Conditions: Chronic Hand Eczema
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 98
Healthy volunteers: no

Brief summary:
The purpose of this trial is to test if delgocitinib cream is effective in treating chronic hand eczema (CHE) and to find out what side effects it may have compared with a cream vehicle with no active medical ingredient in adolescents aged 12-17 years. At each visit to the clinic, the doctor will assess the severity and extent of CHE, and during the trial, the adolescents will assess their CHE signs and symptoms as well as quality of life.

The trial will last up to 22 weeks and has a 1-4 week screening period, a 16-week treatment period and a 2- week follow-up period. During the treatment period, each adolescent participant will use either the delgocitinib cream or cream vehicle twice daily.

Detailed description:

Arms:
arm 1: Delgocitinib cream 20 mg/g twice daily arm 2: Cream vehicle twice daily

Interventions: intervention 1: Delgocitinib intervention 2: 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 medical ingredient.

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
 
 
 
Cover Page 
 
 
Study title: A phase 3 clinical trial to evaluate efficacy and safety of twice-daily applications of 
delgocitinib cream 20 mg/g compared with cream vehicle for a 16-week treatment period in 
adolescents 12-17 years of age with moderate to severe chronic hand eczema (DELTA TEEN) 
LEO Pharma number: LP0133-1426 
NCT number: NCT05355818 
Date: 11-Dec-2023 
 


CONFIDENTIAL 
THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION AND MUST NOT BE COPIED OR MADE AVAILABLE TO ANY THIRD PARTY WITHOUT 
THE PRIOR WRITTEN CONSENT OF THE LEO PHARMA GROUP 
 
Updated clinical trial protocol 
 
LP0133-1426 
 
 
A phase 3 clinical trial to evaluate efficacy and safety of twice-daily applications of 
delgocitinib cream 20 mg/g compared with cream vehicle for a 16-week treatment period in 
adolescents 12-17 years of age with moderate to severe chronic hand eczema 
(DELTA TEEN) 
 
 
 
Phase 3 – efficacy/safety 
 
A randomised, double-blind, vehicle-controlled, parallel-group, multi-site trial 
 
 
 
This clinical trial will be conducted in compliance with the clinical trial protocol, ICH GCP, 
and the applicable regulatory requirement(s). 
LEO Pharma A/S 
Trial ID: 
LP0133-1426 
 
Date: 
 
11-Dec-2023 
 
EudraCT no:  
2021-006340-27 
 
Version: 
2.0 
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Clinical trial protocol statements 
Approval statement LEO Pharma A/S 
Electronic signatures made within LEO Pharma Clinical Vault are legally binding equivalent 
of traditional handwritten signatures. The following persons have approved this clinical trial 
protocol by using electronic signatures as presented on the last page of this document: 
, MD, MSc. 
 
Vice president, Global Clinical Development 
 
 
 
 
, MSc. Eng. PhD  
 
Biostatistics lead, Global Clinical Development 
 
 
, MD 
 
 
 
Medical lead, Global Clinical Development 
 
 
 
 
 BSc. Chemistry 
 
Clinical operations lead, Global Clinical Operations 
 
 
 
 MD 
 
Signatory investigator 
 
 
Acknowledgement statement investigators 
Each participating investigator must agree to the approved clinical trial protocol by signing a 
clinical trial protocol acknowledgement form or similar document. 
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Protocol amendment summary of changes table
Document history
Document 
Date 
Type of protocol amendment 
Amendment 1 
(substantial) 
11-Dec-2023
Global 
Original protocol 
13-Jan-2022
NA 
Amendment 1 (11-Dec-2023) 
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 
This amendment is mainly written to change the statistical methodology to a Bayesian 
analysis where data from the adult population from recently completed pivotal phase 3 trials 
(LP0133-1401 and LP0133-1402) is leveraged to analyze efficacy endpoints in the adolescent 
population. LEO Pharma believes that, based on results from the completed clinical 
development program for delgocitinib, there is now sufficient understanding of CHE 
pathophysiology and the pharmacology of delgocitinib to support using efficacy results from 
the adult trials as prior information to the Bayesian analysis of the adolescent data.
In addition, a maximum 35% of subjects originating from the same country has been added to 
avoid a bias in the estimated efficacy and safety assessments potentially occurring due to 
homogeneity of the population.
Minor clarifications and editorial changes have been made throughout the document.
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Section no. and 
title 
Description of change 
Brief rationale 
Section 4, 
Schedule of trial 
procedures 
and Section 
11.4.3.2, Hand 
Eczema 
Symptom Diary 
Added that a minimum of 4 HESD 
scores per week are required to 
calculate the average.  
For clarification. 
Section 7.2, 
Number of 
subjects needed 
Added that a maximum of 35% of 
subjects are allowed to originate from 
the same country. 
To avoid a bias in the estimated efficacy and 
safety assessments potentially occurring due to 
homogeneity of the population. 
Section 9.5, 
Rescue treatment 
Recording of ‘rescue medication’ 
changed to ‘rescue treatment.’ 
To accommodate that a rescue treatment can 
be either a rescue medication or a rescue 
procedure. 
Sections 14.3.4 to 
14.3.17  
The confirmatory evidence for the 
trial, i.e. the testing hierarchy, has 
been updated to use the Bayesian 
analyses for the primary and key 
secondary endpoints. 
By using the Bayesian methodology, efficacy 
data from adult trials will support the analysis 
of data in adolescents.  
 
Section 14.3.17, 
Description of the 
Bayesian 
analyses and 
design 
characteristics 
New section including a detailed 
description of the Bayesian analyses 
and its design characteristics 
To provide an evaluation/justification for use 
of the Bayesian analyses of primary and key 
secondary endpoints.  
Appendix 4, 
Country-specific 
requirements 
Archiving period for essential trial 
documents and source documents in 
Canada changed from 25 to 15 years 
Change in archival requirements by Health 
Canada. 
Throughout 
document 
Minor editorial revisions. 
Minor, have therefore not been summarized. 
 
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Table of contents 
Clinical trial protocol statements ............................................................................................ 2 
Table of contents ....................................................................................................................... 5 
List of panels ............................................................................................................................. 9 
List of abbreviations and definitions of terms ..................................................................... 11 
1 
Protocol synopsis ........................................................................................................... 14 
2 
Trial identification ........................................................................................................ 20 
3 
Schematic of trial design .............................................................................................. 20 
4 
Schedule of trial procedures ........................................................................................ 21 
5 
Introduction and trial rationale .................................................................................. 27 
5.1 
Chronic hand eczema ............................................................................................. 27 
5.2 
Experience with investigational medicinal product ............................................... 29 
5.3 
Trial rationale ......................................................................................................... 30 
5.4 
Ethical considerations ............................................................................................ 30 
5.4.1 
Parent/guardian ............................................................................................ 31 
5.4.2 
Caregiver ...................................................................................................... 32 
5.5 
Benefit/risk assessment .......................................................................................... 32 
6 
Trial objectives, estimands, and endpoints ................................................................. 35 
7 
Trial design .................................................................................................................... 40 
7.1 
Overall trial design................................................................................................. 40 
7.2 
Number of subjects needed .................................................................................... 41 
7.3 
End-of-trial definition ............................................................................................ 41 
8 
Trial population ............................................................................................................ 43 
8.1 
Subject eligibility ................................................................................................... 43 
8.2 
Inclusion criteria .................................................................................................... 43 
8.3 
Exclusion criteria ................................................................................................... 44 
8.4 
Screening and screening failures ........................................................................... 46 
9 
Treatments ..................................................................................................................... 48 
9.1 
Trial product description ........................................................................................ 48 
9.2 
Administration of investigational medicinal product ............................................ 48 
9.3 
Treatment assignment and blinding ....................................................................... 49 
9.3.1 
Treatment assignment .................................................................................. 49 
9.3.2 
Blinding ....................................................................................................... 50 
9.3.3 
Emergency unblinding of individual subject treatment ............................... 50 
9.4 
Background treatment ............................................................................................ 50 
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9.5 
Rescue treatment .................................................................................................... 51 
9.6 
Concomitant medication and concurrent procedures............................................. 51 
9.7 
Prohibited medications and procedures ................................................................. 52 
9.8 
Treatment logistics and accountability .................................................................. 54 
9.8.1 
Labelling and packaging of trial products ................................................... 54 
9.8.2 
Storage of trial products ............................................................................... 54 
9.8.3 
Investigational medicinal product accountability ........................................ 55 
9.8.4 
Treatment compliance .................................................................................. 56 
9.8.5 
Trial product destruction .............................................................................. 56 
9.9 
Provision for subject care following trial completion ........................................... 56 
9.10 
Reporting product complaints ................................................................................ 56 
10 
Discontinuation and withdrawal ................................................................................. 58 
10.1 
General principles .................................................................................................. 58 
10.2 
Reasons for permanent discontinuation of IMP .................................................... 58 
10.3 
Early termination assessments ............................................................................... 59 
10.4 
Lost to follow-up ................................................................................................... 60 
11 
Trial assessments and procedures ............................................................................... 61 
11.1 
Overview ................................................................................................................ 61 
11.2 
Assessments performed only at screening/baseline ............................................... 61 
11.2.1 
Demographics .............................................................................................. 61 
11.2.2 
Medical history ............................................................................................ 62 
11.2.3 
Height and weight ........................................................................................ 64 
11.2.4 
Determination of treatment area .................................................................. 64 
11.2.5 
Classification of CHE .................................................................................. 64 
11.3 
eDiary assessments ................................................................................................ 65 
11.4 
Efficacy assessments .............................................................................................. 66 
11.4.1 
Investigator’s Global Assessment for chronic hand eczema©...................... 66 
11.4.2 
Hand Eczema Severity Index ....................................................................... 67 
11.4.3 
Patient-reported outcomes (efficacy) ........................................................... 68 
11.5 
Safety assessments ................................................................................................. 69 
11.5.1 
Vital signs .................................................................................................... 69 
11.5.2 
Physical examination ................................................................................... 70 
11.5.3 
Electrocardiography ..................................................................................... 70 
11.5.4 
Local tolerability .......................................................................................... 72 
11.5.5 
Laboratory testing ........................................................................................ 72 
11.6 
Pharmacokinetic assessments ................................................................................ 75 
11.7 
Pharmacodynamics assessments ............................................................................ 76 
11.8 
Other assessments .................................................................................................. 76 
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11.8.1 
Patient-reported outcomes ........................................................................... 76 
11.9 
End of trial ............................................................................................................. 77 
11.10 Estimate of total blood volume collected .............................................................. 77 
11.11 Storage of biological samples ................................................................................ 78 
12 
Scientific rationale for trial design and appropriateness of assessments ................ 79 
12.1 
Scientific rationale for trial design......................................................................... 79 
12.2 
Appropriateness of assessments............................................................................. 80 
13 
Adverse events .............................................................................................................. 82 
13.1 
Definition and classification of adverse events ..................................................... 82 
13.2 
Collection of adverse event reports ....................................................................... 82 
13.3 
Reporting of adverse events ................................................................................... 82 
13.4 
Reporting of serious adverse events ...................................................................... 83 
13.4.1 
Investigator reporting responsibilities ......................................................... 83 
13.4.2 
LEO Pharma reporting responsibilities ........................................................ 84 
13.5 
Other events that require expedited reporting ........................................................ 85 
13.5.1 
Pregnancy ..................................................................................................... 85 
13.6 
Reporting of other events ....................................................................................... 85 
13.6.1 
Adverse events of special interest ................................................................ 85 
13.6.2 
Medication error .......................................................................................... 86 
13.6.3 
Misuse or abuse ........................................................................................... 86 
13.6.4 
Aggravation of condition ............................................................................. 87 
13.7 
Follow-up for final outcome of adverse events ..................................................... 87 
13.8 
Handling of an urgent safety measure ................................................................... 87 
14 
Statistical methods ........................................................................................................ 89 
14.1 
Sample size ............................................................................................................ 89 
14.2 
Trial analysis sets ................................................................................................... 89 
14.3 
Statistical analysis .................................................................................................. 89 
14.3.1 
Disposition of subjects ................................................................................. 89 
14.3.2 
Demographics and other baseline characteristics ........................................ 90 
14.3.3 
Exposure and treatment compliance ............................................................ 90 
14.3.4 
Testing strategy and establishing confirmatory evidence using 
Bayesian analysis ......................................................................................... 90 
14.3.5 
Estimand strategy ......................................................................................... 91 
14.3.6 
Primary endpoint analysis, Frequentist approach ........................................ 95 
14.3.7 
Primary endpoint analysis, Bayesian approach ........................................... 96 
14.3.8 
Key secondary endpoint analysis, Frequentist approach ............................. 96 
14.3.9 
Key secondary endpoint analysis, Bayesian approach ................................ 97 
14.3.10 
Secondary endpoint analysis, Frequentist approach .................................... 97 
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14.3.11 
Exploratory analyses, Frequentist approach ................................................ 98 
14.3.12 
Analysis of pharmacokinetics .................................................................... 100 
14.3.13 
Safety analysis ........................................................................................... 100 
14.3.14 
Interim analysis .......................................................................................... 101 
14.3.15 
General principles ...................................................................................... 101 
14.3.16 
Handling of missing values ........................................................................ 102 
14.3.17 
Description of the Bayesian analyses and design characteristics .............. 102 
15 
References .................................................................................................................... 125 
Appendix 1: Definitions of adverse events and serious adverse events ........................... 130 
Appendix 2: Classification of adverse events ..................................................................... 132 
Appendix 3: Trial governance considerations ................................................................... 134 
Appendix 3A: Regulatory and ethical considerations ................................................ 134 
Appendix 3B: Informed consent/assent process ........................................................ 134 
Appendix 3C: Subject and data confidentiality .......................................................... 135 
Appendix 3D: Record keeping, quality control, and data handling ........................... 137 
Appendix 3E: Registration, reporting, and publication policy ................................... 140 
Appendix 3F: Insurance ............................................................................................. 141 
Appendix 3G: Financial disclosure ............................................................................ 141 
Appendix 3H: Committee structure ........................................................................... 141 
Appendix 3I: Trial and trial site closure ..................................................................... 142 
Appendix 3J: Responsibilities .................................................................................... 143 
Appendix 4: Country-specific requirements ...................................................................... 144 
Appendix 5: Short version eligibility criteria .................................................................... 145 
Appendix 6: Contact list ...................................................................................................... 148 
Appendix 7: COVID-19 pandemic contingency plan........................................................ 149 
Appendix 8: Acceptable methods of birth control ............................................................. 151 
 
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List of panels 
Panel 1: Trial design ................................................................................................................. 20 
Panel 2: Schedule of trial procedures ....................................................................................... 21 
Panel 3: Objectives and estimands for primary, key secondary, and secondary endpoints ...... 36 
Panel 4: Secondary and exploratory objectives and endpoints ................................................ 38 
Panel 5: Identification of investigational medicinal products .................................................. 48 
Panel 6: Excipients of delgocitinib cream 20 mg/g and cream vehicle ................................... 48 
Panel 7: Prohibited medications and procedures ...................................................................... 53 
Panel 8: Fitzpatrick skin classification ..................................................................................... 62 
Panel 9: Definition of subtypes of hand eczema ...................................................................... 65 
Panel 10: Investigator’s Global Assessment for chronic hand eczema© .................................. 67 
Panel 11: HECSI severity score scale and area score scale ..................................................... 68 
Panel 12: Calculation of the total HECSI score ....................................................................... 68 
Panel 13: Subject assessment of local tolerability after IMP application ................................ 72 
Panel 14: Clinical laboratory tests performed by the central laboratory .................................. 73 
Panel 15: Adverse events of special interest ............................................................................ 85 
Panel 16: Graphical display of the testing procedure for primary and secondary 
endpoints ............................................................................................................. 91 
Panel 17: Handling of observed and missing data according to the intercurrent events for 
the primary analysis estimands ........................................................................... 93 
Panel 18: Overview of estimand and missing data strategy used for the key secondary 
endpoints ............................................................................................................. 97 
Panel 19: Overview of estimand and missing data strategy used for secondary endpoints ..... 98 
Panel 20: Overview of estimand and missing data strategy used for exploratory 
endpoints ............................................................................................................. 99 
Panel 21: Results of primary endpoint IGA-CHE TS, trials LP0133-1401 and 
LP0133-1402 ..................................................................................................... 103 
Panel 22: Summary of MAP for cream vehicle ..................................................................... 104 
Panel 23: Forest plot for the MAP for cream vehicle ............................................................. 104 
Panel 24: Parametric mixture density and histogram of the MCMC samples for cream 
vehicle ............................................................................................................... 105 
Panel 25: Prior components for cream vehicle after robustification ...................................... 105 
Panel 26: Summary of MAP for delgocitinib cream 20 mg/g ................................................ 106 
Panel 27: Forest plot for the MAP for delgocitinib cream 20 mg/g ....................................... 106 
Panel 28: Parametric mixture density and histogram of the MCMC samples for 
delgocitinib cream 20 mg/g ............................................................................... 107 
Panel 29: Prior components for delgocitinib cream 20 mg/g after robustification ................ 107 
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Panel 30: The ESS as a function of the level of τ and the weight put on the non-
informative part of the robust prior for the primary endpoint IGA-CHE TS 
at Week 16 ......................................................................................................... 108 
Panel 31: The level of type I error and power as a function of the difference in 
proportion of IGA-CHE TS responders at Week 16, split on the level of τ 
and the weight put on the non-informative part of the robust prior .................. 109 
Panel 32: Hypothetical outcome in trial LP0133-1426, example 1 ....................................... 110 
Panel 33: Sensitivity analysis of the influence of weight on non-informative part of prior 
when results in LP0133-1426 are close to the results in the adult trials 
(LP0133-1401 and LP0133-1402) .................................................................... 111 
Panel 34: Hypothetical outcome in trial LP0133-1426, example 2 ....................................... 111 
Panel 35: Sensitivity analysis when results from the adolescent’s trial differ from the 
results from the adult trials ................................................................................ 112 
Panel 36: HECSI-90 results, trials LP0133-1273, LP013-1401, and LP0133-1402 .............. 113 
Panel 37: The level of type I error and power as a function of the difference in 
proportion of responders, split on the level of τ and the weight put on the 
non-informative part of the robust prior for HECSI-90 .................................... 114 
Panel 38: The ESS as a function of the level of τ and the weight put on the non-
informative part of the robust prior for HECSI-90 ........................................... 115 
Panel 39: Reduction of HESD ≥4 from baseline, trials LP0133-1273, LP0133-1401, and 
LP0133-1402 ..................................................................................................... 116 
Panel 40: The level of type I error and power as a function of the difference in 
proportion of responders, split on the level of τ and the weight put on the 
non-informative part of the robust prior for HESD≥4 ...................................... 117 
Panel 41: The ESS as a function of the level of τ and the weight put on the non-
informative part of the robust prior for HESD≥4 .............................................. 118 
Panel 42: HESD itch ≥4 from baseline, trials LP0133-1273, LP0133-1401, and 
LP0133-1402 ..................................................................................................... 119 
Panel 43: The level of type I error and power as a function of the difference in 
proportion of responders, split on the level of τ and the weight put on the 
non-informative part of the robust prior for HESD itch≥4 ............................... 120 
Panel 44: The ESS as a function of the level of τ and the weight put on the non-
informative part of the robust prior for HESD itch≥4 ....................................... 121 
Panel 45: Reduction of HESD pain ≥4, trials LP0133-1273, LP0133-1401, and 
LP0133-1402 ..................................................................................................... 122 
Panel 46: The level of type I error and power as a function of the difference in 
proportion of responders, split on the level of τ and the weight put on the 
non-informative part of the robust prior for HESD pain≥4 .............................. 123 
Panel 47: The ESS as a function of the level of τ and the weight put on the non-
informative part of the robust prior for HESD pain≥4 ...................................... 124 
 
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List of abbreviations and definitions of terms 
AD 
atopic dermatitis 
AE 
adverse event 
AESI 
adverse event of special interest 
Akaike 
information 
criterion 
a mathematical method for evaluating how well a model fits the data it was 
generated from 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
CDISC 
Clinical Data Interchange Standards Consortium 
cDLQI 
Children’s Dermatology Life Quality Index 
CHE 
Chronic hand eczema 
CI 
confidence interval 
CMH 
Cochran-Mantel-Haenszel 
CMO 
contract manufacturing organisation 
COVID-19 
coronavirus disease 2019 
CRA 
clinical research associate 
CRO 
contract research organisation 
CTR 
clinical trial report 
DLQI 
Dermatology Life Quality Index 
DMC 
data monitoring committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
eDiary 
electronic diary 
EMA 
European Medicine Agency 
EudraCT 
European Union Drug Regulating Authorities Clinical Trials database 
ePRO 
electronic patient-reported outcome 
ESS 
effective sample size 
FDA 
United States Food and Drug Administration 
GCP 
Good Clinical Practice 
HCP 
healthcare professional 
HECSI 
Hand Eczema Severity Index 
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HESCI-90 
at least 90% improvement in HECSI score from baseline 
HESD 
Hand Eczema Symptom Diary© 
HIV 
human immunodeficiency virus 
IA 
informed assent 
IC 
informed consent 
IAF 
informed assent form 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
ID 
identification number 
IE 
intercurrent event 
IEC 
independent ethics committee 
IGA-CHE 
Investigator’s Global Assessment for chronic hand eczema© 
IGA-CHE TS 
IGA-CHE treatment success, i.e. an IGA-CHE score of 0 (clear) or 1 
(almost clear) with a ≥2-step improvement from baseline 
IgE 
Immunoglobulin E 
IL 
Interleukin 
IMP 
investigational medicinal product 
IRB 
institutional review board 
IRT 
interactive response technology 
JAK 
Janus kinase 
LP0133-1273 
A randomized, vehicle-controlled, double-blind, dose-ranging phase 2b trial 
to investigate the efficacy, safety and PK/PD of twice-daily topical 
applications of delgocitinib cream 1, 3, 8, and 20 mg/g for 16 weeks in adult 
subjects with mild to severe chronic hand eczema 
LP0133-1401 
A randomized, vehicle-controlled, double-blind, phase 3 trial to investigate 
efficacy, safety and PD of twice-daily topical applications of delgocitinib 
cream 20 mg/g for a 16-week treatment period in adult subjects with 
moderate to severe chronic hand eczema 
LP0133-1402 
A randomized, vehicle-controlled, double-blind, phase 3 trial to investigate 
efficacy, safety and PK of twice-daily topical applications of delgocitinib 
cream 20 mg/g for a 16-week treatment period in adult subjects with 
moderate to severe chronic hand eczema 
MAP 
meta-analytic-predictive 
MAR 
missing at random 
MCMC 
Markov chain Monte Carlo 
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MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
multiple imputation 
PD 
pharmacodynamic(s) 
PDE-4 
phosphodiesterase-4 
PGA 
Physician’s Global Assessment 
PK 
pharmacokinetic(s) 
PRO 
patient-reported outcome 
PT 
preferred term 
PUVA 
psoralen ultraviolet A 
SAE 
serious adverse event 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SOC 
system organ class 
STAT 
signal transducer and activator of transcription 
Tau (τ) 
the between-trial heterogeneity parameter 
TCS 
topical corticosteroid(s) 
TS 
treatment success 
ULN 
upper limit of normal 
UVA1 
ultraviolet A1 
UVB 
ultraviolet B 
vs. 
versus 
WOCF 
worst observation carried forward  
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1 
Protocol synopsis 
Trial ID 
EudraCT no. 
LP0133-1426 
2021-006340-27 
Title of trial 
A phase 3 clinical trial to evaluate efficacy and safety of twice-daily 
applications of delgocitinib cream 20 mg/g compared with cream vehicle in 
adolescents 12-17 years of age with moderate to severe chronic hand eczema 
Short title of trial 
Efficacy and safety of delgocitinib cream in adolescents 12-17 years of age 
with moderate to severe chronic hand eczema 
Main objectives, 
estimands, and 
endpoints 
Objectives 
Estimand type and 
strategy 
Endpoints 
Primary objective: 
To evaluate the 
efficacy of twice-daily 
applications of 
delgocitinib cream 
20 mg/g compared 
with cream vehicle in 
the treatment of 
adolescents with 
moderate to severe 
CHE. 
Primary: 
• Composite strategy. 
 
Supplementary: 
• Treatment policy 
strategy. 
Primary endpoint: 
• IGA-CHE1 TS at Week 16. 
(IGA-CHE TS refers to a 
score of 0 [clear] or 1 
[almost clear] with a 
≥2-step improvement from 
baseline). 
Primary: 
• Composite strategy. 
Key secondary endpoint: 
• HECSI-902 at Week 16. 
Primary: 
• Composite strategy 
Secondary endpoint: 
• IGA-CHE TS at Weeks 2, 
4, 8, and 12. 
Secondary objective: 
To evaluate the health-
related quality of life 
and efficacy of 
twice-daily 
applications of 
delgocitinib cream 
20 mg/g compared 
with cream vehicle in 
the treatment of 
adolescents with 
moderate to severe 
CHE. 
Primary: 
• Composite strategy 
• Key secondary endpoints: 
• Reduction of HESD3 itch 
score (weekly average) of 
≥4 points from baseline at 
Week 16.4 
• Reduction of HESD pain 
score (weekly average) of 
≥4 points from baseline at 
Week 16.5 
• Reduction of HESD score 
(weekly average) of 
≥4 points from baseline at 
Week 16.6 
• Secondary endpoint: 
• Change in cDLQI score 
from baseline to Week 16. 
Secondary objective: 
To evaluate the safety 
of twice-daily 
Not applicable. 
 
Secondary endpoint: 
• Number of 
treatment-emergent7 AEs 
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applications of 
delgocitinib cream 
20 mg/g in the 
treatment of 
adolescents with 
moderate to severe 
CHE. 
from baseline up to 
Week 18. 
 
1) The IGA-CHE is an instrument used in clinical trials to rate the severity of the 
subject’s global CHE and is based on a 5-point scale ranging from 0 (clear) to 4 
(severe). 
2) The HECSI is an instrument used in clinical trials to rate the severity of 6 clinical 
signs (erythema, infiltration/papulation, vesicles, fissures, scaling, and oedema) and 
the extent of the lesions on each of the 5 hand areas (fingertips, fingers [except 
fingertips], palm of hands, back of hands, and wrists) by use of standard scales. 
3) The HESD is an eDiary in which subjects will assess the worst severity of 6 
symptoms of CHE (itch, pain, cracking, redness, dryness, flaking) over the past 
24 hours using an 11-point scale. 
4) Among subjects with a baseline HESD itch score (weekly average) ≥4 points. 
5) Among subjects with a baseline HESD pain score (weekly average) ≥4 points. 
6) Among subjects with a baseline HESD score (weekly average) ≥4 points. 
7) An event will be considered treatment emergent if started after the first application 
of IMP or if started before the first application of IMP and worsened in severity after 
first dose of IMP. 
Abbreviations: AE = adverse event; cDLQI =  Children’s Dermatology Life Quality 
Index; CHE = chronic hand eczema; eDiary = electronic diary; HECSI = Hand 
Eczema Severity Index; HECSI-75 = at least 75% improvement in HECSI score from 
baseline; HECSI-90 = at least 90% improvement in HECSI score from baseline; 
HESD = Hand Eczema Symptom Diary©; IGA-CHE = Investigator’s Global 
Assessment for chronic hand eczema©; IGA-CHE TS = IGA-CHE treatment success, 
i.e. an IGA-CHE score of 0 (clear) or 1 (almost clear) with a ≥2-step improvement 
from baseline; TS = treatment success. 
Final collection 
of data for the 
primary endpoint 
Week 16. 
Trial design 
The trial is a phase 3 randomised, double-blind, vehicle-controlled, parallel-
group, multi-site trial in which adolescent 12-17 years of age with moderate to 
severe CHE will be treated with delgocitinib cream 20 mg/g or cream vehicle 
for 16 weeks. 
The trial consists of a screening period, a treatment period, and a follow-up 
period. 
Screening period 
The screening period has a minimum duration of 1 week and a maximum 
duration of 4 weeks. At the screening visit, the subjects’ eligibility to enter the 
trial will be checked, and wash-out of treatments listed as exclusion criteria 
will be initiated if applicable. The subjects will receive an eDiary device and 
training in completion of the eDiary. 
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Treatment period 
At baseline (Day 1), the subjects’ eligibility to enter the trial will be 
confirmed. Eligible subjects will be randomised 3:1 to treatment with 
delgocitinib cream 20 mg/g or cream vehicle. The randomisation will be 
stratified by the baseline severity of CHE according to IGA-CHE (moderate 
to severe). 
The first application of IMP will occur at the trial site at baseline (Day 1). All 
subsequent IMP application will be performed by the subjects/caregivers at 
home twice daily for 16 weeks. During the treatment period, the subjects will 
be required to return to the trial site for the visits scheduled at Weeks 2, 4, 8, 
12, and 16. The subject will apply the last IMP application prior to the 
scheduled visit at Week 16. 
Follow-up period 
Subjects will be followed-up via phone (can be a site visit if needed) 
approximately 2 weeks after the last IMP application for assessment of safety.  
 
* For subjects using treatments that are listed as exclusion criteria, the duration of the 
screening period will depend on the required wash-out period as defined in 
Section 8.3. In view of a 28-day wash-out for some of these treatments and the 
allowed visit window (+3 days), the screening period can be extended up to 
31 days. 
Abbreviations: d = day; IGA-CHE = Investigator’s Global Assessment for chronic 
hand eczema©; N = number of subjects; w = week. 
Main assessments 
Investigator assessment of efficacy: 
• 
IGA-CHE for assessment of disease severity. 
• 
HECSI for assessment of the clinical signs of CHE. 
Subject assessment of efficacy and health-related quality of life; PROs 
• 
HESD. 
• 
cDLQI. 
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Safety assessments: 
Vital signs, physical examination, ECG, laboratory testing, subject assessment 
of local tolerability, and AE reporting. 
Main criteria for 
inclusion 
• 
Age 12 to 17 years at screening and baseline. 
• 
Diagnosis of CHE, defined as hand eczema that has persisted for 
more than 3 months or returned twice or more within the last 
12 months.  
• 
Disease severity graded as moderate to severe at screening and 
baseline according to IGA-CHE (i.e. an IGA-CHE score of 3 or 4). 
• 
Subjects who have a documented history of inadequate response to 
treatment with TCS (at any time within 1 year before the screening 
visit) or for whom TCS are documented to be otherwise medically 
inadvisable (e.g. due to important side effects or safety risks). 
− Inadequate response is defined as a history of failure to 
achieve and maintain a low disease activity state (comparable 
to an IGA-CHE score of ≤2) despite treatment with a daily 
regimen of TCS of class III-IV (potent to very potent) for 
Europe and Australia and class IV-I (medium potency to 
very/ultra-high potency) for Canada, applied for at least 28 
days or for the maximum duration recommended by the 
product prescribing information, whichever is shorter. 
− Important side effects or safety risks are those that outweigh 
the potential treatment benefits and include intolerance to 
treatment, hypersensitivity reactions, and significant skin 
atrophy as assessed by the physician. 
Main criteria for 
exclusion 
• 
Concurrent skin disease on the hands, e.g tinea manuum. 
• 
Clinically significant infection (e.g. impetiginised hand eczema) on 
the hands. 
• 
Systemic treatment with immunosuppressive drugs (e.g. methotrexate, 
cyclosporine, azathioprine), immunomodulating drugs, retinoids (e.g. 
alitretinoin), or corticosteroids within 28 days prior to baseline 
(steroid eyedrops and inhaled or intranasal steroids corresponding to 
up to 1 mg prednisolone for allergic conjunctivitis, asthma, or rhinitis 
are allowed). 
• 
Use of tanning beds, phototherapy (e.g. UVB, UVA1, PUVA), or 
bleach baths on the hands within 28 days prior to baseline. 
• 
Previous or current treatment with JAK inhibitors (including 
delgocitinib/LEO 124249), systemic or topical. 
• 
Cutaneously applied treatment with immunomodulators (e.g. 
PDE-4 inhibitors, pimecrolimus, tacrolimus) or TCS on the hands 
within 14 days prior to baseline. 
• 
Use of systemic antibiotics or cutaneously applied antibiotics on the 
hands within 14 days prior to baseline. 
• 
Other cutaneously applied therapy on the hands (except for the use of 
subject’s own emollients) within 7 days prior to baseline. 
• 
Cutaneously applied treatments in regions other than the hands, which 
could interfere with clinical trial evaluations or pose a safety concern 
within 7 days prior to baseline. 
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• 
Any disorder which is not stable and could: 
− Affect the safety of the subject throughout the trial. 
− Impede the subject’s ability to complete the trial. 
Examples include but are not limited to cardiovascular, 
gastrointestinal, hepatic, renal, neurological, musculoskeletal, 
infectious, endocrine, metabolic, haematological, immunological, and 
psychiatric disorders, and major physical impairment. 
Investigational 
medicinal product 
 
• 
Name of IMP: delgocitinib cream. 
• 
Active substance: delgocitinib. 
• 
Dosage form: cream. 
• 
Concentration: 20 m/g and cream vehicle. 
• 
Dose: twice-daily. 
• 
Method of administration: topical administration. 
Duration of trial 
participation 
The duration of trial participation will be approximately 22 weeks, consisting 
of a screening period of up to 4 weeks, a treatment period of 16 weeks, and a 
safety follow-up period of 2 weeks. 
Number of 
subjects 
A total of 92 subjects will be randomised 3:1 to delgocitinib cream 20 mg/g or 
cream vehicle. 
Number and 
distribution of 
trial sites 
Approximately 40 sites in Europe, Canada, and Australia. 
Statistical 
methods 
The Bayesian analyses of the primary estimand for the primary and key 
secondary endpoints are considered the confirmatory evidence for the trial. 
The treatment effect (defined as proportion of responders for delgocitinib 
cream 20 mg/g minus the proportion of responders for cream vehicle) for all 
the binary confirmatory endpoints will be evaluated based on the calculated 
difference of posterior distributions for delgocitinib cream 20 mg/g and cream 
vehicle. Delgocitinib cream 20 mg/g is considered superior to cream vehicle if 
the 2.5% percentile of the posterior distribution of the treatment difference is 
≥0.  
Hierarchical evaluation, which is applied for the Bayesian analyses, will be 
used to control the overall type I error at a nominal one-sided 2.5% level. This 
is based on the principle that the IGA-CHE TS superiority at Week 16 will 
have to be established before sequential testing for additional benefits (key 
secondary endpoints) related to efficacy. The primary estimand will use a 
composite strategy to handle IEs. With a composite strategy, the occurrence 
of an IE is a component of the endpoint.  
For the primary and the key-secondary endpoints, Frequentist analyses will be 
conducted in addition to the Bayesian analysis. The Frequentist analyses for 
the primary estimand for the binary endpoints will be a logistic regression 
model including treatment group and baseline IGA-CHE score as factors. The 
logistic regression model will be applied to estimate the risk difference and 
associated 95% confidence interval.  
Other estimands for the primary and key-secondary endpoints as well as 
secondary endpoints will only be analysed using the Frequentist approach.  
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Signatory 
investigator 
, MD. 
, Canada  
Sponsor 
LEO Pharma A/S, Industriparken 55, DK 2750 Ballerup, Denmark 
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2 
Trial identification 
EudraCT number: 2021-006340-27. 
The clinical trial protocol will be registered in local registries if required by local legislation. 
3 
Schematic of trial design 
Panel 1: Trial design 
 
* For subjects using treatments that are listed as exclusion criteria, the duration of the screening period will depend on the 
required wash-out period as defined in Section 8.3. In view of a 28-day wash-out for some of these treatments and the 
allowed visit window (+3 days), the screening period can be extended up to 31 days. 
Abbreviations: d = day; IGA-CHE = Investigator’s Global Assessment for chronic hand eczema©; N = number of subjects; 
w = week. 
 
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4 
Schedule of trial procedures 
Panel 2: Schedule of trial procedures 
 
Screening 
Treatment period 
 
 
Primary 
endpoint 
visit at 
Week 16, if 
applicable3 
Follow-up2 
Unscheduled 
visit, if 
applicable4 
End of 
treatment 
Early 
termination, 
if applicable1 
Visit 
1 
2 
3 
4 
5 
6 
7 
(8) 
(9) 
10 
Week 
-4 to -1 
0 
2 
4 
8 
12 
16 
- 
- 
18 
Day 
-285 to -7 
1 
15 
29 
57 
85 
113 
- 
- 
1276 
Visit window (days)7 
+3 
NA 
±3 
±3 
±3 
±3 
±3 
- 
- 
±3 
Trial population and eligibility 
IC/IA8 
X 
 
 
 
 
 
 
 
 
 
 
Subject eligibility 
X 
X 
 
 
 
 
 
 
 
 
 
Investigator assessments at screening/baseline only 
Demographics  
X 
 
 
 
 
 
 
 
 
 
 
Fitzpatrick skin type 
X 
 
 
 
 
 
 
 
 
 
 
Medical history (including 
CHE treatment history)9 
X 
 
 
 
 
 
 
 
 
 
 
Classification of CHE 
(including patch test if 
standard clinical practice)10 
X 
 
 
 
 
 
 
 
 
 
(X) 
Height and weight 
 
X 
 
 
 
 
X 
 
 
 
 
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Screening 
Treatment period 
 
 
Primary 
endpoint 
visit at 
Week 16, if 
applicable3 
Follow-up2 
Unscheduled 
visit, if 
applicable4 
End of 
treatment 
Early 
termination, 
if applicable1 
Visit 
1 
2 
3 
4 
5 
6 
7 
(8) 
(9) 
10 
Week 
-4 to -1 
0 
2 
4 
8 
12 
16 
- 
- 
18 
Day 
-285 to -7 
1 
15 
29 
57 
85 
113 
- 
- 
1276 
Visit window (days)7 
+3 
NA 
±3 
±3 
±3 
±3 
±3 
- 
- 
±3 
Determination of treatment 
area(s) 
 
X 
 
 
 
 
 
 
 
 
(X) 
eDiary handout/training 
X 
 
 
 
 
 
 
 
 
 
 
Treatment and randomisation 
Randomisation 
 
X 
 
 
 
 
 
 
 
 
 
Dispensing of IMP 
 
X 
X 
X 
X 
X 
 
 
 
 
(X) 
Instruction for IMP application 
 
X 
 
 
 
 
 
 
 
 
 
Application of IMP 
 
Twice-daily 
 
 
 
Treatment compliance 
 
Daily11 
X11 
X11 
 
 
 
Return of IMP and 
accountability12 
 
 
X 
X 
X 
X 
X 
X 
 
 
(X) 
Concomitant medication and 
concurrent procedures13 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Investigator assessments of efficacy 
IGA-CHE 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
HECSI 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
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Screening 
Treatment period 
 
 
Primary 
endpoint 
visit at 
Week 16, if 
applicable3 
Follow-up2 
Unscheduled 
visit, if 
applicable4 
End of 
treatment 
Early 
termination, 
if applicable1 
Visit 
1 
2 
3 
4 
5 
6 
7 
(8) 
(9) 
10 
Week 
-4 to -1 
0 
2 
4 
8 
12 
16 
- 
- 
18 
Day 
-285 to -7 
1 
15 
29 
57 
85 
113 
- 
- 
1276 
Visit window (days)7 
+3 
NA 
±3 
±3 
±3 
±3 
±3 
- 
- 
±3 
Subject assessment of efficacy – daily 
eDiary completion: HESD14 
Daily 
X 
 
 
Subject assessments of efficacy and health-related quality of life – during trial visits 
cDLQI 
X 
X 
 
X 
 
 
X 
X 
 
 
 
Subject assessment of safety 
Subject assessment of local 
tolerability 
 
Weekly15 
X 
X 
 
 
 
Investigator assessments of safety 
Vital signs 
X 
X 
 
 
 
 
X 
X 
 
 
(X) 
Physical examination 
X 
 
 
 
 
 
X 
X 
 
 
(X) 
ECG 
X 
 
 
 
 
 
X 
X 
 
 
(X) 
Chemistry, haematology 
(central laboratory)16 
X 
X 
 
 
X 
 
X 
X 
  
 
(X) 
Serology, total IgE (central 
laboratory) 
X 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test17 
X 
X 
 
X 
X 
X 
X 
X 
 
 
(X) 
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Screening 
Treatment period 
 
 
Primary 
endpoint 
visit at 
Week 16, if 
applicable3 
Follow-up2 
Unscheduled 
visit, if 
applicable4 
End of 
treatment 
Early 
termination, 
if applicable1 
Visit 
1 
2 
3 
4 
5 
6 
7 
(8) 
(9) 
10 
Week 
-4 to -1 
0 
2 
4 
8 
12 
16 
- 
- 
18 
Day 
-285 to -7 
1 
15 
29 
57 
85 
113 
- 
- 
1276 
Visit window (days)7 
+3 
NA 
±3 
±3 
±3 
±3 
±3 
- 
- 
±3 
Urinalysis  
(urine dipstick) 
X 
 
 
 
 
 
X 
X 
 
 
(X) 
AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Other assessments 
New CHE lesions 
 
 
X 
X 
X 
X 
 
 
 
 
(X) 
PK blood sample18 
 
 
 
 
X 
 
X 
 
 
 
 
Return of eDiary (if 
applicable)19 
 
 
 
 
 
 
X 
X 
X 
 
 
End of treatment/trial 
End-of-treatment form 
 
 
 
 
 
 
X 
X 
 
 
 
End-of-trial form20 
 
 
 
 
 
 
 
X 
X 
X 
(X) 
1. Subjects who discontinue IMP prior to Week 16 or withdraw from trial will be asked to return to the trial site for 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 16 except PK blood sample. Subjects who discontinue IMP 
treatment will also be asked to return to the trial site at Week 16 (see footnote 3). 
2. Subjects will be followed-up via phone (can be a site visit if needed) approximately 2 weeks after the last IMP application for assessment of safety. 
3. Subjects who discontinue IMP treatment prior to Week 16 will be asked to return to the trial site at Week 16 (scheduled 113 days after baseline) for a primary 
efficacy endpoint visit. 
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4. Unscheduled visits may occur if subjects need to make a visit in between the scheduled visit dates e.g. due to an AE or due to a significant change in their 
disease state. Assessment of AEs and concomitant medication will always be performed at unscheduled visits; other assessments to be performed at 
unscheduled visits will be at the discretion of the investigator. 
5. For subjects using treatments that are listed as exclusion criteria, the duration of the screening period will depend on the required wash-out period as defined in 
the relevant exclusion criteria. In view of a 28-day wash-out for some of these treatments and the allowed visit window (+3 days), the screening period can be 
extended up to 31 days. 
6. As the follow-up visit will be scheduled approximately 2 weeks after the last IMP application, the follow-up visit can occur before Week 18/Day 127 for 
subjects who discontinue IMP prior to Week 16. 
7. If the date of a trial visit does not conform to the clinical trial protocol, subsequent visits should be planned to maintain the visit schedule relative to baseline 
(Day 1) (except for the follow-up visit which should be planned relative to the last application of IMP, see footnote 2). 
8. The ICF(s)/IAF(s) must be signed prior to performing any protocol-related procedures, including but not limited to screening evaluations and initiation of 
wash-out of treatments listed as exclusion criteria. 
9. Medical history (including CHE treatment history) within the previous 12 months should be recorded (see Section11.2.2). 
10. CHE subtype(s) will be classified according to local standard clinical practice (see Panel 9). Patch testing is recommended to be performed in accordance with 
the guideline (1) and if this is considered standard clinical practice at the trial site. For subjects who have had a patch test done within 3 years prior to 
screening, the results of the most recent patch test will be recorded in the eCRF. For subjects who have not had a patch test within 3 years prior to screening, a 
patch test will be done. Final reading of the patch test should preferably be performed prior to the baseline visit. If this is not possible, the patch test can be 
performed later but final reading must be available no later than the Week 8 visit. 
11. Treatment compliance will be recorded daily by the subject in the eDiary from Day 1 onwards up to end of treatment/early termination. 
12. All returned, opened IMP tubes will be weighed at the trial site. 
13. Concomitant medication should be included from 3 months prior to baseline (Day 1) until end of trial (see Section 9.6). 
14. Completion of the HESD eDiary will be initiated at least 1 week prior to baseline (Day 1), but preferably already from the date the subjects receive the eDiary. 
Compliance with the eDiary completion will be reviewed by the trial site staff throughout the trial. Subjects who discontinue IMP but remain in the trial will be 
asked to continue completing the eDiary until the primary endpoint visit at Week 16. A minimum of 4 HESD scores per week are required throughout the trial 
to calculate the average. The baseline HESD weekly average will be calculated based on daily assessments during the 7 days immediately preceding the 
baseline visit (Day -7 to Day -1). 
15. Subjects’ assessment of local tolerability will be evaluated weekly by the subject in the eDiary from Day 7 onwards up to end of treatment/early termination. 
16. Subjects do not have to be fasting for safety laboratory samples. 
17. For female subjects of childbearing potential (as defined in the relevant inclusion criterion). 
18. The PK blood samples should be taken 2-6 hours post application of IMP. 
19. Not applicable at the early termination visit if the subject does not withdraw from the trial, as subjects who discontinue IMP but remain in the trial will continue 
completing the eDiary until the primary efficacy endpoint visit at Week 16. 
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20. An end-of-trial form must be completed for all screened subjects. The form will be completed at the subjects’ last visit. 
Abbreviations: AE = adverse event; CHE = chronic hand eczema; cDLQI = Children’s Dermatology Life Quality Index: ECG = electrocardiogram; eCRF = 
electronic case report form; eDiary = electronic diary; HECSI = Hand Eczema Severity Index; HESD = Chronic Hand Eczema Symptom Diary©; IA = informed 
assent; IC = informed consent; IAF = informed assent form; ICF = informed consent form; IGA-CHE = Investigator’s Global Assessment for chronic hand 
eczema©; IgE = immunoglobulin E; IMP = investigational medicinal product; PK = pharmacokinetic. 
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5 
Introduction and trial rationale 
5.1 
Chronic hand eczema 
CHE is an inflammatory skin disorder located anywhere on the hands or wrists. It is clinically 
characterised by erythema, infiltration, hyperkeratosis, oedema, and vesicles. Secondary signs 
include scaling, fissures, and erosions, and the condition may be exacerbated by bacterial 
infections. Important symptoms include itch and pain, and the disease is often characterised 
by chronic relapses and a poor prognosis. 
CHE refers to hand eczema which persists for more than 3 months or returns twice or more 
often within 12 months (1). 
Hand eczema is usually multifactorial, and it is generally agreed that no simple relationships 
exist between clinical patterns and aetiological diagnoses (2). Several different classifications 
have been proposed (1, 3, 4), and the most common subtypes of CHE are found to be irritant 
contact dermatitis, atopic hand eczema, and hyperkeratotic eczema (5). Other subtypes 
include allergic contact dermatitis, contact urticaria/protein contact dermatitis, and recurrent 
vesicular hand eczema (pompholyx) (1). 
The reported prevalence and incidence rates of hand eczema vary considerably, depending on 
the methodology in the collection of data. In a review of data available from 1964 to 2007, the 
point prevalence of hand eczema in the general population was approximately 4%, 1 year 
prevalence about 10%, and life time prevalence approached 15% (6). In another study by 
Thyssen et al. (7), approximately 7–10% of patients with hand eczema reported symptoms 
‘nearly all the time’, implying a chronic state of the disease. Based on data from 7 studies, the 
incidence rate of hand eczema was 5.5 cases/1000 person years with a higher median 
incidence rate among women (1). Several risk factors, such as pre-existing AD, female sex, 
wet work, and contact allergy have been identified (6, 8). The prevalence of hand eczema is 
different across age groups (6) with a mean/median first onset in the early or mid-20’ies (9-
11). However, approximately one third of men and women report their first hand eczema 
before the age of 20 (12). 
Only few studies have dealt with hand eczema in paediatric populations and limited 
information on the prevalence of hand eczema in paediatrics is available. One study (13) 
reported a 1-year prevalence of hand eczema of 7.3% in paediatrics aged 12-16 years and the 
prevalence seems to be lower in the paediatric population than in adults. This is likely to be 
explained by the occupational exposure in adults (13). A more recent study (14) reported a 
1-year prevalence of hand eczema of 5.2% and a life-time prevalence of hand eczema of 9.7% 
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in adolescents at the age of 16 years. This study also confirmed a strong association between 
hand eczema in adolescence and AD in childhood (15). The observation that AD in childhood 
may lead to more persistent and chronic hand eczema in adolescence may be explained by an 
impairment of the skin barrier of patients affected with AD that can facilitate allergic 
sensitisation to several substances (15, 16). 
The socioeconomic burden of CHE is significant. 5 studies in adults from 4 countries have 
found that total societal costs (direct and indirect) ranged between USD $1,924 and 
USD $8,212 (inflated to 2017 cost) per patient per year (1, 17-20). 
Although the molecular mechanisms underlying CHE are not fully understood, a large panel 
of cytokine mediated signalling cascades have been identified as part of the pathophysiology, 
including cytokine responses representing Th2 pathway (IL-4, IL-13), Th22 pathway (IL-22), 
Th17 pathway (IL-17), Th1 pathway (interferon-γ), and the JAK/STAT pathway. As the JAK 
proteins are required for signalling of most cytokines, blocking of JAKs reduces cytokine 
signalling and thereby abrogates the vicious cycle that leads to the development of CHE (16, 
21, 22). 
CHE is generally difficult to treat and presents with periods of flares and periods of 
remissions. Long-term disease control of CHE may require reactive treatment of flares and 
proactive treatment for the prevention of flares. 
Treatment of CHE involves different disease management strategies such as elimination of 
triggers, general skin care, and anti-inflammatory therapy in a step wise approach. General 
skin care in terms of emollients is widely used and recommended by physicians, but evidence 
of efficacy is sparse (1). Elimination of triggers such as allergens and irritants can be effective 
and a necessary prerequisite for successful therapy on a longer term, but elimination may in 
many circumstances be difficult to achieve. Although lacking documented treatment effect, 
TCS remain the mainstay of topical anti-inflammatory therapy for hand eczema. However, 
long-term use of TCS is restricted due to side effects such as skin atrophy and potential 
inhibition of skin barrier repair. 
Whereas mild CHE to some extent may be managed by elimination of triggers and general 
skin care, management of moderate to severe CHE is more cumbersome. Alitretinoin (23) is 
the only approved product specifically indicated for treatment of CHE but is only indicated 
for severe CHE and only approved in few countries worldwide. Alitretinoin treatment has 
various safety limitations and is therefore only indicated for use in adults who have severe 
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CHE that is unresponsive to treatment with potent TCS. There are currently no available 
treatment options indicated specifically for CHE in adolescents. 
Considering the paucity of approved therapies for the treatment of CHE in both adults and 
adolescents, other therapeutic options are limited to those approved for other skin diseases 
with an inflammatory pathophysiology. These treatments lack the clinical documentation for 
use in CHE and are restricted to short-term use which is not suitable in a chronic disorder 
characterised by relapsing features often resulting in long-term treatment exposure. As the 
currently available treatment options either lack documented treatment effect or are limited by 
restrictions of long-term use due to safety concerns (1, 24), there is a high unmet medical 
need for new topical treatment of moderate to severe CHE with high efficacy in combination 
with a favourable safety profile. Delgocitinib has the potential to address the unmet medical 
need associated with this serious skin disorder. 
5.2 
Experience with investigational medicinal product 
Delgocitinib (LEO 124249) is a pan JAK inhibitor, which blocks various cytokine mediated 
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 (25). 
In nonclinical studies, topically administered delgocitinib suppressed skin inflammation in rat 
and mouse AD- and psoriasis-like models and reduced IL-31-induced scratching in mice 
(current investigator’s brochure). Topical administration of delgocitinib was also shown to 
improve the impaired skin barrier function in mouse models and in human skin (26). 
The efficacy and safety of delgocitinib cream in CHE has been demonstrated in in a phase 2b 
dose-ranging trial (LP0133-1273) with delgocitinib cream (1, 3, 8, and 20 mg/g). 
In the phase 2b dose-ranging trial (LP0133-1273), delgocitinib cream (1, 3, 8, or 20 mg/g) 
was applied twice daily for 16 weeks in adult subjects with mild to severe CHE. For the 2 
highest doses of delgocitinib cream (8 mg/g and 20 mg/g), a statistically significant treatment 
effect was observed in terms of IGA-CHE TS at Week 16 (defined as achieving an IGA-CHE 
score of 0 [clear] or 1 [almost clear] with a ≥2-step reduction from baseline) and change from 
baseline in HECSI score at Week 16 compared with cream vehicle. For the population 
selected for the present trial (subjects with moderate to severe CHE), 40.2% of subjects on 
delgocitinib cream 8 mg/g and 20 mg/g (pooled data based on the results from the phase 
2b dose-ranging trial) achieved IGA-CHE TS at Week 16 vs. 10.5% in the cream vehicle 
group (p<0.05) (27). 
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For all doses, delgocitinib cream was well tolerated, and a low systemic exposure to 
delgocitinib was observed. 
Based on currently available nonclinical and clinical data, delgocitinib cream has the potential 
to become a novel local-acting immunomodulatory agent for topical treatment of CHE with a 
favourable safety profile. 
5.3 
Trial rationale 
The purpose of this phase 3 trial is to evaluate efficacy and safety of twice-daily applications 
of delgocitinib cream 20 mg/g compared with cream vehicle in adolescents 12-17 years of age 
with moderate to severe CHE. The trial will evaluate efficacy and safety after 16 weeks of 
twice-daily double-blind vehicle-controlled treatment.  
The strength of delgocitinib cream is selected based on results from the dose-ranging phase 2b 
trial LP013-1273, where delgocitinib cream 20 mg/g was shown to be effective and well-
tolerated (i.e. the majority of AEs were mild or moderate and not considered related to the 
treatment) in adult subjects with mild to severe CHE (see Section 5.2 for details and Section 
12 for the rationale for the selected dose and treatment duration).  
Based on the available nonclinical and clinical data, delgocitinib cream has the potential to 
become an effective and user-friendly treatment for CHE and thereby improve the everyday 
lives of affected patients. 
The primary endpoint defined for the primary estimand, addressing the primary objective, is 
selected to be IGA-CHE TS (an IGA-CHE score of 0 [clear] or 1 [almost clear] with a two-
step improvement from baseline) at Week 16 without IEs (initiation of rescue treatment or 
permanent discontinuation of IMP). IGA-CHE is a static global assessment of the disease 
severity of CHE rated by the investigator and is a feasible instrument in clinical practice. 
Initiation of rescue treatment or discontinuation of IMP may occur at the discretion of the 
investigator or the subject. Since such IEs most often are due to lack of efficacy or treatment 
features considered unacceptable by the subject, a composite strategy is chosen where the IEs 
are part of the primary estimand for the endpoint (i.e. subjects who experience IEs are 
considered non-responders to treatment). 
5.4 
Ethical considerations 
This trial will be conducted in accordance with the ethical principles that have their origins in 
the Declaration of Helsinki (28) and ICH GCP (29), and in compliance with the approved 
protocol and applicable regulatory requirements. 
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The trial design chosen is regarded as scientifically justified (see Section 12.1) and adheres to 
ethical standards that ensure the rights, safety, and wellbeing of the trial subjects. The efficacy 
and safety of delgocitinib cream 20 mg/g will be evaluated in adolescents 12-17 years of age 
with moderate to severe CHE who may benefit from treatment in the trial. Risks associated 
with treatment in this clinical trial (i.e. significant adverse reactions associated with dermal or 
systemic exposure to delgocitinib) are considered minimal due to the low systemic exposure 
observed in previous clinical trials with topically applied delgocitinib (see Section 5.2).  
A 3:1 randomisation is planned to increase the opportunity for subjects to receive active 
treatment. Trial subjects/subject’s parent/guardian will be informed at the screening visit that 
trial procedures prior to baseline may warrant an alteration of the subject’s ongoing 
concomitant treatments. To ensure subjects’ safety, investigators are informed only to enroll 
subjects who are considered able to stop prohibited treatment during the screening period 
without experiencing intolerable worsening of CHE symptoms. To mitigate the risk for 
worsening of CHE signs and/or symptoms during the treatment and follow-up period, rescue 
treatment may be prescribed to trial subjects at the discretion of the investigator (see Section 
9.5). Subjects/caregivers will be instructed to contact the investigator if subject’s CHE 
worsens significantly. 
Female subjects of childbearing potential must agree to use an acceptable birth control 
method to prevent pregnancy throughout the trial up until the last application of IMP.  
Age-appropriate explanations will be given prior to any investigation or procedure to decrease 
the likelihood of anxiety and distress.  
The subject’s and the parent’s/guardian’s right to withdraw from the trial or discontinue IMP 
at any time is ensured. If subjects are withdrawn from the trial, they will be treated at the 
investigator’s discretion or referred to other physician(s) according to standard practice. 
In accordance with the current version of ICH GCP, qualified medical personnel employed by 
LEO Pharma 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 Safety at LEO Pharma and by an independent Data Monitoring Committee (see 
Appendix 3H) to ensure that prompt action is taken, if needed to maximise patient safety. 
5.4.1 
Parent/guardian 
The parent/guardian is the subject’s legally authorised representative(s) authorised under 
applicable law to grant permission on behalf of the subject for their participation in trial 
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activities. The subject’s parent/guardian may also act as the subject’s caregiver (see Section 
5.4.2), but not necessarily vice versa.  
5.4.2 
Caregiver 
By ‘caregiver’ is understood an individual (often a parent or other family member) who can 
provide general care for the paediatric subject during the trial, e.g. assist in applying trial 
product on the subject’s skin. The caregiver will be trained via instructions for use, and such 
training must be documented by the trial site.  
5.5 
Benefit/risk assessment 
There are currently no approved treatment options indicated for adolescents with moderate to 
severe CHE and thus there is a high unmet medical need for new therapies for these subjects. 
Treatment with other therapies will be withheld from the subjects for up to 22 weeks. During 
the 16-week treatment period, 3 out of 4 subjects will receive active treatment with 
delgocitinib cream 20 mg/g which was shown to be effective in CHE in a phase 2b trial in 
adults (LP0133-1273, see Section 5.2). 1 out of 4 subjects will receive cream vehicle. All 
subjects may receive rescue treatment if required (Section 9.5), regardless of their treatment 
allocation.  
Delgocitinib is a topically applied JAK inhibitor. Systemic JAK inhibitors are associated with 
potential safety concerns of serious infections, all-cause mortalities, major adverse 
cardiovascular events, malignancies, deep vein thrombosis and pulmonary embolisms, lipid 
elevations and low blood cell counts. The potential safety concerns for systemic JAK 
inhibitors have also been included in the label for a topically applied JAK inhibitor approved 
for treatment of AD in the US. These potential safety concerns are however not considered a 
risk for delgocitinib cream due to the low systemic exposure and the current safety profile 
observed in completed and ongoing trials with delgocitinib in patients with CHE. 
No important identified risks of delgocitinib have been documented during the overall 
nonclinical and clinical development to date. Nevertheless, as observed with other topical 
therapies, local skin reactions, such as pain (burning and stinging), sensitisation to IMP, 
allergic and irritant contact dermatitis, local immunosuppression, and skin infections, may 
occur. A detailed overview of nonclinical and clinical data on delgocitinib is available in the 
current investigator’s brochure.  
The risk to subjects in this trial will be minimised by fulfilment of all eligibility criteria and 
by close clinical monitoring. To ensure the safety and wellbeing of subjects participating in 
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this trial, safety will be monitored during the trial, and stopping criteria have been defined 
(Section 10.2). 
The blood sampling procedure poses the same low risk as normally associated with this 
procedure (i.e. infection, bleeding into the surrounding tissue, and, very rarely, inflammation 
of the vein, or formation of blood clots). Blood sampling will only be conducted by 
authorised personnel and topical anaesthesia may be applied before venipuncture to minimise 
pain.   
Altogether, the risks associated with participating in this clinical trial are considered low and 
are expected to be outweighed by the benefit of a potential future treatment option for CHE. 
Participation in clinical trials may currently be associated with increased risk and added 
challenges due to the COVID-19 pandemic caused by SARS-CoV-2. The proposed trial is not 
believed to put subjects with CHE at an increased risk for viral infections including 
SARS-CoV-2. However, a risk of exposure to infected people cannot be excluded as the trial 
subjects may enter public areas (e.g. commute to the trial site) and have additional human 
contact (e.g. with trial site staff). Appropriate risk assessments and mitigation measures must 
be considered to protect the subjects and trial site staff and to ensure the integrity of the trial 
data. It is unknown whether treatment with delgocitinib cream 20 mg/g may predispose to 
COVID-19, but ongoing safety monitoring will ensure that all adverse events are 
continuously monitored. 
EMA (30), FDA (31), and national health authorities in Europe, Canada, and Australia have 
issued new guidelines that aim to provide recommendations for conduct of clinical trials 
during the COVID-19 pandemic. Given the circumstances of the potentially relapsing 
pandemic situation with regard to the spread of COVID-19 in the future, special attention will 
be paid to protecting subjects participating in the trial and site staff involved in the 
investigations against infection with SARS-CoV-2 as requested by the EMA or national 
guidelines. 
During the trial, the investigators will be trusted to take appropriate actions to ensure the 
safety of the individual subjects according to local authority issued preventive measures. As 
these can differ across countries and regions, no general instruction from the sponsor can be 
provided concerning subject safety and the need for postponing trial visits. In case of local 
authority issued preventive measures, the investigator can convert on-site visits into phone or 
video consultations. At phone/video visits, no investigator assessments of efficacy can be 
done. Safety monitoring remains an obligation to LEO Pharma, and it is considered feasible to 
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collect safety data such as AE data remotely (via electronic communication) where on-site 
visits are not possible. Other mitigating measures include collecting PRO data via a 
web-based solution and ensuring supply of IMP to the subjects to overcome local authority 
issued preventive measures due to the COVID-19 pandemic (see Appendix 7 for details). 
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6 
Trial objectives, estimands, and endpoints  
Panel 3 presents the objectives and estimands for the primary, key secondary endpoints, and 
secondary endpoints. Further details about the testing strategy, estimand strategy, and analysis 
of the primary, key secondary, and secondary endpoints are provided in Sections 14.3.4 to 
14.3.10. 
The secondary and exploratory objectives and endpoints are presented in Panel 4. The 
estimands and analyses for the exploratory efficacy endpoints are described in Section 
14.3.11.
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Panel 3: Objectives and estimands for primary, key secondary, and secondary endpoints 
Objectives 
Statistical 
approach 
Estimands 
Endpoints 
 
Bayesian/ 
Frequentist 
Estimand type (Primary/ 
Supplementary) 
Interpretation 
Intercurrent events and 
strategy 
Population 
level 
summary 
 
Primary objective:  
To evaluate the 
efficacy of 
twice-daily 
applications of 
delgocitinib cream 
20 mg/g compared 
with cream vehicle 
in the treatment of 
adolescents with 
moderate to severe 
CHE. 
Bayesian 
and 
Frequentist. 
Primary. 
Response 
achieved 
without IEs. 
Initiation of rescue treatment, 
permanent discontinuation of 
IMP. 
Composite strategy. 
Risk 
difference. 
Primary endpoint: 
• 
IGA-CHE TS at Week 16. 
(IGA-CHE TS refers to a 
score of 0 [clear] or 1 
[almost clear] with a 
≥2-step improvement from 
baseline). 
Frequentist. 
Supplementary. 
Response 
achieved 
regardless of 
IEs. 
Initiation of rescue treatment, 
permanent discontinuation of 
IMP. 
Treatment policy strategy. 
Bayesian 
and 
Frequentist. 
Primary. 
Response 
achieved 
without IEs. 
Initiation of rescue treatment, 
permanent discontinuation of 
IMP. 
Composite strategy. 
Risk 
difference. 
Key secondary endpoint: 
• 
HECSI-90 at Week 16. 
Frequentist. 
Primary. 
Response 
achieved 
without IEs. 
Initiation of rescue treatment, 
permanent discontinuation of 
IMP. 
Composite strategy. 
Risk 
difference. 
Secondary endpoint: 
• 
IGA-CHE TS at Weeks 2, 
4, 8, and 12. 
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Objectives 
Statistical 
approach 
Estimands 
Endpoints 
 
Bayesian/ 
Frequentist 
Estimand type (Primary/ 
Supplementary) 
Interpretation 
Intercurrent events and 
strategy 
Population 
level 
summary 
 
Secondary 
objectives:  
To evaluate the 
health-related 
quality of life of 
twice-daily 
applications of 
delgocitinib cream 
20 mg/g compared 
with cream vehicle 
in the treatment of 
adolescents with 
moderate to severe 
CHE. 
Bayesian 
and 
Frequentist. 
Primary. 
Response 
achieved 
without IEs. 
Initiation of rescue treatment, 
permanent discontinuation of 
IMP. 
Composite strategy. 
Risk 
difference. 
Key secondary endpoints: 
• 
Reduction of HESD itch 
score (weekly average) of 
≥4 points from baseline at 
Week 16.1 
• 
Reduction of HESD pain 
score (weekly average) of 
≥4 points from baseline at 
Week 16.2 
• 
Reduction of HESD score 
(weekly average) of 
≥4 points from baseline at 
Week 16.3 
Frequentist. 
Primary. 
Change from 
baseline to 
Week 16 
without IEs. 
Initiation of rescue treatment, 
permanent discontinuation of 
IMP. 
Composite strategy. 
Difference 
in mean 
change. 
Secondary endpoint: 
• 
Change in cDLQI score 
from baseline to Week 16. 
1) 
Among subjects with a baseline HESD itch score (weekly average) ≥4 points. 
2) 
Among subjects with a baseline HESD pain score (weekly average) ≥4 points. 
3) 
Among subjects with a baseline HESD score (weekly average) ≥4 points. 
Abbreviations: cDLQI = Children’s Dermatology Life Quality Index; CHE = chronic hand eczema; HECSI = Hand Eczema Severity Index; HECSI-90 = at least 90% improvement 
in HECSI score from baseline; HESD = Hand Eczema Symptom Diary©; IE = intercurrent event; IGA-CHE = Investigator’s Global Assessment for chronic hand eczema©; 
IGA-CHE TS = IGA-CHE treatment success, i.e. an IGA-CHE score of 0 (clear) or 1 (almost clear) with a ≥2-step improvement from baseline; TS = treatment success.
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Panel 4: Secondary and exploratory objectives and endpoints 
Objectives 
Statistical 
approach 
Endpoints 
Secondary objective 
 
Secondary endpoint1 
To evaluate the safety of 
twice-daily applications of 
delgocitinib cream 
20 mg/g in the treatment of 
adolescents with moderate 
to severe CHE. 
Frequentist. 
• 
Number of treatment-emergent2 AEs from baseline 
up to Week 18. 
Exploratory objectives 
 
Exploratory endpoints 
To evaluate the health-
related quality of life and 
efficacy of twice-daily 
applications of delgocitinib 
cream 20 mg/g compared 
with cream vehicle in the 
treatment of adolescents 
with moderate to severe 
CHE over time. 
Frequentist. 
Efficacy 
• 
HECSI-90 at Weeks 4 and 8. 
• 
HECSI-75 at Weeks 4, 8, and 16. 
• 
Percentage change in HECSI score from baseline to 
Weeks 4, 8, and 16. 
Health-related quality of life and efficacy 
• 
Reduction of HESD itch score (weekly average) of 
≥4 points from baseline at Weeks 2, 4, and 8.3 
• 
Reduction of HESD itch score (weekly average) of 
≥3 points from baseline at Weeks 2, 4, 8, and 16.4. 
• 
Change in HESD itch score (weekly average) from 
baseline to Weeks 2, 4, 8, and 16. 
• 
Reduction of HESD pain score (weekly average) of 
≥4 points from baseline at Weeks 2, 4, and 8.5 
• 
Reduction of HESD pain score (weekly average) of 
≥3 points from baseline at Weeks 2, 4, 8, and 16.6 
• 
Change in HESD pain score (weekly average) from 
baseline to Weeks 2, 4, 8, and 16. 
• 
Reduction of HESD score (weekly average) of 
≥4 points from baseline at Weeks 2, 4, and 8.7 
• 
Reduction of HESD score (weekly average) of 
≥3 points from baseline at Weeks 2, 4, 8, and 16.8 
• 
Change in HESD score (weekly average) from 
baseline to Weeks 2, 4, 8, and 16. 
• 
Change in cDLQI score from baseline to Week 4. 
1) 
In addition to the secondary safety endpoint listed, clinical laboratory tests, vital signs, and physical examination at 
screening and end of treatment; use of rescue treatment; and subjects’ assessment of local tolerability will be evaluated. 
2) 
An event will be considered treatment emergent if started after the first application of IMP or if started before the first 
application of IMP and worsened in severity after first dose of IMP. 
3) 
Among subjects with a baseline HESD itch score (weekly average) ≥4 points. 
4) 
Among subjects with a baseline HESD itch score (weekly average) ≥3 points. 
5) 
Among subjects with a baseline HESD pain score (weekly average) ≥4 points. 
6) 
Among subjects with a baseline HESD pain score (weekly average) ≥3 points. 
7) 
Among subjects with a baseline HESD score (weekly average) ≥4 points. 
8) 
Among subjects with a baseline HESD score (weekly average) ≥3 points. 
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Abbreviations: AE = adverse event; cDLQI = Children’s Dermatology Life Quality Index; CHE = chronic hand eczema; 
HECSI = Hand Eczema Severity Index; HECSI-75 = at least 75% improvement in HECSI score from baseline; HECSI-90 = 
at least 90% improvement in HECSI score from baseline; HESD = Hand Eczema Symptom Diary©. 
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7 
Trial design 
7.1 
Overall trial design 
This trial is a phase 3, randomised, double-blind, vehicle-controlled, parallel-group, multi-site 
trial. The trial is designed to evaluate the efficacy and safety of delgocitinib cream 20 mg/g 
applied twice-daily for 16 weeks in adolescents 12-17 years of age with moderate to severe 
chronic hand eczema. The trial design is illustrated in Section 3. 
Screening period (Week -4 to Week 0) 
The screening period has a minimum duration of 1 week and a maximum duration of 4 weeks 
(i.e. screening visit should take place between Week -4 and Week -1). For subjects using 
treatments that are listed as exclusion criteria, the duration of the screening period will depend 
on the required wash-out period as defined in Section 8.3. In view of a 28-day wash-out for 
some of these treatments and the allowed visit window (+3 days), the screening period can be 
extended up to 31 days. Only subjects who are considered able to stop prohibited treatment 
during the screening period without experiencing intolerable worsening of CHE signs and 
symptoms should be included in the trial.  
At the screening visit, the subjects’ eligibility to enter the trial will be checked. Trial-specific 
measurements will be performed as outlined in the schedule of trial procedures (Section 4). 
Subjects will receive an eDiary and training on how to fill it out during the screening period 
and the initial 16 weeks of treatment. Completion of the eDiary will be initiated preferably 
from the date the subjects receive the eDiary, and at the latest 1 week prior to the baseline 
visit on Day 1 (see Section 11.3). 
The subjects’ CHE subtype(s) will be classified according to standard clinical practice in 
Europe, Canada, and Australia. Patch testing is recommended to be performed in accordance 
with the guideline (1) and if this is considered standard clinical practice at the trial site. For 
subjects who have had a patch test performed within the last 3 years, the results from the most 
recent patch test can be used; otherwise, a new patch test should be performed. Final reading 
of the patch test should preferably be performed prior to the baseline visit. If this is not 
possible, the patch test can be done later but final reading must be available no later than the 
Week 8 visit. 
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Treatment period (Week 0 to 16) 
At baseline (Day 1), the subjects’ eligibility to enter the trial will be confirmed. Eligible 
subjects will be randomised 3:1 to either delgocitinib cream 20 mg/g or cream vehicle.  
Subjects/caregivers will apply the IMP (delgocitinib cream 20 mg/g or cream vehicle) 
twice-daily for 16 weeks. The first application of IMP will occur at the trial site at baseline 
(Day 1) after all baseline assessments have been carried out. All subsequent IMP applications 
will be performed by the subjects/caregivers at home. 
During the 16-week treatment period, subjects will return to the trial sites for efficacy and 
safety assessments at the visits outlined in Section 4. 
Follow-up period (Week 16-18) 
Subjects will be followed-up via phone (can be a site visit if needed) approximately 2 weeks 
after the last IMP application for assessment of safety. Note that for subjects who discontinue 
treatment with IMP prematurely, the 2-week follow-up period will start at the time of last IMP 
application. 
7.2 
Number of subjects needed 
92 subjects will be randomised 3:1 to delgocitinib cream 20 mg/g or cream vehicle. The 
statistical power considerations for this sample size are described in Section 14.3.17 
This trial will be conducted at approximately 40 sites in Europe, Canada, and Australia. The 
targeted minimum number of randomised subjects per trial site is 4, and the maximum 
number of subjects per trial site is 30. 
To avoid a bias in the estimated efficacy and safety assessments potentially occurring due to 
homogeneity of the population, a maximum 35% of subjects are allowed to originate from the 
same country. 
7.3 
End-of-trial definition 
A subject is considered to have completed the trial if, regardless of permanent discontinuation 
of IMP, the subject attends the Week 16 visit (primary endpoint visit) and the follow-up visit. 
The end of the trial overall 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 16. The date that the final 
subject was examined or received an intervention for the purposes of final collection of data 
for the primary outcome will determine the timelines for trial results disclosure on 
ClinicalTrials.gov. 
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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 specified in Panel 2. It will be recorded in the electronic case report form 
(eCRF) if the subject has met all the inclusion criteria and none of the exclusion criteria. 
Any implementation of national requirements/law for the subject’s participation in the clinical 
trial will be ensured and described in submission documentation to regulatory authorities and 
IRBs/IECs, as applicable. 
8.2 
Inclusion criteria 
The subjects must fulfil all of the following criteria to be eligible for the trial: 
1. Signed and dated IC has been obtained prior to any protocol-related procedures. Signed 
and dated IC must be provided by the subject’s parent/guardian and/or by the subject in 
the form of a signed and dated IC/IA (as applicable according to national laws or 
regulation). 
2. Age 12 to 17 years at screening and baseline. 
3. Diagnosis of CHE, defined as hand eczema that has persisted for more than 3 months or 
returned twice or more within the last 12 months. 
4. Disease severity graded as moderate to severe at screening and baseline according to IGA-
CHE (i.e. an IGA-CHE score of 3 or 4). 
5. Subjects who have a documented recent history of inadequate response to treatment with 
TCS (at any time within 1 year before the screening visit) or for whom TCS are 
documented to be otherwise medically inadvisable (e.g. due to important side effects or 
safety risks). 
• Inadequate response is defined as a history of failure to achieve and maintain a 
low disease activity state (comparable to an IGA-CHE score of ≤2) despite 
treatment with a daily regimen of TCS of class III-IV (potent to very potent) 
for Europe and Australia and class IV-I (medium potency to very/ultra-high 
potency) for Canada, applied for at least 28 days or for the maximum duration 
recommended by the product prescribing information, whichever is shorter. 
• Important side effects or safety risks are those that outweigh the potential 
treatment benefits and include intolerance to treatment, hypersensitivity 
reactions, and significant skin atrophy as assessed by the physician. 
6. Subjects adherent to standard non-medicated skin care including avoidance of known and 
relevant irritants and allergens. 
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7. A woman of childbearing potential* must use an acceptable** method of birth control 
throughout the trial up until the last application of IMP. 
* A woman of childbearing potential is defined as a female subject aged ≥ 12 years who, 
at the discretion of the investigator, is deemed to be of reproductive potential. A woman is 
defined as not being of childbearing potential if she is surgically sterile (hysterectomy, 
bilateral salpingectomy, or bilateral oophorectomy). 
** Acceptable methods of birth control are listed in Appendix 8. 
8.3 
Exclusion criteria 
Subjects are not eligible for the trial if they violate any of the following criteria:  
1. Known or suspected hypersensitivity to any component(s) of the IMP (refer to Panel 9.1 
for an overview of all excipients). 
2. Concurrent skin diseases on the hands, e.g. tinea manuum. 
3. Active AD requiring medical treatment in regions other than the hands and feet. 
4. Active psoriasis on any part of the body. 
5. Hyperkeratotic hand eczema in combination with a history of psoriasis on any part of the 
body. 
6. Clinically significant infection (e.g. impetiginised hand eczema) on the hands. 
7. Systemic treatment with immunosuppressive drugs (e.g. methotrexate, cyclosporine, 
azathioprine), immunomodulating drugs, retinoids (e.g. alitretinoin), or corticosteroids 
within 28 days prior to baseline (steroid eyedrops and inhaled or intranasal steroids 
corresponding to up to 1 mg prednisolone for allergic conjunctivitis, asthma, or rhinitis are 
allowed). 
8. Use of tanning beds, phototherapy (e.g. UVB, UVA1, PUVA), or bleach baths on the 
hands within 28 days prior to baseline. 
9. Previous or current treatment with JAK inhibitors (including delgocitinib/LEO 124249), 
systemic or topical. 
10. Cutaneously applied treatment with immunomodulators (e.g. PDE-4 inhibitors, 
pimecrolimus, tacrolimus) or TCS on the hands within 14 days prior to baseline. 
11. Use of systemic antibiotics or cutaneously applied antibiotics on the hands within 14 days 
prior to baseline. 
12. Other cutaneously applied therapy on the hands (except for the use of subject’s own 
emollients) within 7 days prior to baseline. 
13. Cutaneously applied treatments in regions other than the hands, which could interfere with 
clinical trial evaluations or pose a safety concern within 7 days prior to baseline. 
14. Treatment with any marketed biological therapy or investigational biologic agents 
(including immunoglobulin, anti-IgE, and 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. 
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• Other biologics: within 3 months or 5 half-lives, whichever is longer, prior to 
baseline. 
15. Treatment with any non-marketed drug substance (that is, an agent that has not yet been 
made available for clinical use following registration) within the last 28 days prior to 
baseline or 5 half-lives, whichever is the longest. 
16. Clinically significant infection within 28 days 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. 
17. History of any known primary immunodeficiency disorder including a positive HIV virus 
test at screening, or the subject taking antiretroviral medications as determined by medical 
history and/or subject’s verbal report. 
18. Major surgery within 8 weeks prior to screening, or planned in-patient surgery or 
hospitalisation during the trial period. 
19. 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. 
20. Any disorder which is not stable and could: 
• Affect the safety of the subject throughout the trial. 
• Impede the subject’s ability to complete the trial. 
Examples include but are not limited to cardiovascular, gastrointestinal, hepatic, 
renal, neurological, musculoskeletal, infectious, endocrine, metabolic, 
haematological, immunological, and psychiatric disorders, and major physical 
impairment. 
21. Any abnormal finding which may: 
• Put the subject at risk because of their participation in the trial. 
• Influence the subject’s ability to complete the trial. 
The abnormal finding must be clinically significant and observed during the 
screening period. Examples include abnormal findings in physical examination, 
vital signs, ECG, haematology, clinical chemistry, or urinalysis.  
22. Positive hepatitis B surface antigen or hepatitis C virus antibody serology at screeninga.  
23. ALT or AST level ≥2.0×ULN at screening. 
24. Current participation in any other interventional clinical trial. 
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25. Previously randomised in this clinical trial. 
26. Subjects or parents/guardians who have a current or recent chronic alcohol or drug abuse, 
or any other condition associated with poor compliance as judged by the investigator. 
27. Employees of the trial site, or any other individuals directly involved with the planning or 
conduct of the trial, or immediate family members of such individuals. 
28. Subjects who are legally institutionalised. 
29. Women who are pregnant or lactating. 
8.4 
Screening and screening failures 
Subject identification number 
Trial participation begins once written IC/IA is obtained. Refer to Appendix 3B for details on 
the IC/IA process. Once IC/IA is obtained, a subject identification number (subject ID) will be 
assigned by a central interactive response technology (IRT) system and the screening 
evaluations to assess eligibility criteria may begin. The date of first screening activity could 
be on the same day or a later date than the ICF/IAF was signed. The subject ID will be used to 
identify the subject during the screening process and throughout trial participation, if 
applicable. Subjects who have given written IC/IA to participate in the trial (the 
parent/guardian must have given IC, as appropriate and according to national laws and 
regulation) and who have been assigned a subject ID are considered ‘screened’ subjects. 
The investigator will maintain a log of all subjects considered for screening, whether they 
have provided written informed consent or not (screening log). This log will be anonymous 
and will include the reason(s) for not entering the trial, if applicable, or the allocated 
subject ID.  
In addition, the investigator will maintain a log of all consented subjects at the trial site 
(subject identification list). This log will include each subject’s identity, date of consent, and 
corresponding subject ID, so that any subject may be identified if required for any reason. The 
log must not be copied or retained by LEO Pharma. 
Screening failures 
Screening failures are defined as subjects who fail to meet eligibility criteria. A minimal set of 
screen failure information is required to ensure transparent reporting of screen failure subjects 
to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements 
(32) and to respond to queries from regulatory authorities. As a minimum, the following data 
will be collected in the eCRF for screening failures: 
• Date of IC/IA. 
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• Demographics (date of birth [if full date of birth is not allowed to be recorded, month 
and/or year (as allowed by local legislation) of birth should be collected], age, sex, 
ethnicity, race). 
• Reason for screen failure: Failure to meet eligibility criteria (to be specified which 
inclusion and/or exclusion criteria have been violated). 
• Date of screen failure. 
• Any adverse events (AEs) and serious AEs (SAEs). 
In case of any SAEs, these must be followed up as described in Section 13.7. 
Re-screening of screening failures is not allowed. However, if the reason for screening failure 
is not due to the subject failing to meet the eligibility criteria but is administrative (e.g. 
delayed test results or temporary site closure due to the COVID-19 pandemic), re-screening 
may be permitted. This will require approval by the sponsor. Individuals who are re-screened 
will get a new subject ID and they (and/or their parent/guardian) will need to sign a new 
ICF/IAF.  
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9 
Treatments 
9.1 
Trial product description 
Panel 5: Identification of investigational medicinal products 
Investigational 
medicinal product 
Dosage 
form 
Active ingredient and 
concentration 
Pack 
size 
Manufacturer responsible 
for batch release  
Delgocitinib cream 
20 mg/g 
Cream 
Delgocitinib, 20 mg/g 
30 g 
LEO Pharma A/S 
Cream vehicle 
Cream 
Vehicle 
30 g 
LEO Pharma A/S 
Panel 6: Excipients of delgocitinib cream 20 mg/g and cream vehicle 
Excipients 
Citric acid monohydrate 
Sodium citrate 
Benzyl alcohol 
Disodium edetate 
Hydrochloric acid 
Purified water 
Macrogol cetostearyl ether 
Cetostearyl alcohol 
Liquid paraffin 
Butylhydroxyanisole 
Sodium hydroxide (may be used to adjust pH) 
9.2 
Administration of investigational medicinal product 
The IMP will be applied as a topical application twice daily for 16 weeks. The applications 
will be performed approximately 12 hours apart. Instructions for use will be provided to 
subjects and caregivers. 
The IMP will be applied to clean, dry hands, fingers, fingertips, and wrists in a thin layer 
covering the affected areas. The amount of IMP to be used depends on the size of the affected 
area and the size of the hands, fingers, and wrists. 1 tube of 30 g delgocitinib cream is 
considered sufficient for treatment of the whole surface of hands, fingers, and wrists 
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twice daily for 2 weeks; however, a few subjects may need more (based on experience from 
the LP0133-1273 trial), which will be allowed at the discretion of the investigator. 
The first application of IMP will occur at the trial site. Prior to the first IMP application, the 
subject/caregiver will be instructed on how much cream to apply and which area(s) to treat.  
Only the affected area(s) on the hand(s), finger(s), fingertip(s), and wrist(s) will be treated. If 
new CHE lesions occur on initially untreated area(s) of the hand(s), finger(s), fingertip(s), and 
wrist(s), these new lesions will be treated with IMP as well. The subjects/caregivers will 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 end of the treatment 
period regardless of clearance status. The last IMP application will occur at the subject’s 
home before the subject attends the visit scheduled at Week 16.  
At the scheduled trial visits, investigator assessments of efficacy should preferably be done at 
least 2 hours after application of IMP and/or emollient. Recommendations for bathing, 
washing, and hand sanitising in relation to IMP application are provided in Section 9.6. 
The IMP will be dispensed by the investigational staff at scheduled visits as outlined in 
Section 4. The IRT system will assign the required kit number(s) for each subject at each 
dispensing visit. Returned, opened IMP tubes will be weighed at the trial site to determine the 
amount of IMP used (see Section 9.8.3). 
The investigator will use clinical judgement to treat any symptoms connected with an 
overdose. 
9.3 
Treatment assignment and blinding  
9.3.1 
Treatment assignment 
Subjects who have been found to comply with all the inclusion criteria and not to violate any 
of the exclusion criteria will be randomised at baseline (Day 1) in a 3:1 ratio to receive 
treatment with either delgocitinib cream 20 mg/g or cream vehicle. The randomisation will be 
stratified by baseline IGA-CHE score (3 or 4). 
The IRT system will be used to control randomisation and stratification factors, along with 
IMP supply chain and expiry tracking. 
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9.3.2 
Blinding 
This is a double-blind trial. The packaging and labelling of the IMPs will contain no evidence 
of their identity. It is not considered possible to differentiate between the IMPs solely by 
sensory evaluation. 
9.3.3 
Emergency unblinding of individual subject treatment 
While the safety of a subject always comes first, it is still important to carefully consider if 
unblinding is necessary to ensure a subject’s safety. An emergency unblinding request can be 
made by the investigators, HCPs who are not members of the trial staff, or authorised LEO 
Pharma personnel. 
Provisions are in place for 24-hour emergency unblinding of individual subject treatment. If 
emergency unblinding is required, the investigator can unblind a subject’s treatment via an 
unblinding function in the IRT system or unblinding CRO. Only the investigator should be 
unblinded and keep treatment allocation confidential. LEO Pharma must remain blinded until 
the end of the trial (except designated unblinded personnel).  
For a requester who is not a member of the trial staff and who does not have access to the IRT 
system (e.g. a physician at an emergency room), a local contact number for the emergency 
unblinding CRO is provided on the subject card (see Appendix 3B) to be used if the 
investigator or delegated site staff cannot be reached. The requester will provide the trial ID 
and subject ID to the emergency unblinding CRO who will immediately reveal the individual 
treatment allocation without further medical consultation. 
9.4 
Background treatment 
No background treatment is required in this trial. The subjects should not change their usual 
skin care routine for the hands regarding use of emollients. However, emollients should 
preferably not be used on the affected areas within 2 hours before and after application of 
IMP. Use of concomitant medication and concurrent procedures is further described in 
Section 9.6. 
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9.5 
Rescue treatment 
If medically necessary (i.e. to control intolerable CHE symptoms), rescue treatment for CHE 
may be prescribed to trial subjects at the discretion of the investigator. The investigators 
should make every attempt to conduct efficacy and safety assessments (e.g. disease severity 
scores, safety laboratory assessments) immediately before administering any rescue treatment. 
If rescue treatment is initiated, the subject must stop treatment with IMP immediately and will 
not be allowed to restart treatment with IMP. Subjects who discontinue IMP will be asked to 
attend an early termination visit, a follow-up visit (performed via phone, but can be a site visit 
if needed) approximately 2 weeks after the last application of IMP, and also the primary 
endpoint visit at Week 16 (see Section 10.3 for details). 
 
Rescue treatment is defined as treatment (medication or procedure) initiated to treat 
intolerable CHE symptoms during the treatment and follow-up periods. It will be recorded in 
the eCRF if a treatment is given as rescue treatment. 
9.6 
Concomitant medication and concurrent procedures 
Any medication or vaccine that the subject receives from 3 months prior to baseline (Day 1) 
through safety follow-up must be recorded in the subject’s medical record and the eCRF along 
with details such as: 
• Medication name or therapy. 
• Primary indication. 
• Whether the medication or therapy is a rescue medication for the indication. 
• Start and stop date of administration (it will also be recorded if the medication is 
ongoing). 
• Dosage information, including dose per administration, unit, and frequency. 
• Route of administration (oral, topical, subcutaneous, transdermal, ophthalmic, 
intramuscular, respiratory [inhalation], intralesional, intraperitoneal, nasal, vaginal, rectal, 
intravenous, or other [if other, a specification must be provided]). For topical treatments, 
the dosage form (cream, lotion, ointment, foam, other) will also be recorded. 
• For cutaneous treatment, it must also be recorded if the treatment is within 5 cm 
(appr. 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 name (including anatomical area, 
if relevant), primary indication, and start and stop date (it will also be recorded if the 
procedure is ongoing). It will also be recorded if the procedure is inside the treatment area. 
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Investigators may prescribe concomitant medications or treatments to provide adequate 
supportive care as deemed necessary, except for medications listed in Section 9.7. The 
sponsor’s medical expert should be contacted if there are any questions regarding concomitant 
or prior therapy. 
As a rule, the subjects should not change their usual skin care routine for the hands if 
possible; however, emollients should preferably not be used on the treatment areas within 
2 hours before and after application of IMP. Emollients are not considered concomitant 
medication and should not be recorded as such. The subjects will be allowed to apply other 
skin treatments/products to other areas of the body for other skin conditions (including foot 
dermatitis) during the trial, as long as this does not interfere with the trial (i.e. treatment 
should be applied by the caregiver or the subjects will need to wear disposable gloves, of a 
type recommended by the investigator, when applying treatment). If possible, normal bathing, 
washing of hands, and use of hand sanitisers should be avoided within 2 hours following 
application of IMP. Use of cosmetic body care products (e.g. body lotion, shampoo, bath oil), 
which are routinely used by the subjects, is allowed as per instructions for use, but the 
products should preferably not be changed during the trial and application should be avoided 
within 2 hours of IMP application or alternatively using disposable gloves. 
Excessive sunlight and sunlamps should be avoided. Sunscreen products on the body and 
protective gloves on the hands are recommended when exposure cannot be avoided. 
Assessment of the benefit-risk of the concomitant use of COVID-19 vaccine and IMP in 
delgocitinib trials was performed. The result of the risk assessment is that, for topical 
delgocitinib, COVID-19 vaccine should be recorded as a concomitant medication with no 
need to pause or discontinue IMP administration. 
9.7 
Prohibited medications and procedures 
The medications and procedures listed in Panel 7 are prohibited during the trial.
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Panel 7: Prohibited medications and procedures 
Medication/procedure 
Prohibited from 
Prohibited to 
Systemic immunosuppressive/immunomodulating 
drugs (e.g. methotrexate, cyclosporine, azathioprine), 
retinoids (e.g. alitretinoin), or corticosteroids (steroid 
eyedrops1 and inhaled or intranasal steroids 
corresponding to up to 1 mg prednisolone for allergic 
conjunctivitis, asthma, or rhinitis are allowed). 
28 days prior to baseline. 
End of trial. 
JAK inhibitors, systemic or topical (except for the 
IMP). 
The subject’s birth. 
End of trial. 
Tanning beds, phototherapy (e.g. UVB, UVA1, 
PUVA), or bleach baths on the hands. 
28 days prior to baseline. 
End of trial. 
Cutaneously applied treatment with 
immunomodulators (e.g. PDE-4 inhibitors, 
pimecrolimus, tacrolimus) or TCS on the hands. 
14 days prior to baseline. 
End of trial. 
Cutaneously applied antibiotics on the hands. 
14 days prior to baseline. 
End of trial. 
Other cutaneously applied therapy on the hands 
(except for the IMP and the subject’s own emollient). 
7 days prior to baseline. 
End of trial. 
Cutaneously applied treatments in regions other than 
the hands, which could interfere with clinical trial 
evaluations or pose a safety concern.2 
7 days prior to baseline. 
End of trial. 
Treatment with any marketed biological therapy3 or 
investigational biologic agents (including 
immunoglobulin, anti-IgE, and anti-IL-4/IL-13 e.g. 
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). 
28 days prior to baseline or 
5 half-lives, whichever is 
longer. 
End of trial. 
1) 
Note that steroid eyedrops should be recorded with the administration route ‘ophthalmic’, not ‘cutaneous’. 
2) 
This allows for the treatment of eczema and other skin conditions in regions other than the hands, as long as this does 
not interfere with the trial (i.e. treatment should be applied by the caregiver or the subject needs to use gloves when 
applying treatment). 
3) 
Subjects are allowed to receive vaccines during the trial. 
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Abbreviations: IgE = immunoglobulin E; IL= Interleukin; IMP = investigational medicinal product; JAK = Janus kinase; 
PDE-4 = phosphodiesterase-4; PUVA = psoralen ultraviolet A; TCS = topical corticosteroids; UVA1 = ultraviolet A1; UVB 
= ultraviolet B. 
As TCS only require 14 days of wash-out prior to baseline, subjects can be instructed to use 
TCS until 14 days before the baseline visit (Day 1) to alleviate significant worsening of their 
CHE.  
As described in Section 9.5, prohibited medications or procedures used as rescue treatment 
for intolerable CHE symptoms are allowed, but subjects using rescue treatment must 
discontinue IMP immediately and will not be allowed to restart treatment with IMP. 
All prohibited medications used must be recorded as concomitant medication. 
9.8 
Treatment logistics and accountability 
9.8.1 
Labelling and packaging of trial products 
The IMP will be packaged in individually numbered kits. Primary and secondary packaging 
materials will be individually labelled. 
The labelling of IMP will be in accordance with the EU guidelines for Good Manufacturing 
Practices for Medicinal Products for Human and Veterinary use, Annex 13 (33), local 
regulations, and trial requirements. Label text will be translated into local languages as 
required. 
The subjects will receive instructions for use which will be translated into local languages. 
9.8.2 
Storage of trial products 
All LEO Pharma supplied IMPs must be stored in a secure and restricted area under the 
conditions specified on the label and remain in the original container until dispensed. 
Do not store the IMP above 25°C at the trial site. Do not freeze. The temperature during 
storage should be monitored by a calibrated, stationary, and continuously monitoring system. 
Minimum requirement is a calibrated min/max thermometer. 
A temperature log must be kept to document the storage within the right temperature interval. 
Storage facilities should be checked at least every working day.  
Storage of IMP may be delegated, e.g. to a hospital pharmacy, as locally applicable, and must 
be documented in the site signature and designation of responsibility log. 
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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 system and reported as a product complaint 
as described in 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 
Investigational medicinal product accountability 
The investigator is fully responsible for the IMPs at the trial site and for maintaining adequate 
control of the IMPs and for documenting all transactions with them. 
Dispensing of IMPs may be delegated, e.g. to a hospital pharmacy, as locally applicable, and 
must be documented in the site signature and designation of responsibility log. 
Documentation of IMP accountability must be kept for the IMPs administered to each 
individual subject randomised in the trial. This documentation must be available during 
monitoring visits and will be checked by the CRA to verify correct dispensing of the IMPs. 
IMP accountability information will be recorded in the IRT system. The IRT system will also 
maintain the inventory status of all IMPs at the trial site. 
The subject will return used, partly used, and unused IMPs (including packaging material) at 
the visits specified in the schedule of trial procedures (Section 4). 
Returned, opened IMP tubes will be weighed at the trial site to determine the amount of IMP 
used. The weight of the returned tubes will be recorded in the individual drug accountability 
form and in the eCRF (in grams with 1 decimal). 
Returned trial product (used, partly used, and unused IMPs [including packaging material]) 
must be stored separately from non-allocated trial product. 
Refer to the trial product handling manual for information on returning trial products.  
All IMP (including packaging material) supplied by the CMO on behalf of LEO Pharma will 
be returned to the CMO on an ongoing basis. Prior to return, the IMPs must be fully 
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accounted for by the CRA with the help of site staff responsible for dispensing the IMPs. 
Accountability must be documented on the individual drug accountability form and in the IRT 
system. 
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 hands, fingers, and wrists the IMP must be applied and which 
amount of IMP to be used per application. 
Treatment days will be recorded by the subjects in the eDiary. The subject will be asked the 
following question once daily: ‘Did you apply trial cream today?’. 
The investigator (or designee) should review the compliance data entered in the eDiary before 
each visit. In case of non-compliance, the investigator should remind the subject of the 
importance of following the instructions given, including applying the IMP as prescribed. 
Reporting in eCRF 
At baseline, the date of first application of IMP will be recorded. 
9.8.5 
Trial product destruction 
All IMP should be shipped to the CMO for destruction according to approved procedures 
and/or local requirements. 
9.9 
Provision for subject care following trial completion 
In order to ensure appropriate treatment of the subjects after they have completed the trial, the 
subjects will be treated at the investigator’s discretion or referred to other physician(s) 
according to standard practice. 
9.10 Reporting product complaints 
Any defects or issues with the IMP must be reported to the Quality department via Global 
Safety at LEO Pharma on the trial-specific (paper) complaint form within 3 days of first 
knowledge. 
Critical complaints (defined as any defect or issue that has or potentially could have a serious 
impact on the subject [e.g. SAE]) must be reported to the Quality department via Global 
Safety, within 24 hours of knowledge. 
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Complaint forms should contain a detailed description of the defect or issue, including 
whether it led to an AE. (S)AEs which occur due to a defect or issue with the IMP will be 
reported by the investigator as described in Sections 13.3and 13.4. 
Refer to the trial product handling manual for information on how to update the kit status in 
the IRT system and handling of trial product during investigation of a product compliant. 
During the investigation of the product complaint, the IMP must be stored separately from 
other trial medication and at labelled conditions unless otherwise instructed; the trial site will 
be notified whether the IMP needs to be returned for further investigation or may be 
destroyed. 
Global Safety, LEO Pharma contact information for reporting product complaints: 
Fax number: +45 6910 2468 
E-mail address: drug.safety@leo-pharma.com 
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10 Discontinuation and withdrawal 
10.1 General principles 
A subject may withdraw from the trial (prior to first dose or during the treatment period) or 
permanently discontinue trial treatment at any time if the subject, the parent/guardian, the 
investigator, or LEO Pharma considers that it is not in the subject’s best interest to continue. 
If a subject permanently discontinues IMP, the subject will be asked to attend an early 
termination visit, the primary endpoint visit, and the safety follow-up visit. If a subject or the 
subject’s parent/guardian do not agree to attend these visits, the subject withdraws from the 
trial. To obtain a comprehensive efficacy evaluation of delgocitinib, it is of importance to 
assess the efficacy for each subject at the planned primary endpoint visit at Week 16. 
Subjects who withdraw from the trial and subjects who permanently discontinue IMP will not 
be replaced. 
If a subject withdraws from the trial, the subject or the subject’s parent/guardian may request 
destruction of any samples taken and not tested, and the investigator must document this in 
the subject’s medical record. 
10.2 Reasons for permanent discontinuation of IMP 
Subjects will permanently 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 treatment. 
• Clinically important laboratory abnormalities: 
o ALT and/or AST values >3×ULN with total bilirubin >2×ULN (unless elevated 
bilirubin is related to Gilbert Meulengracht Syndrome). 
o Confirmed ALT and/or AST values >5×ULN (for more than 2 weeks). 
It is not allowed to restart IMP treatment after discontinuation of IMP. 
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Data to be recorded in the eCRF 
The primary reason for permanent discontinuation of IMP must be recorded in the medical 
records and on the end-of-treatment form in the eCRF where the following options are 
available: 
• Adverse event. 
• Death. 
• Lost to follow-up. 
• Pregnancy. 
• Withdrawal by subject. 
• Withdrawal by parent/guardian. 
• Lack of efficacy. 
• Other. 
If ‘adverse event’ is selected, the AE in question will be linked to the discontinuation of IMP. 
If ‘other’ is selected as a reason, a specification must be provided in the eCRF. 
It will also be recorded whether the discontinuation of IMP was related to the COVID-19 
pandemic to support the statistical analysis. 
10.3 Early termination assessments 
Permanent discontinuation of IMP 
Subjects who permanently discontinue IMP for any reason will be asked to attend an early 
termination visit as soon as possible after last administration of IMP and return to the trial site 
for 2 additional visits as indicated below. See the schedule of trial procedures (Section 4) for 
data to be collected at these visits. The investigator will review any AEs which will be 
followed up according to Section 13.7, if the subject agrees. 
Subjects who permanently discontinue IMP prior to Week 16 will be asked to attend the 
following visits: 
• Early termination visit (as soon as possible after last administration of IMP). 
• Safety follow-up visit (2 weeks after last administration of IMP, performed via phone, but 
can be a site visit if needed). 
• Primary endpoint visit (16 weeks after randomisation). 
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Withdrawal from trial 
Subjects who withdraw from the trial for any reason will be asked to attend an early 
termination visit as soon as possible after last administration of IMP (see the schedule of trial 
procedures [Section 4] for data to be collected at an early termination visit). The investigator 
will review any AEs which will be followed up according to Section 13.7, if the subject or 
parent/guardian agrees. 
Details on data to be recorded in the eCRF for subjects who withdraw from the trial can be 
found in Section 11.9. 
10.4 Lost to follow-up 
A subject will be considered lost to follow-up if they repeatedly fail to return for scheduled 
visits and if the trial site is not able to get in contact with the subject or their parent/guardian. 
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 or their parent/guardian and reschedule 
the missed visit as soon as possible and counsel the subject or their parent/guardian on the 
importance of maintaining the assigned visit schedule and ascertain whether the subject 
wishes to continue in the trial. 
• Before a subject is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the subject or their parent/guardian. These contact 
attempts should be documented in the subject’s medical record. Should the subject or their 
parent/guardian continue to be unreachable, they will be considered to have withdrawn 
from the trial with a primary reason of lost to follow-up. 
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11 Trial assessments and procedures 
11.1 Overview 
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. 
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 CHE, 
have documented experience and completed training in use of the assessments required by the 
protocol, and must be physicians. 
AEs must be assessed by a physician (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/or year (as 
allowed by local legislation) of birth should be collected together with the subject’s 
age. 
• Sex: female, male. 
• Ethnic origin (self-reported by the subject): ‘Hispanic or Latino’, ‘not Hispanic or 
Latino’. 
• Race (self-reported by the subject): American Indian or Alaska Native, Asian – 
Chinese, Asian, Black or African American, native Hawaiian or other Pacific Islander, 
White, other (requires a specification to be provided). More than 1 race can be 
recorded per subject in the eCRF. 
Fitzpatrick skin type. 
The subject’s skin type will be recorded using the Fitzpatrick skin classification (Panel 8). 
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Panel 8: 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 exposure, 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 lightly complected Black individuals, those of Indian descent. 
VI 
Individuals who have the heaviest constitutive pigmentation, especially dark-skinned Black 
individuals. 
11.2.2 
Medical history 
All medical and surgical history within the previous 12 months, including concurrent/ongoing 
diagnoses, must be recorded. In addition, all relevant medical history including all past and 
current skin diseases (e.g. history of atopic diseases, foot dermatitis, and psoriasis) will be 
collected from the subject’s date of birth. For each condition, diagnosis, or surgical procedure, 
the start date and stop date or whether it is ongoing will be recorded. It will be recorded if the 
disease is/has been present on the hands. 
Relevant medical history also includes diseases which are specifically listed as exclusion 
criteria and diseases for which specific treatments are listed as exclusion criteria (see Section 
8.3). 
CHE history: 
• Date of diagnosis of CHE. 
• Number of flares experienced during the past year. 
• Results of relevant previous diagnostic procedures other than diagnostic patch testing (e.g. 
prick test). 
• Presence of atopy. 
• Presence of atopy in the subject’s family history. 
CHE treatment history: 
• Previous treatments for CHE (name and type of treatment, rationale for discontinuation of 
treatment). Note that for TCS, previous treatments will only be collected for the last 12 
months and the following additional details will be recorded: strength, dose, and date(s) of 
treatment. 
• To support selection of trial subjects specifically on inclusion criterion no. 5: 
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- Has the subject fulfilled the trial inclusion criterion no. 5based on having inadequate 
response to treatment with TCS during the last 12 months? (yes, no). 
- Has the subject fulfilled the trial inclusion criterion no. 5 based on TCS being 
medically inadvisable for the subject? (yes, no). 
- If yes: reason for TCS use being medically inadvisable. 
Exogenous risk factors for CHE: 
• Environmental trigger factors (yes, no, unknown). 
- If yes: Occupational relevance (yes, no, unknown). 
• Attended classes in school in the past year (yes/no). 
- a) If yes: Missed due to CHE (yes/no). 
- b) If yes: Number of days missed due to CHE (days).  
- c) If yes: Negative impact of CHE on school work in the past year (yes/no).  
• Employed during the past year (working for pay, including part time work) (yes/no). 
- If yes: Hours working for pay per week (hours). 
• Onset and worsening of CHE symptoms:  
- a) at work (yes, no, unknown).  
- b) during school (yes, no, unknown). 
• Improvement of CHE symptoms: 
- a) when not at work (yes, no, unknown). 
- b) when not in school (yes, no, unknown). 
• Healing of CHE on vacations (yes, no, unknown). 
• Recurrence of CHE symptoms upon returning to: 
- a) work (yes, no, unknown). 
- b) school (yes, no, unknown). 
• Worsening of CHE symptoms when:  
- a) not at work (yes, no, unknown). 
- b) not in school (yes, no, unknown). 
• Number of daily hand washes (0-10, 11-20, >20). 
• Tobacco smoking history (Never smoked, previous smoker [non-smoker for more than 
1 year], current smoker [smoker for the past year]). 
- If current smoker: Type of tobacco (cigarettes, other). 
- If current smoker: Average daily number of smoked cigarettes during the past year 
(1-4, 5-10, 11-20, >20). For tobacco types other than cigarettes, 1 g of tobacco will be 
considered equal to 1 cigarette. 
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11.2.3 
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. Both assessments will be recorded with one 
decimal accuracy.  
11.2.4 
Determination of treatment area 
Prior to the first application of IMP at baseline, the investigator will determine the treatment 
area(s) on the left and the right hand using the following 5 areas: fingertips, fingers (except 
fingertips), palm of hands, back of hands, and wrists. The treatment areas affected will be 
marked on a scheme showing the back and the front of the left and the right hand as from the 
perspective of the subject. If new CHE lesions occur, the scheme will be updated to document 
these. 
11.2.5 
Classification of CHE 
The investigator will determine the CHE subtype(s) according to the definitions in Panel 9. 
The classification of CHE will be done according to standard clinical practice and thus may 
differ across regions and countries. 
If standard clinical practice at the site, the classification of CHE is recommended to include 
diagnostic patch testing with at least a relevant baseline series including the most important 
contact allergens relevant to the locality of the site. For subjects who have had a diagnostic 
patch test performed within 3 years prior to screening, the results from the most recent patch 
test will be used for the classification. For subjects who have not had a patch test within 3 
years prior to screening, a patch test should be performed. Final reading of the patch test 
should preferably be performed prior to the baseline visit. If this is not possible, the patch test 
can be performed later but final reading must be available no later than the Week 8 visit 
(Section 4). Patch testing is recommended to be performed at trial sites where the staff are 
experienced in performing and reading patch tests and where this is considered standard 
clinical practice. 
The diagnostic patch test is done by applying patches containing standardised samples of 
allergens to the subjects’ upper back. The patches will stay in place for approximately 48 
hours under occlusion, after which they are removed during a visit at the trial site. The 
subjects will return to the trial site for assessment of patch test reactions according to standard 
clinical practice at the trial site. 
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Reporting in eCRF 
The result of the diagnostic patch test (positive, negative, or inconclusive, i.e. unknown in the 
eCRF) will be recorded in the eCRF. If positive, it will be recorded if any of the identified 
allergies are considered relevant for the CHE (yes, no). The CHE subtype being the main 
diagnosis will be recorded, and additional CHE subtypes will be recorded if applicable. 
Panel 9: Definition of subtypes of hand eczema  
Subtype 
Definition 
Allergic contact dermatitis 
Hand eczema caused by relevant contact allergens or cross-reactors identified 
by patch testing. Relevance means that there is a current exposure of the 
allergens to the hands. 
Irritant contact dermatitis 
Hand eczema with documented irritant exposure, which is quantitatively likely 
to cause dermatitis. No relevant contact allergy (no current exposure to 
allergens to which the patient has reacted positive in patch test). 
Contact urticaria/protein 
contact dermatitis 
Hand eczema in patients exposed to proteins (food, latex, and other biological 
material) with a positive prick test, or proven specific IgE, to suspected items. A 
considerable proportion of patients with contact urticaria will also have atopic 
symptoms.  
Atopic hand eczema 
Hand eczema in a patient with a medical history of atopic eczema, previous or 
current. No documented irritant exposure and/or relevant contact allergen likely 
to cause eczema. 
Vesicular hand eczema 
(pompholyx) 
Recurrent hand eczema with vesicular eruptions. No relevant contact allergy, no 
documented irritant exposure likely to cause dermatitis. 
Hyperkeratotic eczema 
(hyperkeratotic dermatitis 
of the palms) 
Chronic eczema with hyperkeratosis in the palms, or pulpitis, and no vesicles or 
pustules. No documented irritant exposure to the involved skin areas, likely to 
cause irritant exposure. 
Reference: Adapted from (1). Note that the terms eczema and dermatitis are used interchangeably in the referenced 
publication. 
Abbreviation: IgE = immunoglobulin E. 
11.3 eDiary assessments 
At the screening visit, the subjects will receive an eDiary device and eDiary training. The 
eDiary will be open for entry from 4 pm until midnight. The subjects must start completing 
the HESD in the eDiary at least 1 week prior to baseline, but preferably from the date the 
subjects receive the eDiary. The HESD must be completed in the eDiary every evening until 
Week 16, regardless of IMP discontinuation. Treatment compliance (daily) and subject 
assessment of local tolerability (weekly) will be evaluated by the subject in the eDiary from 
baseline up to end of treatment/early termination. Compliance with the eDiary completion 
will be reviewed by the trial site staff throughout the trial. 
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Handout, training, and return of the eDiary is outlined in the schedule of trial procedures 
(Section 4). Return of the eDiary is not applicable for subjects who discontinue IMP and 
attend an early termination visit, but do not withdraw from the trial. These subjects will 
continue completing the eDiary until the primary endpoint visit at Week 16 and will return the 
eDiary at that visit.  
The following assessments will be completed in the eDiary by the subjects in the listed order: 
• Daily: HESD (see Section 11.4.3.2). 
• Daily: treatment compliance (see Section 9.8.4). 
• Weekly: subject assessment of local tolerability (see Section 11.5.4). 
11.4 Efficacy assessments 
11.4.1 
Investigator’s Global Assessment for chronic hand eczema© 
The IGA-CHE© (referred to in the protocol as IGA-CHE) is an instrument used in the phase 3 
trials with delgocitinib cream in adults (LP0133-1401 and LP0133-1402). The IGA-CHE 
rates the severity of the subject’s global disease and is based on a 5 point scale ranging from 0 
(clear) to 4 (severe) (Panel 10). The IGA-CHE 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. New 
lesions that occur on previously untreated areas will be included in the assessment. The 
IGA-CHE score will be recorded in the eCRF.  
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Panel 10: Investigator’s Global Assessment for chronic hand eczema© 
IGA-CHE 
severity 
IGA-CHE 
score 
Sign and intensity 
Clear 
0 
No signs of erythema, scaling, hyperkeratosis/lichenification, vesiculation, oedema 
or fissures 
Almost 
clear 
1 
Barely perceptible erythema 
No signs of scaling, hyperkeratosis/ lichenification, vesiculation, oedema or fissures 
Mild 
2 
At least one: 
• 
Slight but definite erythema (pink) 
• 
Slight but definite scaling (mostly fine scales) 
• 
Slight but definite hyperkeratosis/lichenification 
and at least one: 
• 
Scattered vesicles, without erosion 
• 
Barely palpable oedema 
• 
Superficial fissures 
Moderate 
3 
At least one: 
• 
Clearly perceptible erythema (dull red) 
• 
Clearly perceptible scaling (coarse scales) 
• 
Clearly perceptible hyperkeratosis/lichenification 
and at least one: 
• 
Clustered vesicles, without visible erosion 
• 
Definite oedema 
• 
Definite fissures 
Severe 
4 
At least one: 
• 
Marked erythema (deep or bright red) 
• 
Marked and thick scaling 
• 
Marked hyperkeratosis/lichenification 
and at least one: 
• 
High density of vesicles with erosions 
• 
Marked oedema 
• 
One or more deep fissures 
Abbreviation: IGA-CHE = Investigator’s Global Assessment for chronic hand eczema©. 
11.4.2 
Hand Eczema Severity Index  
The HECSI is an instrument used in clinical trials to rate the severity of 6 clinical signs 
(erythema, infiltration/papulation, vesicles, fissures, scaling, oedema) and the extent of the 
lesions on each of the 5 hand areas (fingertips, fingers [except fingertips], palm of hands, back 
of hands, and wrists) by use of standard scales (34). 
For each hand region (total of both hands, e.g. 10 fingers), the investigator rates the average 
severity of each of the 6 clinical signs of hand eczema using a 4-point severity scale ranging 
from 0 (none/absent) to 3 (severe) (Panel 11). The investigator also rates the extent of the 
lesions by assessing the percentage of the hand regions these lesions occupy and converting it 
to a score based on a 5-point scale (the area score) (Panel 11). For each of the hand regions, 
the region score will be calculated by adding up the severity scores for the 6 clinical signs of 
hand eczema and multiplying with the area score (Panel 12). The HECSI score equals the sum 
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of the region scores and will range from 0 (lowest possible score) to 360 (highest possible 
score). 
The HECSI 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. New CHE lesions that occur on previously 
untreated areas will be included in the assessment. 
Panel 11: HECSI severity score scale and area score scale 
Severity score (SS) scale 
(based on both hands) 
 
Area score (AS) scale  
(based on the affected area of both hands) 
0 
None/absent 
 
0 
0% affected area 
1 
Mild 
 
1 
1% to 25% affected area 
2 
Moderate 
 
2 
26% to 50% affected area 
3 
Severe 
 
3 
51% to 75% affected area 
Note: half-scores (0.5, 1.5, 2.5) are not allowed. 
 
4 
76% to 100% affected area 
 
 
Note: half-scores (0.5, 1.5, 2.5, 3.5) are not allowed. 
Panel 12: Calculation of the total HECSI score 
Hand region 
Erythema 
Infiltration/ 
papulation 
Vesicles 
Fissures 
Scaling 
Oedema 
Area score 
Score 
Fingertips 
(SS + 
  SS + 
  SS + 
  SS + 
  SS + 
  SS) 
× AS 
 
Fingers (except 
fingertips) 
(SS + 
  SS + 
  SS + 
  SS + 
  SS + 
  SS) 
× AS 
 
Palm of hands 
(SS + 
  SS + 
  SS + 
  SS + 
  SS + 
  SS) 
× AS 
 
Back of hands 
(SS + 
  SS + 
  SS + 
  SS + 
  SS + 
  SS) 
× AS 
 
Wrists 
(SS + 
  SS + 
  SS + 
  SS + 
  SS + 
  SS) 
× AS 
 
The total HECSI score equals the sum of the 5 above region scores: 
 
(range 0-360) 
Abbreviations: AS = area score; HECSI = Hand Eczema Severity Index: SS = severity score. 
11.4.3 
Patient-reported outcomes (efficacy) 
11.4.3.1 
Overview 
Each subject must make individual assessments relating to their perception of their disease 
independently of the investigator and trial site staff. 
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The PRO HESD is considered an efficacy assessment in this trial. The HESD will be 
completed daily as an eDiary. 
11.4.3.2 
Hand Eczema Symptom Diary©  
The HESD© (referred to in the protocol as HESD) is an instrument used in the phase 3 studies 
with delgocitinib cream in adults (LP0133-1401 and LP0133-1402). The HESD is a 6-item 
PRO instrument designed to assess severity of CHE signs and symptoms. Subjects will assess 
the worst severity of 6 individual signs and symptoms of CHE (itch, pain, cracking, redness, 
dryness, and flaking) over the past 24 hours using an 11-point numeric rating scale with 
anchors of 0 =‘no (symptom)’ and 10 =‘severe (symptom)’. The HESD score is derived as an 
average of the 6 items; a high score is indicative of severe CHE signs and/or symptoms. A 
minimum of 4 HESD scores per week are required throughout the trial to calculate the 
average. The baseline HESD weekly average will be calculated based on daily assessments 
during the 7 days immediately preceding the baseline visit (Day -7 to Day -1). Subjects will 
complete the HESD on a daily basis in an eDiary as outlined in Section 4.  
11.5 Safety assessments 
11.5.1 
Vital signs 
Vital signs (resting blood pressure and pulse) must be assessed according to the schedule of 
trial procedures (Section 4). Vital signs will be measured 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. 21). 
In case of abnormal findings, the vital sign measurement can be repeated approximately 
15 minutes later to verify the first measurement. Should the repeated measurement result in a 
normal value, the measurement must be repeated once more. If the third measurement verifies 
the second (normal) value, the first measurement should be considered false and the second 
measurement should be recorded in the eCRF. If the third measurement confirms the first 
measurement (abnormal), the second measurement will be considered false and the first 
measurement should be recorded in the eCRF. 
Reporting in eCRF 
It will be recorded in the eCRF if vital signs were measured; if not, a reason should be 
provided. Vital signs (resting blood pressure and pulse) 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 
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pre-existing condition as well as any new clinically significant sign, symptom, or illness 
occurring after randomisation will be reported as an AE in accordance with Section 13.3. 
11.5.2 
Physical examination 
A physical examination of the subject including general appearance and dermatologic 
examination of the skin must be performed according to the schedule of trial procedures 
(Section 4). Presence of foot dermatitis will be documented. The investigator should perform 
the same examinations as in clinical practice as a minimum. 
If an abnormal physical finding 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 clinical trial (respecting exclusion criterion 21). In case only CHE is identified, the 
physical examination should be considered as normal.  
Reporting in eCRF 
It will be recorded in the eCRF if a physical examination was performed and, if applicable, 
the investigator’s evaluation (‘normal’, ‘abnormal, not clinically significant’, ‘abnormal, 
clinically significant’). If a physical examination was not performed, a reason should 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 
occurring after randomisation will be reported as an AE in accordance with Section 13.3. 
11.5.3 
Electrocardiography 
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 pre-evaluation of the ECGs will be performed by the investigators to evaluate immediate 
subject safety. At a minimum, the date of ECG recording will be documented in the source. 
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 any ECG abnormalities. The investigator will document the review of the 
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ECG result by signing the ECG report at the trial site or in an electronic portal hosted by the 
ECG vendor.  
If an abnormal ECG finding 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 clinical trial (respecting exclusion criterion nr. 21. 
The collection and transmission of ECG data will be described in a separate ECG manual. 
Test dummy transmissions will be undertaken prior to 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, if applicable, the investigator’s 
assessment of ECG results (‘normal’, ‘abnormal, not clinically significant’, ‘abnormal, 
clinically significant’). If an ECG was not performed, a reason should be given. 
Clinically significant abnormal findings at the screening visit will be documented as medical 
history in the eCRF. At subsequent visits, any clinically significant deterioration of a 
pre-existing condition as well as any new clinically significant sign, symptom, or illness 
occurring after randomisation will be reported as an AE in accordance with Section 13.3. 
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11.5.4 
Local tolerability 
Subjects will provide an assessment of local tolerability according to the schedule of trial 
procedures (Section 4).  
The subject will complete a weekly assessment of stinging/burning in connection with the 
IMP applications in the eDiary from Day 7 onwards. The subject will be asked to 
retrospectively assess the worst stinging/burning in connection with the IMP application 
during the last week. In addition, the subjects will be asked by the investigator at the end-of-
treatment/early termination visit to assess the local tolerability during the last week (see 
Section 4). The assessment will be done using the 4-point scale shown in Panel 13. 
The subject’s assessment of local tolerability may be reported as an AE at the discretion of the 
investigator, even if the investigator does not suspect a local skin reaction related to 
application of IMP (reporting of e.g. pain or stinging/burning by the subject). 
Panel 13: Subject assessment of local tolerability after IMP application 
Grade (severity) 
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. 
Abbreviation: IMP: investigational medicinal product. 
 
Reporting in eCRF 
For the subject’s assessment of local tolerability, the highest (worst) skin reaction score across 
treatment area(s) will be recorded in the eCRF. 
11.5.5 
Laboratory testing 
11.5.5.1 
Overview 
Blood and urine samples will be collected according to the schedule of trial procedures 
(Section 4).  
The evaluations shown in Panel 14 will be performed by the central laboratory. 
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Panel 14: Clinical laboratory tests performed by the central laboratory  
Chemistry 
Haematology P2 
Liver and renal parameters: 
Albumin 
Creatinine 
Alkaline phosphatase  
Aspartate aminotransferase  
Alanine aminotransferase  
BilirubinP1 
Electrolytes and glucose: 
Sodium 
Potassium 
Glucose (non-fasting) 
Cholesterol 
LDL cholesterol 
HDL cholesterol 
Triglycerides 
Haemoglobin 
Thrombocytes 
White blood cells: 
Leukocytes 
Neutrophils 
Lymphocytes  
Monocytes  
Eosinophils  
Basophils 
Serology2,3 
Hepatitis B virus surface antigen 
Hepatitis C virus antibody 
HIV-1 antibody 
HIV-2 antibody 
UrinalysisP4 
Protein 
Glucose 
Ketones 
Leukocytes 
Erythrocytes 
Nitrite 
1) 
If bilirubin is above upper limit of normal, direct and indirect bilirubin will also be measured. 
2) 
In case additional analysis are needed to support the interpretation of the initial test results for hepatitis B, hepatitis C, or 
HIV, these will be performed by the central laboratory as applicable. 
3) 
Measured at screening only. 
4) 
Urinalysis will only be performed if considered required by the investigator based on dipstick results. 
Abbreviations: HDL = high density lipoprotein; HIV = human immunodeficiency virus; LDL = low density lipoprotein. 
 
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11.5.5.2 
Investigator evaluation of laboratory samples 
Central laboratory 
Chemistry, haematology, urinalysis (if applicable), and serology will be analysed by a central 
laboratory which will provide results to the trial sites. Laboratory parameters will be classified 
as ‘low’, ‘normal’, or ‘high’, depending on whether the value is below, within, or above the 
reference range for the relevant age group, respectively. The investigator must evaluate all 
results outside the reference range (‘clinically significant’ or ‘not clinically significant’) and 
sign and date the evaluation. The signed and dated version will be filed with the investigator’s 
trial documentation. In case of clinically significant abnormal results, appropriate action, as 
judged by the investigator, must be taken.  
If a screening laboratory result is abnormal and clinically significant, it will be at the 
investigator’s discretion to decide if the subject should be randomised into the trial (respecting 
exclusion criterion no. 21). 
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. 
In case of an increase of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) 
≥5×ULN re-sampling for alkaline phosphatase (ALP), ALT, AST, and bilirubin (BILI) should 
be done immediately, without undue delay and no later than within 72 hours from initial 
sampling time to confirm abnormalities. Re-sampling may be relevant at lower levels at the 
discretion of the investigator. 
Abnormal liver function tests of concurrent measurements of alanine aminotransferase (ALT) 
or aspartate aminotransferase (AST) ≥3×ULN and bilirubin (BILI) ≥2× ULN (Hy’s law) 
should be reported as an SAE (see Section 13.4 for reporting of SAEs).  
Tests performed at the trial site 
Urine samples will be tested with a dipstick according to the schedule of trial procedures 
(Section 4). It will be at the investigators discretion to decide whether a urine sample should 
be sent to the central laboratory for further analysis.  
Female subjects of childbearing potential will have a urine pregnancy test performed at the 
trial site at baseline prior to randomisation. The test will be repeated every 4 weeks as shown 
in the schedule of trial procedures in Section 4. 
 
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Reporting in eCRF 
At each visit, the site staff will record in the eCRF if a blood sample was taken. If not, a 
reason should be provided. The investigator’s assessment of the results (‘normal’, ‘abnormal, 
not clinically significant’, ‘abnormal, clinically significant’) will be recorded in the eCRF. 
It will be recorded in the eCRF if a urine dipstick was performed and whether urinalysis is 
required for further assessment, as judged by the investigator. If so, a urine sample should be 
sent to the central laboratory. If the urine sample was not tested with a dipstick, a reason will 
be provided. The investigator’s assessment of the urine dipstick results (‘normal’, ‘abnormal’) 
will be recorded in the eCRF. In case urinalysis is performed, the investigator’s assessment of 
the results (‘normal’, ‘abnormal, not clinically significant’, ‘abnormal, clinically significant’) 
will be recorded in the eCRF. 
It will be recorded in the eCRF if the subject is a woman of childbearing potential and if a 
urine pregnancy test was performed. If not, a reason should be provided. Also, the date and 
the outcome of the urine pregnancy test will be recorded in the eCRF (‘positive’, ‘negative’). 
Clinically significant abnormal laboratory results at the screening visit will be documented as 
medical history in the eCRF. At subsequent visits, any clinically significant deterioration of a 
pre-existing condition will be reported as an AE. Any new clinically significant sign, 
symptom, or illness occurring after screening will be reported as an AE in accordance with 
Section 13.3. 
11.6 Pharmacokinetic assessments 
Blood samples for PK assessments should be collected according to the schedule of trial 
procedures (Section 4). 
Collection, handling, and shipment instructions for PK blood samples are provided in a 
laboratory manual. 
PK samples for determination of delgocitinib concentrations will be analysed by a laboratory 
using a validated bioanalytical method. Details of the analytical method used will be 
described in the bioanalytical report.  
PK samples from 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. 
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Reporting in eCRF 
It will be recorded in the eCRF if the PK sample was taken; if not, a reason will be provided. 
The data and time of the last IMP application prior to the PK sample must be recorded in the 
eCRF.  
11.7 Pharmacodynamics assessments 
Not applicable. 
11.8 Other assessments 
11.8.1 
Patient-reported outcomes 
Each subject must make individual assessments relating to their perception of their disease 
and quality of life. These are recommended to be performed independently of the investigator 
and trial site staff, and prior to the investigator performing his/her efficacy assessments. 
The PRO HESD (eDiary) is considered an efficacy assessment in this trial and is described in 
Section 11.4.3. 
The PRO cDLQI (completed in an electronic device by the subjects at the trial sites) is 
described in Section 11.8.1.1 below.  
11.8.1.1 
Children Dermatology Life Quality Index  
The cDLQI is a validated questionnaire with content specific to those with dermatologic 
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 such as 
dermatology-related symptoms and feelings, friendships, leisure, school or holiday, adverse 
comments, sleep, and the treatment (35). 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 cDLQI 
will be completed at the trial site according to the schedule of trial procedures in Section 4. 
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11.9 End of trial 
End-of-treatment form 
An end-of-treatment form will be completed in the eCRF for all randomised subjects when 
exposed to IMP when they have had their last administration of IMP. This form will also be 
completed for subjects who permanently discontinue IMP prior to Week 16 and subjects who 
withdraw from trial, unless they were never exposed to IMP (see Section 10.3 for early 
termination assessments). 
The date of last administration of IMP will be recorded on the end-of-treatment form. It will 
also be recorded if the subject completed the treatment (i.e. did not discontinue IMP prior to 
the Week 16 visit) and, if not, whether the reason for not completing the treatment period was 
related to COVID-19. If the subject did not complete the treatment, the primary reason for 
permanent discontinuation of IMP must be recorded (see Section 10.2). 
End-of-trial form 
An end-of-trial form must be completed in the eCRF for all screened subjects when they have 
had their last visit. The following data will be collected: 
• Date of last contact. 
• Did the subject complete the trial? Refer to Section 7.3 for a definition of trial completion.  
• Primary reason for not completing the trial based on the following categories: death, 
adverse event, lack of efficacy, lost to follow-up, withdrawal by subject or 
parent/guardian, screen failure (failure to meet eligibility criteria), or other. 
• Was the reason for not completing the trial related to COVID-19? 
If ‘adverse event’ is selected, the AE in question will be linked to the non-completion of the 
trial. If ‘other’ is selected as a reason, a specification must be provided in the eCRF. If 
‘withdrawal by subject or parent/guardian’ is selected, it will be recorded whether the subject 
or parent/guardian withdrew informed consent or not. 
11.10 Estimate of total blood volume collected 
Blood samples will be drawn for haematology, biochemistry, serology, and PK. The total 
volume of blood to be drawn is approximately 42 mL. If additional blood samples are 
required, the amount of blood drawn may be more than this stated value, but total volume of 
blood drawn  will be kept to a minimum as required in the clinical guideline regarding 
investigation of medicinal products in the paediatric population (36). 
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11.11 Storage of biological samples 
The blood and urine samples for laboratory testing (serology, haematology, chemistry, and 
urinalysis) are only taken to ensure and monitor subject safety during this trial and will only 
be stored until the analysis is completed by the central laboratory. 
PK samples will be retained for as long as the quality of the material permits evaluation but 
for no longer than 12 months after completion of the CTR.  
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12 Scientific rationale for trial design and appropriateness of 
assessments 
12.1 Scientific rationale for trial design 
This trial is a randomised, double-blind, vehicle-controlled, parallel-group, multi-site trial. 
The trial will be conducted in accordance with the protocol, ICH GCP, and applicable 
regulatory requirements. The trial will be conducted at multiple trial sites located in Europe, 
Canada, and Australia. High quality trial sites with shared standards of practice will be 
selected. 
Subjects with CHE represent a heterogeneous population as CHE is associated with different 
aetiologies, morphologies, and severities. To mitigate any potential difference in trial outcome 
based on baseline characteristics, the trial subjects will be randomised in a stratified manner. 
Randomisation and blinding will minimise selection bias and minimise influence of 
confounding factors, and the stratification will ensure a balance of the treatment groups with 
respect to baseline disease severity (IGA-CHE score 3 or 4). IGA-CHE severity is viewed as a 
strong prognostic factor for persistent disease (37). 
The vehicle control group included in the trial will serve as reference and has been added to 
establish the efficacy and safety of delgocitinib cream in the adolescent population in a 
blinded trial design. The randomisation ratio of 3:1 allows the majority of subjects to receive 
active treatment with delgocitinib cream 20 mg/g. Subjects who have intolerable CHE 
symptoms may receive rescue treatment if needed. 
Topical application is considered the preferred route of administration for treatments for CHE, 
since CHE is a cutaneous disease characterised by local lesions affecting localised areas of the 
skin. Topical administration will minimise the systemic exposure to the IMP and hence reduce 
the risk of AEs due to systemic exposure.  
The dose and treatment duration of delgocitinib cream are based on data from the phase 2b 
dose-ranging trial in adults with mild to severe CHE (LP0133-1273), showing a treatment 
effect of delgocitinib cream 8 mg/g and 20 mg/g vs. cream vehicle (p<0.05) according to 
IGA-CHE TS (IGA-CHE score of 0 [clear] or 1 [almost clear] with a ≥2 step improvement 
from baseline) at Week 16. Since the benefit/risk profile for both strengths was favourable, it 
warranted the use of delgocitinib cream 20 mg/g to ensure a dose that is sufficient for the 
more severe segment of subjects and likely to provide the best possible treatment effect for all 
subjects across the moderate to severe population. 
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Although the underlying pathophysiological mechanism of CHE has not been studied in 
adolescents, there is no reason to believe that it is different from adult pathophysiology, and as 
the systemic exposure with delgocitinib cream is low and has shown to be comparable 
between adults and adolescents with atopic dermatitis (LP0133-1181 trial, part 1), it is 
considered to be appropriate to extrapolate the dose for adults (20 mg/g) to adolescents. 
In trial LP0133-1273, a clear treatment effect of delgocitinib cream 20 mg/g vs. cream vehicle 
(p<0.05) was demonstrated in terms of IGA-CHE TS and change from baseline in HECSI 
score from Week 8 in the moderate to severe population. Further, an increase in the 
IGA-CHE TS response rate was observed from Week 12 to Week 16 in both the delgocitinib 
cream 20 mg/g and cream vehicle groups, supporting a treatment duration with a primary 
efficacy endpoint at Week 16. 
The trial population is selected to reflect the adolescent population with CHE to ensure that 
the trial results will be generalisable to this part of the target population. The eligibility 
criteria are designed to comply with standard safety precautions and to avoid confounding 
diagnoses (e.g. psoriasis on the hands) which may interfere with the trial results. The target 
population is subjects with moderate to severe CHE based on the pronounced unmet medical 
need for this population, whereas subjects with mild CHE are generally well managed by 
elimination of trigger factors, general skin care, and TCS treatment. 
The trial endpoints have been selected to evaluate the efficacy and safety of delgocitinib 
cream in improving the severity and extent of CHE in adolescents. The trial endpoints will 
also address subject’s perception of disease severity and the impact on health-related quality 
of life. 
12.2 Appropriateness of assessments 
The clinical efficacy of delgocitinib cream will be assessed by IGA-CHE and HECSI. The 
IGA-CHE is an instrument based on a modification of the Physician’s Global Assessment for 
hand eczema (PGA) by removing the subjective subject assessments, area scoring, and by 
adjusting the description of score 1. The IGA-CHE is used in the phase 3 trials in adults 
(LP0133-1401 and LP0133-1402). HECSI is a validated measure used in clinical practice and 
clinical trials to assess the severity and extent of CHE (38). 
By validated PROs, this trial will also address the subjects’ perception of disease severity and 
the impact on health-related quality of life. 
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Safety will be assessed using standard clinical methods such as AE reporting, ECG, vital 
signs, and clinical laboratory measurements. 
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13 Adverse events 
13.1 Definition and classification of adverse events 
Adverse events and serious adverse events are defined in Appendix 1. 
Classification of AEs in terms of severity, causality, and outcome is defined in Appendix 2. 
13.2 Collection of adverse event reports 
AE data must be collected from time of first trial-related activity after the subject and/or the 
parent/guardian has signed the ICF/IAF until subject’s completion of the clinical trial (as 
defined in Section 7.3). 
AEs must be assessed by a physician.  
At all visits, the subject and/or the parent/guardian will be asked a non-leading question by 
the investigator about AEs, e.g.: “How have you felt since I saw you last?” No specific 
symptoms should be asked for, except subject-reported local tolerability which will be queried 
specifically (see Section 11.5.4) and reported as AE(s) if deemed relevant by the investigator. 
If the AE qualifies as an SAE, expedited reporting is required (Section 13.4). It is important 
that the investigator also observes the subject for any changes not reported by the subject and 
records these changes. 
Refer to Sections 11.5.1 to 11.5.5 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 
(e.g. ‘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: 
• Lesional/perilesional (≤2 cm from the border of lesion(s) treated with IMP). 
• Distant (>2 cm from the border of lesion(s) treated with IMP). 
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The duration of the AE must be reported by the start date and stop date of the event, unless the 
event is ongoing. If the event is ongoing, it will be marked as ongoing. In addition, it will be 
recorded if the AE started prior to first administration of IMP.  
AEs must be classified in terms of severity, causality, and outcome according to the 
definitions in Appendix 2. 
Action taken with IMP: any action taken with IMP as a consequence of the AE must be 
recorded (dose not changed, drug withdrawn, not applicable, unknown).  
Withdrawal from trial due to this AE: it must be recorded whether the AE led to withdrawal 
from the trial. 
Other action taken: any other action taken as a result of the AE must be recorded (none, 
concomitant medication, concurrent procedure). 
13.4 Reporting of serious adverse events 
The criteria that define an AE as serious (that is, an SAE) are defined in Appendix 1. SAE 
criteria are also listed on the SAE form. 
13.4.1 
Investigator reporting responsibilities 
Any SAE must be reported to LEO Pharma on the (paper) SAE form immediately, without 
undue delay and no later than U24 hours of obtaining knowledge. This report should contain 
amongst others an assessment of available information on seriousness, severity, causal 
relationship to the IMP or trial procedure, the action taken, the outcome to date, and a 
narrative description of the course of the event. For more details regarding reporting of any 
SAE, please see the guidance text on the SAE form. 
By signing and dating the SAE form, the investigator acknowledges that he/she is aware of 
the SAE and has assessed the causal relationship of the IMP(s) and any of the other 
medications to the SAE. 
The actual reporter, if not the investigator, should also sign and date the SAE form. 
The completed SAE form must be faxed or scanned and e-mailed to Global Safety at LEO 
Pharma using the e-mail address or fax number below: 
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UGlobal Safety at LEO Pharma 
E-mail address: drug.safety@leo-pharma.com  
Fax number: +45 6910 2468 
If relevant, the investigator will enclose other information with the SAE form, such as 
anonymised reports of diagnostic procedures, hospital records, autopsy reports, etc. 
Additionally, Global Safety at LEO Pharma may request further information in order to fully 
assess the SAE. The investigator must forward such information to LEO Pharma upon request 
by fax or e-mail (see contact details above). 
The investigator must notify the local IRB(s)/IEC(s) of SAEs, as required by current 
applicable legislation for the concerned country. 
SAEs occurring after the completion of the clinical trial should not be routinely sought or 
recorded. However, such events should be reported immediately without undue delay and no 
later than 24 hours of obtaining knowledge to Global Safety at LEO Pharma (see contact 
details above) if the investigator becomes aware of them. 
13.4.2 
LEO Pharma reporting responsibilities 
Global Safety at LEO Pharma is responsible for assessing whether an SAE is expected. The 
relevant reference safety information document for this clinical trial is: 
• For the IMP, investigator’s brochure Section 7.3, current edition and subsequent updates 
must be used.  
Global Safety at LEO Pharma will notify the regulatory authorities and concerned 
investigators of SAEs according to the current applicable legislation for the concerned 
countries. 
The IRB(s)/IEC(s) will be notified of SAEs according to the current applicable legislation for 
the concerned countries.  
For all countries, the following reporting requirements apply: all SAEs which are assessed as 
causally related to the IMP(s) by either the investigator or LEO Pharma (39), and which are 
unexpected (suspected, unexpected serious adverse reactions [SUSARs]), are subject to 
expedited reporting to regulatory authorities, and IEC(s)/IRB(s), according to the current 
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applicable legislation in the concerned countries. Investigators will be notified of the evolving 
safety profile of the IMP on an ongoing basis. 
13.5 Other events that require expedited reporting 
13.5.1 
Pregnancy 
Any pregnancy occurring after first exposure to IMP and until the subject has completed the 
trial must be reported to LEO Pharma within 24 hours of first knowledge using the (paper) 
pregnancy form (part I). All pregnancies must be followed up until delivery or termination, 
and outcome must be reported on the (paper) pregnancy form (part II) within 24 hours of first 
knowledge.  
The completed pregnancy forms must be faxed or scanned and e-mailed to Global Safety at 
LEO Pharma. Contact details are given in Section 13.4.1. 
Pregnant subjects must immediately discontinue IMP permanently (Sections 10.2 and 10.3). 
13.6 Reporting of other events 
13.6.1 
Adverse events of special interest 
The events listed in Panel 15 are considered AESIs in this trial and will require additional 
details to be recorded. LEO Pharma may request that the investigator forward additional test 
results, as appropriate. An AESI may be serious or non-serious. Serious AESIs require 
expedited reporting via the SAE form as described in Section 13.4 in addition to the 
requirements specified in Panel 15. AESIs will be part of the data that a DMC will have 
access to.  
Panel 15: Adverse events of special interest 
Adverse event of 
special interest 
Additional data to be recorded 
Eczema herpeticum 
Skin findings: 
• Lesion type (papules, vesicles, crusts, eroded pits, other). 
• Disseminated / localised. 
• Location (face, scalp, back, chest, upper limb, lower limb, genitals). 
• Present in an area with visible eczema / no visible eczema / present in areas with 
and without eczema. 
• Monomorphic / polymorphic. 
• Confirmation of herpes simplex virus (not confirmed, polymerase chain reaction 
[PCR], viral culture, Tzanck, other). 
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13.6.2 
Medication error  
Medication error refers to any unintentional error in the dispensing or administration of an 
IMP.  
Medication errors include accidental overdose or underdose, inappropriate schedule of 
product administration, incorrect route of product administration, wrong product 
administered, and expired product administered]. 
Accidental overdose or underdose where a clinical consequence occurred or could have 
occurred should be recorded based on investigator judgement.  
Inappropriate schedule of product administration where a clinical consequence occurred or 
could have occurred should be recorded based on investigator judgement.  
Treatment non-compliance (incl. missed doses) where no clinical consequence occurred or 
could have occurred should not be recorded as medication errors. See Section 9.8.4 for 
recording of treatment non-compliance. 
Medication error must be recorded on the other event involving IMP form in the eCRF. In 
addition, any clinical consequences of the medication error must be recorded as separate AEs 
on the AE form. If the AE originating from the medication error qualifies as an SAE, 
expedited reporting is required (Section 13.4). 
13.6.3 
Misuse or abuse 
The terms misuse and abuse are similar in that they both represent the intentional use of a 
drug in a way other than intended. 
Misuse refers to situations where the IMP is intentionally and inappropriately used for 
therapeutic purposes not in accordance with the protocol. 
Abuse refers to intentional use of an IMP for what could be considered desirable non-
therapeutic effects (e.g. sedative, stimulant, euphoric effects). 
Misuse and abuse must be recorded on the other event involving IMP form in the eCRF. In 
addition, any clinical consequences of misuse or abuse must be recorded as separate AEs on 
the AE form. If the AE originating from the misuse or abuse qualifies as an SAE, expedited 
reporting is required (Section 13.4). 
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13.6.4 
Aggravation of condition 
Any clinically significant aggravation/exacerbation/worsening of any medical condition(s) 
(including the trial disease), compared to screening, must be reported as an (S)AE in 
accordance with Sections 13.3 and 13.4. 
As CHE is a fluctuating disease, consider to only report an AE if aggravation/exacerbation 
exceeds normal disease fluctuation or if lesions appear in an area which is normally not 
affected by CHE. 
13.7 Follow-up for final outcome of adverse events 
During the trial, the investigator should follow up for final outcome on all AEs (including 
SAEs). Once a subject leaves the clinical trial, the investigator should follow up on the 
outcome of all non-serious AEs classified as possibly or probably related to the IMP for 
14 days after end of treatment, or until the final outcome is determined, whichever comes 
first. Non-serious AEs classified as not related to the IMP do not need to be followed up for 
the final outcome. 
All SAEs must be followed up until a final outcome has been established, that is, the 
follow-up may continue beyond the end of the clinical trial. For SAEs which have stabilised 
and from which the subject cannot be expected to recover during the trial or the safety 
follow-up periods, e.g. chronic or stabilised conditions, the final outcome at the investigator’s 
discretion should be reported as ‘recovering/resolving’ or ‘not recovered/not resolved’. In 
addition, a statement detailing why the subject cannot be expected to recover during the trial, 
e.g. that the SAE has stabilised or is chronic, should be added to the narrative description of 
the SAE on the SAE form. 
Any pregnancy occurring during the trial will be followed up as described in Section 13.5.1. 
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.” (40). 
If the investigator becomes aware of information that requires an immediate change in a 
clinical trial procedure or a temporary halt of the clinical trial to protect clinical trial subjects 
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from any immediate hazard to their health and safety, the investigator can do so without prior 
approval from LEO Pharma, regulatory authorities, or IRBs/IECs. 
The investigator must immediately inform LEO Pharma – by contacting the clinical project 
manager or medical expert – of this change in a clinical trial procedure or of the temporary 
halt; the investigator will provide full details of the information and the decision-making 
process leading to the implementation of the urgent safety measure. 
LEO Pharma must act immediately upon receipt of the urgent safety measure notification in 
accordance with internal procedures and local legislation. 
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14 Statistical methods 
Endpoints will be analyzed using 2 different statistical approaches: the Bayesian and the 
Frequentist approach. 
14.1 Sample size 
92 subjects will be randomised 3:1 to delgocitinib cream 20 mg/g or cream vehicle.  
Based on response rates from the phase 2b dose-ranging trial in adults (LP0133-1273), a one-
sided significance level at 2.5% and a sample size of 92 subjects will provide at least 80% 
power for detecting a treatment difference in the primary endpoint assuming an IGA-CHE TS 
response at Week 16 of 40.2% for delgocitinib cream 20 mg/g and 10.5% for cream vehicle.  
When the response rates from LP0133-1401 and LP0133-1402 are included in the sample size 
calculation, this will result in a power which is lower than first anticipated.  
The power obtained when using the Bayesian approach on a sample size of 92 subjects is 
explained in Section 14.3.17. 
14.2 Trial analysis sets 
All screened subjects will be accounted for in the CTR. 
All subjects randomised and exposed to IMP will be included in the full analysis set and will 
be analysed for efficacy. Exclusions from the full analysis set can be considered in special 
cases as described in ICH E9, Section 5.2.1., Full Analysis Set. If it is decided to exclude a 
randomised subject exposed to IMP from the full analysis set, a justification addressing ICH 
E9 will be given. 
A safety analysis set will be defined as all subjects exposed to IMP.  
The decisions regarding inclusion/exclusion of subjects or subject data from the trial analysis 
sets will be documented in the analysis set definition document before breaking the 
randomisation code.  
14.3 Statistical analysis 
14.3.1 
Disposition of subjects 
The reasons for permanent discontinuation of IMP or withdrawal from trial will be presented 
for all randomised subjects by last visit attended and by treatment group. 
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An overall summary of subject disposition will be presented for all randomised subjects. The 
disposition summary will include information on the number of randomised, exposed, 
included in the full analysis set, permanently discontinuing IMP, and not completing the trial 
by treatment group and overall. 
14.3.2 
Demographics and other baseline characteristics 
Descriptive statistics of demographics and other baseline characteristics will be presented for 
all randomised subjects and by treatment group. Presentations of age, sex, ethnicity, race, and 
baseline IGA-CHE by treatment will also be given.  
Other baseline characteristics include height, weight, body mass index, region, country, 
Fitzpatrick skin type, CHE history, CHE treatment history, past and current medical history, 
and prior and concomitant medication. In addition, the baseline assessment for the primary 
and key secondary endpoints will be presented. 
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.  
The average weekly and total amount of IMP used will be presented for the safety analysis set 
by treatment group for each visit interval and for the total treatment period. 
Treatment compliance will be presented for the safety analysis set per treatment group. 
14.3.4 
Testing strategy and establishing confirmatory evidence using Bayesian 
analysis 
The Bayesian analyses of the primary estimand for the primary and key secondary endpoints 
are considered the confirmatory evidence for the trial. The treatment effect (defined as 
proportion of responders for delgocitinib cream 20 mg/g minus the proportion of responders 
for cream vehicle) for all the binary confirmatory endpoints will be evaluated based on the 
calculated difference of posterior distributions for delgocitinib cream 20 mg/g and cream 
vehicle. Delgocitinib cream 20 mg/g is considered superior to cream vehicle if the 2.5% 
percentile of the posterior distribution of the treatment difference is ≥0.  
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Hierarchical evaluation, which is applied for the Bayesian analyses, will be used to control the 
overall type I error at a nominal one sided 2.5% level. This is built on the principle that the 
IGA-CHE TS superiority at Week 16 will have to be established before sequential testing for 
additional benefits (key secondary endpoints) related to efficacy. 
If superiority is claimed for the primary endpoint, then evaluation of the next endpoints will 
be done in a fixed sequential order as specified in Panel 16. This process will be repeated until 
no further tests are significant. 
Only analyses based on the Bayesian approach will be part of the testing hierarchy.  
Panel 16: Graphical display of the testing procedure for primary and secondary 
endpoints 
 
 
Abbreviations: HECSI-90 = at least 90% improvement in HECSI score from baseline; HESD = Hand Eczema Symptom 
Diary©; IGA-CHE = Investigator’s Global Assessment for chronic hand eczema©; IGA-CHE TS = IGA-CHE treatment 
success, i.e. an IGA-CHE score of 0 (clear) or 1 (almost clear) with a ≥2-step improvement from baseline. 
14.3.5 
Estimand strategy 
14.3.5.1 
Overview 
The analysis of endpoints related to efficacy and health-related quality of life will be based on 
the full analysis set. 
For the analyses based on the Bayesian approach, only the primary estimand using the 
composite strategy will be used. 
For the analyses based on the Frequentist approach, both the primary estimand (using the 
composite strategy) and the supplementary estimand (using the treatment policy strategy) will 
be considered for the primary endpoint while only the primary estimand will be considered 
for the key secondary endpoints (remaining binary endpoints) and other continuous endpoints.  
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The primary estimand will use a composite strategy to handle IEs. With a composite strategy, 
the occurrence of an IE is a component of the endpoint. 
A supplementary estimand will use a treatment policy strategy which attempts to quantify the 
effect of the randomised treatment, ignoring the occurrence of IEs. Data collected for the 
endpoint of interest are used regardless of whether an IE occurred. 
For the composite and treatment policy estimands, prespecified sensitivity analyses will be 
conducted to assess the robustness of the results with respect to the handling of missing data. 
The pre-specified sensitivity analysis will only be performed for the primary endpoint as a 
low IMP discontinuation rate is anticipated in the relatively small sample size (69 subjects on 
delgocitinib cream vs. 23 subjects on cream vehicle) and the expected low amount of the 
missing data. These sensitivity analyses will only be performed for the analyses based on the 
Frequentist approach when mentioned. 
In addition, sensitivity analyses of the influence of weight on the non-informative part of the 
prior will be made for the Bayesian approach, see Section 14.3.17. 
The following IEs are considered to affect the interpretation of the estimated treatment 
effects: 
• Initiation of rescue treatment: This IE occurs when a subject initiates rescue 
treatment. This IE can occur at the discretion of the investigator. If rescue treatment is 
initiated, the subject must stop treatment with IMP immediately and will not be 
allowed to restart treatment with IMP (refer to Section 9.5 for details).  
• Permanent discontinuation of IMP: This IE occurs when a subject permanently 
discontinues IMP. This IE can occur at the subject's own initiative, at the subject’s 
parent’s/guardian’s initiative, at the discretion of the investigator or the sponsor, or if 
the subject is lost to follow-up. 
Panel 17 presents an overview of how observed and missing data will be handled according to 
the IEs for the primary analysis for estimands.
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Panel 17: Handling of observed and missing data according to the intercurrent events for the primary analysis estimands 
 
 
Estimand strategy for binary endpoints 
Estimand strategy for continuous 
endpoints 
Intercurrent event 
Data observed 
or missing 
Composite 
 
 
(Primary) 
Treatment policy 
 
 
(Supplementary)1 
Composite 
 
 
(Primary) 
Initiation of rescue 
treatment. 
Observed. 
Non-response. 
Value will be used 
as observed. 
WOCF (including baseline value). 
Missing. 
Non-response. 
MI (MAR). 
WOCF (including baseline value). 
Permanent 
discontinuation of IMP.  
Observed. 
Non-response. 
Value will be used 
as observed. 
WOCF (including baseline value). 
Missing. 
Non-response. 
MI (MAR). 
WOCF (including baseline value). 
No intercurrent events. 
Observed. 
Value will be used as 
observed. 
Value will be used 
as observed. 
Value will be used as observed. 
Missing. 
Non-response. 
MI (MAR). 
WOCF (including baseline value). 
1. Supplementary estimand will only be performed for the primary endpoint. 
Abbreviations: IMP = investigational medicinal product; MAR = missing at random; MI = multiple imputation; WOCF = worst observation carried forward. 
 
 
 
 
 
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14.3.5.2 
Estimands for binary endpoints 
The population level summary will be the risk difference between delgocitinib cream 20 mg/g 
and cream vehicle. 
Primary estimand: composite strategy (used for both the Bayesian approach and the 
Frequentist approach) 
This primary estimand evaluates the treatment effect in adolescents 12-17 years of age with 
moderate to severe CHE, without initiation of rescue treatment or permanent discontinuation 
of IMP. 
For subjects who received rescue treatment or who have permanently discontinued IMP prior 
to the endpoint of interest, observed data after the IEs will be considered non-response, 
reflecting an assumption that initiation of rescue treatment and permanent discontinuation of 
IMP indicate failure of the randomised treatment. 
For example, the primary composite endpoint of IGA-CHE TS at Week 16 without initiation 
of rescue treatment or permanent discontinuation of IMP can take the values: 
• ‘1’ (response), if the subject achieves IGA-CHE TS at Week 16 and has not initiated 
rescue treatment nor permanently discontinued IMP prior to Week 16. 
• ‘0’ (non-response), if the subject has not achieved IGA-CHE TS at Week 16 or has 
initiated rescue treatment or permanently discontinued IMP prior to Week 16. 
Supplementary estimand: treatment policy strategy (used for the Frequentist approach) 
This supplementary estimand evaluates the treatment effect in adolescents 12-17 years of age 
with moderate to severe CHE, regardless of initiation of rescue treatment or permanent 
discontinuation of IMP. 
Observed data will be used in the analysis, including the data observed after the occurrence of 
IEs. To support the treatment policy strategy, subjects who experience IEs prior to Week 16 
will be asked to attend the primary endpoint visit at Week 16 for collection of data. 
14.3.5.3 
Estimand for continuous endpoints (used for the Frequentist approach) 
The population level summary will be the difference in mean change (or percentage change) 
from baseline to the endpoint of interest between delgocitinib cream 20 mg/g and cream 
vehicle. 
Primary estimand: composite strategy 
This primary estimand evaluates the treatment effect in adolescents with moderate to severe 
CHE, without initiation of rescue treatment or permanent discontinuation of IMP. 
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For subjects who received rescue treatment or who have permanently discontinued IMP prior 
to the endpoint of interest, observed data after the IEs will be considered non-response by 
using WOCF (including the baseline value) which is considered an extremely unfavourable 
value. 
14.3.6 
Primary endpoint analysis, Frequentist approach  
The primary endpoint will be analysed as follows: Let the treatment effect be defined as 
μ = (delgocitinib cream 20 mg/g minus cream vehicle), then the hypothesis to be tested is: 
• 𝐻଴: 𝜇≤0 𝑎𝑔𝑎𝑖𝑛𝑠𝑡 𝐻௔: 𝜇> 0. 
The hypothesis will be tested for delgocitinib cream 20 mg/g vs. cream vehicle based on the 
primary analysis for the primary estimand. 
Primary analysis for the primary estimand 
Missing data for subjects who do not attend the visit for the endpoint of interest and do not 
experience an IE prior to this visit will be imputed as non-response. 
The risk difference between the 2 treatment groups will be based on a logistic regression 
model including treatment group and baseline IGA-CHE score as factors. The logistic 
regression model will be used to estimate the risk difference and associated 95% confidence 
interval based on the standardised estimator presented in Ge M et al. (41). 
Sensitivity analysis for the primary estimand 
Missing data at the endpoint of interest, for subjects who do not experience the IEs prior to 
that, will be handled as follows. For subjects in the delgocitinib cream 20 mg/g group and the 
cream vehicle group, missing data will be imputed from a Bernoulli distribution with 
parameter p value 0.1. The same parameter p will be used for both treatment groups. The 
parameter value 0.1 is based on the response rate of IGA-CHE TS at Week 16 in the cream 
vehicle group in the phase 2b trial in adults (LP0133-1273) and will introduce uncertainty due 
to missing data. A MI procedure (100 iterations) will be used. For each of the 100 complete 
datasets, the risk difference will be based on a logistic regression model including treatment 
group and baseline IGA-CHE score as factors. The results of the analyses will be combined 
using Rubin’s rule to provide the estimated treatment difference and associated standard error, 
and the 95% CI for the treatment difference will be calculated. In case of no missing data this 
analysis will not be performed. 
Supplementary analysis for primary estimand using historical and trial data 
Historical data used for this analysis is from trials LP0133-1401 and LP0133-1402. 
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The 95% CI of interaction between treatment and trial ID for the logistic regression model, 
(including the factors: treatment group, baseline IGA-CHE score, trial ID [i.e., trials 
LP0133-1401, LP0133-1402, and LP0133-1426] and interaction between treatment and trial 
ID) will be presented. The 95% confidence interval is based on the standardised estimator 
presented by Ge M et al. (41). 
Analysis for the supplementary estimand 
Missing data at Week 16 will be imputed using MI (100 iterations) assuming MAR within 
treatment group. 
For each of the 100 imputed datasets, the risk difference will be based on a logistic regression 
model including treatment group and baseline IGA-CHE score as factors. The results of the 
analyses will be combined using Rubin’s rule to provide the estimated treatment difference 
and associated standard error, and the 95% CI for the treatment difference will be calculated. 
This will only be performed for the primary endpoint. In case of no missing data this analysis 
will not be performed. 
Sensitivity analysis for the supplementary estimand 
Missing data at Week 16 will be imputed as non-response. 
The risk difference will be analysed as described above for the primary analysis for the 
supplementary estimand. This will only be performed for the primary endpoint. In case of no 
missing data this analysis will not be performed. 
14.3.7 
Primary endpoint analysis, Bayesian approach  
The Bayesian analysis of the primary endpoint is only done for the primary estimand. The 
treatment effect (defined as proportion of responders for delgocitinib cream 20 mg/g minus 
the proportion of responders for cream vehicle) will be evaluated based on the calculated 
posterior distribution of the treatment difference. Delgocitinib cream 20 mg/g is considered 
superior to cream vehicle if the 2.5% percentile of the posterior distribution of the treatment 
difference is ≥ 0.  
The methodology for calculating the posterior distribution and extracting the mean treatment 
difference along with 95% credibility intervals and the likelihood that the treatment effect is 
larger than 0 is described in Section 14.3.17. 
14.3.8 
Key secondary endpoint analysis, Frequentist approach 
The key secondary endpoints will be analysed in the same manner as described in Section 
14.3.6 for the primary endpoint. 
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Panel 18 provides an overview of which estimand (the composite strategy) and missing data 
strategy (non-responder imputation) is to be used in the analyses of the key secondary 
endpoints. 
Panel 18: Overview of estimand and missing data strategy used for the key secondary 
endpoints 
Key secondary endpoint 
Type of 
endpoint 
Primary estimand 
Strategy to 
handle IEs 
Handling of missing 
data and data 
collected after IE 
HECSI-90 at Week 16. 
Binary. 
Composite. 
  
Non-response 
imputation. 
Reduction of HESD itch score (weekly average) 
of ≥4 points from baseline at Week 161. 
Reduction of HESD pain score (weekly average) 
of ≥4 points from baseline at Week 162. 
Reduction of HESD score (weekly average) of ≥4 
points from baseline at Week 163. 
1) Among subjects with a baseline HESD itch score (weekly average) ≥4 points. 
2) Among subjects with a baseline HESD pain score (weekly average) of ≥4 points. 
3) Among subjects with a baseline HESD score (weekly average) of ≥4 points. 
Abbreviations: HECSI = Hand Eczema Severity Index; HECSI‑90 = at least 90% improvement in HECSI from baseline; 
HESD = Hand Eczema Symptom Diary©; IE = intercurrent event. 
14.3.9 
Key secondary endpoint analysis, Bayesian approach 
The confirmatory hypotheses for key secondary endpoints (for testing hierarchy, see Panel 16) 
will be tested based on the primary endpoint analysis (see Section 14.3.7) for the primary 
estimand described in Section 14.3.5.2. Missing data will be handled in the same manner as 
for the Frequentist approach, see Panel 18.   
14.3.10 
Secondary endpoint analysis, Frequentist approach 
The analysis of secondary endpoints will be based on the full analysis set. 
The analysis of the binary secondary endpoints will resemble the primary analysis for the 
primary estimand detailed in Section 14.3.6. Continuous endpoints will be analysed as 
follows: 
Analysis of continuous endpoints for the primary estimand 
Missing data for subjects who do not attend the visit for the endpoint of interest and do not 
experience an IE prior to this visit will be imputed as WOCF (including the baseline value). 
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The change (or percentage change) from baseline to the endpoint of interest will be analysed 
using an ANCOVA model with effects of treatment group, baseline IGA-CHE score, and 
baseline value (endpoint of interest). 
Panel 19 provides an overview of the estimands and missing data strategy used for the 
secondary endpoints. 
Panel 19: Overview of estimand and missing data strategy used for secondary endpoints 
Secondary endpoints 
Statistical 
approach 
Type of 
endpoint 
Primary estimand 
Strategy 
to handle 
IEs 
Handling of missing data and data 
collected after IE 
Efficacy 
IGA-CHE TS at Weeks 
2, 4, 8, and 12. 
Frequentist. 
Binary. 
Composite. 
Non-response imputation. 
Health-related quality of life and efficacy 
Change in cDLQI score 
from baseline to Week 
16. 
Frequentist. 
Continuous. 
Composite. 
WOCF (including baseline value). 
Abbreviations: cDLQI = Children’s Dermatology Life Quality Index; IE = intercurrent event; IGA-CHE = Investigator’s 
Global Assessment for chronic hand eczema©; IGA-CHE TS = IGA-CHE treatment success, i.e. an IGA-CHE score of 0 
(clear) or 1 (almost clear) with a ≥2 step improvement from baseline; WOCF = worst observation carried forward. 
14.3.11 
Exploratory analyses, Frequentist approach 
The analysis of exploratory endpoints will be based on the full analysis set. 
The analysis of exploratory endpoints will resemble the primary analysis for the primary 
estimand related to a specific endpoint type: binary or continuous. For details refer to Section 
14.3.6 for binary endpoints and for continuous endpoints refer to Section 14.3.8). 
Panel 20 provides an overview of the estimand and missing data strategy used for the 
exploratory endpoints. 
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Panel 20: Overview of estimand and missing data strategy used for exploratory 
endpoints 
Exploratory endpoints 
Statistical 
approach 
Type of 
endpoint 
Primary estimand 
Strategy to 
handle IEs 
Handling of 
missing data and 
data collected 
after IE 
Efficacy 
HECSI-75 at Weeks 4, 8, and 16 
Frequentist 
Binary 
Composite 
Non-response 
imputation 
HECSI-90 at Weeks 4 and 8 
Frequentist 
Binary 
Composite 
Non-response 
imputation 
Percentage change in HECSI score from 
baseline to Weeks 4, 8, and 16 
Frequentist 
Continuous 
Composite 
WOCF (including 
baseline value) 
Health-related quality of life and efficacy 
Reduction of HESD itch score (weekly 
average) of ≥3 points from baseline at Weeks 
2, 4, and 81 
Frequentist 
Binary 
Composite 
Non-response 
imputation 
Reduction of HESD itch score (weekly 
average) of ≥4 points from baseline at Weeks 
2, 4, 8, and 162 
Frequentist 
Binary 
Composite 
Non-response 
imputation 
Change in HESD itch score (weekly average) 
from baseline to Weeks 2, 4, 8, and 16 
Frequentist 
Continuous 
Composite 
WOCF (including 
baseline value) 
Reduction of HESD pain score (weekly 
average) of ≥3 points from baseline at Weeks 
2, 4, and 83 
Frequentist 
Binary 
Composite 
Non-response 
imputation 
Reduction of HESD pain score (weekly 
average) of ≥4 points from baseline at Weeks 
2, 4, and 84 
Frequentist 
Binary 
Composite 
Non-response 
imputation 
Change in HESD pain score (weekly 
average) from baseline to Weeks 2, 4, 8, and 
16 
Frequentist 
Continuous 
Composite 
WOCF (including 
baseline value) 
Reduction of HESD score (weekly average) 
of ≥3 points from baseline at Weeks 2, 4, 8, 
and 165 
Frequentist 
Binary 
Composite 
Non-response 
imputation 
Reduction of HESD score (weekly average) 
of ≥4 points from baseline at Weeks 2, 4, 8, 
and 166 
Frequentist 
Binary 
Composite 
Non-response 
imputation 
Change in HESD score (weekly average) 
from baseline to Weeks 2, 4, 8, and 16 
Frequentist 
Continuous 
Composite 
WOCF (including 
baseline value) 
Change in cDLQI score from baseline to 
Week 4 
Frequentist 
Continuous 
Composite 
WOCF (including 
baseline value) 
1) 
Among subjects with a baseline HESD itch score (weekly average) ≥3 points. 
2) 
Among subjects with a baseline HESD itch score (weekly average) ≥4 points. 
3) 
Among subjects with a baseline HESD pain score (weekly average) ≥3 points. 
4) 
Among subjects with a baseline HESD pain score (weekly average) ≥4 points. 
5) 
Among subjects with a baseline HESD score (weekly average) ≥3 points. 
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6) 
Among subjects with a baseline HESD score (weekly average) ≥4 points. 
Abbreviations: cDLQI = Children’s Dermatology Life Quality Index; HECSI = Hand Eczema Severity Index; HECSI-75 = 
at least 75% improvement in HECSI from baseline; HECSI-90 = at least 90% improvement in HECSI from baseline; HESD 
= Hand Eczema Symptom Diary©; IE = intercurrent event; WOCF = worst observation carried forward. 
14.3.12 
Analysis of pharmacokinetics 
Delgocitinib plasma concentration will be summarised for the safety analysis set by visit 
using geometric mean, coefficient of variation (derived based on a log-normal distribution 
assumption), median, 1st quartile, 3rd quartile, minimum, and maximum values. 
14.3.13 
Safety analysis 
The analysis of safety will be based on the safety analysis set. 
14.3.13.1 
Adverse events 
AEs will be coded during the course of the trial according to Medical Dictionary for 
Regulatory Activities (MedDRA). AEs will be presented by preferred term and primary 
system organ class (SOC). 
Treatment-emergent AEs will be summarised; however, all AEs recorded during the course of 
the trial will be included in subject data listings. An event will be considered 
treatment-emergent if started after the first application of IMP or if started before the first 
application of IMP and worsened in severity after first application of IMP. The tabulations 
described in the following will only include the treatment-emergent AEs. In each of the 
tabulations, AEs are defined by MedDRA preferred terms within primary SOC. 
An overall summary of the number of events and the number (percentage) of subjects with 
any treatment-emergent AEs, deaths, SAEs, premature discontinuations from IMP and/ or 
withdrawals 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.  
Related AEs are defined as AEs for which the investigator has not described the causal 
relationship to IMP as ‘not related’. The number of related AEs and the number of subjects 
with each type of related AE will be tabulated.  
SAEs will be evaluated separately, and a narrative will be given. 
AESIs will be listed by treatment group. No narratives will be given.  
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AEs leading to withdrawal from trial or permanent discontinuation of IMP will be listed. The 
detailed listing will provide an overview of the individual cases and include the age and sex of 
the participant, treatment received at the time of AE onset, the AE preferred and reported 
terms, causality and severity of the AE, the action taken with the IMP, AE outcome, start and 
stop date of AE, duration of AE, and number of days since first and last IMP administration. 
No narratives will be given.  
Other events (medication error, misuse, and abuse of IMP) will be tabulated and listed. No 
narratives will be given. 
14.3.13.2 
Vital signs and physical examination 
The change in vital signs (resting blood pressure and pulse) from baseline to Week 16 will be 
summarised as mean, standard deviation (SD), median, minimum, and maximum values for 
each treatment group. 
14.3.13.3 
Clinical laboratory evaluation 
For laboratory parameters, the absolute values as well as the changes from baseline will be 
summarised by visit for each treatment group. 
A shift table will be produced for relevant parameters showing the categories at baseline 
against those at end of treatment (Week 16). 
14.3.14 
Interim analysis 
No interim analysis is planned. 
14.3.15 
General principles 
All significance tests will be one-sided using the 2.5% significance level. All confidence 
intervals will be presented with 95% degree of confidence, unless otherwise specified. 
An observed-cases approach will be used for tabulations of data by visit (that is, involving 
only those subjects who attended each specific visit). 
Categorical data will be summarised using the number and percentage of subjects in each 
category and treatment group. Continuous data will be summarised using the mean, median, 
SD, 1st quartile, 3rd quartile, minimum, and maximum values. 
All the analyses specified in the protocol will be reviewed in relation to the blinded data 
actually obtained, and the statistical analysis plan will be finalised before breaking the 
randomisation code. 
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Any changes from the statistical analyses planned in this clinical trial protocol will be 
described and justified in a protocol amendment, the statistical analysis plan and/or in the 
CTR, dependent on the type of change. 
14.3.16 
Handling of missing values 
The methods for handling of missing values in the different analyses are described in 
Section 14.3.5. 
14.3.17 
Description of the Bayesian analyses and design characteristics 
The design characteristics is based on 92 randomised subjects (69 in the delgocitinib cream 
20 mg/g group and 23 in the cream vehicle group). 
For each endpoint, the choice of the between-trial heterogeneity parameter (τ) and the weight 
on the non-informative part of the prior is described. In addition, the degree of borrowing is 
described by the ESS and finally, the influence of the type I error and power investigated. 
14.3.17.1 
Overview of the Bayesian procedure 
The R Bayesian evidence synthesis tools (R package RBesT) (42, 43) will be applied. The 
steps in the analysis are listed below. 
1. Create informative prior: The MAP approach, using a hierarchical model for 
between-study heterogeneity, will be applied to derive an informative prior from 
historical data (the pivotal trials LP0133-1401 and LP0133-1402 and where 
applicable, phase 2b trial LP0133-1273) for the cream vehicle as well as for the 
delgocitinib cream 20 mg/g treatment group.  
2. Parametric mixture densities: The expectation maximization algorithm is used to 
approximate parametric mixture densities to the MCMC samples representing the 
MAP prior. The mixture providing the best Akaike information criterion value is 
selected. 
3. Robustification of the informative prior: The informative mixture prior is 
robustified by adding a non-informative component which protects against type I error 
inflation in presence of prior-data conflict, i.e. if the adolescent trial data strongly 
deviate from the historical information. The weight put on the non-informative part is 
prespecified for each endpoint. The influence of the weight on the ESS, the type I 
error and power for the trial will be described. 
4. Posterior distribution: Once the data from the adolescent trial is unblinded, the 
posterior distributions for the proportion of responders for each treatment group, given 
the robust mixture priors, are calculated. 
5. Treatment effect evaluation: Conclusion on treatment effect will be based on the 
calculated difference in the posterior distributions. 
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a. Statistically significant treatment effect is concluded if the probability that the 
difference (delgocitinib cream 20 mg/g minus cream vehicle) is larger than 
zero, is larger than 0.975. 
b. 95% credibility interval is generated as the 2.5% and 97.5% quantiles of the 
difference in posterior distributions. 
c. Median and mean are calculated from the difference in posterior distributions. 
6. Sensitivity/tipping point analyses (given the unblinded results): Will be done to 
evaluate the influence of the prespecified selected τ and the prespecified selected 
weight parameter for the non-informative part of the prior. 
14.3.17.2 
Evaluation of design characteristics (type I error, power and bias) for the 
Bayesian analysis of the primary endpoint 
The between-trial heterogeneity for the primary endpoint IGA-CHE TS is set to τ = 0.5, the 
weight on the non-informative part of the prior is set to 0.2 (20%).  
This ensures a type I error <5% for efficacy rates <10% (average observed efficacy rates for 
cream vehicle was 8.4% in the adult trials LP0133-1401 and LP0133-1402) and a high power 
(>75%) for efficacy levels above observed efficacy levels (average difference in adult trials is 
15.9%).  
In the following sections, the selection of the parameters for the primary endpoint 
IGA-CHE TS are justified and discussed.  
Results of primary endpoint from the pivotal phase 3 trials LP0133-1401 and LP0133-
1402 
Results are shown in Panel 21. 
Panel 21: Results of primary endpoint IGA-CHE TS, trials LP0133-1401 and 
LP0133-1402 
 
Delgocitinib 
cream 20 mg/g 
Responders (%), 
N 
Cream vehicle 
Responders (%), 
N 
Average 
response rate 
for cream 
vehicle 
Average 
response rate 
for delgocitinib 
cream 20 mg/g 
Average 
treatment 
effect 
LP0133-1401 
64 (19.7),  
N = 325 
16 (9.9),  
N = 162 
8.4% 
24.3% 
15.9% 
LP0133-1402 
91 (29.1),  
N = 313 
11 (6.9),  
N = 159 
Abbreviations: IGA-CHE: Investigator’s Global Assessment for chronic hand eczema©; N: number of subjects. 
Notes: IGA-CHE TS = IGA-CHE treatment success, i.e. an IGA-CHE score of 0 (clear) or 1 (almost clear) with a ≥2-step 
improvement from baseline. 
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14.3.17.2.1 
Creating informative prior for cream vehicle 
The variability in the estimated proportion of responders is low for cream vehicle. A summary 
of the MAP is shown in Panel 22. 
Panel 22: Summary of MAP for cream vehicle 
 
Mean 
SD 
Median 
2.5% quantile 
97.5% quantile 
Between-trial heterogeneity 
of τ prediction stratum 
0.33 
0.26 
0.27 
0.01 
0.97 
MAP Prior MCMC sample 
0.097 
0.058 
0.086 
0.031 
0.245 
Abbreviations: MAP: meta-analytic-predictive, MCMC: Markov chain Monte Carlo, SD = standard deviation. 
A forest plot of trials LP0133-1401 and LP0133-1402 and the MAP is shown in Panel 23. 
Panel 23: Forest plot for the MAP for cream vehicle 
 
Abbreviation: MAP: meta-analytic-predictive.  
Notes: Solid line represents the MAP model predictions. Dashed line represents the stratified estimates.  
The MCMC samples are fitted with a mixture of beta models. A histogram of the MCMC 
samples and the fitted mixture model is shown in Panel 24. 
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Panel 24: Parametric mixture density and histogram of the MCMC samples for cream 
vehicle  
 
Abbreviation: MCMC: Markov chain Monte Carlo. 
Robustification of informative prior for cream vehicle 
The informative prior is robustified by adding a non-informative part (here with a weight of 
0.2, and thereby reducing weight for the other components with a factor of 0.8), see Panel 25. 
Panel 25: Prior components for cream vehicle after robustification 
Parameters 
Component 1 
Component 2 
Component 3 
Component 4 
Robust 
Weight in mix 
0.41 
0.31 
0.05 
0.03 
0.20 
a 
18 
4 
3 
1 
1 
b 
190 
39 
17 
3 
1 
a and b are parameter in the beta-distribution (Be(a,b)). 
14.3.17.2.2 
Creating informative prior for delgocitinib cream 20 mg/g 
The variability in the estimated proportion of responders is slightly higher for delgocitinib 
cream 20 mg/g compared to cream vehicle. A summary of the MAP is shown in Panel 26. 
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Panel 26: Summary of MAP for delgocitinib cream 20 mg/g 
 
Mean 
SD  
Median 
2.5% quantile 
97.5% quantile 
Between-trial heterogeneity 
of τ prediction stratum 
0.43 
0.25 
0.38 
0.08 
1.04 
MAP Prior MCMC sample 
0.26 
0.11 
0.25 
0.09 
0.55 
Abbreviations: MAP: meta-analytic-predictive, MCMC: Markov chain Monte Carlo, SD = standard deviation. 
A forest plot of trials LP0133-1401 and LP0133-1402 and the MAP is shown in Panel 27. 
Panel 27: Forest plot for the MAP for delgocitinib cream 20 mg/g 
 
Abbreviation: MAP: meta-analytic-predictive. 
Notes: Solid line represents the MAP model predictions. Dashed line represents the stratified estimates. 
The MCMC samples is fitted with a mixture of beta models. A histogram of the MCMC 
samples and the fitted mixture model is shown in Panel 28. 
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Panel 28: Parametric mixture density and histogram of the MCMC samples for 
delgocitinib cream 20 mg/g  
 
Abbreviation: MCMC: Markov chain Monte Carlo. 
Robustification of informative prior for delgocitinib cream 20 mg/g 
The informative prior is robustified by adding a non-informative part (here with a weight of 
0.2, and thereby reducing weight for the other components with a factor of 0.8), see Panel 29. 
Panel 29: Prior components for delgocitinib cream 20 mg/g after robustification 
Parameters 
Component 1 
Component 2 
Component 3 
Component 4 
Robust 
Weight in mix 
0.38 
0.17 
0.13 
0.13 
0.20 
a 
22 
7 
14 
2 
1 
b 
67 
32 
26 
3 
1 
a and b are parameter in the beta-distribution (Be(a,b)). 
14.3.17.2.3 
The ESS as a function of the level of τ and the weight put on the 
non-informative part of the robust prior 
The ESS represents the additional information added to the trial data from the historical data 
and is a way to quantify the amount of information borrowed from the historical data. The 
ESS is calculated using the elir approach (44). 
Adding a robust mixture component reduces the ESS of the MAP prior and thereby the degree 
of influence of the MAP prior in the final analysis. The ESS as a function of τ and weight on 
the non-informative part is shown in Panel 30. The curves level out as τ increases above 0.5. 
The choice of τ = 0.5 and a weight = 0.2 corresponds to an ESS of approximately 55 for the 
cream vehicle arm and approximately 20 for the delgocitinib cream 20 mg/g arm. The larger 
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degree of borrowing of information in the cream vehicle arm as compared to the delgocitinib 
cream 20 mg/g arm is due to less variability in the historical data for cream vehicle. 
Panel 30: The ESS as a function of the level of τ and the weight put on the non-
informative part of the robust prior for the primary endpoint IGA-CHE TS at 
Week 16 
 
Abbreviation: ESS = effective sample size. IGA-CHE = Investigator’s Global Assessment for chronic hand eczema©.  
 
The level of type I error and power as a function of the difference in proportion of 
IGA-CHE TS at Week 16 
The influence of τ and weight on the type I error and the power is shown in Panel 31. Overall, 
the type I error decreases as τ and weight increase, and it peaks just above the average 
observed response rate in the historical data. The power is increasing with increasing 
difference and lower τ and weight. 
The average response rate for cream vehicle on IGA-CHE TS at Week 16 in the adult trials 
(LP0133-1401 and LP0133-1402) is 8.4% (Panel 21), corresponding to a type-I error of <5% 
(Panel 31). The average treatment effect is 15.9% (Panel 21), corresponding to a power of 
>75% (Panel 31). 
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Panel 31: The level of type I error and power as a function of the difference in 
proportion of IGA-CHE TS responders at Week 16, split on the level of τ and 
the weight put on the non-informative part of the robust prior 
Abbreviations: IGA-CHE = Investigator’s Global Assessment for chronic hand eczema©. IGA-CHE TS = IGA-CHE 
treatment success, i.e. an IGA-CHE score of 0 (clear) or 1 (almost clear) with a ≥2-step improvement from baseline. 
Notes: tau = τ, the between-trial heterogeneity. Weigh represents the non-informative part of the prior. The blue circles mark 
the anticipated type I error and power with the predefined selections of τ = 0.5 and weight = 0.2, for the average response 
rates for cream vehicle and delgocitinib cream 20 mg/g in the adult trials. 
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Hypothetical sensitivity analyses of the influence of weight on the non-informative part 
of the prior  
To illustrate the influence of a selection of τ = 0.5 and weight = 0.2, 2 examples of 
hypothetical outcomes of the adolescent trial have been generated. In example 1, the efficacy 
is at par with the observed data and in example 2, the efficacy is markedly lower. 
Example of sensitivity analysis if results from the adolescent trial (LP0133-1426) is close 
to the results from the adult trials (LP0133-1401 and LP0133-1402) 
Panel 32: Hypothetical outcome in trial LP0133-1426, example 1 
 
Delgocitinib 
cream 20 
mg/g 
Cream 
vehicle 
Observed difference in 
IGA-CHE TS response 
rates 
Number of subjects randomized 
69 
23 
- 
Number of responders at week 16 (%) 
22 (31.9%) 
3 (13.3%) 
18.8% 
Using the hypothetical difference in response rate in trial LP0133-1426 (Panel 32), the result 
gets significant when the weight is below 70%, see Panel 33. This is seen as the 95% 
credibility bands no longer overlap 0. Very little bias is observed as the point estimate is fairly 
constant. 
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Panel 33: Sensitivity analysis of the influence of weight on non-informative part of prior 
when results in LP0133-1426 are close to the results in the adult trials 
(LP0133-1401 and LP0133-1402) 
 
Abbreviation: IGA-CHE = Investigator’s Global Assessment for chronic hand eczema©. 
Example of sensitivity analysis if results from the adolescent trial (LP0133-1426) differ 
from the results from adult trials (LP0133-1401 and LP0133-1402) 
Panel 34: Hypothetical outcome in trial LP0133-1426, example 2 
 
Delgocitinib 
cream 20 
mg/g 
Cream 
vehicle 
Observed difference in 
IGA-CHE TS response 
rates 
Number of subjects randomized 
69 
23 
- 
Number of responders at week 16 (%) 
22 (31.9%) 
7 (30.4%) 
1.4% 
Panel 34 presents example where the hypothetical difference in response rates in trial 
LP0133-1426 is markedly lower than the observed data. 
As shown in Panel 35, the results remain non-significant when the results are far from the 
observed data. The bias increases when the weight decreases below 20%.  
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Panel 35: Sensitivity analysis when results from the adolescent’s trial differ from the 
results from the adult trials  
 
Abbreviation: IGA-CHE = Investigator’s Global Assessment for chronic hand eczema©. 
Conclusion on hypothetical examples 
The hypothetical examples illustrate that if the treatment difference between delgocitinib 
cream 20 mg/g and cream vehicle in trial LP0133-1426 is similar to the treatment difference 
in the adult trials (example 1), then the Bayesian analysis gives a confirmatory result for 
IGA-CHE TS. If the treatment difference is markedly lower in trial LP0133-1426 than in 
adult trials (example 2), then the Bayesian analysis will not confirm a difference between 
delgocitinib cream 20 mg/g and cream vehicle in IGA-CHE TS. 
14.3.17.3 
Evaluation of design characteristics (type I error and power) for the 
Bayesian analysis of key secondary endpoints 
The between-trial heterogeneity (τ) and the weight on the non-informative part of the prior for 
key secondary endpoints are justified and discussed in the following. For all key secondary 
endpoints, τ = 0.5 and weight = 0.2. 
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14.3.17.3.1 
HECSI-90 
The average response rate for cream vehicle on HECSI-90 in the adult trials (LP0133-1273, 
LP0133-1401 and LP0133-1402) is 10.9% (Panel 36), corresponding to a type I error <5% 
(Panel 37). The average treatment effect is 19.3% (Panel 36), corresponding to a power >80% 
(Panel 37). 
Panel 36: HECSI-90 results, trials LP0133-1273, LP013-1401, and LP0133-1402 
 
Delgocitinib 
cream 20 
mg/g 
Responders 
(%), N 
Cream 
vehicle 
Responders 
(%), N 
Average 
response 
rate for 
cream 
vehicle 
Average 
response 
rate for 
delgocitinib 
cream 20 
mg/g 
Average 
treatment 
effect 
Type
1 
error 
Power 
LP0133-
1273 
12 (29.3),  
N = 41 
5 (13.2),  
N = 38 
10.9% 
30.2% 
19.3% 
<5% 
>80% 
LP0133-
1401 
96 (29.5),  
N = 325 
20 (12.3),  
N = 162 
LP0133-
1402 
97 (31.0),  
N = 313 
14 (8.8),  
N = 159 
Abbreviations: HECSI = Hand Eczema Severity Index. HECSI-90 = at least 90% improvement in HECSI from baseline. N 
= number of subjects 
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Panel 37: The level of type I error and power as a function of the difference in 
proportion of responders, split on the level of τ and the weight put on the non-
informative part of the robust prior for HECSI-90 
 
Abbreviation: HECSI = Hand Eczema Severity Index. HECSI-90 = at least a 90% improvement in HECSI score from 
baseline. 
Notes: tau = τ, the between-trial heterogeneity. Weigh represents the non-informative part of the prior. The blue circles mark 
the anticipated type I error and power with the predefined selections of τ = 0.5 and weight = 0.2, for the average response 
rates for cream vehicle and delgocitinib cream 20 mg/g in the adult trials. 
 
 
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Panel 38 shows the ESS for various values of τ and weight. For τ = 0.5 and weight = 0.2, the 
ESS of using LP0133-1273, LP0133-1401, and LP0133-1402 is approximately 70 for cream 
vehicle arm and approximately 110 for delgocitinib cream 20 mg/g. 
Panel 38: The ESS as a function of the level of τ and the weight put on the non-
informative part of the robust prior for HECSI-90 
 
Abbreviation: ESS = effective sample size; HECSI = Hand Eczema Severity Index. HECSI-90 = at least a 90% 
improvement in HECSI score from baseline. 
 
14.3.17.3.2 
Reduction of HESD≥4 from baseline 
The average response rate for cream vehicle in the adult trials (LP0133-1273, LP0133-1401 
and LP0133-1402) is 21.6% (Panel 39), corresponding to a type I error of <5% (Panel 40). 
The average treatment effect is 23.9% (Panel 39), corresponding to a power > 80% 
(Panel 40).  
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Panel 39: Reduction of HESD ≥4 from baseline, trials LP0133-1273, LP0133-1401, and 
LP0133-1402 
 
Delgocitinib 
cream 20 
mg/g 
Responders 
(%), N 
Cream 
vehicle 
Responders 
(%), N 
Average 
response 
rate for 
cream 
vehicle 
Average 
response 
rate for 
delgocitinib 
cream 20 
mg/g 
Average 
treatment 
effect 
Type
1 
error 
Power 
LP0133-
1273 
10 (37.0),  
N = 27 
2 (8.3),  
N = 24 
21.6% 
45.5% 
23.9% 
<5% 
>80% 
LP0133-
1401 
146 (47.2),  
N = 309 
38 (24.4),  
N = 156 
LP0133-
1402 
137 (44.5),  
N = 308 
32 (20.9), 
N=153 
Abbreviations: HESD = Hand Eczema Symptom Diary©. N = number of subjects. 
 
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Panel 40: The level of type I error and power as a function of the difference in 
proportion of responders, split on the level of τ and the weight put on the non-
informative part of the robust prior for HESD≥4 
 
Abbreviation: HESD = Hand Eczema Symptom Diary©. 
Notes:  tau = τ, the between-trial heterogeneity. Weigh represents the non-informative part of the prior. The blue circles mark 
the anticipated type I error and power with the predefined selections of τ = 0.5 and weight = 0.2, for the average response 
rates for cream vehicle and delgocitinib cream 20 mg/g in the adult trials. 
 
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Panel 41 shows the ESS for various values of τ and weight. For τ = 0.5 and weight = 0.2, the 
ESS of using LP0133-1273, LP0133-1401, and LP0133-1402 is approximately 40 for the 
cream vehicle arm and approximately 90 for the delgocitinib cream arm.  
Panel 41: The ESS as a function of the level of τ and the weight put on the non-
informative part of the robust prior for HESD≥4 
 
Abbreviation: ESS = effective sample size; HESD = Hand Eczema Symptom Diary©. 
 
14.3.17.3.3 
Reduction of HESD itch≥4 from baseline 
The average response rate for cream vehicle in the adult trials (LP0133-1273, LP0133-1401 
and LP0133-1402) is 21.1% (Panel 42), corresponding to a type-I error of <5% (Panel 43). 
The average treatment effect is 26.3% (Panel 42), corresponding to a power > 80% 
(Panel 43). 
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Panel 42: HESD itch ≥4 from baseline, trials LP0133-1273, LP0133-1401, and 
LP0133-1402 
 
Delgocitinib 
cream 20 
mg/g 
Responders 
(%), N 
Cream 
vehicle 
Responders 
(%), N 
Average 
response 
rate for 
cream 
vehicle 
Average 
response 
rate for 
delgocitinib 
cream 20 
mg/g 
Average 
treatment 
effect 
Type
1 
error 
Power 
LP0133-
1273 
14 (53.8%),  
N = 26 
4 (16.7%),  
N = 24 
21.1% 
47.4% 
 
26.3% 
<5% 
>80% 
LP0133-
1401 
152 (47.1%),  
N = 323 
37 (23.0%),  
N = 161 
LP0133-
1402 
146 (47.2%),  
N = 309 
31 (19.9%),  
N = 156 
Abbreviations: HESD = Hand Eczema Symptom Diary©. N = number of subjects. 
 
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Panel 43: The level of type I error and power as a function of the difference in 
proportion of responders, split on the level of τ and the weight put on the non-
informative part of the robust prior for HESD itch≥4 
 
Abbreviation: HESD = Hand Eczema Symptom Diary©. 
Notes:  tau = τ, the between-trial heterogeneity. Weigh represents the non-informative part of the prior. The blue circles mark 
the anticipated type I error and power with the predefined selections of τ = 0.5 and weight = 0.2, for the average response 
rates for cream vehicle and delgocitinib cream 20 mg/g in the adult trials. 
 
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Panel 44 shows the ESS for various values of τ and weight. For τ = 0.5 and a weight = 0.2, the 
ESS of using LP0133-1273, LP0133-1401, and LP0133-1402 is approximately 60 for the 
cream vehicle arm and approximately 90 for the delgocitinib cream arm.  
Panel 44: The ESS as a function of the level of τ and the weight put on the non-
informative part of the robust prior for HESD itch≥4 
 
Abbreviation: ESS = effective sample size; HESD = Hand Eczema Symptom Diary©. 
14.3.17.3.4 
Reduction of HESD pain≥4 from baseline 
The average response rate for cream vehicle in the adult trials (LP0133-1273, LP0133-1401 
and LP0133-1402) is 24.3% (Panel 45), corresponding to a type-I error of <5% (Panel 46).  
The average treatment effect is 25.3% (Panel 45), corresponding to a power of >80% 
(Panel 46). 
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Panel 45: Reduction of HESD pain ≥4, trials LP0133-1273, LP0133-1401, and 
LP0133-1402 
 
Delgocitinib 
cream 20 
mg/g 
Responders 
(%), N 
Cream 
vehicle 
Responders 
(%), N 
Average 
response 
rate for 
cream 
vehicle 
Average 
response 
rate for 
delgocitinib 
cream 20 
mg/g 
Average 
treatment 
effect 
Type
1 
error 
Power 
LP0133-
1273 
14 (70.0%),  
N = 20 
1 (6.7%),  
N = 15 
24.3% 
49.6% 
25.3% 
<5% 
>80% 
LP0133-
1401 
143 (49.1%),  
N = 291 
41 (27.5%),  
N = 149 
LP0133-
1402 
143 (48.6%),  
N = 294 
32 (22.7%),  
N =141 
Abbreviations: HESD = Hand Eczema Symptom Diary©. N = number of subjects. 
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Panel 46: The level of type I error and power as a function of the difference in 
proportion of responders, split on the level of τ and the weight put on the non-
informative part of the robust prior for HESD pain≥4 
 
Abbreviation: HESD = Hand Eczema Symptom Diary©. 
Notes: tau = τ, the between-trial heterogeneity. Weigh represents the non-informative part of the prior. The blue circles mark 
the anticipated type I error and power with the predefined selections of τ = 0.5 and weight = 0.2, for the average response 
rates for cream vehicle and delgocitinib cream 20 mg/g in the adult trials. 
 
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Panel 47 shows the ESS for various values of τ and weight. For τ = 0.5 and a weight = 0.2, the 
ESS of using LP0133-1273, LP0133-1401, and LP0133-1402 is approximately 35 for the 
cream vehicle arm and approximately 40 for the delgocitinib cream arm. 
Panel 47: The ESS as a function of the level of τ and the weight put on the non-
informative part of the robust prior for HESD pain≥4 
 
Abbreviation: ESS = effective sample size; HESD = Hand Eczema Symptom Diary©. 
 
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27. 
LEO Pharma. Clinical Trial Report (CTR) - LP0133-1273: Phase 2b dose-ranging trial 
to evaluate delgocitinib cream 1, 3, 8, and 20 mg/g compared to delgocitinib cream 
vehicle over a 16-week treatment period in adult subjects with chronic hand eczema. 
2020. 
 
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28. 
WMA. World Medical Association. Declaration of Helsinki – ethical principles for 
medical research involving human subjects. Amended by the 64th WMA General 
Assembly, Fortaleza, Brazil. 2013. 
 
29. 
Guidelines for good pharmacoepidemiology practice (GPP). Pharmacoepidemiol Drug 
Saf. 2016;25(1):2-10. 
 
30. 
EMA. European Medicines Agency. Guidance on the management of clinical trials 
during the COVID-19 pandemic (Coronavirus) pandemic. Version 4. 2021. 
 
31. 
FDA. The Food and Drug Administration. Conduct of Clinical Trials of Medical 
Products During the COVID-19 Public Health Emergency. Guidance for Industry, 
Investigators, and Institutional Review Boards. 2020;Updated on August 30, 2021. 
 
32. 
Schulz KF, Altman DG, Moher D. CONSORT 2010 Statement: updated guidelines for 
reporting parallel group randomised trials. BMC Med. 2010;8:18. 
 
33. 
European Commission. EudraLex: The Rules Governing Medicinal Products in the 
European Union. Guidelines for good manufacturing practices for medicinal products 
for human and veterinary use. 2010;Volume 4. 
 
34. 
Held E, Skoet R, Johansen JD, Agner T. The hand eczema severity index (HECSI): a 
scoring system for clinical assessment of hand eczema. A study of inter- and 
intraobserver reliability. Br J Dermatol. 2005;152(2):302-307. 
 
35. 
Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI)--a simple practical 
measure for routine clinical use. Clin Exp Dermatol. 1994;19(3):210-216. 
 
36. 
ICH. International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use: Clinical Investigation of Medicinal Products in the 
Pediatric Population. (E11), Step 4; 20-Jul. 2000. 
 
37. 
Meding B, Wrangsjö K, Järvholm B. Fifteen-year follow-up of hand eczema: 
predictive factors. J Invest Dermatol. 2005;124(5):893-897. 
 
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38. 
Held E, Skoet R, Johansen JD, Agner T. The hand eczema severity index (HECSI): a 
scoring system for clinical assessment of hand eczema. A study of inter- and 
intraobserver reliability. Br J Dermatol. 2005;152(2):302-307. 
 
39. 
ICH. International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use. Integrated addendum to ICH E6(R1): Guideline for 
good clinical practice E6(R2). 2016. 
 
40. 
European Parliament Union, European CoT. Directive 2001/20/EC of the European 
Parlament and of the Council of 4 April 2001 on the approximation of the laws, 
regulations and administrative provisions of the Member States relating to the 
implementation of good clinical practice in the conduct of clinical trials on medicinal 
products for human use, 2001.  (Ema ed. 2001. 
 
41. 
Ge M, Durham LK, Meyer RD, Xie W, Thomas N. Covariate-Adjusted Difference in 
Proportions from Clinical Trials Using Logistic Regression and Weighted Risk 
Differences. Drug Information Journal. 2011;45(4):481-493. 
 
42. 
Weber S, Li Y, Seaman Iii JW, Kakizume T, Schmidli H. Applying Meta-Analytic-
Predictive Priors with the R Bayesian Evidence Synthesis Tools. Journal of Statistical 
Software. 2021;100(19):1 - 32. 
 
43. 
The R Project for Statistical Computing [https://www.r-project.org/] 
 
44. 
Neuenschwander B, Weber S, Schmidli H, O'Hagan A. Predictively consistent prior 
effective sample sizes. Biometrics. 2020;76(2):578-587. 
 
45. 
ICH. International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use: Clinical Safety Data Management. Definitions and 
Standards for Expected Reporting (E2A), Step 4; 27-Oct. 1994. 
 
46. 
CIOMS. International Ethical Guidelines for Health-related Research Involving 
Humans. Council for International Organizations of Medical Sciences. 4th. Geneva. 
2016. 
 
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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 (45). 
This definition includes: 
• Accidental injuries. 
• Events related to trial procedures. 
• Reasons for any unfavourable and unplanned change in medication (drug and/or dose). 
• Clinically significant worsening of pre-existing conditions. 
• Reasons for admission to hospital or surgical procedures*.  
• AEs commonly observed and AEs anticipated based on the pharmacological effect of the 
IMP.  
• Any laboratory abnormality assessed as clinically significant by the investigator (see 
Section 11.5.5.2). 
Serious adverse event definition 
An SAE is any untoward medical occurrence that: 
• Results in death. 
• Is life-threatening – at risk of death at the time of the SAE (not an event that 
hypothetically might have caused death if more severe). 
• Requires inpatient hospitalisation or prolongation of existing hospitalisation*. 
• Results in persistent or significant disability or incapacity. 
• Is a congenital anomaly or birth defect. 
• Is a medically important condition. Events that may not be immediately life-threatening or 
result in death or hospitalisation but may jeopardise the subject or may require 
intervention to prevent one of the other outcomes listed in the definition above. Examples 
are intensive treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias, and convulsions that do not result in hospitalisation, development of drug 
dependency, or drug abuse.  
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*Hospitalisation for procedures or treatments planned prior to the subject consented to trial 
participation does not constitute an AE and should therefore not be reported as an AE or SAE. 
*Hospitalisation for elective treatment of a pre-existing condition which did not worsen from 
the subject consented to trial participation is not considered an AE and should therefore not be 
reported as an AE or SAE, even if not planned before consent to trial participation. 
*Hospitalisation for routine scheduled treatment or monitoring of the studied indication not 
associated with any aggravation of the condition does not constitute an AE and should 
therefore not be reported as an AE or SAE. 
*Hospitalisation for administrative, trial-related, or social purpose does not constitute an AE 
and should therefore not be reported as an AE or SAE. 
*Complications that occur during hospitalisation are (S)AEs. If a complication prolongs 
hospitalisation, the event is an SAE. 
*When in doubt as to whether hospitalisation occurred or was necessary, the AE should be 
considered serious. 
Additionally, all malignancies, incl. skin malignancies, should be reported as SAEs. 
Definition of adverse events of special interest 
An AESI (serious or non-serious) is an event type of scientific and medical concerns specific 
to the product or development programme, for which additional monitoring may be 
appropriate. Such an event might warrant further investigation in order to characterise and 
understand it. Depending on the nature of the event, rapid communication by the investigator 
to the sponsor and/or from the sponsor to other parties (e.g. regulators) might also be 
warranted. 
AESIs are described in Section 13.6.1. 
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Appendix 2: Classification of adverse events 
Severity 
The severity of the AE should be described in terms of mild, moderate, or severe according to 
the investigator’s clinical judgement. If the AE worsens in severity, the new severity, 
including date of worsening, should be recorded. However, if an AE with onset prior to IMP 
initiation worsens after IMP administration, a new AE should be recorded.  
Mild 
An AE that is usually transient and may require only minimal treatment or therapeutic 
intervention. The event does not generally interfere with usual activities of daily living. 
Moderate 
An AE that is usually alleviated with additional specific therapeutic intervention. The event 
interferes with usual activities of daily living, causing discomfort, but poses no significant 
or permanent risk of harm to the subject. 
Severe 
An AE that interrupts usual activities of daily living, or significantly affects clinical status, 
or may require intensive therapeutic intervention. 
Causality 
The causal relation of the AE to the use of the IMP should be described in terms of probably, 
possibly, or not related according to the investigator’s clinical judgement.  
Probably 
related 
Follows a reasonable temporal sequence from administration of the IMP. 
 
Could not be reasonably explained by the subject’s clinical state, environmental or toxic 
factors, or other therapies administered to the subject. 
 
Follows a known pattern of response to the IMP. 
 
Disappears or decreases on cessation or reduction in dose of the IMP. 
 
Reappears or worsens upon re-challenge. 
Possibly 
related 
 
Follows a reasonable temporal sequence from the administration of the IMP. 
 
Could also be reasonably explained by the subject’s clinical state, environmental or toxic 
factors, or other therapies administered to the subject. 
 
Follows a known pattern of response to the IMP. 
Not related 
 
Does not follow a reasonable temporal sequence from administration of the IMP. 
 
Is better explained by other factors like the subject’s clinical state, environmental or toxic 
factors, or other therapies administered to the subject. 
 
Does not reappear or worsen upon re-challenge. 
 
Does not follow a known pattern of response to the IMP. 
 
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Outcome 
The outcome of the event according to the investigator’s clinical judgement should be 
classified using the categories below. 
Fatal 
The subject has died as a consequence of the event. Date of death is recorded as stop date for 
the AE. 
Not recovered/ 
not resolved 
Event is still ongoing.  
Recovering/ 
resolving 
The subject is clearly recovering from an event. The event is not yet completely resolved.  
Recovered/ 
resolved 
The event has stopped. The stop date of the event must be recorded. 
Recovered/         
resolved with 
sequelae 
The event has reached a state where no further changes are expected and the residual 
symptoms are assumed to persist. An example is hemiparesis after stroke. 
 
The stop date of the event must be recorded. In case of an SAE, the sequelae should be 
specified. 
Unknown 
Unknown to investigator, e.g. subject lost to follow-up. 
 
LEO Pharma definitions versus CDISC definitions 
Note that as per the above definition, LEO Pharma uses ‘recovered/resolved’ only if an event 
has actually stopped. According to the CDISC definition, the category ‘recovered/resolved’ 
also includes events which have improved. However, following the LEO Pharma definitions 
above, such an improved event will instead be classified as ‘not recovered/not resolved’ or 
‘recovering/resolving’. 
Similarly, it should be noted that as per the above definition, LEO Pharma uses 
‘recovered/resolved with sequelae’ only if an event has reached a state where the residual 
symptoms are assumed to persist. According to CDISC, an event is considered ‘with 
sequelae’, if it has ‘retained pathological conditions’. Consequently, it is likely that some of 
the events classified by LEO Pharma with the outcome ‘recovered/resolved with sequelae’ 
could have been classified with the outcome ‘recovered/resolved’ according to the CDISC 
definition. 
In summary, the definitions used by LEO Pharma are more conservative than those used by 
CDISC. 
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Appendix 3: Trial governance considerations 
Appendix 3A: Regulatory and ethical considerations 
This trial will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines including the current 
version of the Declaration of Helsinki (28) and Council for International Organizations of 
Medical Sciences (CIOMS) International Ethical Guidelines (46). 
• Current version of applicable International Council for Harmonisation Good Clinical 
Practice (ICH GCP) Guidelines (39). 
• EU General Data Protection Regulation 2016/679 of 27 April 2016. 
• Applicable laws and regulations. 
The appropriate regulatory authority(ies) must be notified of/approve the clinical trial as 
required. 
Any documents that the IRB/IEC may need to fulfil its responsibilities (such as the trial 
protocol, protocol amendments, investigator’s brochure, subject information sheet, and 
informed consent and assent form(s), or advertisements) will be submitted to the IRB/IEC. 
These documents must be reviewed and approved by the IRB/IEC before the trial is initiated. 
Any amendments to the protocol must be approved by/receive favourable opinion from 
relevant regulatory authorities and IRBs/IECs, as required, prior to implementation. 
The principal investigator will be responsible for the following, if required by local 
legislation: 
• Providing written summaries of the status of the trial to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC. 
• Notifying the local IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures. 
• Providing oversight of the conduct of the trial at the trial site and ensuring adherence to 
applicable national and international legislation. 
Appendix 3B: Informed consent/assent process 
Subjects and parents/guardians will receive written and verbal information concerning the 
clinical trial. This information will emphasise that participation in the clinical trial is 
voluntary and that the subject may withdraw from the clinical trial at any time and for any 
reason. All subjects and parents/guardians will be given an opportunity to ask questions and 
will be given sufficient time to consider before consenting. 
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The subject’s signed and dated IC/IA to participate in the clinical trial and/or their 
parent’s/guardian’s signed and dated IC will be obtained prior to any clinical trial-related 
procedure being carried out in accordance with ICH GCP and all applicable laws and 
regulations. The authorised person obtaining the IC/IA must also sign the ICF/IAF. The 
subject’s decision not to participate or to withdraw will be respected, even if consent is given 
by the parent/guardian. 
Subjects and parents/guardians will be re-consented/assented to the most current version of 
the ICF/IAF during their participation in the trial, if required. Subjects who become of legal 
age during the trial, will be consented to the most current version of the ICF for subjects being 
or becoming of legal age during the trial, if required by national laws and regulations. 
Subsequently, these subjects will be re-consented to the most current version of the ICF for 
subjects being or becoming of legal age during the trial, if applicable.  
A copy of the ICF/IAF must be provided to the subject or the parent/guardian.  
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 
system cannot be performed. 
Appendix 3C: Subject and data confidentiality 
This clinical trial protocol as well as all other information, data, and results relating to this 
clinical trial and/or to the IMP is confidential information of LEO Pharma and shall not be 
used by the investigator for purposes other than this clinical trial. 
The investigator agrees that LEO Pharma may use any and all information, data, and results 
from this clinical trial in connection with the development of the IMPs and, therefore, may 
disclose and/or transfer information, data, and/or results to other investigators, regulatory 
authorities, and/or commercial partners. 
Trial subjects will be assigned a unique identifier (subject ID) by LEO Pharma. Any subject’s 
records or datasets that are transferred to LEO Pharma will contain the identifier only; subject 
names or any information which would make the subject identifiable will not be transferred. 
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Trial subjects must be informed that their personal trial-related data will be used by LEO 
Pharma in accordance with local data protection law.   
Trial subjects must be informed and agree to that their medical records may be examined by 
clinical quality assurance auditors or other authorised personnel appointed by LEO Pharma, 
by appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
Trial subjects must be informed that LEO Pharma will keep their trial-related data for as long 
as they are useful for developing treatments for the disease or other diseases and future 
research and for at least 25 years after the end of the clinical trial. 
Processing of personal data 
This protocol specifies the personal data on trial subjects (e.g. race, ethnicity, age, sex, health 
condition, medical history, test results, etc.) which shall be collected as part of the clinical trial 
and processed during and after trial completion. 
Personal data collected as part of the clinical trial will be transferred to/from the 
institution/investigator, LEO Pharma, and third parties acting on behalf of LEO Pharma. 
Processing of personal data on behalf of LEO Pharma requires a written agreement between 
LEO Pharma and the relevant party which covers collection, processing, and transfer of 
personal data in the clinical trial as well as reporting obligations in the event of any data 
breach. In certain cases, an agreement on transfer of personal data may also be required. 
Investigators and LEO Pharma must ensure that collection, processing, and transfer of 
personal data are in compliance with applicable legislation on data protection and privacy, 
including but not limited to the EU General Data Privacy Regulation. 
Participation of the subjects in the clinical trial requires 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 such as future research. 
LEO Pharma has obtained the necessary authorisations for the processing of personal data 
collected in the trial. 
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Appendix 3D: Record keeping, quality control, and data handling 
Source data at trial sites 
For all data recorded, the source document must be defined in a source document agreement 
or similar document at each trial site. There must only be 1 source defined at any time for any 
data elements. 
Source data should as a general rule be recorded in the subject’s medical record or other 
defined document normally used at the trial site. Source data not normally collected as a 
routine part of the clinical practice at the site may be entered on a worksheet. Clinical 
assessments/safety evaluations must be signed and dated by the physians. 
The date and time of the sampling must be recorded at the laboratory requisition form. 
If the worksheet does not become part of the subject’s medical record, the following should as 
a minimum be added to the subject’s medical record: 
• Subject ID. 
• A statement from the investigator to verify that each of the eligibility criteria are met and 
documented. 
• Randomisation code number. 
• The fact that the subject is participating in a clinical trial in CHE including treatment with 
delgocitinib cream 20 mg/g or cream vehicle for 16 weeks.   
• Other relevant medical information. 
Trial monitoring 
The trial will be monitored on an ongoing basis to verify that (i) the rights and well-being of 
the trial subjects is protected; (ii) the reported trial data are accurate, complete, and verifiable 
from source documents; and (iii) the conduct of the trial is in compliance with the currently 
approved protocol/amendment(s), ICH GCP, and all applicable regulatory requirement(s). 
The monitoring will be performed in a systematic, prioritised, risk-based approach, and as a 
combination of on-site, remote, and centralised monitoring. For more details, please refer to 
the trial-specific monitoring guideline and data review plan.  
In order to perform their role effectively, CRAs and persons involved in quality assurance and 
inspections will need direct access to source data, e.g. medical records, laboratory reports, 
appointment books, etc. If the electronic medical record does not have a visible audit trail, the 
investigator must provide the CRA with signed and dated printouts. In addition, relevant site 
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staff should be available for discussions at monitoring visits and between monitoring visits 
(e.g. by telephone). 
Protocol compliance 
Protocol deviations will be documented and notified to the investigator. Protocol deviations 
will be assessed by LEO Pharma and important protocol deviations described in the CTR. 
Sponsor audits, IRB/IEC review, and regulatory agency inspections 
The clinical trial will be subject to audits conducted by LEO Pharma or inspections from 
domestic or foreign regulatory authorities or from IRBs/IECs. Audits and inspections may 
take place during or after the trial. The investigator and the site staff as well as LEO Pharma 
staff have an obligation to cooperate and assist in audits and inspections. This includes giving 
auditors and inspectors direct access to all source documents and other documents at the trial 
site relevant to the clinical trial. This includes permission to examine, verify, and reproduce 
any records and reports that are important to the evaluation of the trial. 
If the trial site is contacted for an inspection by competent authorities, LEO Pharma must be 
notified immediately. 
Data handling 
Data will be collected by means of electronic data capture unless transmitted electronically to 
LEO Pharma or designee (e.g. laboratory data). The investigator or staff authorised by the 
investigator will enter subject data into an electronic CRF (eCRF). Data recorded in the eCRF 
will be accessible to the trial site and LEO Pharma personnel immediately after entry. The 
eCRF must be maintained in an up-to-date state by the trial site at all times. 
The investigator must verify the correctness of the data entered by the site by electronically 
dating and signing the eCRF. This signature information will be kept in the audit trail and 
cannot be altered. Any correction(s) made by the investigator or authorised site staff to the 
eCRF after original entry will be documented in the audit trail. Changes to data already 
approved will require re-signature by the investigator. The person making the change to the 
data, and the date, time, and reason for the change will be identified in the audit trail. 
Subject data should be entered into the eCRF no later than 5 working days after each visit, 
unless a different deadline is stated in the clinical trial agreement. Queries for discrepant data 
will be generated automatically by the system upon entry or manually by the CRA, sponsor’s 
medical expert, or the data manager. All queries will be raised electronically within the 
electronic data capture system. This systematic validation will ensure that a clean and 
consistent database is provided for the statistical analysis. 
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An electronic PRO (ePRO) solution will be used to capture patient-reported data (data from 
questionnaires completed at the trial site and eDiary data). By the use of an ePRO, data will 
be available immediately after data entry and available for CRAs and site personnel, including 
the investigator, with reader access only. The ePRO system is a separate application from the 
eCRF and data captured from the eCRF and the ePRO will be stored on different servers 
during data capture. Data from both systems will be included in the final trial database. 
External data transfers from vendors to LEO Pharma will be transmitted and handled via a 
secure file transfer protocol site.  
Transmissions of data are documented in more detail in a data flow plan which is part of the 
trial master file. 
Statistical programming standards 
CDISC controlled terminology version 06 Nov 2020 or newer was used for definition of 
controlled terminology throughout this protocol. Standard data tabulation model (SDTM) 
version 1.4 will be used for data tabulations. 
Archiving of trial documentation 
The investigator at each trial site must make arrangements to store the essential trial 
documents, including the investigator trial file (39). Essential trial documents must be stored 
until LEO Pharma informs the investigator that the documents are no longer to be retained, or 
longer if required by local regulations. 
In addition, the investigator is responsible for the archiving of all relevant source documents 
so that the trial data can be compared against source data after the completion of the trial (e.g. 
in case of an inspection from regulatory authorities). 
The investigator is required to ensure the continued storage of the documents even if the 
investigator leaves the trial site or retires before the end of the required storage period. 
No documents may be destroyed during the retention period without the written approval of 
LEO Pharma. No documents may be transferred to another location or party without written 
acceptance from LEO Pharma. 
The destruction process must ensure confidentiality of data and must be done in accordance 
with local regulatory requirements. 
For archiving purposes, each investigator will be supplied with an electronic copy of the 
eCRFs and ePRO data for all screened subjects at the trial site. This is done after completion 
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of the trial and before access to the eCRF/ePRO is revoked. Audit trail information will be 
included. eCRFs and ePRO data must be available for inspection by authorised 
representatives from LEO Pharma, from regulatory authorities and/or IRBs/ IECs. 
Appendix 3E: Registration, reporting, and publication policy 
Trial disclosure 
LEO Pharma is committed to be transparent with respect to its clinical trials. 
Basic information of this clinical trial will be registered in the global data registry, 
www.ClinicalTrials.gov. before the first subject enters into the trial. The trial may also 
become registered in other online data registries, according to applicable law and regulations. 
Results of this clinical trial will be posted at leopharmatrials.com in accordance with our 
Position on Public Access to Clinical Trial Information 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. 
Publications 
The investigator shall be entitled to make publications of the results generated by the 
investigator in accordance with the process described here. 
A multi-site publication will be submitted for publication within 12 months after the clinical 
trial has been completed or terminated at all trial sites and all data have been received, defined 
as final database lock of the clinical trial. After such multi-site publication is made public, or 
if no multi-site publication has been submitted with the above-described deadline, the 
investigator shall have the right to publish the results from the clinical trial generated by the 
investigator, subject to the following notice requirements: 
Prior to submission for publication or presenting a manuscript relating to the clinical trial, the 
investigator shall provide to LEO Pharma a copy of all such manuscripts and/or presentations. 
LEO Pharma shall have rights to review and comment. The investigator shall consider 
comments provided by LEO Pharma but is not required to modify the manuscript and/or 
presentation based on such comments, provided, however, that the investigator upon the 
request of LEO Pharma remove any confidential information (other than results generated by 
the investigator) prior to submitting or presenting the manuscripts. The investigator shall, 
upon the request of LEO Pharma withhold the publication or presentation to allow LEO 
Pharma to protect its inventions and other intellectual property rights described in any such 
manuscripts.  
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In case no multi-site publication has been made public at the time of investigator’s 
notification of an independent publication to LEO Pharma, LEO Pharma and the writing 
group may also delay the publication or presentation if the manuscript is deemed to harm the 
ongoing multi-site publication. 
In case of publications made by the investigator after the first multi-site publication has been 
published, the above-mentioned requirements must still be followed. 
Any publication must comply with Good Publication Practice (GPP3) standards. 
LEO Pharma complies with GPP3 standards and the recommendations from the International 
Committee of Medical Journal Editors. LEO Pharma complies with the positions of the 
International Federation of Pharmaceutical Manufacturers & Associations (IFPMA), 
European Federation of Pharmaceutical Industries and Associations (EFPIA), Japan 
Pharmaceutical Manufacturers Association (JPMA), Pharmaceutical Research and 
Manufacturers of America (PhRMA), and the joint position statement by the American 
Medical Writers Association (AMWA), the European Medical Writers Association (EMWA), 
and the International Society for Medical Publication Professionals (ISMPP) on disclosure of 
information about clinical trials, trial results, and authorship. LEO Pharma also follows the 
CONSORT reporting guidelines (32). 
Appendix 3F: Insurance 
LEO Pharma has taken out relevant insurances covering the subjects in the present clinical 
trial in accordance with applicable laws and regulations. 
Appendix 3G: Financial disclosure 
Investigators will provide LEO Pharma with sufficient, accurate financial information as 
requested to allow LEO Pharma to submit complete and accurate financial certification or 
disclosure statements to the appropriate regulatory authorities. Investigators are responsible 
for providing information on financial interests and update this information, should any 
relevant change occur, during the course of the clinical trial and for 1 year after completion of 
the clinical trial, or for a longer period of time if required by local legislation. 
Appendix 3H: Committee structure 
Patient safety will be carefully assessed by an independent DMC. All members will be 
independent of the trial and of LEO Pharma. The DMC members are experienced with 
clinical trials and will be responsible for evaluating the safety of the subjects through 
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assessment of the safety of the treatment regimen during the trial and through monitoring of 
the overall conduct of the trial.  
The DMC will review data on a regular basis. Additional meetings may also be called on an 
ad hoc basis, as requested by the DMC or LEO Pharma. All data collected at the time of the 
data cut-off/scheduled meetings will be included in the summaries for the DMC, including 
data from subjects still ongoing in the trial. The DMC will examine summaries and listings of 
AEs, specific laboratory parameters, and subject disposition data as detailed in the DMC 
charter. Full details of the analyses to be presented to the DMC will be specified in a separate 
DMC statistical analysis plan. 
The DMC will have an independent statistician and an independent administrator who will 
remain independent of the trial management team.  
Further details on all aspects relating to the DMC are provided in the DMC charter. 
Appendix 3I: Trial and trial site closure 
Premature termination of trial or trial site 
LEO Pharma, the investigator, the IRBs/IECs, or competent authorities may decide to stop the 
clinical trial, part of the trial, or a trial site at any time, but agreement on procedures to be 
followed must be obtained. 
If a clinical trial is suspended or prematurely terminated, the investigator must inform the 
subjects promptly and ensure appropriate therapy and follow-up. As specified by applicable 
regulatory requirements, the investigator or LEO Pharma must promptly inform IRBs/IECs 
and provide a detailed written explanation. Relevant competent authorities must be informed. 
The trial must be terminated if the perception of the benefit/risk ratio (judged from clinical 
signs and symptoms, [S]AEs, and/or remarkable safety laboratory changes) becomes 
unfavourable for the continuation of the trial. 
Reasons for the premature closure of a trial site by LEO Pharma or investigator may include 
but are not limited to: 
• Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, LEO Pharma procedures, or GCP guidelines. 
• Inadequate recruitment of subjects by the investigator. 
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Completion of trial 
Investigators will be informed when subject recruitment is to cease. Screening activities will 
be stopped at a trial site when the total requested number of subjects for the clinical trial has 
been obtained, irrespective of the specific site’s planned inclusion number. 
Trial sites will be closed upon trial completion. LEO Pharma will undertake arrangements for 
the collection and disposal of any unused trial material that the investigator is not required to 
keep in his/her files. A trial site is considered closed when all required documents and trial 
supplies have been collected and a trial site closure visit has been performed. 
When the randomisation code has been broken, the investigators will receive information 
about the treatment allocation for the subjects randomised at their respective sites and will be 
asked to record this in the subject’s medical record. 
Appendix 3J: Responsibilities 
The signatory investigator is responsible for the approval of the clinical trial protocol and 
the CTR on behalf of all clinical trial investigators and as agreed to in a signatory investigator 
agreement. 
The national coordinating investigators are responsible for national issues relating to the 
clinical trial as agreed to in a national coordinating investigator agreement. 
Each participating investigator is responsible for all aspects of the clinical trial conduct at 
his/her trial site as agreed to in a clinical trial agreement.  
 
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Appendix 4: Country-specific requirements 
This appendix describes requirements and procedures that are specific for France and Canada. 
For each section, the text from the protocol is presented in normal font. The specific country 
requirements or procedures are presented below in bold font. 
France 
Section 8.3 Exclusion criteria 
Subjects are not eligible for the trial if they violate any of the following criteria: 
 
30. Subject not affiliated with or not a beneficiary of a social security scheme. 
 
Canada 
As per Health Canada standards, all essential trial documents and source documents 
will be archived for 15 years.  
 
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Appendix 5: Short version eligibility criteria 
 
Inclusion criteria 
No. 
Short version 
1 
Signed and dated IC and IA (as applicable according to national laws or regulation) has been obtained prior to any protocol-related 
procedures. 
2 
Age 12 to 17 years at screening and baseline. 
3 
Diagnosis of CHE, defined as hand eczema that has persisted for more than 3 months or returned twice or more within the last 12 months. 
4 
Disease severity graded as moderate to severe at screening and baseline according to IGA-CHE (i.e. an IGA-CHE score of 3 or 4). 
5 
Subjects who have a documented recent history of inadequate response to treatment with TCS or TCS treatment being medically inadvisable. 
6 
Subjects adherent to standard non-medicated skin care including avoidance of known and relevant irritants and allergens. 
7 
A woman of childbearing potential must use an acceptable method of birth control throughout the trial up until the last application of IMP. 
 
 
 
Exclusion criteria  
No. 
Short version 
1 
Known or suspected hypersensitivity to any component(s) of the IMP. 
2 
Concurrent skin diseases on the hands, e.g. tinea manuum. 
3 
Active AD requiring medical treatment in regions other than the hands and feet. 
4 
Active psoriasis on any part of the body. 
5 
Hyperkeratotic hand eczema in combination with a history of psoriasis on any part of the body. 
6 
Clinically significant infection (e.g. impetiginised hand eczema) on the hands. 
7 
Systemic treatment with immunosuppressive drugs, immunomodulating drugs, retinoids, or corticosteroids within 28 days prior to baseline. 
8 
Use of tanning beds, phototherapy (e.g. UVB, UVA1, PUVA), or bleach baths on the hands within 28 days prior to baseline. 
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9 
Previous or current treatment with JAK inhibitors (including delgocitinib/LEO 124249), systemic or topical. 
10 
Cutaneously applied treatment with immunomodulators (e.g. PDE-4 inhibitors, pimecrolimus, tacrolimus) or TCS on the hands within 14 
days prior to baseline. 
11 
Use of systemic antibiotics or cutaneously applied antibiotics on the hands within 14 days prior to baseline. 
12 
Other cutaneously applied therapy on the hands (except for the use of subject’s own emollients) within 7 days prior to baseline. 
13 
Cutaneously applied treatments in regions other than the hands, which could interfere with clinical trial evaluations or pose a safety concern 
within 7 days prior to baseline. 
14 
Treatment with any marketed biological therapy or investigational biologic agents (including immunoglobulin, anti-IgE, and dupilumab) 
within 6 months or 5 half-lives prior to baseline or until cell counts return to normal, whichever is longer. 
15 
Treatment with any non-marketed drug substance within the last 28 days prior to baseline or 5 half-lives, whichever is the longest. 
16 
Clinically significant infection (systemic infection or serious skin infection requiring parenteral treatment) within 28 days prior to baseline. 
17 
History of any known primary immunodeficiency disorder including a positive HIV virus test at screening, or the subject taking antiretroviral 
medications. 
18 
Major surgery within 8 weeks prior to screening, or planned in-patient surgery or hospitalisation during the trial period. 
19 
History of cancer. 
20 
Any disorder which is not stable and could affect the safety of the subject, influence the findings of the trials, or impede the subject’s ability 
to complete the trial. 
21 
Any abnormal finding which may put the subject at risk, influence the results of the trial, or influnece the subject’s ability to complete the 
trial. 
22 
Positive hepatitis B surface antigen or hepatitis C virus antibody serology at screening. 
23 
ALT or AST level ≥2.0×ULN at screening. 
24 
Current participation in any other interventional clinical trial. 
25 
Previously randomised in this clinical trial. 
26 
Subject or parents/guardians who have a current or recent chronic alcohol or drug abuse, or any other condition associated with poor 
compliance as judged by the investigator. 
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27 
Employees of the trial site, or any other individuals directly involved with the planning or conduct of the trial, or immediate family members 
of such individuals. 
28 
Subjects who are legally institutionalised. 
29 
Women who are pregnant or lactating. 
 
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Appendix 6: Contact list 
Contact details for the clinical project manager, national lead CRA, and sponsor’s medical 
expert are provided to the trial sites as a separate contact list. 
Sponsor 
ULEO Pharma A/SU (referred to as ‘LEO Pharma’ or ‘the sponsor’ in this clinical trial protocol) 
is the sponsor of the clinical trial: 
LEO Pharma A/S  
Industriparken 55 
DK-2750 Ballerup 
Denmark 
Coordinating investigator 
, MD 
 
 
, Canada 
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Appendix 7: COVID-19 pandemic contingency plan 
Without compromising the safety of subjects and trial integrity, it is expected that efforts are 
made to secure attendance at sites for all visits, ensuring important efficacy and safety 
assessments for the trial. 
If on-site visits are not possible due to local authority issued preventive measures, the affected 
site will postpone screening and randomisation of new subjects until on-site visits can be 
conducted. For already randomised subjects, post baseline visits can be done remotely via 
phone or video. At phone/video visits, no investigator assessments of efficacy can be done, 
but the following data will be collected remotely (according to the schedule of trial 
procedures in Section 4): 
• AE reporting. 
• Treatment compliance (daily completion in the eDiary). 
• Concomitant medication and concurrent procedures. 
• HESD (daily completion in the eDiary). 
• Subject assessment of local tolerability (weekly completion in the eDiary). 
• PRO (cDLQI). The subjects will receive a link to complete the cDLQI in a web browser 
from their own computer/laptop. 
• New CHE lesions. 
• Urine pregnancy test. Women of childbearing potential will receive 1 extra urine 
pregnancy test at the randomisation visit to keep at home in case on-site visits become 
impossible during the trial. The subject will perform the test at home and inform the 
investigator about the result via phone. Additional urine pregnancy tests can be shipped to 
the subject’s home together with IMP (see below) if needed. 
In the eCRF, it will be recorded whether a visit or a given assessment was done remotely or 
not done. If not done, it will be recorded if this was due to the pandemic. 
It will be at the discretion of the investigator to decide whether clinical laboratory samples are 
considered necessary to ensure subject safety in periods when on-site visits are not possible. If 
possible, a home visit can be arranged for a healthcare professional to collect relevant clinical 
laboratory samples. 
Contingency plans due to COVID-19 must follow the authorities' COVID-19 guidelines and 
local requirements. Written procedures describing the contingency plan must be in place at 
site/depot. To ensure availability of IMP, the trial sites may dispense additional IMP if 
considered relevant (i.e. if local authority issued preventive measures are to be expected at the 
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given trial site). This will allow subjects to continue treatment with IMP although they are not 
able to go to the trial site. If a subject will not be able to attend on-site visits due to the 
pandemic before running out of IMP, the trial site will ensure shipping of IMP to the subject’s 
home. As the subjects’ IMP supply is secured, the IE of initiation of rescue treatment will be 
considered independent of the pandemic in the statistical analysis. 
If a subject is tested positive for COVID-19, the investigator will evaluate whether this is an 
AE that contraindicates further dosing, in which case the subject will permanently discontinue 
IMP as described in Section 10.2.
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Appendix 8: Acceptable methods of birth control 
Acceptable methods of birth control include: 
• Bilateral tubal occlusion or ligation (tubal sterilisation methods). 
• 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] or without inhibition of ovulation as the primary mode of action 
[oral]). 
• Sexual abstinence (when this is in line with the preferred and usual lifestyle of the subject 
and not just being without a current partner). 
• Same-sex partner. 
• Vasectomised partner (given that the subject is monogamous). 
• Male or female condom with or without spermicide. 
• Cap, diaphragm, or sponge with spermicide. 
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