughout the trial. The eDiary 
should be returned to the trial site as outlined in the schedule of trial procedures (Section 4). 
In addition, 8 PROs will be completed on an electronic device by the subjects at the trial sites 
at the visits specified in the schedule of trial procedures (Section 4). The PROs will be 
completed in the following order: 
 POEM. 


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indicative of a worse disease severity. The POEM will be completed at the trial site according 
to the schedule of trial procedures (Panel 2). 
11.7.1.4 Dermatology Life Quality Index (DLQI) 
DLQI is a validated questionnaire with content specific to those with dermatology conditions. 
It consists of 10 items addressing the subject’s perception of the impact of their skin disease 
on different aspects of their quality of life over the last week. These include dermatology-
related symptoms and feelings, daily activities, leisure, work or school, personal relationships 
and the treatment (Finlay & Khan 1994). Each item is scored on a 4-point Likert scale (0=’not 
at all/not relevant’; 1=’a little’; 2=’a lot’; 3=’very much”). The total score is the sum of the 10 
items (0 to 30); a high score is indicative of a poor quality of life. The DLQI will be 
completed at the trial site according to the schedule of trial procedures in Section 4.  
11.7.1.5 Patient Global Impression of Severity (PGI-S) 
PGI-S is a single item designed to capture the subject’s overall perception of their eczema 
over the past week on a 4-point categorical response scale (‘none’ to ‘severe’). The PGI-S will 
be completed at the trial site according to the schedule of trial procedures (Section 4). 
11.7.1.6 Patient Global Impression of Change (PGI-C) 
The PGI-C is a 1-item questionnaire designed to assess the subject’s overall impression of 
changes (FDA public workshop on Guidance 3 2018). The subjects have to select the one 
response from the response options (‘much better’, ‘a little better’, ‘no change’, ‘a little 
worse’, or ‘much worse’) that best describes the overall change in their eczema since they 
started IMP treatment. The PGI-C will be completed at the trial site according to the schedule 
of trial procedures in Section 4. 
11.7.1.7 36-item Short Form Health Survey (SF-36) 
The SF-36v2 (Acute Recall) is a 36-item scale constructed to survey health status and quality 
of life (Ware & Sherbourne 1992). The acute recall version asks subjects to reply to questions 
according to how they have felt over the previous week. Subjects will be asked to answer 
each item by selecting one of 3 to 6 categorical response options. 
The SF-36v2 (Acute Recall) yields scores for 8 health domains (physical functioning, role 
physical, bodily pain, general health, vitality, social functioning, role emotional, and mental 
health) and 2 psychometrically derived summary scores (a physical component summary and 
a mental component summary). 


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The SF-36 will be completed according to the schedule of trial procedures in Section 4.  
11.7.1.8 EuroQol 5-dimension health questionnaire 5-level (EQ-5D-5L) 
EQ-5D-5L is a standardised measure of health status developed by the EuroQoL group to 
provide a simple, generic measure of health for clinical and economic appraisal (Greiner et al. 
2003). The 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 will be assessed by 
the subject using a 5-point Likert 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’). The EQ-5D-5L will be completed at the trial site according to 
the schedule of trial procedures in Section 4. 
11.7.1.9 Work Limitation Questionnaire (WLQ) 
WLQ is a validated questionnaire to measure the degree to which health problems interfere 
with specific aspects of job performance and the productivity impact of these work 
limitations (Lerner et al. 2001). It asks subjects to rate their level of difficulty or ability to 
perform 25 specific job demands in the last 2 weeks. Responses to the 25 items are combined 
into 4 work limitation scales: time management, physical demands, mental/interpersonal, and 
output demands. These capture the multidimensionality of job roles and also reflect an 
important characteristic of many chronic illnesses, in that they may result in limitations in 
performing some activities but not others. Scale score range from 0 (‘limited none of the 
time’) to 100 (‘limited all the time’). The WLQ will be completed at the trial site for subjects 
with a paid job according to the schedule of trial procedures in Section 4.  
11.7.1.10 Treatment Satisfaction Questionnaire for Medicine (TSQM) 
The TSQM v. II is a generic questionnaire assessing subject’s satisfaction with the treatment 
(Atkinson et al. 2004). The tool consists of 11 items addressing four domains (effectiveness, 
side effects, convenience and overall satisfaction). Ten items will be assessed by the subject 
using a 7-point scale (‘extremely dissatisfied’, ‘very dissatisfied’, ‘dissatisfied’, ‘somewhat 
satisfied’, ‘satisfied’, ‘very satisfied’, and ‘extremely satisfied’). However, one item will be 
assessed using a 2-point scale (‘yes’ and ‘no’). The score ranges from 0 to 100 with higher 
scores indicating higher satisfaction. The TSQM will be completed at the trial site according 
to the schedule of trial procedures (Panel 2). 


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11.7.2 Atopic dermatitis lesions on scalp 
Subjects with AD lesions on scalp are not allowed to enter the trial and if AD lesions occur on 
the scalp during the trial these should not be treated with IMP.  
Whether subjects have AD lesions on scalp will be captured in the eCRF as specified in the 
schedule of trial procedures (Section 4). 
11.8 Estimate of total blood volume collected 
Blood samples will be drawn for haematology, biochemistry, serology, PK, and serum 
pregnancy test (females of childbearing potential only). The total volume of blood to be 
drawn is approximately 39 mL.  
11.9 End of trial 
An end of trial form must be completed in the eCRF for all randomised subjects (including 
subjects who permanently discontinue IMP and subjects who withdraw from trial). The 
following data will be collected:  
 Whether the subjects completed the trial. 
 Last trial site visit or contact number for which data is recorded. 
 Date and time of last application of IMP.  
 Primary reasons for discontinuation from IMP, withdrawal from trial, and not 
attending primary endpoint visit, if applicable (lack of efficacy, AE, 
withdrawal by subject, lost to follow-up, pregnancy, death, other). 
The end of trial form will be completed when the subject has had their last visit (at the early 
termination visit, the safety follow-up visit, or the primary endpoint visit, whichever comes 
last). 
11.10 
Storage of biological samples 
PK 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 unless 
specific additional consent has been obtained that allows storage for future research (see 
below). 
 
 


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Biobank 
This protocol includes the collection and analysis of different biological samples. If consent is 
given by the subject, LEO will store skin biopsies and skin swabs collected in a biobank 
established by LEO and hosted by BioStorage Technologies GmbH. The residual biological 
samples will be used for future research performed by LEO. Donation of the samples for 
future research is voluntary and subjects must give their separate written consent to confirm 
donation and storage and the terms associated herewith. The samples will be transferred from 
the relevant laboratory to the biobank. The samples will be labelled with the trial ID, subject 
ID, and the sample date to protect the privacy of the subjects and to allow continued blinding 
for future analyses. The samples from this trial will be stored in the biobank for up to 10 years 
after the end of the trial and will then be destroyed. 


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12 Scientific rationale for trial design and appropriateness of assessments 
This is a multi-centre, randomised, vehicle-controlled, double-blind, parallel-group trial, 
which will be conducted in accordance with the protocol, ICH-GCP and applicable regulatory 
requirements. 
The trial will be conducted at multiple trial sites located in North America (USA and Canada) 
and Australia. High-quality trial sites with shared standards of practice and values will be 
selected. 
Patients with AD represent a heterogeneous patient population with disease severity ranging 
from mild to severe. To mitigate any potential difference in trial outcome based on baseline 
characteristics, eligibility criteria for inclusion have been carefully selected and trial subjects 
will be randomised in stratified manner as described in Section 9.3. The randomisation will 
minimise selection bias and minimise influence of (intrinsic) confounding factors and the 
stratification will ensure a certain balance of the treatment groups with respect to disease 
severity and region.  
The most important inclusion criteria for entry into the trial is a diagnosis of AD (as defined 
by the Hanifin and Rajka 1980 criteria (Hanifin & Rajka 1980, Appendix 6) and history of 
AD for at least 1 year, to ensure correct diagnosis and rule out differential diagnosis. 
The inclusion of 4 active treatment arms with 1, 3, 8 and 20 mg/g of delgocitinib cream and a 
vehicle control group is considered enough to establish a dose-response signal. The vehicle 
control group will serve as reference and has been added to establish the efficacy and safety 
of the delgocitinib cream in a blinded trial design. 
The trial endpoints have been selected to evaluate the efficacy of delgocitinib in improving 
the severity and extent of AD. EASI, vIGA-AD and SCORAD will be used in this clinical 
trial as investigator-rated assessments of disease severity. EASI is a validated measure used in 
clinical practice and clinical trials to assess the severity and extent of AD (Hanifin et al. 2001, 
Tofte et al. 1998). vIGA-AD is a validated instrument used in clinical trials to assess the 
subject’s global AD and SCORAD is a validated tool to assess the extent and severity of AD 
lesions and subjective symptoms (European Task Force on Atopic Dermatitis 1993). The 
primary endpoint of the trial is to evaluate the change in EASI score from baseline to Week 8. 
The trial endpoints will also address subject’s perception of disease severity and the impact on 
sleep, daily activity, and health-related quality of life, and safety.  


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The duration of this trial is 8 weeks. This duration - based on results from a phase 2a trial in 
adults with the ointment formulation (Nakagawa et al. 2018) - is considered to be sufficient to 
evaluate the duration required for optimal treatment effect. 
 


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13 Adverse events 
13.1 Definition and classification of adverse events 
AEs and 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 
AEs must be collected from time of first trial-related activity after the subject has signed the 
ICF until completion of the clinical trial for the individual subject (defined as safety follow-up 
visit 2 weeks after the last IMP administration). 
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, 
for example: “How have you felt since I saw you last?” No specific symptoms should be 
asked for. It is important that the investigator also observes the subject for any changes not 
reported by the subject and records these changes. If a subject report an AE during the phone 
call on Day 4, it is up to the investigator’s discretion to perform an unscheduled visit. 
Refer to Sections 11.4.1 to 11.4.4 for principles for data entry in the eCRF.  
13.3 Reporting of adverse events 
AEs reported by the subject or observed by the investigator must be recorded on the AE form 
of the eCRF and should be described in the following manner: 
The AE term must be in precise English medical terminology (that is, not necessarily the exact 
words used by the subject). Whenever possible, a specific diagnosis should be stated (for 
example ‘allergic contact dermatitis’). 
For cutaneous AEs, the location must be part of the AE description and may be described as 
[e.g. the face, scalp, back, chest, arm, leg, trunk or limb]. Additionally, the location should be 
described using the following terminology: 
 Lesional/perilesional (≤2 cm from the border of lesion(s) treated with IMP).  
 Distant (>2 cm from the lesion border). 


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Additionally, Global Pharmacovigilance at LEO may request further information in order to 
fully assess the SAE. The investigator must forward such information to LEO 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 
collected. However, such events should be reported to Global Pharmacovigilance at LEO (see 
contact details above) if the investigator becomes aware of them. 
13.4.2 LEO reporting responsibilities 
Global Pharmacovigilance at LEO is responsible for assessing whether or not an SAE is 
expected. The relevant reference safety information document for this clinical trial is:  
For the IMP, the Investigator’s Brochure for delgocitinib cream, edition 1 and subsequent 
updates must be used.  
Global Pharmacovigilance at LEO will notify the regulatory authorities and concerned 
investigators of SAEs according to the current applicable legislation for the concerned 
country.  
The IRB(s)/IEC(s) will be notified of SAEs according to the current applicable legislation for 
the concerned country. 
For all non-US countries, the following reporting requirements apply: all SAEs which are 
assessed as causally related to the IMP(s) by either the investigator or LEO (ICH E2A 
Guideline), and which are unexpected (SUSARs), are subject to expedited reporting to 
regulatory authorities and IEC(s)/IRB(s) according to the current applicable legislation in the 
concerned country. Investigators will be notified of the evolving safety profile of the IMP on 
an ongoing basis. 
For the US, the following reporting requirements apply: all SAEs which are assessed as 
causally related to the IMP(s) by LEO (Guidance for Industry and Investigators - Safety 
Reporting Requirements for INDs and BA/BE Studies; Guidance for Clinical Investigators, 
Sponsors, and IRBs: Adverse Event Reporting to IRBs – Improving Human Subject 
Protection) and which are unexpected (Serious and Unexpected Suspected Adverse Reactions 
[IND safety report]) are subject to expedited reporting to regulatory authorities and IRB(s). 
Investigators will be notified of the evolving safety profile of the IMP on an ongoing basis. 


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13.5 Other events that require expedited reporting 
13.5.1 Pregnancy 
Any pregnancy occurring during the clinical trial must be reported to LEO within 24 hours of 
first knowledge using the (paper) Pregnancy Form (Part I). All pregnancies must be followed 
up until delivery or termination and final outcome must be reported on the (paper) Pregnancy 
Form (Part II) within 24 hours of first knowledge. 
The completed Pregnancy Forms must be faxed or scanned and e-mailed to Global 
Pharmacovigilance at LEO. Contact details are given in Section 13.4.1. 
Pregnant subjects must immediately discontinue IMP permanently (Sections 10.2.1 and 10.3). 
13.6 Reporting of other events 
13.6.1 Adverse events of special interest 
The event listed in Panel 13 is considered an AESI in this trial and will require that the 
investigator provides additional details to be recorded in the eCRF. An AESI may be serious 
(requiring expedited reporting, Section 13.4) or non-serious. 
Panel 13: Adverse events of special interest 
Adverse event of special interest 
Additional information to be provided 
Eczema herpeticum 
Skin findings: 
 
Lesion type. 
 
Disseminated/localized. 
 
Location. 
 
Present in area with visible eczema/no 
visible eczema/present in areas with and 
without eczema. 
 
Monomorphic/polymorphic. 
Confirmation of herpes simplex virus. 
 


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13.6.2 Overdose 
An overdose is defined as a subject using more than the recommended quantity of IMP 
specified in this protocol in Section 9.2 (at the investigator’s discretion). An overdose is either 
accidental or intentional.  
The term ‘overdose’ including a specification of why it occurred (accidental or intentional) 
must be documented on the AE form of the eCRF. In addition, AEs originating from overdose 
must be documented on a separate line. If the AE originating from the overdose qualifies as 
an SAE, expedited reporting is required (Section 13.4). 
13.6.3 Medication error 
Medication error refers to any unintentional error in the dispensing or administration of an 
IMP while in the control of the investigator or subject. Broadly, medication errors fall into 
4 categories: wrong medication, wrong dose (including strength, form, concentration, 
amount), wrong route of administration, or wrong subject. 
The medication error category must be documented on the AE form in the eCRF. In addition, 
AEs originating from a medication error must be documented on a separate line. If the AE 
originating from the medication error qualifies as an SAE, expedited reporting is required 
(Section 13.4). 
13.6.4 Misuse 
Misuse refers to situations where the IMP is intentionally and inappropriately used not in 
accordance with the protocol. 
The term ‘misuse’ must be documented on the AE form in the eCRF. In addition, AEs 
originating from misuse must be documented on a separate line. If the AE originating from 
misuse qualifies as an SAE, expedited reporting is required (Section 13.4). 
13.6.5 Abuse 
Abuse relates to the sporadic or persistent, intentional excessive use of an IMP which is 
accompanied by harmful physical or psychological effects. 
The term ‘abuse’ must be documented on the AE form in the eCRF. In addition, AEs 
originating from abuse must be documented on a separate line. If the AE originating from 
abuse qualifies as an SAE, expedited reporting is required (Section 13.4). 


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13.6.6 Aggravation of condition 
Any clinically significant aggravation/exacerbation/worsening of any medical condition(s) 
(including the trial disease), compared to baseline, must be reported as an AE in accordance 
with Section 13.3 and 13.4. 
13.7 Follow-up for final outcome of adverse events 
During the trial, the investigator should follow up for final outcome on all AEs (including 
SAEs). Once a subject leaves the clinical trial, the investigator should follow up on the 
outcome of all non-serious AEs classified as of possibly/probably relationship to the IMP for 
14 days or until the final outcome is determined, whichever comes first. SAEs must be 
followed up until a final outcome has been established, that is, the follow-up may continue 
beyond the end of the clinical trial. For SAEs which have stabilised and cannot be expected to 
recover during the trial or the safety follow-up periods, for example chronic or stabilised 
conditions, ‘not recovered’ is accepted as a final outcome and a statement that the SAE has 
stabilised or is chronic should be added to the narrative in 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.”  (EU Directive 2001/20/EC). 
If the investigator becomes aware of information that necessitates an immediate change in the 
clinical trial procedure or a temporary halt to the clinical trial in order to protect clinical trial 
subjects from any immediate hazard to their health and safety, the investigator can do so 
without prior approval from LEO, regulatory authorities, or IRBs/IECs. 
The investigator must immediately inform LEO – by contacting the clinical project manager 
or medical expert – of this change in the clinical trial procedure or of the temporary halt 
providing full details of the information and the decision making process leading to the 
implementation of the urgent safety measure. 
LEO 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 250 subjects will be randomised 1:1:1:1:1 to one for the following 5 treatment 
groups: delgocitinib cream 1 mg/g, 3 mg/g, 8 mg/g, 20 mg/g or delgocitinib cream vehicle. 
The sample size is based on the following pairwise consideration, even though the primary 
objective of the trial is to establish the dose-response relationship: With a significance level of 
5% when comparing two treatment groups and assuming a difference in the mean change 
from baseline to Week 8 in EASI of 7 (with a standard deviation of 9 for each treatment 
group) between an investigational dose (delgocitinib cream) and delgocitinib vehicle, then 50 
subjects per treatment group will provide a nominal power of at least 95% to detect a 
difference between two treatment groups. With 35–40 subjects per treatment group (e.g. in the 
subgroups of subjects with moderate or severe AD), there is approximately 90% power to 
detect a difference of 7 in mean change from baseline to Week 8 in EASI. 
14.2 Trial analysis sets 
All screened subjects will be accounted for in the CTR. 
All randomised subjects exposed to IMP will be included in the full analysis set and will be 
analysed for efficacy parameters up to Week 8. 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 per protocol analysis set will be defined by excluding subjects from the full analysis set 
who fulfil any of the following criteria:  
 Did not provide EASI or vIGA-AD data following start of treatment. 
 Are known to have taken the wrong IMP throughout the treatment period of 
the trial. 
 Did not fulfil the disease defining inclusion criteria (that is, inclusion criteria 3, 
4, 5, and 6). 
 Did not apply IMP at least 80% of the time in the period from date of first 
application of IMP to date of last application of IMP. 
A safety analysis set will be defined as all randomised subjects exposed to IMP.  


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The decisions regarding inclusion/exclusion of subjects and/or subject data from the trial 
analysis sets will be documented in the analysis set definition document before breaking the 
randomisation code. 
14.3 Statistical analysis 
14.3.1 Disposition of subjects 
The reasons for permanent discontinuation of IMP and withdrawal from trial will be presented 
for all randomised subjects by treatment group. 
14.3.2 Demographics and other baseline characteristics 
Descriptive statistics of demographics and other baseline characteristics will be presented for 
all randomised subjects by treatment group. Presentations of demographics, baseline disease 
severity, and proportion of subjects with baseline worst pruritus (“itch” – one of the symptoms 
captured in ADSD) (weekly average) above/below 4 on the NRS scale will also be given by 
region (North America (US and Canada) and Australia) and baseline disease severity (baseline 
vIGA-AD of 2, 3, and 4). 
Demographics include age, sex, race, and ethnicity. Other baseline characteristics include vital 
signs, height, weight, body mass index, total IgE, Fitzpatrick skin classification, duration of 
AD, concurrent diagnoses (from medical history and indications for concomitant medication), 
concomitant medication, and previous AD treatments. 
14.3.3 Exposure and treatment compliance 
The duration of exposure to treatment in a specific visit interval will be calculated as the 
number of days from date of first application of IMP in that period to the date of last 
application 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. 
Drug accountability data will be calculated by subtracting the weight of the used tubes from 
the mean normal weight of full tubes. Average weekly/bi-weekly and total usage will be 
presented per treatment group, respectively, both for time intervals between visits (1 or 2-
week periods depending on the time between site visits) and total period.  
Adherence to treatment regimen will be recorded in the eCRF. If any complications or 
deviations in administration are observed, these will be described as protocol deviations. 


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Adherence will be presented for the safety analysis set for each treatment group via the 
percentage of applications missed.  
14.3.4 Testing strategy 
This is a dose-ranging trial with the primary objective to establish the dose-response 
relationship. For the primary endpoint, change from baseline to Week 8 in EASI score, and 
the secondary endpoints, EASI75 at Week 8 and vIGA-AD TS, the selection of the dose-
response model that fits data best will be controlled using a family-wise error rate of 5%. 
There will be no adjustment for the multiple testing of primary and secondary endpoints, all 
p-values will be considered nominal.  
14.3.5 Analysis of primary efficacy endpoint 
The primary endpoint, change from baseline to Week 8 in EASI, will be analysed for the full 
analysis set and for the per protocol analysis set. The per protocol analysis is regarded as 
supportive. 
For the analysis of the change from baseline to Week 8 in EASI, data collected after 
permanent discontinuation of IMP or after initiation of rescue medication will not be included 
in the analysis. Missing data at Week 8 will be imputed using the MMRM predicted values 
from the below specified model for repeated measurements. 
The MCP-Mod approach (see e.g. EMA Qualification Opinion of MCP-Mod or Bretz et al. 
2005 for further details of the framework) will be used to guide dose selection. The dose-
response relationship for the continuous endpoint Change from baseline to Week 8 in EASI 
will be modelled by the following 3 identified candidate models. These candidate models are 
selected based on the expected dose-response.  
Linear in log: E0 + δ × log(d + c), 
Emax: E0 + Emax × d / (ED50 + d), 
Sigmoid Emax: E0 + Emax × d h/ (ED50
h  + d h), 
where d is the dose (incl. vehicle), E0 is the efficacy offset (anticipated vehicle effect), Emax is 
the asymptotic maximum effect, ED50 is the half-life value of Emax, h is the steepness at ED50,  
δ is the slope parameter, and c is a fixed offset parameter. 


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The models will be adjusted for the stratification variables region and disease severity 
(baseline vIGA-AD of 2, 3, and 4). The model parameters (ED50, h) will be prespecified a 
priori by suitable guesses based on data from Japan Tobacco’s dose-ranging trial QBA2-1 
(Nakagawa et al. 2018). Akaike’s Information Criteria will be used as the goodness-of-fit 
criterion that will drive the selection of the dose-response model that fits data best while 
controlling the family-wise error rate at 5%. Based on the selected model, the dose-response 
relationship will be estimated and presented with 2-sided 95% CI. If none of the candidate 
models converge, other possibilities of models and goodness-of-fit criteria will be explored. 
The dose-response modelling will be performed on both the total population and subjects 
having a baseline vIGA-AD of 3 or 4, in order to further explore heterogeneity in the disease 
population. 
In addition to the dose-response modelling approach, the continuous endpoint will be 
analysed using an MMRM on the post baseline responses up to Week 8 with an unstructured 
covariance matrix, Kenward-Roger approximation to estimate denominator degrees of 
freedom, and the mean modelled as follows: 
Change from baseline in EASI 
 
= treatment × visit + baseline EASI × visit + region + baseline vIGA-AD 
The estimates will be presented with nominal p-values and 95% CI at each visit. The primary 
comparison between each delgocitinib dose and vehicle will be at Week 8. 
Sensitivity analysis will be performed as applicable in order to assess the robustness of results 
of the primary analysis with respect to the retrieved data at Week 8 and assumptions regarding 
missing data. This will be described in further detail in the statistical analysis plan. 
14.3.6 Analysis of secondary efficacy endpoints 
The secondary endpoints, vIGA-AD TS and EASI75 at Week 8, and time to vIGA-AD TS 
will be analysed for the full analysis set and for the per protocol analysis set. The per protocol 
analysis is regarded as supportive. 
For the analysis of the secondary binary endpoints, subjects who initiate rescue medication 
before Week 8 or permanent discontinue IMP and have no retrieved data at Week 8, will all be 
considered non-responders. 
The dose-response modelling approach suggested for the primary endpoint will also be 
applied for the binary secondary endpoints, vIGA-AD TS and EASI75 at Week 8. 


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In addition to the dose-response modelling approach, difference in response rates between the 
delgocitinib doses and vehicle will be analysed separately for each of the dose groups using 
the Cochran-Mantel-Haenszel test stratified by region and disease severity. The null 
hypothesis of no difference in response rates between the delgocitinib doses and vehicle will 
be tested against the 2-sided alternative that there is a difference. Furthermore, a shift table for 
the vIGA-AD will be presented for baseline to Week 8 per treatment group. 
The time to vIGA-AD TS response is defined as the time from baseline to first assessment of 
a vIGA-AD TS. Subjects will be censored at the date of the last assessment visit or at 
initiation of rescue medication, whichever occurs first. Kaplan-Meier curves of time to vIGA-
AD TS will be estimated and presented by treatment for the full analysis set. Treatment 
groups will be compared using a 2-sided log-rank test stratified by region and baseline vIGA-
AD.  
Sensitivity analysis will be performed as applicable in order to assess the robustness of results 
of the primary analysis with respect to the retrieved data at Week 8, use of rescue medication, 
and assumptions regarding missing data. This will be described in further detail in the 
statistical analysis plan. 
14.3.7 Analysis of other endpoints 
To support the primary and secondary endpoints, EASI50 at Week 8 and EASI90 at Week 8 
will be analysed and presented for the full analysis set. Both endpoints will be analysed using 
the Cochran-Mantel-Haenszel approach as described for the analysis for the secondary binary 
endpoints. 
To support the primary and secondary endpoints on severity and extent of AD, at least 75% 
reduction in SCORAD score (SCORAD75) at Week 8, SCORAD50 at Week 8, and the 
change from baseline to Week 8 in SCORAD score will be analysed and presented for the full 
analysis set. SCORAD50 and SCORAD75 will be analysed using the Cochran-Mantel-
Haenszel approach as described for the analysis for the secondary binary endpoints, and the 
change from baseline to Week 8 will be analysed using the MMRM approach as described for 
the analysis for the primary endpoint. 
14.3.7.1 Analysis of patient-reported outcomes 
The PROs POEM, DLQI, PGI-S, PGI-C, SF-36, EQ-5D-5L, WLQ and TSQM will be 
summarised by treatment group and visit using descriptive statistics. The summaries will be 
presented for the full analysis set.  


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The ADSD and Eczema-related Sleep NRS collected in the eDiaries on a daily basis (all 
individual symptoms) will be summarised over time by treatment group using descriptive 
statistics. The summaries will be presented for the full analysis set. 
The daily diary recordings of the ADSD will be derived into discrete weekly endpoints based 
on calendar time (with the exception of Week 8) from baseline visit, i.e. the endpoints 
represent the nominal week and are not directly related to the actual visit in contrast to other 
visit-based assessments. The algorithm for deriving the endpoints at each time point is 
described as follows: baseline weekly average will be defined by average of measurements 
from Day -7 to Day -1, Week 1 weekly average will be defined by the average of 
measurements from Day 1 to Day 7, Week 2 weekly average will be defined by the average of 
measurements from Day 8 to Day 14 and so on, until Week 7. Week 8 will be calculated based 
on the 7 days preceding the Week 8 visit. A minimum of 4 ADSD scores out of the 7 days are 
required to calculate the average score. This will be derived for each individual symptom, 
respectively. The same derivation rules will be applied for the Eczema-related Sleep NRS. 
In the subgroup of subjects with a baseline worst pruritus (one of the symptoms captured in 
the ADSD) (weekly average) score of ≥4, the proportion of subjects with reduction in worst 
pruritus (weekly average) of ≥4 from baseline to Week 8 will be summarised by treatment 
group and analysed using the Cochran-Mantel-Haenszel approach as described for the 
analysis of the secondary binary endpoints.  
In the subgroup of subjects with a baseline DLQI score of ≥4, the proportion of subjects with 
a reduction in DLQI score of ≥4 at Week 8 will be summarised by treatment group and 
analysed as described using the Cochran-Mantel-Haenszel approach for the analysis of the 
secondary binary endpoints. In addition, the proportion of subjects achieving a DLQI score of 
0 or 1 at Week 8 will be presented.  
In the subgroup of subjects with a baseline POEM score of ≥4, the proportion of subjects with 
a reduction in POEM score of ≥4 at Week 8 will be summarised by treatment group and 
analysed using the Cochran-Mantel-Haenszel approach as described for the analysis of the 
secondary binary endpoints. 
The change from baseline to Week 8 in ADSD (weekly average for each individual symptom), 
Eczema-related Sleep NRS (weekly average), POEM, DLQI, SF-36, EQ-5D-5L and WLQ 
will be summarised by treatment group and domain, where applicable, and analysed using the 
MMRM approach as described for the analysis of the primary endpoint. 


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The TSQM at Week 8 will be summarised by treatment group and domain and compared 
between treatments using an analysis of variance model including treatment, region and 
baseline vIGA-AD as factors. 
14.3.7.2 Efficacy over time 
To further explore possible early onset of effect and general efficacy over time, the following 
endpoints will be evaluated at each scheduled assessment up to Week 6 or each week up to 
Week 7: 
 vIGA-AD TS at each scheduled assessment until Week 6. 
 EASI75 at each scheduled assessment until Week 6. 
 Change in SCORAD from baseline to each scheduled assessment until Week 6.  
 Change from baseline to each week through Week 1 to 7 in ADSD (weekly 
average for each individual symptom). 
o Reduction of worst pruritus (one of the symptoms captured in 
the ADSD) (weekly average) of ≥4 points from baseline to each 
week through Week 1 to 7 among subjects with baseline worst 
pruritus (weekly average) of ≥4.  
 Change from baseline to each week through Week 1 to 7 in Eczema-related 
Sleep NRS (weekly average). 
 Change in DLQI score from baseline to each scheduled assessment until 
Week 6.  
 Reduction in DLQI of ≥4 from baseline to each scheduled assessment until 
Week 6 among subjects with baseline DLQI ≥4. 
For the binary endpoints, the same Cochran-Mantel-Haenszel test as for the Week 8 
assessment will be applied. For the continuous endpoints, the repeated measurements model 
already described previously for the Week 8 assessments facilitates that the p-values, 
treatment differences, and 95% CIs can be derived for each visit up to Week 6 (or Week 7 for 
the change in ADSD (weekly average for each individual symptom) and Eczema-related 
Sleep NRS [weekly average]). 
14.3.8  Analysis of pharmacodynamics and pharmacogenomics 
Exploratory analyses of biomarkers will be performed for the total population as well as by 
disease severity.  


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A summary of the results will be included in the CTR if it is available in time for this. The full 
set of biomarker results will be reported in an addendum report to the CTR. 
14.3.9 Analysis of safety 
The analysis of safety will be based on the safety analysis set. 
14.3.9.1 Adverse events 
AEs will be coded during the course of the trial according to MedDRA. AEs will be presented 
by preferred terms and primary SOC. 
Treatment-emergent AEs will be summarised; however, all AEs recorded during the course of 
the trial will be included in subject data listings. An event will be considered 
treatment-emergent if started after the first use of IMP or if started before the first use of IMP 
and worsened in severity after first dose of IMP. The tabulations described in the following 
will only include the treatment-emergent events. In each of the tabulations, AEs are defined 
by MedDRA preferred terms within primary SOC. 
An overall summary of the number of events and the number (percentage) of subjects with 
any treatment-emergent AEs, deaths, SAEs, premature discontinuations from the trial due to 
AEs, treatment-related AEs and severe AEs will be presented. 
The number of AEs and number of subjects with each type of AEs will be tabulated by 
treatment group.  
The severity for each type of AE will be tabulated by treatment group. Where there are several 
recordings of severity for a given type of AE, severity will be taken as the most severe 
recording for that AE. 
The causal relationship to IMP for each type of AE will be tabulated by treatment group. 
Where there are several recordings of causal relationship to the IMP for a given type of AE, 
causal relationship will be taken as the most-related recording from the last report of that AE, 
since that is when the investigator will be in possession of most information and therefore be 
best able to judge causal relationship.  
Related AEs are defined as AEs for which the investigator has not described the causal 
relationship to IMP as ‘not related’. The number of subjects with each type of related AE will 
be tabulated.  
SAEs will be evaluated separately and a narrative for each will be given.  


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Adverse events of special interest will be tabulated by treatment group and listed. 
AEs leading to withdrawal from trial and AEs leading to permanent discontinuation of IMP 
will be tabulated by treatment group and listed. 
14.3.9.2 Vital signs 
The change in vital signs (blood pressure, pulse, body temperature) from baseline to each visit 
will be summarised as mean, standard deviation, median, minimum, and maximum values for 
each treatment group.  
14.3.9.3 Clinical laboratory evaluation 
The change in each of the laboratory parameters from baseline to each visit will be 
summarised by visit and treatment group as mean, standard deviation, median, minimum, and 
maximum values. 
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 end of treatment. Subjects with 
laboratory parameters outside the reference range will be listed.   
14.3.9.4 Subject assessment of local tolerability 
Subject assessment of local tolerability will be summarised by visit and treatment group. 
14.3.10 
Pharmacokinetics 
A separate report will be written by the respective bioanalytical CRO and added as an 
addendum to the CTR. 
Plasma concentrations of delgocitinib will be listed and plotted versus time since last IMP 
application by treatment group.  
14.3.11 
 Interim analysis 
No interim analysis is planned. 
14.3.12 
General principles 
Unless otherwise stated, all significance tests will be 2-sided using the 5% significance level. 
All CIs will be presented with 95% degree of confidence. 


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An observed-cases approach will be used for tabulations of data by visit (i.e. involving only 
those subjects who attended each specific visit). 
Categorical data will be summarised using the number and percentage of subjects in each 
category and treatment group. Continuous data will be summarised using the mean, median, 
standard deviation, minimum, and maximum values. 
All the analyses specified in the protocol will be reviewed in relation to the blinded data 
actually obtained and the statistical analysis plan will be finalised before breaking the 
randomisation code. 
Any changes from the statistical analysis planned in this clinical trial protocol will be 
described and justified in a protocol amendment, the statistical analysis plan and/or in the 
CTR dependent on the type of deviation.  
14.3.13 
Handling of missing values 
Procedures for handling of missing values are included under the sections describing the 
individual analyses. 


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Appendix 1: Definitions of adverse events and serious adverse events 
Adverse event definition 
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavourable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product. (ICH GCP Guideline) 
This definition includes: 
 Accidental injuries. 
 Events related to trial procedures. 
 Reasons for any unfavourable and unplanned change in medication (drug 
and/or dose). 
 Clinically significant worsening of pre-existing conditions. 
 Reasons for admission to hospital or surgical procedures unless these were 
planned before the subject consented to trial participation. 
 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). 
Serious adverse event definition 
An SAE is any untoward medical occurrence that 
 Results in death. 
 Is life-threatening. 
 Requires inpatient hospitalisation or prolongation of existing hospitalisation. 
Planned hospitalisation or planned prolonged hospitalisation do not fulfil the 
criteria for being an SAE but should be documented in the subject’s medical 
record. 


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 Results in persistent or significant disability/incapacity. 
 Is a congenital anomaly/birth defect. 
or  
 Is a medically important condition. Events that may not be immediately 
life-threatening or result in death or hospitalisation but may jeopardise the 
subject or may require intervention to prevent one of the other outcomes listed 
in the definition above. Examples are intensive treatment in an emergency 
room or at home for allergic bronchospasm, blood dyscrasias and convulsions 
that do not result in hospitalisation, development of drug dependency or drug 
abuse 


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Appendix 2: Classification of adverse events 
Severity 
The severity of the AE should be described in terms of mild, moderate or severe according to 
the investigator’s clinical judgement. 
Mild 
An AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual 
activities of daily living. 
Moderate 
An AE that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, 
causing discomfort but poses no significant or permanent risk of harm to the 
subject. 
Severe 
An AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention. 
If the severity of an AE worsens, a new AE should be recorded. 
Causality 
The causal relation of the AE to the use of the IMP should be described in terms of probable, 
possible, or not related according to the investigator’s clinical judgement. The categories are 
defined below. 
Probably 
related 
Follows a reasonable temporal sequence from administration of the IMP. 
 
Could not be reasonably explained by the subject’s clinical state, 
environmental or toxic factors or other therapies administered to the 
subject. 
 
Follows a known pattern of response to the IMP. 
 
Disappears or decreases on cessation or reduction in dose of the IMP. 
 
Reappears or worsens upon re-challenge. 


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Possibly 
related 
 
Follows a reasonable temporal sequence from the administration of the 
IMP. 
 
Could also be reasonably explained by the subject’s clinical state, 
environmental or toxic factors or other therapies administered to the 
subject. 
 
Follows a known pattern of response to the IMP. 
Not related 
 
Does not follow a reasonable temporal sequence from administration of the 
IMP. 
 
Is better explained by other factors like the subject’s clinical state, 
environmental or toxic factors or other therapies administered to the 
subject. 
 
Does not reappear or worsen upon re-challenge. 
 
Does not follow a known pattern of response to the IMP. 
 
Outcome 
The outcome of the event according to the investigator’s clinical judgement should be 
classified using the categories below. 


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Recovered/ 
resolved 
The event has stopped. The stop date of the event must be recorded. 
Recovering/ 
resolving 
The subject is clearly recovering from an event. The event is not yet 
completely resolved.  
Not 
recovered/ 
not resolved 
Event is still ongoing.  
Recovered/   
resolved with 
sequelae 
The event has reached a state where no further changes are expected and the 
residual symptoms are assumed to persist. An example is hemiparesis after 
stroke. 
 
The stop date of the event must be recorded. In case of a SAE, the sequelae 
should be specified. 
Fatal 
The subject has died as a consequence of the event. Date of death is recorded 
as stop date for the AE. 
Unknown 
Unknown to investigator, e.g. subject lost to follow-up. 
 
Note that as per the above definition, LEO 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 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 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 with the outcome “RECOVERED/RESOLVED 
WITH SEQUELAE” could have been classified with the outcome 
“RECOVERED/RESOLVED” according to the CDISC definition. 
For SAEs which have stabilised and cannot be expected to recover during study or safety 
follow-up periods, for example chronic illnesses, the final outcome should be considered to be 
‘recovered’ and a statement that the SAE has stabilised should be added to the narrative in the 
SAE form. Please note that the event should not be reported as ‘recovered’ on the SAE form.  


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Appendix 3: Trial governance considerations 
Appendix 3A: Regulatory and ethical considerations 
This trial will be conducted in accordance with the protocol and with the following: 
 Consensus ethical principles derived from international guidelines including 
the current version of the Declaration of Helsinki and CIOMS International 
Ethical Guidelines. 
 Current version of applicable ICH GCP Guidelines. 
 EU’s 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 leaflet, 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 favourable opinion from 
relevant regulatory authorities and IRBs/IECs, as required, prior to implementation. 
The principal investigator will be responsible for the following, if required by local 
legislation: 
 Providing written summaries of the status of the trial to the IRB/IEC annually 
or more frequently in accordance with the requirements, policies, and 
procedures established by the IRB/IEC. 
 Notifying the local IRB/IEC of SAEs or other significant safety findings as 
required by IRB/IEC procedures. 
 Providing oversight of the conduct of the trial at the trial site and adherence to 
applicable national and international legislation. 
Appendix 3B: Informed consent process  
Subjects will receive written and verbal information concerning the clinical trial. This 
information will emphasise that participation in the clinical trial is voluntary and that the 


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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 (4.8) and all applicable laws and regulations. The authorised person obtaining the 
informed consent must also sign the ICF. 
Subjects will be re-consented to the most current version of the ICF(s) during their 
participation in the trial, if applicable. 
A copy of the ICF(s) must be provided to the subject.  
Subject card 
At screening, subjects will be provided with a card stating that they are participating in a 
clinical trial and which contains contact address(es) and telephone number(s) of relevant trial 
site staff including the number for the investigator in case of emergency situations. The 
subject card also includes a local telephone number for the emergency unblinding CRO to be 
used if the investigator or delegated site staff cannot be reached or if unblinding in the IRT 
cannot be performed. 
Appendix 3C: Subject and data confidentiality 
This clinical trial protocol as well as all other information, data, and results relating to this 
clinical trial and/or to the IMP is confidential information of LEO and shall not be used by the 
investigator for purposes other than this clinical trial. 
The investigator agrees that LEO 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. Any subject’s records 
or datasets that are transferred to LEO will contain the identifier only; subject names or any 
information which would make the subject identifiable will not be transferred.  
Trial subjects must be informed and consent to that their personal trial-related data will be 
used by LEO in accordance with local data protection law.   


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Trial subjects must be informed and consent to that their medical records may be examined by 
Clinical Quality Assurance auditors or other authorised personnel appointed by LEO, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
Processing of personal data 
This protocol specifies the personal data on trial subjects (for example race, age, gender, 
health condition, medical history, test results, etc.) which shall be collected as part of the 
clinical trial and processed during and after trial completion. 
Personal data collected as part of the clinical trial will be transferred to/from the 
institution/investigator, LEO and third parties acting on behalf of LEO. 
Processing of personal data on behalf of LEO requires a written agreement between LEO 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 must ensure that collection, processing and transfer of personal data 
are in compliance with applicable legislation on data protection and privacy, including but not 
limited to the EU General Data Privacy Regulation. 
Subjects must be asked to consent to the collection, processing and transfer of their personal 
data to EU and non-EU countries for the purpose of conducting the clinical trial, research and 
development of new or existing products/services, improving existing products/services, 
applying for marketing authorisations for products/services, marketing of products/services 
and other related activities. 
LEO has obtained the necessary authorisations for the processing of personal data collected in 
the trial. 
Appendix 3D: Record keeping, quality control, and data handling 
Source data 
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 by medically qualified investigators. 


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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: 
 Date(s) of conducting the informed consent process, including date of 
provision of subject information. 
 A statement from the investigator to verify that each of the eligibility criteria 
are met and documented. 
 Subject ID. 
 The fact that the subject is participating in a clinical trial in AD including 
treatment arms of delgocitinib cream (1, 3, 8 0r 20 mg/g) or delgocitinib cream 
vehicle for 8 weeks plus 2 weeks of follow-up. 
 Other relevant medical information. 
Trial monitoring 
During the course of the trial, CRA(s) will visit the trial site. These visits have the following 
objectives: (i) to continually verify source data to confirm that data entered into the eCRF by 
authorised site personnel are accurate, complete, and verifiable from source documents; (ii) to 
confirm that the safety and rights of subjects are being protected; and (iii) to confirm that the 
trial is being conducted in accordance with the currently approved protocol and any other trial 
agreements, ICH-GCP, and all applicable regulatory requirements. 
The monitoring visit intervals will depend on the trial site’s recruitment rate and the 
compliance of the trial site with the protocol and ICH GCP. 
In order to perform their role effectively, CRAs and persons involved in quality assurance and 
inspections will need direct access to source data, e.g. medical records, laboratory reports, 
appointment books, etc. If the electronic medical record does not have a visible audit trail, the 
investigator must provide the CRA with signed and dated printouts. In addition, relevant site 
staff should be available for discussions at monitoring visits and between monitoring visits 
(e.g. by telephone). 
Protocol compliance 
Protocol deviations will be documented and notified to the investigator. Protocol deviations 
will be assessed by LEO and major deviations described in the CTR. 
Sponsor audits, IRB/IEC review, and regulatory agency inspections 
The clinical trial will be subject to audits conducted by LEO or inspections from domestic or 
foreign regulatory authorities or from IRBs/IECs. Audits and inspections may take place 


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during or after the trial. The investigator and the site staff as well as LEO 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 must be notified 
immediately. 
Risk assessment 
In this trial, the risks to critical processes and data have been evaluated. 
Risk mitigation activities for endpoints include: 
 Ensuring consistent data with respect to investigator assessment of efficacy 
(EASI, vIGA-AD and SCORAD), all assessors will receive training and 
whenever possible, the efficacy assessments will be made by the same 
investigator at each visit for a given subject to reduce inter-rater variability. 
 Ensuring subjects and investigational staff are well instructed and trained about 
the use of the eDiary and the eDevice which will be used to collect the PROs 
(ADSD, Eczema-related Sleep NRS, POEM, DLQI, PGI-S, SF-36, EQ-5D-5L, 
WLQ, and TSQM). 
 Ensuring investigational staff are well instructed and trained in collecting 
biomarker samples. 
 Ensuring administration of IMP is controlled and documented at the site. This 
will be done by providing training and clear instructions to trial sites. 
 Ensuring that trial sites are well trained in safety procedures such as collection 
and reporting of adverse events. 
Throughout the trial, data quality review meetings will be held to ensure that data collections 
can be improved and mistakes prevented. During monitoring visits to the trial sites, the CRAs 
will verify that investigators work according to the protocol. 
Data handling 
Data will be collected by means of electronic data capture unless transmitted to LEO or 
designee electronically (e.g. laboratory data). The investigator or staff authorised by the 
investigator will enter subject data into eCRFs. Data recorded in the eCRFs will be accessible 


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to the trial site and LEO personnel immediately after entry. The eCRFs 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 all eCRFs used. This signature information will be kept in the audit trail 
and cannot be altered. Any correction(s) made by the investigator or authorised site staff to 
the eCRF after original entry will be documented in the audit trail. Changes to data already 
approved will require re-signature by the investigator. The person making the change to the 
data, and the date, time and reason for the change will be identified in the audit trail. 
Subject data should be entered into the eCRF no later than 5 working days after each visit, 
unless a different deadline is stated in the Clinical Trial Agreement. Queries for discrepant 
data will be generated automatically by the system upon entry or manually by the CRA, 
sponsor’s medical expert, or the data manager. All queries will be raised electronically within 
the electronic data capture system. This systematic validation will ensure that a clean and 
consistent database is provided for the statistical analysis. 
An ePRO solution will be used to capture patient-reported data (data from questionnaires 
completed at the trial site and eDiary data). By the use of an ePRO solution, data will be 
available immediately after data entry and available for monitors and site personnel, including 
the investigator, with read 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 will be transmitted and handled via a secure file 
transfer protocol site. Transmissions of electronic data from external data providers and of 
ePRO data to the clinical database are illustrated in Panel 14. 


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Panel 14: Transmission of electronic data 
 
Abbreviations: CTR, clinical trial report; ECG, electrocardiogram; eCRF, electronic case report form; ePRO, 
electronic patient-reported outcome 
 
Archiving of trial documentation 
The investigator at each trial site must make arrangements to store the essential trial 
documents, including the investigator trial file (EU Directive 2001/20/EC). Essential trial 
documents must be stored until LEO informs the investigator that the documents are no 
longer to be retained, or longer if required by local regulations. 
In addition, the investigator is responsible for the archiving of all relevant source documents 
so that the trial data can be compared against source data after the completion of the trial (for 
example in case of an inspection from regulatory authorities). 
The investigator is required to ensure the continued storage of the documents even if the 
investigator leaves the trial site or retires before the end of the required storage period. 
No documents may be destroyed during the retention period without the written approval of 
LEO. No documents may be transferred to another location or party without written 
acceptance from LEO. 
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 and ePRO data for all screened and randomised subjects enrolled at the trial site. This 
is done after completion of the trial and before access to the eCRF/ePRO is revoked. Audit 
trail information will be included. eCRFs and ePRO data must be available for inspection by 
authorised representatives from LEO, from regulatory authorities and/or IRBs/ IECs. 
Appendix 3E: Registration, reporting and publication policy 
Trial disclosure 
LEO is committed to be transparent with respect to its clinical trials. 
Basic information of this clinical trial will be registered in the global data registry, 
www.ClinicalTrials.gov before the first subject enters into the trial. The trial may also become 
registered in other online data registries, according to applicable law and regulations. 
Results of this clinical trial will be posted on the corporate website of LEO in accordance with 
its Position on Public Access to Clinical Trial Information no later than 12 months after trial 
completion. Trial results may also become reported in www.ClinicalTrials.gov, 
www.clinicaltrialsregister.eu and national data registries in accordance with applicable law 
and regulations after clinical trial completion or premature termination.   
LEO may also provide researchers access to anonymised patient level data for further 
research. Publication and access will be in accordance with the Position on Public Access to 
Clinical Trials which can be found on the website of LEO. 
Publications 
The investigator shall be entitled to make publications of the results generated by investigator 
in accordance with the process described here. 
A multi-centre publication will be submitted for publication within 18 months after the 
clinical trial has been completed or terminated at all trial sites and all data have been received, 
defined as database lock of the clinical trial. After such multi-centre publication is made 
public, or if no multi-centre publication has been submitted with the above-described 
deadline, the investigator shall have the right to publish the results from the clinical trial 
generated by the investigator, subject to the following notice requirements: 
Prior to submission for publication or presenting a manuscript relating to the clinical trial, the 
investigator shall provide to LEO a copy of all such manuscripts and/or presentations. LEO 
shall have rights to review and comment. The investigator shall consider comments by LEO 
but is not required to modify the manuscript and/or presentation based on such comments, 


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provided, however, that the investigator upon the request of LEO remove any confidential 
information (other than results generated by the investigator) prior to submitting or presenting 
the manuscripts. The investigator shall, upon the request of LEO withhold the publication or 
presentation to allow LEO to protect its inventions and other intellectual property rights 
described in any such manuscripts.  
In case no multi-centre publication has been made public at the time of investigator’s 
notification of an independent publication to LEO, LEO and the writing group may also delay 
the publication or presentation if the manuscript is deemed to harm the ongoing multi-centre 
publication. 
In case of publications made by the investigator after the first multi-centre publication has 
been published, the above-mentioned requirements must still be followed. 
Any publication must comply with GPP3 standards. 
LEO complies with Good Publication Practice (GPP3) standards and the recommendations 
from the International Committee of Medical Journal Editors. LEO complies with the 
positions of the International Federation of Pharmaceutical Manufacturers & Associations, 
European Federation of Pharmaceutical Industries and Associations, Japan Pharmaceutical 
Manufacturers Association, Pharmaceutical Research and Manufacturers of America, and the 
joint position statement by the American Medical Writers Association, the European Medical 
Writers Association, and the International Society for Medical Publication Professionals on 
disclosure of information about clinical trials, trial results and authorship. LEO also follows 
the CONSORT reporting guidelines (Schulz et al. 2010). 
Appendix 3F: Insurance 
LEO 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 with sufficient, accurate financial information as requested to 
allow LEO to submit complete and accurate financial certification or disclosure statements to 
the appropriate regulatory authorities. Investigators are responsible for providing information 
on financial interests during the course of the clinical trial and for 1 year after completion of 
the clinical trial, or for a longer period of time if required by local legislation. 


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Appendix 3H: Trial and site closure 
Premature termination of trial or trial site 
LEO, the investigator, the IRB/IECs or competent authorities may decide to stop the clinical 
trial, part of the trial or a trial site at any time, but agreement on procedures to be followed 
must be obtained. 
If a clinical trial is suspended or prematurely terminated, the investigator must inform the 
subjects promptly and ensure appropriate therapy and follow-up. As specified by applicable 
regulatory requirements, the investigator or LEO must promptly inform IRB/IECs and 
provide a detailed written explanation. Relevant competent authorities must be informed. 
The trial must be terminated if the perception of the benefit/risk ratio (judged from clinical 
signs and symptoms, (S)AEs and/or remarkable safety laboratory changes) becomes 
unfavourable for the continuation of the trial. 
Reasons for the early closure of a trial site by LEO 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’s 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 will undertake arrangements for the 
collection and disposal of any unused trial material that the investigator is not required to 
keep in his/her files. A trial site is considered closed when all required documents and trial 
supplies have been collected and a trial site closure visit has been performed. 
When the randomisation code has been broken, the investigators will receive information 
about the treatment allocation for the subjects randomised at their respective sites and will be 
asked to record this in the subject’s medical record. 


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Appendix 3I: Responsibilities 
The signatory investigator is responsible for the approval of the clinical trial protocol and 
the CTR on behalf of all clinical trial investigators and as agreed to in a Signatory Investigator 
Agreement. 
The national coordinating investigators are responsible for national issues relating to the 
clinical trial as agreed to in a National Coordinating Investigator Agreement. 
Each participating investigator is responsible for all aspects of the clinical trial conduct at 
his/her trial site as agreed to in a Clinical Trial Agreement. 


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Appendix 4: Short version of eligibility criteria 
This appendix provides a short form (maximum 200 characters) of each of the eligibility 
criteria to be used when data are submitted to regulatory authorities in CDISC format. 
No. 
Inclusion criteria 
1 
Signed and dated informed consent has been obtained prior to any protocol related procedures. 
2 
Age 18 years and above. 
3 
Diagnosis of AD as defined by the Hanifin and Rajka criteria for AD (Hanifin & Rajka 1980). 
4 
History of AD for 1 year or more. 
5 
AD involvement of 5–50% treatable body surface area at screening and at baseline (excluding scalp). 
6 
Disease severity graded as mild to severe according to vIGA-AD (i.e. vIGA-AD of 2 or more) at screening and at 
baseline. 
7 
Able and willing to follow trial procedures including application of IMP to all AD lesions. 
8 
A woman of childbearing potential must use a highly effective form of birth control throughout the trial and at 
least for 2 weeks after last application of IMP. 
 
No. 
Exclusion criteria 
1 
AD lesion(s) on scalp at screening and/or baseline. 
2 
Active dermatologic conditions that may confound the diagnosis of AD or would interfere with assessment of 
treatment, such as scabies, cutaneous lymphoma, rosacea, urticaria, or psoriasis. 
3 
Known active allergic or irritant contact dermatitis that is likely to interfere with the assessment of severity of AD. 
4 
Use of tanning beds or phototherapy (NBUVB, UVB, UVA1, PUVA) within 4 weeks prior to baseline. 
5 
Systemic treatment with immunosuppressive/modulating drugs or corticosteroids within 4 weeks prior to baseline 
or 3 or more bleach baths any week within 4 weeks prior to baseline. 
6 
Treatment with TCSs, TCIs, topical PDE-4 inhibitors, or oral antibiotics within 2 weeks prior to baseline. 
7 
Change in systemic antihistamine therapy within 2 weeks prior to baseline i.e. the subjects must not start 
antihistamine treatment or change the current dosage regime within 2 weeks prior to baseline. 
8 
Receipt of live attenuated vaccines 4 weeks prior to baseline. 
9 
Receipt of blood products within 4 weeks prior to screening. 
10 
Treatment with any marketed or investigational biologic agents within 6 months or 5 half-lives prior to baseline, 
or until cell counts return to normal, whichever is longer. 
11 
Treatment with any non-marketed drug substance within the last 4 weeks prior to baseline or 5 half-lives, 
whichever is longer. 
12 
History of any active skin infection within 1 week prior to baseline. 
13 
A helminth parasitic infection within 6 months prior to screening that has not been treated with, or has failed to 
respond to, standard of care therapy. 
14 
Clinically significant infection (systemic infection or serious skin infection requiring parenteral treatment) within 
4 weeks prior to baseline.  
15 
Tuberculosis requiring treatment within the 12 months prior to screening and/or subjects with a positive blood test 
for tuberculosis at screening (subjects with high risk of latent tuberculosis must be tested).  


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16 
History of any known primary immunodeficiency disorder including a positive HIV test at screening, or the 
subject taking antiretroviral medications.  
17 
Major surgery within 8 weeks prior to screening, or planned in-patient surgery or hospitalisation during the trial 
period. 
18 
History of cancer. 
19 
Any disorder, which is not stable, and in the investigator’s opinion could affect the safety of the subject, influence 
the results of the trial or impede the subject’s ability to complete the trial. 
20 
Any abnormal finding, which in the investigator’s opinion may put the subject at risk, influence the results of the 
trial or influence the subject’s ability to complete the trial. 
21 
Positive HBsAg, HBsAb, HBcAb or hepatitis C virus serology at screening. Subjects with positive HBsAb may be 
randomised provided they are hepatitis B vaccinated and have negative HBsAg and HBcAb. 
22 
Alanine aminotransferase or aspartate aminotransferase level 2.0 times the upper limit of normal range or more at 
screening. 
23 
Known or suspected hypersensitivity to any component(s) of the IMP. 
24 
Current participation in any other interventional clinical trial. 
25 
Previous randomisation in this clinical trial. 
26 
History of chronic alcohol or drug abuse within 12 months prior to screening, or any condition associated with 
poor compliance as judged by the investigator. 
27 
Employed at the trial site or directly involved with the planning or conduct of the trial, or immediate family 
members of such individuals. 
28 
Legally institutionalised. 
29. 
Pregnant or lactating. 


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Appendix 5: Contact list 
Contact details for the CPM, appointed CRA, and sponsor’s medical expert are provided to 
the trial sites as a separate contact list. 
Sponsor 
LEO Pharma A/S (referred to as ‘LEO’ 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 
 
 


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Appendix 6: Hanifin and Rajka (1980) diagnostic criteria for AD 
From Hanifin JM, Rajka G. Diagnostic features of atopic dermatitis. Acta Derm Venereol. 
1980;92: 44-47 (Hanifin & Rajka 1980).  
Must have 3 or more basic features: 
 Pruritus. 
 Typical morphology and distribution: 
o Flexural lichenification or linearity in adults. 
o Facial and extensor involvement in infants and children. 
 Chronic or chronically-relapsing dermatitis. 
 Personal or family history of atopy (asthma, allergic rhinitis, atopic dermatitis). 
 
Plus 3 or more minor features: 
 Xerosis. 
 Ichthyosis, palmar hyperlinearity, or keratosis pilaris. 
 Immediate (type 1) skin-test reactivity. 
 Elevated serum IgE. 
 Early age of onset. 
 Tendency toward cutaneous infections (especially S. aureus and herpes 
simplex)/impaired cell-mediated immunity. 
 Tendency toward non-specific hand or foot dermatitis. 
 Nipple eczema. 
 Cheilitis. 
 Recurrent conjunctivitis. 
 Dennie-Morgan infraorbital fold. 
 Keratoconus. 
 Anterior subcapsular cataracts. 
 Orbital darkening. 
 Facial pallor/facial erythema. 
 Pityriasis alba. 
 Anterior neck folds. 
 Itch when sweating. 
 Intolerance to wool and lipid solvents. 
 Perifollicular accentuation. 
 Food intolerance. 
 Course influenced by environmental/emotional factors. 
 White dermographism/delayed blanc. 
 


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Appendix 7: Protocol amendment history 
The  protocol amendment summary of changes table for the current amendment is located 
directly before the table of contents.  
Amendment 1 (09-Jan-2019) 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union 
or subsequent regulation. 
Overall rationale for the amendment 
The main reason for the amendment is to address comments to the protocol received from the 
US Food and Drug Administration. Miscellaneous other changes/updates have also been 
implemented. 
The table below summarises changes made in each section and a brief rationale for each 
change.  
Section no. and name Description of change 
Brief rationale 
Section 1 
Protocol synopsis 
Change of treatment success 
abbreviation from vIGA-AD 0/1 to 
vIGA-AD TS. 
Patient Global Impression of 
Change (PGI-C) has been added to 
the list of subject assessments of 
efficacy and health-related quality 
of life; PROs. 
Subject assessment of local 
tolerability has been added as a 
safety assessment. 
Revision of exclusion criterion on 
tuberculosis to also include 
subjects with a positive blood test 
for tuberculosis at screening. 
Subjects with high risk of latent 
To reflect changes in the 
protocol. 


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Section no. and name Description of change 
Brief rationale 
tuberculosis (e.g. prior residence in 
or travel to countries with high 
prevalence of tuberculosis, close 
contact with a person with active 
tuberculosis, or a history of active 
or latent tuberculosis where an 
adequate course of treatment 
cannot be confirmed) must be 
tested. 
Section 4 
Schedule of trial 
procedures 
Assessment of PGI-C added. 
 
 
 
 
 
 
Assessment of vital signs 
(including body temperature) 
added at Visits 4, 5, 6, and 7. 
 
Tuberculosis test added. 
 
 
 
 
 
 
 
 
 
 
 
 
 
Added as a PRO anchor 
scale to generate a threshold 
for improvement that 
represents a meaningful 
amount of change in the 
target population. 
 
To include an active 
assessment for infection at 
all on-site visits. 
 
To reflect that subjects with 
high risk of latent 
tuberculosis (e.g. prior 
residence in or travel to 
countries with high 
prevalence of tuberculosis, 
close contact with a person 
with active tuberculosis, or a 
history of active or latent 
tuberculosis where an 
adequate course of treatment 
cannot be confirmed) must 
be tested. 
 


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Section no. and name Description of change 
Brief rationale 
Subject assessment of local 
tolerability added. 
 
 
 
 
AD lesions on scalp changed to 
New AD lesions and procedure 
added at Visit 3 and deleted at Visit 
9. 
 
 
 
Change to footnote on medical 
history. 
 
 
 
 
Addition of footnote on WLQ. 
Added to have an active 
subject assessment of local 
tolerability 
(stinging/burning) in the 
trial.  
 
To correct inconsistency 
between protocol text and 
eCRF and to reflect how 
data is captured in the eCRF. 
 
 
 
To clarify that it is not the 
intention that full medical 
history is to be recorded 
both at screening and at 
baseline. 
 
To clarify that only subjects 
with a paid job are to answer 
the WLQ. 
Section 6 
Trial objectives and 
endpoints 
Change of treatment success 
abbreviation from vIGA-AD 0/1 to 
vIGA-AD TS. 
 
 
 
 
 
 
The endpoint Change in PGI-S 
from baseline to Week 8 has been 
deleted. 
To avoid misunderstandings 
between a vIGA-AD score 
of 0 (clear) or 1 (almost 
clear) and vIGA-AD 
treatment success defined as 
an IGA score of 0 (clear) or 
1 (almost clear) with at least 
a 2-step improvement. 
 
Due to an update of the 
wording of the PGI-S 
questionnaire (see Section 


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Section no. and name Description of change 
Brief rationale 
11.7.1.5), the sample size for 
the updated PGI-S will 
likely not be sufficient to 
perform a statistical analysis. 
PGI-S will still be 
summarised descriptively 
and used as an anchor scale. 
Section 8.3 
Exclusion criteria 
Revision of exclusion criterion 15 
to also include subjects with a 
positive blood test for tuberculosis 
at screening. Subjects with high 
risk of latent tuberculosis (e.g. 
prior residence in or travel to 
countries with high prevalence of 
tuberculosis, close contact with a 
person with active tuberculosis, or 
a history of active or latent 
tuberculosis where an adequate 
course of treatment cannot be 
confirmed) must be tested. 
To further safeguard subjects 
in risk of (re)activation of 
latent tuberculosis. 
Section 9.7 
Prohibited medication 
and procedures 
Bleach baths have been added to 
list of prohibited medication and 
procedures (prohibited from 4 
weeks prior to baseline to end of 
trial). 
 
Wet wraps have been added as an 
example of topical treatments 
(drug, non-drug) not allowed on 
lesional skin. 
To clarify that bleach baths 
are not allowed. 
 
 
 
 
To provide example of 
topical treatments not 
allowed. 


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Section no. and name Description of change 
Brief rationale 
Section 10.2.1 
Reasons for 
discontinuation of 
IMP 
Two new criteria for 
discontinuation of IMP have been 
added: 
Any infection that is opportunistic, 
such as active tuberculosis and 
other infections whose nature or 
course may suggest an immuno-
compromised status. 
Lymphopenia (lymphocytes 
<0.5x109/l; grade 3 according to 
CTCAE v5.0) confirmed by 
repeated measurement within 7 
days. 
To further safeguard subjects 
in case of opportunistic 
infections and/or 
lymphopenia. 
Section 11.1 
Overview 
Panel 6 has been revised: 
 
“Investigator assessments” has 
been changed to “Efficacy 
assessments by the investigator”.  
 
Box with text: “Baseline visit (Day 
1) only: Check capping limits in 
IRT before randomization” has 
been deleted.  
 
“Safety and laboratory 
assessments” has been changed to 
“Safety assessments by the 
investigator”. 
 
A new box after “Safety 
assessments by the investigator” 
has been added: “Subject 
assessment of local tolerability”. 
 
 
For clarification. 
 
 
 
Capping check will not be 
done in IRT but will be done 
by LEO Pharma A/S. 
 
 
For clarification. 
 
 
 
 
To reflect that subject 
assessment of local 
tolerability is added to the 
trial and that assessment 


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Section no. and name Description of change 
Brief rationale 
 
 
 
 
“Other assessments” has been 
changed to “Laboratory and other 
assessments”. 
should be performed after 
safety assessments by the 
investigator. 
 
For clarification. 
Section 11.4.4 
Laboratory testing 
Panel 11 (Clinical laboratory tests): 
 
Interferon gamma release test has 
been added. 
 
 
 
C-reactive protein has been added. 
 
 
Added to test for 
tuberculosis in subjects with 
high risk of latent 
tuberculosis. 
 
Added as an active 
assessment for infection. 
Section 11.4.5 
Subject assessment of 
local tolerability 
New section. 
Added to have an active 
subject assessment of local 
tolerability 
(stinging/burning) in the 
trial.  
Section 11.6.3 
Skin biopsies and 
photographs (all sites, 
but optional) 
It has been added that biopsies will 
not be taken if the investigator 
considers the procedure unsuitable 
for the subject (e.g. subjects 
receiving anticoagulant therapy). 
 
It has been deleted that no further 
biopsies will be taken after 
biopsies from 100 subjects have 
been obtained. 
 
 
To clarify that biopsies are 
only to be taken if the 
procedure is suitable for the 
subject. 
 
 
The data from the analysis 
of the biopsies will after 
completion of this trial be 
shared with the Innovative 
Medicines Initiative (IMI) 
consortium, BIOMAP. In 


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Section no. and name Description of change 
Brief rationale 
 
 
 
 
 
It has been added that if deemed 
relevant transcriptome profiling of 
some or all of the biopsies may be 
done. 
order to generate robust data 
on AD baseline 
characteristics a larger 
dataset is needed. 
 
BIOMAP will most likely 
need full transcriptomics 
dataset for their disease 
characterisation. For this 
reason, some of the biopsies 
(biopsies obtained at 
baseline) will undergo 
transcriptomics profiling. 
Section 11.7.1 
Patient-reported 
outcomes (PROs) 
PGI-C added to the list of PROs to 
be completed in the electronic 
device by the subjects. The number 
of PROs to be completed has 
changed from 7 to 8. 
To reflect the addition of 
PGI-C assessment in the 
trial. 
Section 11.7.1.5 
Patient Global 
Impression of Severity 
(PGI-S) 
Wording of PGI-S questionnaire 
has been updated. 
As per advice from the US 
Food and Drug 
Administration. 
Section 11.7.1.6 
Patient Global 
Impression of Change 
(PGI-C) 
New section. 
To reflect the addition of 
PGI-C assessment in the 
trial. 
Section 11.7.1.9 
Work Limitation 
Questionnaire (WLQ) 
It has been added that the WLQ 
will be completed at the trial site 
for subjects with a paid job.  
To clarify that only subjects 
with a paid job are to answer 
the WLQ. 


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Section no. and name Description of change 
Brief rationale 
Section 11.8 
Estimate of total 
blood volume 
collected 
The total volume to be drawn has 
been changed from approximately 
35 mL to approximately 39 mL. 
Total volume of blood 
needed by laboratory has 
been revised. 
Section 11.10 
Storage of biological 
samples 
Skin swabs will also be stored in 
biobank and has been added to the 
biobank section. 
Skin swabs were by mistake 
not mentioned in relation to 
biobanking in the original 
protocol. 
Section 14.3.1 
Disposition of 
subjects 
The sentence on presentation of 
reasons for permanent 
discontinuation of IMP and 
withdrawal from trial has been 
revised. Reasons will not be 
presented by last visit attended. 
Reasons for permanent 
discontinuation of IMP and 
withdrawal from trial will be 
presented by treatment 
group only. 
Section 14.3.4 
Testing strategy 
 
Section 14.3.6 
Analysis of secondary 
efficacy endpoints 
 
Section 14.3.7.2 
Efficacy over time 
Change of treatment success 
abbreviation from vIGA-AD 0/1 to 
vIGA-AD TS.  
To avoid misunderstandings 
between an vIGA-AD score 
of 0 (clear) or 1 (almost 
clear) and vIGA-AD 
treatment success defined as 
an IGA score of 0 (clear) or 
1 (almost clear) with at least 
a 2-step improvement. 
Section 14.3.7.1 
Analysis of patient-
reported outcomes 
PGI-C has been added to the list of 
PROs to be summarised by 
treatment group and visit using 
descriptive statistics.  
 
Time interval calculations of 
weekly average of ADSD have 
been revised (e.g. baseline weekly 
average of ADSD will be defined 
To reflect the addition of 
PGI-C assessment in the 
trial. 
 
 
The approach for calculation 
of weekly average has been 
revised since ADSD is 
completed in the evening 


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Section no. and name Description of change 
Brief rationale 
by average of measurements from 
Day -7 to Day -1 instead of from 
Day -6 to Day 1) and text has been 
slightly revised. 
 
The description of how to analyse 
PGI-S has been deleted. 
 
 
throughout the trial. 
 
 
 
 
PGI-S has been deleted as an 
endpoint and will only be 
summarised descriptively. 
Section 14.3.9.1 
Adverse events 
It has been added that adverse 
events of special interest will be 
tabulated by treatment group and 
listed. 
 
AEs leading to withdrawal from 
trial and AEs leading to permanent 
discontinuation of IMP will be 
tabulated by treatment group. No 
narratives will be made for these 
AEs. 
To clarify how adverse event 
of special interest will be 
summarised. 
 
 
AEs leading to withdrawal 
from trial and AEs leading to 
permanent discontinuation 
of IMP, as well as AEs of 
special interest will be 
tabulated and listed as this is 
a more informative way of 
presenting data on these 
event types. 
Section 14.3.9.4 
Subject assessment of 
local tolerability 
New section. 
To describe statistical 
handling of the subject 
assessment of local 
tolerability. 
Appendix 4 
Short version of 
eligibility criteria 
Revision of exclusion criterion 15 
to also include subjects with a 
positive blood test for tuberculosis 
at screening (subjects with high 
To further safeguard subjects 
in risk of (re)activation of 
latent tuberculosis. 


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Date: 22-Aug-2019 
Version: 3.0 
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Section no. and name Description of change 
Brief rationale 
risk of latent tuberculosis must be 
tested). 
Throughout 
Minor editorial and document 
formatting changes. 
Minor, have therefore not 
been summarised. 
 
 
 


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