Conditions: Chronic Hand Eczema
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 487
Healthy volunteers: no

Brief summary:
This was a 16-week study in adult participants with chronic hand eczema (CHE). \> The participants visited the clinic regularly to have the study doctor assess their CHE and to answer questions about itch, pain, CHE symptoms, and quality of life.

\> The purpose was to assess how delgocitinib cream works to treat CHE when compared to a placebo cream with no active substance.

Detailed description:

Arms:
arm 1: Twice-daily topical application for 16 weeks arm 2: Twice-daily topical application for 16 weeks

Interventions: intervention 1: Delgocitinib cream 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 ingredient.

Protocol document:
Prot_SAP_000.pdf: 
Cover Page 
Official title: A phase 3 clinical trial to confirm efficacy and evaluate safety of twice-daily delgocitinib cream 20 mg/g compared 
with cream vehicle for a 16-week treatment period in adult subjects with moderate to severe chronic hand eczema (DELTA 1) 
LEO Pharma number: LP0133-1401 
NCT number: NCT04871711
Date: 20-Aug-2021


CONFIDENTIAL 
THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION AND MUST NOT BE COPIED OR MADE AVAILABLE TO ANY THIRD PARTY WITHOUT 
THE PRIOR WRITTEN CONSENT OF THE LEO PHARMA GROUP 
Clinical trial protocol 
LP0133-1401 
A phase 3 clinical trial to confirm efficacy and evaluate safety of twice-daily delgocitinib 
cream 20 mg/g compared with cream vehicle for a 16-week treatment period in adult 
subjects with moderate to severe chronic hand eczema (DELTA 1) 
Phase 3 – efficacy and 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: 
LP0133-1401 
Date: 
20-Aug-2021
EudraCT no: 
2020-002960-30 
Version: 
4.0, Final 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 2 of 160 
 
THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION AND MUST NOT BE COPIED OR MADE AVAILABLE TO ANY THIRD PARTY WITHOUT 
THE PRIOR WRITTEN CONSENT OF THE LEO PHARMA GROUP 
 
Clinical trial protocol 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 
 
Vice president, Medical Sciences 
 
 
 
 
 MSc Stat 
 
Biostatistics lead, Medical Sciences 
 
 
 MD 
 
 
 
Medical lead, Medical Sciences 
 
 
 
 
 MA 
 
Clinical operations lead, Global Clinical Operations 
 
 
 
 
Robert Bissonnette, MD MS FAAD FRCPC 
 
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. 
TMF-000340756 - Version
5. 0
PPD
PPD
PPD
PPD
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 3 of 160 
 
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 
 
Protocol amendment summary of changes table 
Document history 
Document 
Date 
Type of protocol amendment 
Amendment 1 
(substantial) 
20-Aug-2021 
Global 
Original protocol 
(Protocol version 3.0) 
04-Feb-2021 
NA 
 
Amendment 1 (20-Aug-2021) 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union 
or subsequent regulation. 
Overall rationale for the amendment 
This amendment was written to comply with requests from health authorities, to 
accommodate for the conduct of the trial in Russia, and to proceed with administrative and 
editorial changes. 
Section no. and title 
Description of change 
Brief rationale 
Section 4 Schedule of 
trial procedures 
Section 7.1 Overall 
trial design 
Section 11.2.4 
Classification of 
chronic hand eczema 
Wording that does not mandate diagnostic patch 
testing for Russia implemented. 
Russia added as country in the 
trial.  
Section 4 Schedule of 
trial procedures 
Section 9.8.4 
Treatment compliance 
Deleted that at the end-of-treatment/early 
termination visit, the subject will be asked about 
their overall compliance with the IMP. 
To avoid data duplication and 
inconsistencies in the data. 
Section 5.5 Benefit/risk 
assessment 
 
Clarification that treatment with other therapies 
will be withheld from the subjects for up to 22 
weeks added. 
VHP requests. 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 4 of 160 
 
THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION AND MUST NOT BE COPIED OR MADE AVAILABLE TO ANY THIRD PARTY WITHOUT 
THE PRIOR WRITTEN CONSENT OF THE LEO PHARMA GROUP 
 
Section no. and title 
Description of change 
Brief rationale 
 
Text on potential skin reactions, such as pain 
(burning and stinging), sensitisation to IMP, 
allergic and irritant contact dermatitis, local 
immunosuppression, and skin infections added. 
Section 6 Trial 
objective, estimands, 
and endpoints 
῾Change in skin barrier and inflammatory 
markers protein expression from baseline to 
Week 16.’ deleted as exploratory endpoint in 
Panel 4. 
For clarity, as protein 
expression will not be 
measured. 
Section 9.2 
Administration of IMP 
Fingertips added in the list of areas to be 
treated. 
For completeness. 
Section 9.6 
Concomitant 
medication and 
concurrent procedures  
Section 9.7 Prohibited 
medications and 
procedures 
Guidance regarding COVID-19 vaccines added. 
COVID-19 vaccines can be administered to 
subjects without the need to pause or 
discontinue IMP. 
MHRA request. 
Section 10.2 Reasons 
for permanent 
discontinuation of IMP 
Positive patch test reaction to the IMP added as 
a reason for permanent discontinuation of IMP. 
For consistency with Section 
11.5.5.1. 
Section 11.1 Overview 
Section 13.2 Collection 
of adverse event 
reports 
Text regarding assessment of AEs updated. AEs 
will be assessed by a physician. 
To clarify the responsibilities 
and who should perform certain 
tasks. 
Section 11.2.1 
Demographics 
Asian - Chinese added as race. 
To support a potential future 
submission in China. 
Section 11.4.3.1 
Overview 
Section 11.7.1.5 
Patient’s Global 
Assessment of disease 
severity (PaGA) 
PaGA TS is removed from the list of secondary 
endpoints. PaGA score will be analysed 
descriptively as an exploratory endpoint. 
The modified PaGA used in this 
trial is considered less 
informative as an endpoint for 
the evaluation of the clinical 
relevance of delgocitinib in 
CHE. As a consequence, PaGA 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 5 of 160 
 
THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION AND MUST NOT BE COPIED OR MADE AVAILABLE TO ANY THIRD PARTY WITHOUT 
THE PRIOR WRITTEN CONSENT OF THE LEO PHARMA GROUP 
 
Section no. and title 
Description of change 
Brief rationale 
Section 14.3.5 Testing 
strategy 
Section 14.3.8 Analysis 
of keys secondary 
endpoints 
Section 14.3.9 Analysis 
of exploratory 
endpoints 
Section 14.3.10 
Analysis of patient-
reported outcomes 
TS is removed from the 
confirmatory testing procedure. 
Section 11.5.1 Vital 
signs 
Text regarding vital signs updated. The vital 
signs will be measured in a sitting position. 
Vital signs are not critical data, 
thus a supine position for 
measuring is not required. 
Section 11.5.5.1 IMP 
patch test procedure 
Added that photographs of a positive patch test 
reaction should be taken if a device is available 
at the site. 
For clarity 
Section 11.7.2 Exit 
interviews (selected 
trial sites) 
Deleted that a date and time for the exit 
interview will be agreed with the subject at 
Week 16. 
Exit interview could be 
scheduled earlier or changes 
could occur after Week 16. 
Further details are provided in 
the exit interview training 
material. 
Section 11.8 End of 
trial 
Specification added to indicate that for subjects 
not completing the trial, it will be recorded if 
the reason for not completing the trial was 
related to COVID-19. 
This information is needed to 
fully assess and report the 
impact of COVID-19 on the 
trial. 
Section 13.2 Collection 
of adverse reports 
Text on potential AEs reported by the subject 
during an exit interview updated. 
For clarity. 
Section 13.3 Reporting 
of adverse events 
Text regarding cutaneous AEs updated. 
To provide more guidance for 
the reporting of cutaneous AEs. 
Section 13.4.1 
Investigator reporting 
responsibilities 
A more detailed specification on the timing of 
reporting of SAEs added (i.e., immediately, 
without undue delay). 
To align with updated text in the 
EU CT regulation on reporting 
of SAEs. 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 6 of 160 
 
THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION AND MUST NOT BE COPIED OR MADE AVAILABLE TO ANY THIRD PARTY WITHOUT 
THE PRIOR WRITTEN CONSENT OF THE LEO PHARMA GROUP 
 
Section no. and title 
Description of change 
Brief rationale 
Section 14.1 Sample 
size 
Basis for the assumptions on response rate for 
delgocitinib and vehicle for sample size 
calculation added. 
VHP request. 
Section 14.3.12.1 
Adverse events 
Paragraph added indicating that other events 
will be tabulated and listed. 
For completeness. 
Appendix 1 
Hospitalisation definition clarified. 
For clarity. 
Appendix 2 
Instructions added regarding reporting of AEs 
with onset prior to initiation of IMP that worsen 
after administration of IMP. 
To align with the updated 
procedure for AE reporting. 
Appendix 3D 
Specified that clinical assessments/safety 
evaluations must be signed and dated by 
physicians. 
To clarify the responsibilities 
and who should perform certain 
tasks. 
Appendix 4 
France-specific exclusion criterion 'Subjects not 
affiliated with or not a beneficiary of a social 
security scheme' added. 
Added that for Canada all essential trial 
documents and source documents will be 
archived for 25 years. 
Mandatory exclusion criteria for 
France. 
 
Health Canada request. 
Throughout document 
Number of subjects increased to 470. 
Due to the addition of Russia. 
Throughout document 
References to US, US sites, and US-specific 
provisions removed. 
No US sites will be involved in 
this trial. 
Throughout document 
Minor editorial revisions. 
Minor, have therefore not been 
summarised. 
 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 7 of 160 
 
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 
 
Protocol version summary of changes table 
Document history 
Document 
Date 
Type of protocol version 
Protocol version 3.0 
04-Feb-2021 
Version with reduction in sample size from N=600 to N=450. 
Version created after internal approval of version 2.0, but before 
submission to any regulatory authorities or IECs/IRBs. 
Protocol version 2.0 
26-Jan-2021 
Version with updates made after receipt of EMA scientific advice; 
i.e. after internal approval of version 1.0, but before submission to 
any regulatory authorities or IECs/IRBs. 
Protocol version 1.0 
09-Nov-2020 
Version for internal use 
 
Overall rationale for protocol version 3.0 (04-Feb-2021) 
Description of change 
Brief rationale 
Reduction in sample size from 
N=600 to N=450. 
The sample size has been reduced based on the trial design as agreed with 
EMA during the scientific advice procedure. 
Reduction in number of sites 
from 75 to 55. 
The reduction in sample size led to a reduction in the number of sites to 
safeguard data quality. 
 
Overall rationale for protocol version 2.0 (26-Jan-2021) 
Description of change 
Brief rationale 
Addition of inclusion criterion 
related to avoidance of 
irritants and allergens. 
Based on EMA scientific advice dated 16-Nov-2020, it was decided to add 
an inclusion criterion related to avoidance of irritants and allergens as mean 
to evaluate inadequate response to standard non-medicated skin care. 
Assessment of 
pharmacokinetics (PK) was 
moved from this trial to 
companion trial LP0133-1402. 
Based on EMA scientific advice dated 16-Nov-2020, it was decided to 
increase the number of subjects who will have PK samples collected from 
80-90 subjects at selected trial sites in trial LP0133-1401 to all subjects 
participating in a trial. As PK samples are not to be taken at sites where tape 
stripping assessments are planned (only in trial LP0133-1401), it was 
decided to move the PK assessments to trial LP0133-1402. 
Removal of skin biopsies. 
Skin biopsies were removed from the trial due to operational challenges. 
Minor editorial revisions 
throughout document. 
Minor, have therefore not been summarised. 
 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 8 of 160 
 
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 
 
Table of contents 
Table of contents ....................................................................................................................... 8 
List of panels ........................................................................................................................... 12 
List of abbreviations and definition of terms ....................................................................... 14 
1 Protocol synopsis ................................................................................................................ 17 
2 Trial identification ............................................................................................................. 24 
3 Schematic of trial design ................................................................................................... 24 
4 Schedule of trial procedures ............................................................................................. 25 
5 Introduction and trial rationale ....................................................................................... 31 
5.1 Chronic hand eczema .................................................................................................. 31 
5.2 Experience with IMP .................................................................................................. 33 
5.3 Trial rationale .............................................................................................................. 34 
5.4 Ethical considerations ................................................................................................. 34 
5.5 Benefit/risk assessment ............................................................................................... 35 
6 Trial objectives, estimands, and endpoints ...................................................................... 37 
7 Trial design ......................................................................................................................... 44 
7.1 Overall trial design ..................................................................................................... 44 
7.2 Number of subjects needed ......................................................................................... 45 
7.3 End of trial definition.................................................................................................. 46 
8 Trial population ................................................................................................................. 47 
8.1 Subject eligibility ........................................................................................................ 47 
8.2 Inclusion criteria ......................................................................................................... 47 
8.3 Exclusion criteria ........................................................................................................ 48 
8.4 Screening and screening failures ................................................................................ 50 
9 Treatments .......................................................................................................................... 52 
9.1 Trial product description ............................................................................................. 52 
9.2 Administration of IMP ................................................................................................ 52 
9.3 Treatment assignment and blinding ............................................................................ 53 
9.3.1 
Treatment assignment .................................................................................... 53 
9.3.2 
Blinding ......................................................................................................... 53 
9.3.3 
Emergency unblinding of individual subject treatment ................................ 54 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 9 of 160 
 
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 
 
9.4 Background treatment ................................................................................................. 54 
9.5 Rescue treatment ......................................................................................................... 54 
9.6 Concomitant medication and concurrent procedures ................................................. 55 
9.7 Prohibited medications and procedures ...................................................................... 56 
9.8 Treatment logistics and accountability ....................................................................... 57 
9.8.1 
Labelling and packaging of trial products ..................................................... 57 
9.8.2 
Storage of trial products ................................................................................ 58 
9.8.3 
IMP accountability ........................................................................................ 58 
9.8.4 
Treatment compliance ................................................................................... 59 
9.8.5 
Trial product destruction ............................................................................... 60 
9.9 Provision for subject care following trial completion ................................................ 60 
9.10 Reporting product complaints..................................................................................... 60 
10 Discontinuation and withdrawal ...................................................................................... 62 
10.1 General principles ....................................................................................................... 62 
10.2 Reasons for permanent discontinuation of IMP ......................................................... 62 
10.3 Early termination assessments .................................................................................... 63 
10.4 Lost to follow-up ........................................................................................................ 64 
11 Trial assessments and procedures .................................................................................... 65 
11.1 Overview..................................................................................................................... 65 
11.2 Assessments performed only at screening/baseline .................................................... 66 
11.2.1 Demographics................................................................................................ 66 
11.2.2 Fitzpatrick skin type ...................................................................................... 66 
11.2.3 Medical history .............................................................................................. 67 
11.2.4 Classification of chronic hand eczema .......................................................... 69 
11.2.5 Height and weight ......................................................................................... 70 
11.2.6 Determination of treatment area .................................................................... 70 
11.3 eDiary assessments ..................................................................................................... 71 
11.4 Efficacy assessments .................................................................................................. 71 
11.4.1 Investigator’s Global Assessment for chronic hand eczema (IGA-CHE) ..... 71 
11.4.2 Hand Eczema Severity Index (HECSI) ......................................................... 72 
11.4.3 Patient-reported outcomes (efficacy) ............................................................ 74 
11.5 Safety assessments ...................................................................................................... 74 
11.5.1 Vital signs ...................................................................................................... 74 
11.5.2 Physical examination..................................................................................... 75 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 10 of 160 
 
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 
 
11.5.3 Electrocardiography ...................................................................................... 75 
11.5.4 Laboratory testing ......................................................................................... 76 
11.5.5 Assessment of local tolerability .................................................................... 79 
11.6 Pharmacodynamics assessments ................................................................................. 82 
11.6.1 Overview ....................................................................................................... 82 
11.6.2 Tape stripping (selected trial sites) ................................................................ 83 
11.7 Other assessments ....................................................................................................... 84 
11.7.1 Patient-reported outcomes (health-related quality of life and work 
productivity) .................................................................................................. 84 
11.7.2 Exit interviews (selected trial sites) .............................................................. 88 
11.8 End of trial .................................................................................................................. 89 
11.9 Estimate of total blood volume collected ................................................................... 90 
11.10 Storage of biological samples ..................................................................................... 90 
12 Scientific rationale for trial design and appropriateness of assessments ..................... 92 
12.1 Scientific rationale for trial design ............................................................................. 92 
12.2 Appropriateness of assessments ................................................................................. 93 
13 Adverse events ................................................................................................................... 95 
13.1 Definition and classification of adverse events .......................................................... 95 
13.2 Collection of adverse event reports ............................................................................ 95 
13.3 Reporting of adverse events........................................................................................ 96 
13.4 Reporting of serious adverse events ........................................................................... 97 
13.4.1 Investigator reporting responsibilities ........................................................... 97 
13.4.2 LEO Pharma reporting responsibilities ......................................................... 98 
13.5 Other events that require expedited reporting ............................................................ 98 
13.5.1 Pregnancy ...................................................................................................... 98 
13.6 Reporting of other events............................................................................................ 99 
13.6.1 Adverse events of special interest ................................................................. 99 
13.6.2 Medication error .......................................................................................... 100 
13.6.3 Misuse or abuse ........................................................................................... 100 
13.6.4 Aggravation of condition ............................................................................ 101 
13.7 Follow-up for final outcome of adverse events ........................................................ 101 
13.8 Handling of an urgent safety measure ...................................................................... 101 
14 Statistical methods ........................................................................................................... 103 
14.1 Sample size ............................................................................................................... 103 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 11 of 160 
 
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 
 
14.2 Trial analysis sets ...................................................................................................... 103 
14.3 Statistical analysis ..................................................................................................... 103 
14.3.1 Aspects related to the COVID-19 pandemic ............................................... 103 
14.3.2 Disposition of subjects ................................................................................ 104 
14.3.3 Demographics and other baseline characteristics........................................ 105 
14.3.4 Exposure and treatment compliance ........................................................... 105 
14.3.5 Testing strategy ........................................................................................... 105 
14.3.6 Estimand strategy ........................................................................................ 109 
14.3.7 Analysis of primary endpoint ...................................................................... 120 
14.3.8 Analysis of key secondary endpoints .......................................................... 120 
14.3.9 Analysis of exploratory endpoints .............................................................. 127 
14.3.10 Analysis of patient-reported outcomes ........................................................ 129 
14.3.11 Analysis of pharmacodynamics .................................................................. 129 
14.3.12 Analysis of safety ........................................................................................ 130 
14.3.13 Interim analysis ........................................................................................... 131 
14.3.14 General principles ....................................................................................... 131 
14.3.15 Handling of missing values ......................................................................... 132 
15 References ......................................................................................................................... 133 
Appendix 1: Definitions of adverse events and serious adverse events ........................... 139 
Appendix 2: Classification of adverse events ..................................................................... 141 
Appendix 3: Trial governance considerations ................................................................... 144 
Appendix 3A: Regulatory and ethical considerations .............................................. 144 
Appendix 3B: Informed consent process ................................................................. 144 
Appendix 3C: Subject and data confidentiality ....................................................... 145 
Appendix 3D: Record keeping, quality control, and data handling ......................... 147 
Appendix 3E: Registration, reporting, and publication policy ................................ 150 
Appendix 3F: Insurance ........................................................................................... 151 
Appendix 3G: Financial disclosure .......................................................................... 151 
Appendix 3H: Trial and trial site closure ................................................................. 151 
Appendix 3I: Responsibilities .................................................................................. 152 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 12 of 160 
 
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 
 
Appendix 4: Country-specific requirements ...................................................................... 153 
Appendix 5: Short version of eligibility criteria ................................................................ 154 
Appendix 6: Contact list ...................................................................................................... 157 
Appendix 7: COVID-19 pandemic contingency plan........................................................ 158 
Appendix 8: Acceptable methods of birth control ............................................................. 160 
 
List of panels 
Panel 1: Trial design ................................................................................................................. 24 
Panel 2: Schedule of trial procedures ....................................................................................... 25 
Panel 3: Objectives and estimands for primary and key secondary endpoints ........................ 38 
Panel 4: Secondary and exploratory objectives and endpoints ................................................ 42 
Panel 5: Identification of IMPs ................................................................................................ 52 
Panel 6: Excipients of delgocitinib cream 20 mg/g and cream vehicle ................................... 52 
Panel 7: Prohibited medications and procedures ...................................................................... 56 
Panel 8: Sequence of assessments ............................................................................................ 65 
Panel 9: Fitzpatrick skin classification ..................................................................................... 67 
Panel 10: Definition of subtypes of hand eczema .................................................................... 70 
Panel 11: Investigator’s Global Assessment for chronic hand eczema (IGA-CHE) ................ 72 
Panel 12: HECSI severity score scale and area score scale ..................................................... 73 
Panel 13: Calculation of the total HECSI score ....................................................................... 73 
Panel 14: Clinical laboratory tests performed by the central laboratory .................................. 77 
Panel 15: Subject assessment of local tolerability after IMP application ................................ 79 
Panel 16: Berger and Bowman scoring scales if investigator suspects a local skin reaction 
related to IMP application ................................................................................ 81 
Panel 17: Patch test reading criteria ......................................................................................... 82 
Panel 18: Patient Global Impression of Severity (PGI-S) questionnaires ................................ 85 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 13 of 160 
 
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 
 
Panel 19: Patient Global Impression of Change (PGI-C) questionnaires ................................ 86 
Panel 20: Patient’s Global Assessment of disease severity (PaGA) ........................................ 87 
Panel 21: Adverse events of special interest ............................................................................ 99 
Panel 22: Graphical display of closed testing procedure for primary and key secondary 
endpoints ........................................................................................................ 107 
Panel 23: Handling of observed and missing data according to the intercurrent events for the 
primary analysis for estimands ....................................................................... 111 
Panel 24: Overview of the primary analysis of the key secondary endpoints related to the 
primary and supplementary estimands ........................................................... 121 
Panel 25: Overview of the statistical analysis of exploratory endpoints ................................ 127 
 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 14 of 160 
 
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 
 
List of abbreviations and definition of terms 
AD 
atopic dermatitis 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
CDISC 
Clinical Data Interchange Standards Consortium 
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 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
eDiary 
electronic diary 
EMA 
European Medicine Agency 
ePRO 
electronic patient-reported outcome 
EQ-5D-5L 
EuroQol 5-Dimension Health Questionnaire 5 Level 
EU 
European Union 
FAS 
full analysis set 
FDA 
United States Food and Drug Administration 
GCP 
Good Clinical Practice 
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 
HEIS 
Hand Eczema Impact Scale 
HESD 
Hand Eczema Symptom Diary 
HIV 
human immunodeficiency virus 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 15 of 160 
 
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 
 
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 at least 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 
LEO 124249 
delgocitinib 
LEO Pharma 
LEO Pharma A/S 
LP0133-1403 
open-label long-term extension trial with delgocitinib cream 20 mg/g for 
36 weeks 
LTE trial 
long-term extension trial (LP0133-1403) 
MAR 
missing at random 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
multiple imputation 
PaGA 
Patient’s Global Assessment of disease severity 
PDAL 
Proximal Daily Activity Limitations 
PDE-4 
phosphodiesterase-4 
PGA 
Physician’s Global Assessment 
PGI-C 
Patient Global Impression of Change 
PGI-S 
Patient Global Impression of Severity 
PK 
pharmacokinetic(s) 
PRO 
patient-reported outcome 
PUVA 
psoralen ultraviolet A 
SAE 
serious adverse event 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 16 of 160 
 
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 
 
 
SD 
standard deviation 
SOC 
system organ class 
STAT 
signal transducer and activator of transcription 
TCS 
topical corticosteroid(s) 
TS 
treatment success 
ULN 
upper limit of normal 
UVA1 
ultraviolet A1 
UVB 
ultraviolet B 
VHP 
Voluntary Harmonization Procedure 
WPAI:CHE 
Work Productivity and Activity Impairment: Chronic Hand Eczema 
WOCF 
worst observation carried forward 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 17 of 160 
 
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 
 
1 Protocol synopsis 
Trial ID 
EudraCT no. 
LP0133-1401 
2020-002960-30 
Title of trial 
A phase 3 clinical trial to confirm efficacy and evaluate safety of twice-daily 
delgocitinib cream 20 mg/g compared with cream vehicle for a 16-week 
treatment period in adult subjects with moderate to severe chronic hand eczema 
(DELTA 1). 
Short title of trial 
Efficacy and safety of delgocitinib cream in adults with moderate to severe 
chronic hand eczema. 
Main objectives, 
estimands, and 
endpoints 
Objectives 
Estimand type 
and strategy 
Endpoints 
Primary objective: 
To confirm the 
efficacy of 
twice-daily 
applications of 
delgocitinib cream 
20 mg/g compared 
with cream vehicle 
in the treatment of 
adult subjects with 
moderate to severe 
CHE. 
Primary. 
‘Composite’ 
strategy. 
First 
supplementary. 
‘Pandemic 
modified 
composite’ 
strategy. 
Second 
supplementary for 
endpoints at 
Week 16. 
‘Treatment policy’ 
strategy. 
Primary endpoint: 
• IGA-CHE1 TS at Week 16. 
Key secondary endpoints: 
• HECSI-75 at Week 16. 
• HECSI-75 at Week 8. 
• HECSI-90 at Week 16. 
• IGA-CHE TS at Week 8. 
• IGA-CHE TS at Week 4. 
• Percentage change in HECSI2 score 
from baseline to Week 16. 
Secondary 
objective: 
To confirm 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 
adult subjects with 
moderate to severe 
CHE. 
Primary. 
‘Composite’ 
strategy. 
First 
supplementary. 
‘Pandemic 
modified 
composite’ 
strategy. 
Second 
supplementary for 
endpoints at 
Week 16. 
‘Treatment policy’ 
strategy. 
Key secondary endpoints: 
• Reduction of HESD3 itch score 
(weekly average) of ≥4 points from 
baseline at Week 16.4 
• Reduction of HESD itch score 
(weekly average) of ≥4 points from 
baseline at Week 8.4 
• Reduction of HESD itch score 
(weekly average) of ≥4 points from 
baseline at Week 4.4 
• Reduction of HESD itch score 
(weekly average) of ≥4 points from 
baseline at Week 2.4 
• Reduction of HESD 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 8.5 
• Reduction of HESD score (weekly 
average) of ≥4 points from baseline 
at Week 4.5 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 18 of 160 
 
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 
 
• Reduction of HESD pain score 
(weekly average) of ≥4 points from 
baseline at Week 16.6 
• Reduction of HESD pain score 
(weekly average) of ≥4 points from 
baseline at Week 8.6 
• Reduction of HESD pain score 
(weekly average) of ≥4 points from 
baseline at Week 4.6 
• Reduction of DLQI score of ≥4 
points from baseline at Week 16.7 
• Change in HESD itch score (weekly 
average) from baseline to Week 16. 
• Change in HESD score (weekly 
average) from baseline to Week 16. 
• Change in HESD pain score 
(weekly average) from baseline to 
Week 16. 
• Change in HEIS8 score from 
baseline to Week 16. 
• Change in HEIS PDAL score from 
baseline to Week 16. 
• Change in DLQI score from 
baseline to Week 16. 
Secondary 
objective: 
To evaluate the 
safety of twice-daily 
applications of 
delgocitinib cream 
20 mg/g compared 
with cream vehicle 
in the treatment of 
adult subjects with 
moderate to severe 
CHE. 
Not applicable. 
Secondary endpoint: 
• Number of treatment-emergent9 
AEs from baseline up to Week 16 
(Week 18 for subjects not 
participating in the LTE trial) per 
subject. 
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 in each of the 5 hand regions (fingertips, fingers [except 
fingertips], palm of hands, back of hands, and wrists) by use of standard scales. The 
HECSI score will range from 0 (lowest possible score) to 360 (highest possible score). 
3) The HESD is an eDiary in which subjects will assess the worst severity of 
 individual signs and symptoms of CHE 
 
) over the past 24 hours using an 11-point numeric rating scale throughout the 
trial on a daily basis. 
4) Among subjects with a baseline HESD itch score (weekly average) ≥4 points. 
5) Among subjects with a baseline HESD score (weekly average) ≥4 points. 
6) Among subjects with a baseline HESD pain score (weekly average) ≥4 points. 
7) Among subjects with a baseline DLQI score ≥4 points. 
TMF-000340756 - Version
5. 0
CC
CCI
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 19 of 160 
 
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 
 
8) The HEIS addresses  items within the following domains: 
 
 
. Each item is scored on a 5-point scale ranging from 0 (not at all) to 4 
(extremely). 
9) 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: CHE = chronic hand eczema; DLQI = Dermatology Life Quality 
Index; 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; HEIS = Hand Eczema Impact Scale; 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; IMP = investigational 
medicinal product; PDAL = Proximal Daily Activity Limitations. 
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 adult subjects 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. In view of a 28-day wash out for some of these 
treatments, the screening period can be extended up to 31 days. The subjects 
will receive an eDiary device and training in completion of the eDiary. 
Treatment period 
At baseline (Day 1), the subjects’ eligibility to enter the trial will be confirmed. 
If still eligible, the subjects will be randomised 2:1 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 
and severe) and region (Europe and North America). 
The first application of IMP will occur at the trial site at baseline (Day 1). The 
subsequent IMP applications will be performed by the subjects at home twice 
daily for 16 weeks. During the treatment period, the subjects will be required to 
return to the trial site for the visits scheduled at Weeks 1, 2, 4, 8, 12, and 16. 
The last IMP application will occur at the subject’s home before the subject 
attends the visit scheduled at Week 16. 
Follow-up period 
The subjects will attend a follow-up visit (performed via phone, but can be a 
site visit if needed) approximately 2 weeks after the last IMP application for 
assessment of safety. Eligible subjects who complete the treatment period (i.e. 
who do not permanently discontinue IMP prior to Week 16) will be invited to 
TMF-000340756 - Version
5. 0
CC
CCI
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 20 of 160 
 
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 
 
participate in an open-label LTE trial (LP0133-1403, conducted under a 
separate protocol). Subjects who continue in the LTE trial will not be required 
to complete the follow-up period, as collection of safety data and safety 
surveillance will continue in the LTE trial. 
 
* 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, 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; LTE = long term extension; w = week. 
Main assessments 
Investigator assessments of efficacy: 
• 
IGA-CHE for assessment of disease severity. 
• 
HECSI for assessment of the clinical signs of CHE. 
Subject assessments of efficacy and health-related quality of life; PROs: 
• 
Hand Eczema Symptom Diary (HESD). 
• 
Hand Eczema Impact Scale (HEIS). 
• 
Dermatology Life Quality Index (DLQI). 
Safety assessments: 
Vital signs, physical examination, ECG, laboratory testing, subject assessment 
of local tolerability, and AE reporting. 
Main criteria for 
inclusion 
• 
Age 18 years or above at screening. 
• 
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). 
• 
HESD itch score (weekly average) of ≥4 points at baseline. 
• 
Subjects who have a documented recent history of inadequate response 
to treatment with TCS (at any time within 1 year before the screening 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 21 of 160 
 
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 
 
visit) or for whom TCS are documented to be otherwise medically 
inadvisable (e.g. due to important side effects or safety risks). 
• 
Subjects adherent to standard non-medicated skin care including 
avoidance of known and relevant irritants and allergens. 
Main criteria for 
exclusion 
• 
Concurrent skin diseases on the hands, e.g. tinea manuum. 
• 
Active AD requiring medical treatment in regions other than the hands 
and feet. 
• 
Active psoriasis on any part of the body. 
• 
Hyperkeratotic hand eczema in combination with a history of psoriasis 
on any part of the body. 
• 
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 transdermal or 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. 
• 
Treatment with any marketed biological therapy or investigational 
biologic agents (including immunoglobulin, anti-IgE, and dupilumab): 
o Any cell-depleting agents including but not limited to 
rituximab: within 6 months prior to baseline, or until 
lymphocyte count returns to normal, whichever is longer. 
o Other biologics: within 3 months or 5 half-lives, whichever is 
longer, prior to baseline. 
• 
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: 
o A systemic infection. 
o A serious skin infection requiring parenteral (intravenous or 
intramuscular) antibiotics, antiviral, or antifungal medication. 
• 
History of any known primary immunodeficiency disorder including a 
positive HIV test at screening, or the subject taking antiretroviral 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 22 of 160 
 
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 
 
medications as determined by medical history and/or subject’s verbal 
report. 
• 
Any disorder which is not stable and could: 
o Affect the safety of the subject throughout the trial. 
o 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. 
• 
Positive hepatitis B surface antigen or hepatitis C virus antibody 
serology at screening. 
Investigational 
medicinal product 
• 
Name of IMP: delgocitinib cream. 
• 
Active substance: delgocitinib. 
• 
Dosage form: cream. 
• 
Concentration: 20 mg/g and cream vehicle. 
• 
Dose and method of administration: topical application twice daily. 
Duration of trial 
participation 
The duration of trial participation will be up to 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 (safety follow-up period not applicable for 
subjects participating in the LTE trial). 
Number of 
subjects 
A total of 470 eligible subjects will be randomised in a 2:1 ratio to delgocitinib 
cream 20 mg/g or cream vehicle. 
Number and 
distribution of 
trial sites 
Approximately 55 sites in Europe and Canada. 
Statistical 
methods 
For the primary and key secondary endpoints, confirmatory one-sided 
(superiority) hypotheses will be tested for delgocitinib cream 20 mg/g vs. 
cream vehicle based on the primary analysis for the primary estimand. A closed 
testing procedure with hierarchical tests, alpha splitting, and alpha recycling 
will be used to control the overall type I error at a nominal one-sided 2.5% 
level. The statistical testing strategy is built on the principle that the IGA-CHE 
TS superiority at Week 16 will have to be established before testing for 
additional benefits (key secondary endpoints) related to efficacy and 
health-related quality of life. 
The primary estimand for the primary and key secondary endpoints will use a 
‘composite’ strategy where the occurrence of pre-defined IEs (initiation of 
rescue treatment and permanent discontinuation of IMP) is a component of the 
endpoint. A first supplementary estimand will use a ‘pandemic modified 
composite’ strategy which follows a ‘composite’ strategy for IEs independent 
of the COVID-19 pandemic, attempting to quantify the effect of the 
randomised treatment in a world without COVID-19 pandemic. A second 
supplementary estimand will use a ‘treatment policy’ strategy which attempts 
to quantify the effect of the randomised treatment regardless of whether an IE 
occurs. The second supplementary estimand will be used for endpoints related 
to Week 16 (primary endpoint visit). 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 23 of 160 
 
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 
 
The primary analysis for the primary estimand for the binary endpoints will be 
CMH test stratified by region and baseline IGA-CHE score. The primary 
analysis for the primary estimand for the continuous endpoints will be 
ANCOVA with effects of treatment group, region, baseline IGA-CHE score, 
and baseline value (endpoint of interest). 
Signatory 
investigator 
Robert Bissonnette, MD, dermatologist 
Innovaderm Research Inc., Montreal (Quebec), Canada 
Sponsor 
LEO Pharma A/S, Industriparken 55, DK-2750 Ballerup, Denmark 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 24 of 160 
 
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 
 
2 Trial identification 
EudraCT number: 2020-002960-30. 
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, 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; LTE = long-term extension; w = week. 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 25 of 160 
 
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 
 
4 Schedule of trial procedures 
Panel 2: Schedule of trial procedures 
 
Screening 
 
Follow-up3 
Primary 
endpoint 
visit at 
Week 16, if 
applicable5 
Unscheduled 
visit, if 
applicable6 
References 
(protocol 
section) 
Treatment period 
End of 
treatment1 
Early termination, 
if applicable2 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
(9) 
10 
Week 
-4 to -1 
0 
1 
2 
4 
8 
12 
16 
- 
184 
Day 
-287 to -7 
1 
8 
15 
29 
57 
85 
113 
- 
1274 
Visit window (days)8 
- 
- 
±3 
±3 
±3 
±3 
±3 
±3 
- 
±3 
Trial population and eligibility 
Informed consent(s)9 
X 
 
 
 
 
 
(X)10 
(X)10 
 
 
 
 
Appendix 3B 
Subject eligibility 
X 
X 
 
 
 
 
 
 
 
 
 
 
8.2, 8.3 
Investigator assessments at screening/baseline only 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
11.2.1 
Fitzpatrick skin type 
X 
 
 
 
 
 
 
 
 
 
 
 
11.2.2 
Medical history (including 
CHE treatment history) 
X 
 
 
 
 
 
 
 
 
 
 
 
11.2.3 
Classification of CHE 
(including patch test if 
standard clinical practice)11 
X 
 
 
 
 
 
 
 
 
 
 
(X) 
11.2.4 
Height and weight 
 
X 
 
 
 
 
 
 
 
 
 
 
11.2.5 
Determination of treatment 
area(s) 
 
X 
 
 
 
 
 
 
 
 
 
(X) 
11.2.6 
eDiary handout/training 
X 
 
 
 
 
 
 
 
 
 
 
 
11.3 
Treatments and randomisation 
Randomisation 
 
X 
 
 
 
 
 
 
 
 
 
 
9.3 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 26 of 160 
 
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 
 
 
Screening 
 
Follow-up3 
Primary 
endpoint 
visit at 
Week 16, if 
applicable5 
Unscheduled 
visit, if 
applicable6 
References 
(protocol 
section) 
Treatment period 
End of 
treatment1 
Early termination, 
if applicable2 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
(9) 
10 
Week 
-4 to -1 
0 
1 
2 
4 
8 
12 
16 
- 
184 
Day 
-287 to -7 
1 
8 
15 
29 
57 
85 
113 
- 
1274 
Visit window (days)8 
- 
- 
±3 
±3 
±3 
±3 
±3 
±3 
- 
±3 
Dispensing of IMP 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
(X) 
9.2 
Instruction for IMP 
application 
 
X 
 
 
 
 
 
 
 
 
 
 
9.2 
Application of IMP 
 
Twice daily 
 
 
 
9.2 
Treatment compliance 
 
Daily12 
X12 
X12 
 
 
 
9.8.4 
Return of IMP and 
accountability13 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
(X) 
9.8.3 
Concomitant medication 
and concurrent procedures14 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
9.6 
Investigator assessments of efficacy 
IGA-CHE 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
11.4.1 
HECSI 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
11.4.2 
Subject assessment of efficacy – daily 
eDiary completion: HESD15 
Daily 
 
X 
 
11.4.3.2 
Subject assessments of efficacy and health-related quality of life – during trial visits 
PGI-S16 
 
X 
 
X 
X 
X 
 
X 
X 
 
 
 
11.7.1.2 
PGI-C17 
 
 
 
X 
X 
X 
 
X 
X 
 
 
 
11.7.1.3 
HEIS 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
11.7.1.4 
PaGA 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
11.7.1.5 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 27 of 160 
 
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 
 
 
Screening 
 
Follow-up3 
Primary 
endpoint 
visit at 
Week 16, if 
applicable5 
Unscheduled 
visit, if 
applicable6 
References 
(protocol 
section) 
Treatment period 
End of 
treatment1 
Early termination, 
if applicable2 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
(9) 
10 
Week 
-4 to -1 
0 
1 
2 
4 
8 
12 
16 
- 
184 
Day 
-287 to -7 
1 
8 
15 
29 
57 
85 
113 
- 
1274 
Visit window (days)8 
- 
- 
±3 
±3 
±3 
±3 
±3 
±3 
- 
±3 
DLQI 
 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
 
11.7.1.6 
EQ-5D-5L 
 
X 
X 
 
X 
X 
X 
X 
X 
 
 
 
11.7.1.7 
WPAI:CHE 
 
X 
 
 
X 
X 
 
X 
X 
 
 
 
11.7.1.8 
Subject assessment of safety 
Subject assessment of local 
tolerability 
 
Weekly18 
X 
X 
 
 
 
11.5.5 
Investigator assessments of safety 
Vital signs 
X 
X 
 
 
 
 
 
X 
X 
 
 
(X) 
11.5.1 
Physical examination 
X 
 
 
 
 
 
 
X 
X 
 
 
(X) 
11.5.2 
ECG 
X 
 
X 
 
 
 
 
X 
X 
 
 
(X) 
11.5.3 
Chemistry, haematology 
(central laboratory)19 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
(X) 
11.5.4 
Serology, total IgE (central 
laboratory) 
X 
 
 
 
 
 
 
 
 
 
 
 
11.5.4 
Urine pregnancy test20 
X 
X 
 
 
X 
X 
X 
X 
X 
 
 
(X) 
11.5.4 
Urinalysis (urine dipstick)21 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
(X) 
11.5.4 
Investigator assessment of 
local tolerability 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
(X) 
11.5.5 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 28 of 160 
 
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 
 
 
Screening 
 
Follow-up3 
Primary 
endpoint 
visit at 
Week 16, if 
applicable5 
Unscheduled 
visit, if 
applicable6 
References 
(protocol 
section) 
Treatment period 
End of 
treatment1 
Early termination, 
if applicable2 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
(9) 
10 
Week 
-4 to -1 
0 
1 
2 
4 
8 
12 
16 
- 
184 
Day 
-287 to -7 
1 
8 
15 
29 
57 
85 
113 
- 
1274 
Visit window (days)8 
- 
- 
±3 
±3 
±3 
±3 
±3 
±3 
- 
±3 
Scoring of suspected local 
skin reaction related to IMP 
(if applicable)22 
 
 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
 
 
(X) 
11.5.5 
IMP patch test (if 
applicable)22 
 
 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
 
 
(X) 
11.5.5.1 
AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
13 
Other assessments 
New CHE lesions 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(X) 
9.2, 11.2.6 
Return of eDiary (if 
applicable) 
 
 
 
 
 
 
 
X23 
X24 
 
X 
 
11.3 
Exit interview (selected 
trial sites)25 
 
 
 
 
 
 
 
X25 
 
 
 
 
11.7.2 
Pharmacodynamic assessments  
Tape stripping (selected 
trial sites)26 
 
X 
 
X 
X 
X 
 
X 
X 
 
 
 
11.6.2 
End of treatment/trial 
End-of-treatment form 
 
 
 
 
 
 
 
X 
X 
 
 
 
11.8 
End-of-trial form27 
 
 
 
 
 
 
 
X 
X 
X 
X 
(X) 
11.8 
1) End-of-treatment assessments will be conducted at Week 16. For subjects who participate in the LTE trial (LP0133-1403), the Week 16 visit in the present trial 
will coincide with the baseline visit in the LTE trial. 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 29 of 160 
 
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 
 
2) 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. Subjects who discontinue IMP will also be asked to 
return at Week 16 (see footnote 5). 
3) All subjects not participating in the LTE trial will be asked to attend a follow-up visit (performed via phone, but can be a site visit if needed) approximately 
2 weeks after the last IMP application for assessment of safety. Subjects who will participate in the LTE trial will not be required to complete the safety 
follow-up period, as collection of safety data and safety surveillance will continue in the LTE trial. 
4) 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. 
5) Subjects who discontinue IMP treatment prior to Week 16 will be asked to return to the trial site at Week 16 (scheduled 112 days after baseline) for a primary 
endpoint visit. 
6) Unscheduled visits 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. Assessments to be performed at unscheduled visits will be at the discretion of the investigator. 
7) 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, the screening period can be extended up to 31 days. 
8) 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 3). 
9) The ICF(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. 
10) If applicable, the ICF for the LTE trial should preferably be signed no later than the Week 16 visit in the present trial. The screening visit in the LTE trial will 
ideally coincide with the Week 12 visit in the present trial. The baseline visit of the LTE trial will coincide with the Week 16 visit in the present trial. Applicable 
data from the screening, baseline, Week 12, and Week 16 visits in the present trial will be transferred to the LTE trial to avoid duplicate assessments. 
11) CHE subtype(s) will be classified according to local standard clinical practice. This includes patch testing in Europe (except for Russia, where patch testing is 
not mandatory). For subjects who have had a patch test done within 3 years prior to screening, the results of the most recent patch test (i.e. the CHE subtype[s]) 
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. The patch test should 
preferably be completed prior to the baseline visit. If this is not possible, the patch test can be postponed but must be completed no later than the Week 8 visit. 
Patch testing is not mandatory in Canada but is recommended to be performed if this is considered standard clinical practice at the trial site. 
12) Treatment compliance will be recorded daily by the subject in the eDiary from Day 1 onwards up to end of treatment/early termination.  
13) All returned, opened IMP tubes will be weighed at the trial site. 
14) Relevant prior/concomitant medication should be included from 3 months prior to baseline (Day 1) until end of trial (see Section 9.6). 
15) Completion of HESD in the eDiary will be initiated at least 1 week prior to baseline (Day 1), but preferably 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 
continue completing HESD in the eDiary until the primary endpoint visit at Week 16. 
16) Includes Itch PGI-S, Pain PGI-S, and HESD PGI-S. 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 30 of 160 
 
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 
 
17) Includes Itch PGI-C, Pain PGI-C, and HESD PGI-C. 
18) Subject 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. 
19) Subjects do not have to be fasting for safety laboratory samples. 
20) For women of childbearing potential (as defined in inclusion criterion no. 8, Section 8.2). 
21) It will be at the investigator’s discretion to decide whether a urine sample should be sent to the central laboratory for further analysis. 
22) Only applicable if the investigator suspects a local skin reaction related to IMP application based on the initial inspection of the subject’s hands and the 
subject’s assessment of local tolerability (Section 11.5.5). The investigator will score the local skin reaction (Section 11.5.5) and perform an IMP patch test 
with the subject’s (blinded) IMP to classify the aetiology of the reaction (see Section 11.5.5.1). 
23) Subjects who continue to the LTE trial must bring the eDiary to the Week 16 visit so the trial site staff can set up the eDiary for the LTE trial. Daily completion 
of the eDiary will continue in the LTE trial. 
24) 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 endpoint visit at Week 16. 
25) An exit interview will be conducted for approximately 40 subjects, not including subjects who discontinue IMP or withdraw from the trial. The interview will 
be conducted in English via phone or using a video conferencing platform and will be scheduled to occur as soon as possible and within a maximum of 2 weeks 
after Week 16. Exit interviews require additional informed consent and will be conducted for subjects at selected sites in Canada and UK. 
26) Tape stripping will only be performed at selected trial sites. This procedure will be included in the main informed consent form for these trial sites. 
27) An end-of-trial form must be completed for all screened subjects. The form will be completed at the subjects’ last trial visit (for subjects not participating in the 
LTE trial) or at the baseline visit in the LTE trial (for subjects participating in the LTE trial). 
Abbreviations: AE = adverse event; CHE = chronic hand eczema; DLQI = Dermatology Life Quality Index: ECG = electrocardiogram; eCRF = electronic case 
report form; eDiary = electronic diary; EQ-5D-5L = EuroQol 5-Dimension Health Questionnaire 5 Level; HECSI = Hand Eczema Severity Index; HEIS = 
Hand Eczema Impact Scale; HESD = Hand Eczema Symptom Diary; ICF = informed consent form; IGA-CHE = Investigator’s Global Assessment for chronic 
hand eczema; IgE = immunoglobulin E; IMP = investigational medicinal product; LTE = long-term extension; PaGA = Patient’s Global Assessment of disease 
severity; PGI-C = Patient Global Impression of Change; PGI-S = Patient Global Impression of Severity; WPAI:CHE = Work Productivity and Activity 
Impairment: Chronic Hand Eczema. 
 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 31 of 160 
 
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 
 
5 Introduction and trial rationale 
5.1 
Chronic hand eczema 
CHE is a serious 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). 
The socioeconomic burden of CHE is significant. 5 studies 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, 13-16). CHE is associated with increased sick 
leave (17, 18) as well as job loss and change in jobs (5, 19, 20). Overall, CHE has a 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 32 of 160 
 
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 
 
significant detrimental effect on quality of life, work productivity, daily activities, and health 
care costs (13). 
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 (21-
23). 
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 (24) 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 
CHE that is unresponsive to treatment with potent TCS. 
Considering the paucity of approved therapies for the treatment of CHE, other therapeutic 
options are limited to those approved for other skin diseases with an inflammatory 
pathophysiology. These applied 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. 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 33 of 160 
 
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 
 
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, 25), there is a high unmet 
medical need for new topical treatment of moderate to severe CHE with high efficacy in 
combination with a good safety profile especially for long-term use. New and better 
treatments would potentially improve the everyday lives of patients with moderate to severe 
CHE. Delgocitinib has the potential to address the unmet medical need associated with this 
serious disease. 
5.2 
Experience with IMP 
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 (26). 
In nonclinical studies, topically administered delgocitinib inhibited inflammation in rat and 
mouse models of contact dermatitis and reduced IL-31-induced scratching in mice. Topical 
administration of delgocitinib was also shown to improve the impaired skin barrier function in 
mouse models and in human skin (27). 
The efficacy and safety of delgocitinib in CHE has been demonstrated in a phase 2a trial 
(LP0133-1180) with delgocitinib ointment 30 mg/g and in a phase 2b dose-ranging trial 
(LP0133-1273) with delgocitinib cream (1, 3, 8, and 20 mg/g). 
In the LP0133-1180 trial, delgocitinib ointment 30 mg/g was applied twice daily for 8 weeks 
in adult subjects with mild to severe CHE. A statistically significant difference between 
delgocitinib ointment 30 mg/g and ointment vehicle was observed for the primary endpoint 
PGA treatment success at Week 8 (defined as achieving a Physician’s Global Assessment 
score of 0 [clear] or 1 [almost clear] with a ≥2-step reduction from baseline). 
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 dose 
and population selected for the present trial (delgocitinib cream 20 mg/g and subjects with 
moderate to severe CHE), 39.0% of subjects achieved IGA-CHE TS at Week 16 vs. 10.5% in 
the cream vehicle group (p<0.05) (28). 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 34 of 160 
 
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 
 
In both trials and for all doses, delgocitinib was well tolerated, and a low systemic exposure to 
delgocitinib was observed. 
Based on currently available nonclinical and clinical data, delgocitinib has the potential to 
become a novel local-acting anti-inflammatory and immunomodulatory agent for topical 
treatment of CHE, with skin-barrier-improving properties and a favourable safety profile. 
5.3 
Trial rationale 
There is a clear unmet need for new long-term treatment options in the treatment of patients 
suffering from moderate to severe CHE. The purpose of this phase 3 trial is to confirm the 
efficacy and evaluate the safety of twice-daily applications of delgocitinib cream 20 mg/g for 
16 weeks compared with cream vehicle in the treatment of adult subjects with moderate to 
severe CHE. The strength of delgocitinib cream is selected based on results from the 
dose-ranging phase 2b trial LP0133-1273, where delgocitinib cream 20 mg/g was shown to be 
effective and well-tolerated 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 (Section 5.2), delgocitinib cream has the 
potential to become an effective, well-tolerated, 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]) 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 (29) and ICH GCP (30), and in compliance with the approved 
protocol and applicable regulatory requirements. 
The trial design chosen is regarded as scientifically justified and adheres to ethical standards 
that ensure the rights, safety, and wellbeing of the trial subjects. The efficacy and safety of 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 35 of 160 
 
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 
 
delgocitinib cream 20 mg/g will be evaluated in adults 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. 
Pregnant or breastfeeding women and women trying to become pregnant will not be included 
in the trial. Women of childbearing potential must agree to use an acceptable birth control 
method to prevent pregnancy during the trial. 
Trial subjects will be informed at the screening visit that trial procedures prior to baseline 
may warrant an alteration of their ongoing concomitant treatments. To ensure subjects’ safety, 
investigators are informed only to enrol 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 symptoms during the treatment and 
follow-up periods, rescue treatment may be prescribed to trial subjects at the discretion of the 
investigator (see Section 9.5). Subjects will be instructed to contact the investigator if their 
CHE worsens significantly. 
The subject’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. 
5.5 
Benefit/risk assessment 
There is a clear unmet medical need for new long-term therapies for subjects with moderate to 
severe CHE. The only currently approved treatment option indicated for patients with CHE is 
alitretinoin, which is associated with significant safety precautions and is only indicated for 
the most severe disease state. Alitretinoin is only approved in few countries worldwide. 
Treatment with other therapies will be withheld from the subjects for up to 22 weeks. 
However, 2 out of 3 subjects will receive active treatment with delgocitinib cream 20 mg/g 
which was shown to be effective in CHE in the phase 2b trial LP0133-1273 (see Section 5.2). 
1 out of 3 subjects will receive cream vehicle. All subjects may receive rescue treatment if 
required (Section 9.5), regardless of their treatment allocation. Eligible subjects who do not 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 36 of 160 
 
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 
 
permanently discontinue IMP prior to Week 16 will be invited to participate in an open-label 
LTE trial (LP0133-1403, hereafter referred to as ‘the LTE trial’). 
Delgocitinib is a topically applied JAK inhibitor. Systemic JAK inhibitors are associated with 
potential adverse reactions and a black box warning concerning the risk of serious infections, 
malignancy, and thrombosis. These risks are not considered relevant for delgocitinib cream 
due to the very low systemic exposure observed in previous trials with topically applied 
delgocitinib. 
No specific adverse drug reactions or important identified risks have been identified for 
delgocitinib cream during the 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 non-clinical and 
clinical data on delgocitinib is available in the current investigator’s brochure (31). 
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 
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 qualified 
medical personnel. 
Tape stripping is a widely used, standard non-invasive procedure and the number of tape 
strips used in this trial is not associated with any known risks. 
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. 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 37 of 160 
 
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 
 
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 (32),  FDA (33), and national health authorities in Europe and Canada 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 guideline. 
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 
collect safety 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). 
6  Trial objectives, estimands, and endpoints 
Panel 3 presents the objectives and estimands for the primary and key secondary endpoints. 
Further details about the testing strategy, estimand strategy, and analysis of the primary and 
key secondary endpoints are provided in Sections 14.3.5 to 14.3.8. 
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 14.3.9. 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 38 of 160 
 
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 
 
Panel 3: Objectives and estimands for primary and key secondary endpoints 
Objectives 
Estimands 
Endpoints 
 
Estimand type 
(primary or 
supplementary) 
Interpretation  
Intercurrent events and strategy 
Population 
level summary 
 
Primary objective: 
To confirm the 
efficacy of 
twice-daily 
applications of 
delgocitinib cream 
20 mg/g compared 
with cream vehicle in 
the treatment of adult 
subjects with 
moderate to severe 
CHE. 
Primary.  
Response 
achieved without 
IEs. 
Initiation of rescue treatment, 
permanent discontinuation of 
IMP. 
‘Composite’ strategy. 
Difference in 
response rates. 
Primary endpoint: 
• 
IGA-CHE TS at Week 16. 
Key secondary endpoints: 
• 
HECSI-75 at Week 16. 
• 
HECSI-75 at Week 8. 
• 
HECSI-90 at Week 16. 
• 
IGA-CHE TS at Week 8. 
• 
IGA-CHE TS at Week 4. 
First 
supplementary. 
Response 
achieved without 
IEs in a world 
without 
COVID-19 
pandemic. 
Initiation of rescue treatment, 
permanent discontinuation of 
IMP independent of the 
COVID-19 pandemic, 
permanent discontinuation of 
IMP related to the COVID-19 
pandemic. 
‘Pandemic modified composite’ 
strategy. 
Second 
supplementary 
for endpoints 
at Week 16. 
Response 
achieved 
regardless of IEs. 
Initiation of rescue treatment, 
permanent discontinuation of 
IMP. 
‘Treatment policy’ strategy. 
Primary.  
Percentage 
change from 
baseline to 
Week 16 without 
IEs. 
Initiation of rescue treatment, 
permanent discontinuation of 
IMP. 
‘Composite’ strategy. 
Difference in 
mean 
percentage 
change. 
Key secondary endpoint: 
• 
Percentage change in HECSI score 
from baseline to Week 16. 
 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 39 of 160 
 
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 
 
Objectives 
Estimands 
Endpoints 
 
Estimand type 
(primary or 
supplementary) 
Interpretation  
Intercurrent events and strategy 
Population 
level summary 
 
First 
supplementary. 
Percentage 
change from 
baseline to 
Week 16 without 
IEs in a world 
without 
COVID-19 
pandemic. 
Initiation of rescue treatment, 
permanent discontinuation of 
IMP independent of the 
COVID-19 pandemic, 
permanent discontinuation of 
IMP related to the COVID-19 
pandemic. 
‘Pandemic modified composite’ 
strategy. 
Second 
supplementary 
for endpoints 
at Week 16. 
Percentage 
change from 
baseline to 
Week 16 
regardless of IEs. 
Initiation of rescue treatment, 
permanent discontinuation of 
IMP. 
‘Treatment policy’ strategy. 
Secondary objective: 
To confirm 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 adult 
subjects with 
moderate to severe 
CHE. 
Primary.  
Response 
achieved without 
IEs. 
Initiation of rescue treatment, 
permanent discontinuation of 
IMP. 
‘Composite’ strategy. 
Difference in 
response rates. 
Key secondary endpoints: 
• 
Reduction of HESD itch score 
(weekly average) of ≥4 points from 
baseline at Week 16.1 
• 
Reduction of HESD itch score 
(weekly average) of ≥4 points from 
baseline at Week 8.1 
• 
Reduction of HESD itch score 
(weekly average) of ≥4 points from 
baseline at Week 4.1 
• 
Reduction of HESD itch score 
(weekly average) of ≥4 points from 
baseline at Week 2.1 
First 
supplementary. 
Response 
achieved without 
IEs in a world 
without 
COVID-19 
pandemic. 
Initiation of rescue treatment, 
permanent discontinuation of 
IMP independent of the 
COVID-19 pandemic, 
permanent discontinuation of 
IMP related to the COVID-19 
pandemic. 
‘Pandemic modified composite’ 
strategy. 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 40 of 160 
 
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 
 
Objectives 
Estimands 
Endpoints 
 
Estimand type 
(primary or 
supplementary) 
Interpretation  
Intercurrent events and strategy 
Population 
level summary 
 
Second 
supplementary 
for endpoints 
at Week 16.  
Response 
achieved 
regardless of IEs. 
Initiation of rescue treatment, 
permanent discontinuation of 
IMP. 
‘Treatment policy’ strategy. 
• 
Reduction of HESD 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 8.2 
• 
Reduction of HESD score (weekly 
average) of ≥4 points from baseline 
at Week 4.2 
• 
Reduction of HESD pain score 
(weekly average) of ≥4 points from 
baseline at Week 16.3 
• 
Reduction of HESD pain score 
(weekly average) of ≥4 points from 
baseline at Week 8.3 
• 
Reduction of HESD pain score 
(weekly average) of ≥4 points from 
baseline at Week 4.3 
• 
Reduction of DLQI score of ≥4 
points from baseline at Week 16.4 
 
Primary. 
 
Change from 
baseline to 
Week 16 without 
IEs. 
Initiation of rescue treatment, 
permanent discontinuation of 
IMP. 
‘Composite’ strategy. 
Difference in 
mean change. 
Key secondary endpoints: 
• 
Change in HESD itch score (weekly 
average) from baseline to Week 16. 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 41 of 160 
 
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 
 
Objectives 
Estimands 
Endpoints 
 
Estimand type 
(primary or 
supplementary) 
Interpretation  
Intercurrent events and strategy 
Population 
level summary 
 
First 
supplementary. 
Change from 
baseline to 
Week 16 without 
IEs in a world 
without 
COVID-19 
pandemic. 
Initiation of rescue treatment, 
permanent discontinuation of 
IMP independent of the 
COVID-19 pandemic, 
permanent discontinuation of 
IMP related to the COVID-19 
pandemic. 
‘Pandemic modified composite’ 
strategy. 
• 
Change in HESD score (weekly 
average) from baseline to Week 16. 
• 
Change in HESD pain score 
(weekly average) from baseline to 
Week 16. 
• 
Change in HEIS score from 
baseline to Week 16.5 
• 
Change in HEIS PDAL score from 
baseline to Week 16.5 
• 
Change in DLQI score from 
baseline to Week 16. 
Second 
supplementary 
for endpoints 
at Week 16. 
Change from 
baseline to 
Week 16 
regardless of IEs. 
Initiation of rescue treatment, 
permanent discontinuation of 
IMP. 
‘Treatment policy’ strategy. 
Note: The order of endpoints in this panel does not reflect that in the testing hierarchy, see Section 14.3.5 for details. 
1) Among subjects with a baseline HESD itch score (weekly average) ≥4 points. 
2) Among subjects with a baseline HESD score (weekly average) ≥4 points. 
3) Among subjects with a baseline HESD pain score (weekly average) ≥4 points. 
4) Among subjects with a baseline DLQI score ≥4 points. 
5) As the HEIS is not assessed at the primary endpoint visit, the second supplementary estimand is not applicable for this endpoint. 
Abbreviations: CHE = chronic hand eczema; COVID-19 = coronavirus disease 2019; DLQI = Dermatology Life Quality Index; 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; HEIS = 
Hand Eczema Impact Scale; 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; IMP = 
investigational medicinal product; PDAL = Proximal Daily Activity Limitations.
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 42 of 160 
 
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 
 
Panel 4: Secondary and exploratory objectives and endpoints 
Objectives 
Endpoints 
Secondary objective 
Secondary endpoint 
To evaluate the safety of twice-daily 
applications of delgocitinib cream 
20 mg/g compared with cream vehicle in 
the treatment of adult subjects with 
moderate to severe CHE. 
• 
Number of treatment-emergent1 AEs from baseline up 
to Week 16 (Week 18 for subjects not participating in 
the LTE trial) per subject. 
 
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 adult subjects with 
moderate to severe CHE over time. 
 
Efficacy 
• 
IGA-CHE TS at Weeks 1, 2, and 12. 
• 
HECSI-75 at Weeks 1, 2, 4, and 12. 
• 
HECSI-90 at Weeks 1, 2, 4, 8, and 12. 
• 
Percentage change in HECSI score from baseline to 
Weeks 1, 2, 4, 8, and 12. 
• 
Reduction of HESD itch score (weekly average) 
of ≥4 points from baseline at Weeks 1 and 12.2 
• 
Reduction of HESD itch score (weekly average) 
of ≥3 points from baseline at Weeks 1, 2, 4, 8, 12, and 
16.3 
• 
Time to reduction of HESD itch score (weekly average) 
of ≥4 points.2 
• 
Change in HESD itch score (weekly average) from 
baseline to Weeks 1, 2, 4, 8, and 12. 
• 
Reduction of HESD score (weekly average) of ≥4 points 
from baseline at Weeks 1, 2, and 12.4 
• 
Reduction of HESD score (weekly average) of ≥3 points 
from baseline at Weeks 1, 2, 4, 8, 12, and 16.5 
• 
Time to reduction of HESD score (weekly average) of 
≥4 points.4 
• 
Change in HESD score (weekly average) from baseline 
to Weeks 1, 2, 4, 8, and 12. 
• 
Reduction of HESD pain score (weekly average) of 
≥4 points from baseline at Weeks 1, 2, and 12.6 
• 
Reduction of HESD pain score (weekly average) of 
≥3 points from baseline at Weeks 1, 2, 4, 8, 12, and 16.7 
• 
Time to reduction of HESD pain score (weekly average) 
of ≥4 points.6 
• 
Change in HESD pain score (weekly average) from 
baseline to Weeks 1, 2, 4, 8, and 12. 
• 
Change in HESD (weekly average for each individual 
symptom [excluding itch and pain]) score from baseline 
to Week 16. 
Health-related quality of life and efficacy 
• 
Change in HEIS score from baseline to Weeks 1, 2, 4, 8, 
and 12. 
• 
Reduction of HEIS score of ≥1.5 points at Weeks 1, 2, 4, 
8, 12, and 16.8 
• 
Change in HEIS PDAL score from baseline to Weeks 1, 
2, 4, 8, and 12. 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 43 of 160 
 
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 
 
• 
Reduction of HEIS PDAL score of ≥1.5 points at 
Weeks 1, 2, 4, 8, 12, and 16.9 
• 
Change in HEIS (each individual domain [excluding 
PDAL]) score from baseline to Weeks 1, 2, 4, 8, 12, 
and 16. 
• 
Reduction in DLQI score of ≥4 points at Weeks 1, 4, 8, 
and 12.10 
• 
Change in DLQI score from baseline to Weeks 1, 4, 8, 
and 12. 
To evaluate the effect of twice-daily 
applications of delgocitinib cream 
20 mg/g on health-related quality of life 
and work productivity compared with 
cream vehicle in the treatment of adult 
subjects with moderate to severe CHE. 
• 
Change in EQ-5D-5L index score from baseline to 
Weeks 1, 4, 8, 12, and 16. 
• 
Change in EQ-5D-5L visual analogue scale score from 
baseline to Weeks 1, 4, 8, 12, and 16. 
• 
Change in WPAI:CHE absenteeism score from baseline 
to Week 4, 8, and 16.11 
• 
Change in WPAI:CHE presenteeism score from 
baseline to Week 4, 8, and 16.11 
• 
Change in WPAI:CHE work productivity loss score 
from baseline to Week 4, 8, and 16.11 
• 
Change in WPAI:CHE activity impairment score from 
baseline to Week 4, 8, and 16. 
To evaluate the effect of delgocitinib 
cream 20 mg/g on skin inflammation, 
barrier function, and skin integrity in 
lesional skin compared with cream vehicle 
in adult subjects with moderate to severe 
CHE. 
• 
Change in gene expression measured in skin tape strips 
from baseline to Week 16. 
 
1) 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. 
2) Among subjects with a baseline HESD itch score (weekly average) ≥4 points. 
3) Among subjects with a baseline HESD itch score (weekly average) ≥3 points. 
4) Among subjects with a baseline HESD score (weekly average) ≥4 points. 
5) Among subjects with a baseline HESD score (weekly average) ≥3 points. 
6) Among subjects with a baseline HESD pain score (weekly average) ≥4 points. 
7) Among subjects with a baseline HESD pain score (weekly average) ≥3 points. 
8) Among subjects with a baseline HEIS score ≥1.5 points. 
9) Among subjects with a baseline HEIS PDAL score ≥1.5 points. 
10) Among subjects with a baseline DLQI score ≥4 points. 
11) Among subjects with paid work at baseline. 
Abbreviations: AE = adverse event; CHE = chronic hand eczema; DLQI = Dermatology Life Quality Index; 
EQ-5D-5L = EuroQol 5-Dimension Health Questionnaire 5 Level; 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; HEIS = Hand Eczema Impact Scale; 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; PDAL = Proximal Daily Activity Limitations; WPAI:CHE = Work 
Productivity and Activity Impairment: Chronic Hand Eczema. 
 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 44 of 160 
 
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 
 
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 confirm the efficacy and evaluate the safety of delgocitinib cream 
20 mg/g applied twice daily for 16 weeks in adult subjects with moderate to severe CHE. 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, 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 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. 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 
Canada and Europe. This includes patch testing in Europe (except for Russia, where patch 
testing is not mandatory). 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 
will be performed. The patch test should preferably be completed prior to the baseline visit. If 
this is not possible, the patch test can be postponed but must be completed no later than the 
Week 8 visit. Patch testing is not mandatory in Canada but is recommended to be performed if 
this is considered standard clinical practice at the trial site. 
Treatment period (Week 0 to Week 16) 
At baseline (Day 1), the subjects’ eligibility to enter the trial will be confirmed. Eligible 
subjects will be randomised 2:1 to either delgocitinib cream 20 mg/g or cream vehicle. 
Subjects 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 on Day 1 after all baseline 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 45 of 160 
 
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 
 
assessments have been carried out. All subsequent IMP applications will be performed by the 
subjects 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. The last IMP application will occur at 
the subject’s home before the subject attends the visit scheduled at Week 16. Efficacy and 
safety assessments during the treatment period will be performed as described in the schedule 
of trial procedures (Section 4). 
At the Week 12 visit, subjects may be invited to participate in the LTE trial. For subjects who 
continue to the LTE trial, the following visits will (ideally) coincide to facilitate a seamless 
transition between the trials and continuous treatment with IMP (if applicable): 
• The Week 12 visit in the present trial will ideally coincide with the screening visit in the 
LTE trial. 
• The Week 16 visit in the present trial will coincide with the baseline visit in the LTE trial. 
Subjects must complete the 16-week treatment period (i.e. must not permanently 
discontinue IMP prior to Week 16) and the Week 16 visit in the present trial to be eligible 
for the LTE trial. 
All eligible subjects who do not permanently discontinue IMP prior to Week 16 will be 
invited to participate in the LTE trial. 
Follow-up period (Week 16 to Week 18) 
Those subjects not participating in the LTE trial will attend a follow-up visit (performed via 
phone, but can be a site visit if needed) approximately 2 weeks after the last IMP application 
for assessment of safety. Note that for subjects who permanently discontinue IMP, the 2-week 
follow-up period will start at the time of last IMP application. 
Subjects who will participate in the LTE trial will not be required to complete the follow-up 
period, as collection of safety data and safety surveillance will continue in the LTE trial. 
7.2 
Number of subjects needed 
A total of 470 subjects will be randomised 2:1 to delgocitinib cream 20 mg/g or cream 
vehicle. The statistical power considerations for this sample size are described in 
Section 14.1. 
This trial will be conducted at approximately 55 sites in Europe and Canada. The anticipated 
minimum number of randomised subjects per trial site is 6, and the maximum number of 
subjects per trial site is 30. 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 46 of 160 
 
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 
 
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 
(for subjects not transferring to the LTE trial). For subjects transferring to the LTE trial, the 
subject is considered to have completed the trial if attending the Week 16 visit in this trial and 
the baseline visit of the LTE trial. 
For subjects not participating in the LTE trial, end of trial is defined as attending the last visit 
in this trial. For subjects participating in the LTE trial, the end of the present trial is defined as 
attending the baseline visit in the LTE trial. 
The end of the trial overall is defined as the date of the last visit of the last subject in the trial 
globally. 
Final collection of data for the primary endpoint occurs at Week 16. 
 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 47 of 160 
 
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 
 
8 Trial population 
8.1 
Subject eligibility 
The investigator should only include subjects who meet all eligibility criteria, are not put at 
undue risk by participating in the trial, and can be expected to comply with the protocol. 
The subject’s eligibility for the clinical trial must be verified according to the inclusion and 
exclusion criteria at the visits specified in Panel 2. It will be recorded in the eCRF if the 
subject has met all the inclusion criteria and none of the exclusion criteria. 
Any implementation of national requirements/law for the subject’s participation in the clinical 
trial will be ensured and described in submission documentation to regulatory authorities and 
IRBs/IECs, as applicable. 
8.2 
Inclusion criteria 
The subjects must fulfil all of the following criteria to be eligible for the trial: 
1. Signed and dated informed consent has been obtained prior to any protocol-related 
procedures. 
2. Age 18 years or above at screening. 
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. HESD itch score (weekly average) of ≥4 points at baseline. The baseline weekly average 
will be calculated from daily assessments of itch severity during the 7 days immediately 
preceding the baseline visit (Day -7 to Day -1). A minimum of 4 itch scores out of the 7 
days is required to calculate the baseline average score. 
6. 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 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. 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 48 of 160 
 
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 
 
• 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. 
7. Subjects adherent to standard non-medicated skin care including avoidance of known and 
relevant irritants and allergens. 
8. 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 or a 
younger girl who, at the discretion of the investigator, is deemed to be of reproductive 
potential. A woman is defined as not being of childbearing potential if she is 
postmenopausal (at least 12 months with no menses without an alternative medical 
cause prior to screening), or surgically sterile (hysterectomy, bilateral salpingectomy, 
or bilateral oophorectomy). 
** Acceptable methods of birth control are listed in Appendix 8. 
8.3 
Exclusion criteria 
Subjects are not eligible for the trial if they fulfil any of the following criteria: 
1. Concurrent skin diseases on the hands, e.g. tinea manuum. 
2. Active AD requiring medical treatment in regions other than the hands and feet. 
3. Active psoriasis on any part of the body. 
4. Hyperkeratotic hand eczema in combination with a history of psoriasis on any part of the 
body. 
5. Clinically significant infection (e.g. impetiginised hand eczema) on the hands. 
6. 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). 
7. Use of tanning beds, phototherapy (e.g. UVB, UVA1, PUVA), or bleach baths on the 
hands within 28 days prior to baseline. 
8. Previous or current treatment with JAK inhibitors (including delgocitinib/ LEO 124249), 
systemic or topical. 
9. Cutaneously applied treatment with immunomodulators (e.g. PDE-4 inhibitors, 
pimecrolimus, tacrolimus) or TCS on the hands within 14 days prior to baseline. 
10. Use of systemic antibiotics or cutaneously applied antibiotics on the hands within 14 days 
prior to baseline. 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 49 of 160 
 
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 
 
11. Other transdermal or cutaneously applied therapy on the hands (except for the use of 
subject’s own emollients) within 7 days prior to baseline. 
12. 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. 
13. 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. 
• Other biologics: within 3 months or 5 half-lives, whichever is longer, prior to 
baseline. 
14. 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. 
15. 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. 
16. 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. 
17. Major surgery within 8 weeks prior to screening, or planned in-patient surgery or 
hospitalisation during the trial period. 
18. History of cancer: 
• Subjects who have had basal cell carcinoma, localised squamous cell 
carcinoma of the skin or in situ carcinoma of the cervix are eligible provided 
that the subject is in remission and curative therapy was completed at least 
12 months prior to screening. 
• Subjects who have had other malignancies are eligible provided that the 
subject is in remission and curative therapy was completed at least 5 years 
prior to screening. 
19. Any disorder which is not stable and could: 
• Affect the safety of the subject throughout the trial. 
• Impede the subject’s ability to complete the trial. 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 50 of 160 
 
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 
 
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. 
20. 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. 
21. Positive hepatitis B surface antigen or hepatitis C virus antibody serology at screening. 
22. ALT or AST level ≥2.0×ULN at screening. 
23. Known or suspected hypersensitivity to any component(s) of the IMP (refer to Section 9.1 
for an overview of all excipients). 
24. Current participation in any other interventional clinical trial. 
25. Previously randomised in this clinical trial. 
26. 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 informed consent is obtained. Refer to Appendix 3B 
for details on the informed consent process. Once informed consent is obtained, a subject ID 
will be assigned by a central 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 informed consent form was signed. The subject ID will be used to identify the subject 
during the screening process and throughout trial participation, if applicable. Subjects who 
have given written informed consent to participate in the trial and who have been assigned a 
subject ID are considered ‘screened’ subjects. 
The investigator will maintain a log of all 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 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 51 of 160 
 
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 
 
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 
(34) and to respond to queries from regulatory authorities. As a minimum, the following data 
will be collected in the eCRF for screening failures: 
• Date of informed consent(s). 
• Demographics (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 AEs and 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 will need to sign a new ICF. 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 52 of 160 
 
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 
 
9 Treatments 
9.1 
Trial product description 
Panel 5: Identification of IMPs 
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 
15 g 
LEO Pharma A/S 
Cream vehicle 
Cream  
Vehicle 
15 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 IMP 
The IMP (delgocitinib cream 20 mg/g or cream vehicle) 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. 
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, fingertips, and wrists. 1 tube of 15 g delgocitinib cream 
is considered sufficient for treatment of the whole surface of hands, fingers, fingertips, and 
wrists twice daily for 1 week; 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. 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 53 of 160 
 
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 
 
The first application of IMP will occur at the trial site. Prior to the first IMP application, the 
subject 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 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 Week 16 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 the visits scheduled in Section 4. 
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 2:1 ratio to receive 
treatment with either delgocitinib cream 20 mg/g or cream vehicle. The randomisation will be 
stratified by region (Europe or North America) and 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. 
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. 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 54 of 160 
 
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 
 
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, healthcare professionals 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 the 
unblinding IRT system or unblinding CRO. Only the investigator should be unblinded and 
keep treatment allocation confidential. LEO Pharma staff must remain blinded until the end of 
the trial. 
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. Furthermore, emollients must not be used on the hands and wrists for at least 2 hours 
prior to trial visits that include tape stripping. Use of concomitant medication and concurrent 
procedures is further described in Section 9.6. 
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) 2 weeks after the last application of IMP, and also the primary endpoint visit at 
Week 16 (see Section 10.3 for details). 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 55 of 160 
 
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 
 
Rescue treatment is defined as treatment initiated to treat intolerable CHE symptoms during 
the treatment and follow-up periods. It will be recorded in the eCRF if a medication 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 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 treatment for CHE (yes, no). 
• 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, cutaneous, subcutaneous, transdermal, ophthalmic, 
intramuscular, respiratory [inhalation], intralesional, intraperitoneal, nasal, vaginal, rectal, 
intravenous, or other [if other, a specification must be provided]). For cutaneous 
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 
(approximately 2 inches) of the IMP 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. 
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 must 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. the subjects 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 56 of 160 
 
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 
 
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 (from 
screening until end of trial for the individual subject as defined in Section 7.3). Details 
regarding prohibited medications and procedures prior to screening and baseline are described 
in Section 8.3. 
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 or 
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 transdermal or cutaneously applied therapy on the 
hands (except for the IMP and the subject’s own 
emollient). 
7 days prior to baseline. 
End of trial. 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 57 of 160 
 
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 
 
Medication/procedure 
Prohibited from 
Prohibited to 
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 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 foot eczema, as long as this does not interfere with the trial (i.e. the subjects 
need to use gloves when applying treatment). 
3) Subjects are allowed to receive vaccines during the trial. 
Abbreviations: IgE = immunoglobulin E; 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 for the first 14 days of wash-out of systemic treatment to alleviate significant worsening 
of their CHE. 
As described in Section 9.5, prohibited medications 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. 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 58 of 160 
 
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 
 
The labelling of IMPs will be in accordance with the EU guidelines for Good Manufacturing 
Practices for Medicinal Products for Human and Veterinary use, Annex 13 (35), 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. 
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 IMP accountability 
The investigator is fully responsible for the IMPs at the trial site and for maintaining adequate 
control of the IMPs and for documenting all transactions with them. 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 59 of 160 
 
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 
 
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 
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. 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 60 of 160 
 
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 
 
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. 
In addition, all eligible subjects who complete the treatment period (i.e. who do not 
permanently discontinue IMP prior to Week 16) will be invited to participate in the LTE trial. 
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. 
Complaint forms should contain a detailed description of the defect or issue, including 
whether it led to an AE. (S)AEs which occur due to a defect or issue with the IMP will be 
reported by the investigator as described in Sections 13.3 and 13.4. 
Refer to the trial product handling manual 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. 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 61 of 160 
 
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 
 
Global Safety, LEO Pharma contact information for reporting product complaints: 
Fax number: +45 7226 3287 
E-mail address: drug.safety@leo-pharma.com 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 62 of 160 
 
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 
 
10 Discontinuation and withdrawal 
10.1 General principles 
A subject may: 
• withdraw from the trial (i.e. stop all further protocol-defined trial activities) or 
• permanently discontinue trial treatment (i.e. stop all further trial treatment but 
continue to participate in protocol-defined trial activities as outlined in 
Section 10.3) 
at any time if the subject, 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 the primary 
endpoint visit and the safety follow-up visit. If a subject does not agree to attend these visits, 
the subject withdraws from the trial. To obtain the most representative 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, they 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. 
• Positive patch test reaction to the IMP 
• 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. 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 63 of 160 
 
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 
 
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. 
• 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). 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 64 of 160 
 
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 
 
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 
agrees. 
Details on data to be recorded in the eCRF for subjects who withdraw from the trial can be 
found in Section 11.8. 
10.4 Lost to follow-up 
A subject will be considered lost to follow-up if they repeatedly fail to return for scheduled 
visits and if the trial site is not able to get in contact with the subject. 
The following actions must be taken if a subject fails to return to the trial site for a required 
visit: 
• The trial site must attempt to contact the subject and reschedule the missed visit as soon as 
possible and counsel the subject on the importance of maintaining the assigned visit 
schedule and ascertain whether the subject wishes to continue in the trial. 
• Before a subject is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the subject. These contact attempts should be 
documented in the subject’s medical record. Should the subject continue to be 
unreachable, they will be considered to have withdrawn from the trial with a primary 
reason of lost to follow-up. 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 65 of 160 
 
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 
 
11 Trial assessments and procedures 
11.1 Overview 
Evaluations to be done at each visit are shown in the schedule of trial procedures in Section 4. 
Refer to Section 7.1 for further details on the trial design. 
Assessments and procedures at each trial visit are recommended to be performed in the order 
shown in Panel 8. 
Panel 8: Sequence of assessments 
 
 
* pharmacodynamic assessments (tape stripping). 
Abbreviations: IMP = investigational medicinal product; PRO = patient-reported outcome. 
PROs
Investigator assessments of efficacy
Investigator assessments of safety and 
laboratory assessments
Other assessments*
Application of IMP (baseline visit 
only)
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 66 of 160 
 
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 
 
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). 
To reduce inter-rater variability, the same investigator should perform all the evaluations for a 
given subject throughout the entire trial period, whenever possible. 
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. 
 
11.2.2 Fitzpatrick skin type 
The subject’s skin type will be recorded using the Fitzpatrick skin classification (Panel 9). 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 67 of 160 
 
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 
 
Panel 9: 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. 
11.2.3 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. 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 68 of 160 
 
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 
 
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. 6: 
- 
Has the subject fulfilled the trial inclusion criterion no. 6 based on having 
inadequate response to treatment with TCS during the last 12 months? (yes, no). 
- 
Has the subject fulfilled the trial inclusion criterion no. 6 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). 
• Onset and worsening of CHE symptoms during work (yes, no, unknown). 
• Improvement of CHE symptoms when not at work (yes, no, unknown). 
• Healing of CHE on vacations (yes, no, unknown). 
• Recurrence of CHE symptoms upon returning to work (yes, no, unknown). 
• Worsening of CHE symptoms when not at work (yes, no, unknown). 
• Wet-work exposure (defined as skin exposed to liquids longer than 2 hours per day, using 
occlusive gloves longer than 2 hours per day, or more than 20 hand washes per day) (yes, 
no, unknown). 
• Number of daily hand washes (0-10, 11-20, >20). 
• Employment status during the past year (part-time employed, full-time employed, not 
employed). In case more than one option applies, the status that the subject had for the 
longest period during the past year should be captured. 
- 
If employed during the past year: Days home from work due to CHE during the 
last year (yes, no). 
- 
If yes: Total number of days home from work due to CHE during the last year 
(<7 days, 7-21 days, >21 days). 
• 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). 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 69 of 160 
 
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 
 
- 
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. 
11.2.4 Classification of chronic hand eczema 
The investigator will determine the CHE subtype(s) according to the definitions in Panel 10. 
The classification of CHE will be done according to standard clinical practice and thus may 
differ across regions and countries. 
In Europe, the classification of CHE will include mandatory diagnostic patch testing with at 
least a relevant baseline series including the most important contact allergens relevant to the 
locality of the site (except for Russia, where patch testing is not mandatory). 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 will be performed. The patch test 
should preferably be completed prior to the baseline visit. If this is not possible, the patch test 
can be postponed but must be completed no later than the Week 8 visit (Section 4). Patch 
testing is not mandatory in Canada but 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. 
Reporting in eCRF 
The result of the diagnostic patch test (positive, negative) 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. 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 70 of 160 
 
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 
 
Panel 10: 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. 
11.2.5 Height and weight 
The subject’s height (without shoes) will be measured; the subject’s weight (in indoor 
clothing and without shoes) will be measured. 
11.2.6 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. 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 71 of 160 
 
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 
 
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. 
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. Subjects who will participate in the LTE trial must bring the eDiary to the 
Week 16 visit, so the trial site staff can set up the eDiary for the LTE trial. Daily completion 
of the eDiary will continue in the LTE trial. 
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 11.5.5). 
11.4 Efficacy assessments 
11.4.1 Investigator’s Global Assessment for chronic hand eczema 
(IGA-CHE) 
The IGA-CHE is an instrument used in the phase 2b trial with delgocitinib (LP0133-1273) 
and has been further revised for the current trial. 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 11). 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. 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 72 of 160 
 
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 
 
Panel 11: Investigator’s Global Assessment for chronic hand eczema (IGA-CHE) 
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 (HECSI) 
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 regions (fingertips, fingers [except fingertips], palm of 
hands, back of hands, and wrists) by use of standard scales (36). 
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 12). 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 12). For each of the hand regions, 
the region score will be calculated by adding up the severity scores for the 6 clinical signs of 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 73 of 160 
 
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 
 
hand eczema and multiplying with the area score (Panel 13). The HECSI score equals the sum 
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 12: 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 13: 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. 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 74 of 160 
 
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 
 
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. 
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 (HESD) 
The HESD is an instrument used in the phase 2b trial with delgocitinib (LP0133-1273) and 
has been further revised for the current trial. The HESD is a 
 PRO instrument designed 
to assess severity of CHE signs and symptoms. Subjects will assess the worst severity of 
 individual signs and symptoms of CHE 
 
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 
 items. 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, pulse, and body temperature) must be assessed according 
to the schedule of trial procedures (Section 4). Vital signs will be measured in a sitting 
position following at least 5 minutes of rest. 
If an abnormal vital sign at screening is considered to be clinically significant by the 
investigator, it will be at the discretion of the investigator if the subject should be randomised 
into the trial (respecting exclusion criterion no. 20). 
In case of abnormal findings, the vital sign measurement can be repeated approximately 
15 minutes later 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. 
TMF-000340756 - Version
5. 0
CCI
CCI
CCI
CCI
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 75 of 160 
 
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 
 
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, pulse, and body temperature) will be recorded in 
the eCRF. Clinically significant abnormal vital signs at the screening visit will be documented 
as medical history in the eCRF. At subsequent visits, any clinically significant deterioration of 
a pre-existing condition as well as any new clinically significant sign, symptom, or illness 
occurring after randomisation will be reported as an AE in accordance with Section 13.3. 
11.5.2 Physical examination 
A thorough physical examination of the subject including whole body inspection of the skin, 
auscultation of heart, lungs, and abdomen, palpation of the abdominal organs, and basic 
neurological status 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 trial (respecting exclusion criterion no. 20). 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. 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 76 of 160 
 
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 
 
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 
ECG results 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 trial (respecting exclusion criterion no. 20). 
The collection and transmission of ECG data will be described in a separate ECG manual. 
Test dummy transmissions will be undertaken prior to 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. 
11.5.4 Laboratory testing 
11.5.4.1 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. 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 77 of 160 
 
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 
 
Panel 14: Clinical laboratory tests performed by the central laboratory 
Chemistry 
Haematology 
Sodium 
Potassium 
Creatinine 
Urea nitrogen 
Calcium 
Alkaline phosphatase 
Aspartate aminotransferase 
Alanine aminotransferase 
Gamma glutamyl transferase 
BilirubinP1 
Lactate dehydrogenase 
Cholesterol 
LDL cholesterol 
HDL cholesterol 
Triglycerides 
Glucose (non-fasting) 
Albumin 
Protein 
Erythrocytes 
Haematocrit 
Haemoglobin 
Erythrocyte mean corpuscular volume 
Erythrocyte mean corpuscular haemoglobin 
concentration 
Leukocytes 
Neutrophils 
% neutrophils 
Lymphocytes 
% lymphocytes 
Monocytes 
% monocytes 
Eosinophils 
% eosinophils 
Basophils 
% basophils 
Thrombocytes  
UrinalysisP2 
Serology3,4 
Protein 
Glucose 
Ketones 
Occult blood 
Leukocytes 
Nitrite 
Hepatitis B virus surface antigen 
Hepatitis C virus antibody 
HIV-1 antibody 
HIV-2 antibody 
Immunoglobulin E 
1) If bilirubin is above upper limit of normal, direct and indirect bilirubin will also be measured. 
2) Urine samples will be tested at the trial site (dipstick). It will be at the investigator’s discretion to decide 
whether a urine sample should be sent to the central laboratory for microscopic examination (WBC; RBC; 
epithelial cells, squamous; epithelial cells, transitional; epithelial cells, renal tubular; hyaline casts; WBC 
casts; RBC casts; waxy casts; granular casts; calcium oxalate crystals; uric acid crystals; triphosphate 
crystals; yeast; and bacteria). 
3) Measured at screening only. 
4) In case additional analyses are needed to support the interpretation of the initial test results for hepatitis B, 
hepatitis C, or HIV, these will be performed by the central laboratory as applicable. 
Abbreviations: HDL = high density lipoprotein; HIV = human immunodeficiency virus; LDL = low density 
lipoprotein; RBC = red blood cells; WBC = white blood cells. 
 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 78 of 160 
 
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 
 
11.5.4.2 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, 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. 20). 
A laboratory manual will be provided to the trial sites specifying the procedures for 
collection, processing, storage, and shipment of samples, as well as laboratory contact 
information specific to this trial. 
Tests performed at the trial site 
Urine samples will be tested with a dipstick according to the schedule of trial procedures 
(Section 4). It will be at the investigator’s discretion to decide whether a urine sample should 
be sent to the central laboratory for further analysis. 
Women of childbearing potential will have a urine pregnancy test performed at the trial site at 
screening and at baseline prior to randomisation. The test will be repeated every 4 weeks as 
shown in the schedule of trial procedures in Section 4. 
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 test 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 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 79 of 160 
 
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 
 
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 randomisation will be reported as an AE in accordance 
with Section 13.3. 
11.5.5 Assessment of local tolerability 
Subjects and investigators will each 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 subject 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 15. 
Panel 15: 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. 
The investigator will assess whether he/she suspects a local skin reaction related to 
application of the IMP. If the investigator suspects a local skin reaction related to application 
of the IMP, the skin reaction will be scored according to the Berger and Bowman scales in 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 80 of 160 
 
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 
 
Panel 16. The scoring should only assess skin signs suspected to be related to application of 
the IMP and not signs or symptoms related to the subject’s CHE. 
Following scoring according to the Berger and Bowman scales, an IMP patch test will be 
performed to confirm a possible diagnosis of allergic contact dermatitis caused by the IMP, 
see procedure described in Section 11.5.5.1. The aetiology of the local skin reaction will be 
captured in the eCRF and the final diagnosis will be captured as an AE. 
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). 
Reporting in eCRF 
For the subject’s assessment of local tolerability at the end-of-treatment/early termination 
visit, the highest (worst) skin reaction score across treatment area(s) will be recorded in the 
eCRF. 
For the investigator’s assessment of local tolerability, it will be reported in the eCRF if the 
investigator suspects a local skin reaction to be related to application of IMP (yes, no). If the 
investigator suspects a local skin reaction to be related to application of IMP, the scores in 
Panel 16 (one score for Scale 1 and zero, one, or multiple scores for Scale 2) will be recorded 
in the eCRF. The aetiology of the local skin reaction (irritant contact dermatitis caused by 
IMP, allergic contact dermatitis caused by IMP [requires a positive IMP patch test, see 
Section 11.5.5.1], or other [specify]) will be captured in the eCRF and the final diagnosis will 
be captured as an AE. 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 81 of 160 
 
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 
 
Panel 16: Berger and Bowman scoring scales if investigator suspects a local skin reaction 
related to IMP application 
Scale 1 
Skin appearance 
Score 
No evidence of irritation 
0 
Minimal erythema that is barely perceptible 
1 
Definite erythema that is readily visible and minimal oedema or minimal papular response 
2 
Erythema and papules 
3 
Definite oedema 
4 
Erythema, oedema, and papules 
5 
Vesicular eruption 
6 
Strong reaction spreading beyond the test field 
7 
Select the appropriate score (only one score) if a local skin reaction is suspected to be related to application of 
the IMP. 
Scale 2 
Other observations 
Letter score  
Slightly glazed appearance 
A 
Markedly glazed appearance 
B 
Glazing with peeling and cracking 
C 
Glazing with fissures 
F 
Film of dried serous exudates covering all or part of the patch site 
G 
Small petechial erosions and/or scabs 
H 
Other observations (multiple scores allowed) will be recorded if applicable. 
11.5.5.1 IMP patch test procedure 
Only if the investigator suspects a local skin reaction related to application of the IMP, an IMP 
patch test will be performed following scoring according to the Berger and Bowman scales 
described in Section 11.5.5. The subject’s own (blinded) IMP will be used for the IMP patch 
test. To avoid contamination, approximately 1 cm of cream should be squeezed out of the tube 
before performing the IMP patch test. If this is not possible, a new tube of IMP will be used 
(dispensed at the given visit) for the procedure. The trial site staff will apply a small amount 
of IMP ‘as is’ in a patch test chamber which will be placed on the subject’s upper back and 
secured with hypoallergenic tape. The patch will be removed after 2 days. The investigator 
will perform readings of any apparent patch test reaction 3-4 days and 5-7 days after applying 
the patch. If a photography device is available at the site, the positive patch test reaction 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 82 of 160 
 
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 
 
should be documented by photography. The patch test reaction will be scored (Panel 17) 
according to guidelines (37). If the subject has a positive reaction to the IMP patch test, the 
subject must discontinue treatment with IMP. 
Further instructions for the IMP patch test procedure, scoring of the IMP patch test reactions, 
and photographing positive patch test reactions will be provided in a separate IMP patch test 
manual. 
Panel 17: Patch test reading criteria 
Morphology 
Patch test reaction score 
No reaction 
Negative reaction 
Faint erythema only 
Doubtful reaction 
Erythema, infiltration, possibly papules 
Weak positive reaction 
Erythema, infiltration, papules, vesicles 
Strong positive reaction 
Intense erythema, infiltrate, coalescing vesicles 
Extreme positive reaction 
Various morphologies, e.g. soap effect, bulla, necrosis 
Irritant reaction 
Reading criteria for patch test reactions based on morphology, modified from Johansen et al. (37). 
Reporting in eCRF 
For the IMP patch test, the date of placement of the IMP patch test, the date of each reading, 
and the patch test reaction scores will be recorded in the eCRF (negative reaction, doubtful 
reaction, weak positive reaction, strong positive reaction, extreme positive reaction, or irritant 
reaction). 
The photograph(s) of any positive patch test reactions will be uploaded to the eCRF. 
11.6 Pharmacodynamics assessments 
11.6.1 Overview 
A hallmark of CHE is an impaired skin barrier function leading to dry skin and excoriations. 
Based on its mechanism of action and on findings in a previous study (27), delgocitinib is 
expected to improve the skin barrier in people with eczema. This will be investigated further 
in a subset of subjects in this trial by demonstrating improved skin barrier function on the 
hand by non-invasive tape stripping. The filaggrin mutation status will be included in the 
overall assessment of the skin barrier function. Mutations in filaggrin lead to decreased skin 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 83 of 160 
 
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 
 
barrier function and may thus be linked to a higher disease prevalence as well as to a lower 
degree of improvement of skin barrier function in response to treatment. 
Finally, treatment with delgocitinib is expected to lead to a reduction of immune cells and 
inflammation in the skin and a normalisation of the epidermis, which will be further explored 
in this trial. 
The following parameters will be assessed in subsets of subjects at selected trial sites: 
• mRNA expression in skin tape strips (including but not limited to skin barrier and 
inflammatory markers). 
• Filaggrin gene mutation status (measured from skin tape strips). 
A summary of the pharmacodynamic results will be included in the CTR if they are available 
in time for this. The full pharmacodynamic results will be reported in an addendum to the 
CTR. 
11.6.2 Tape stripping (selected trial sites) 
Non-invasive tape stripping will be done for a subset of subjects to investigate gene 
expression and filaggrin mutations in the skin. Tape strips will be taken for up to 
approximately 75 subjects at selected trial sites which will be identified prior to trial start. 
Tape stripping will be performed at the visits specified in the schedule of trial procedures 
(Section 4). At baseline, the assessment will be done in 2 areas: in a representative lesional 
area from the wrist, hand, or fingers, and in a non-lesional area which is anatomically similar 
to the lesional area. The dorsal side of hand or fingers is preferred, but if no appropriate lesion 
amenable for tape stripping is present on the dorsal side, tape stripping can be performed on 
the palmar side. If an anatomically similar non-lesional area cannot be found on the hands or 
wrists, the volar forearm may be used instead. At all other visits, tape stripping will only be 
done in the lesional area. 
The lesional skin areas selected for tape stripping at baseline should be used for all 
subsequent tape stripping assessments, regardless of whether the skin is lesional or not at this 
time. In this context, ‘lesional’ refers to the status of the skin at baseline, even if the lesion 
clears during the trial. 
Subjects will be instructed not to apply IMP or any emollients on their hands and wrists for at 
least 2 hours prior to visits that include tape stripping. 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 84 of 160 
 
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 
 
It will be recorded in the eCRF if the tape stripping was done; if not, a reason will be 
provided. The location of the selected lesional and non-lesional areas will also be recorded 
(dorsal hand, palmar hand, dorsal wrist, palmar wrist, finger, or volar forearm [only applicable 
for the non-lesional area]). Details on how to register sample location is provided in the hand 
landscape map for tape strip samples. In addition, the date and time of last IMP application 
prior to tape stripping and the start time for tape stripping will be recorded in the eCRF. 
Further instructions for tape stripping are provided in a laboratory manual. 
11.7 Other assessments 
11.7.1 Patient-reported outcomes (health-related quality of life and work 
productivity) 
11.7.1.1 Overview 
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 following PROs will be completed in an electronic device by the subjects at the trial sites 
at the visits specified in the schedule of trial procedures (Section 4) in the following order: 
• Itch PGI-S. 
• Itch PGI-C. 
• Pain PGI-S. 
• Pain PGI-C. 
• HESD PGI-S. 
• HESD PGI-C. 
• HEIS. 
• PaGA. 
• DLQI. 
• EQ-5D-5L. 
• WPAI:CHE. 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 85 of 160 
 
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 
 
11.7.1.2 Patient Global Impression of Severity (PGI-S) questionnaires 
The PGI-S is a 1-item questionnaire designed to assess the subject’s global perception of their 
itch, pain, or chronic hand eczema signs and symptoms over the past week on a 4-point 
categorical response scale (‘none’, ‘mild’, ‘moderate’, or ‘severe’). 
The subjects will be asked to complete 3 PGI-S questionnaires, one each to assess itch (Itch 
PGI-S), pain (Pain PGI-S), and their overall impression of their chronic hand eczema (HESD 
PGI-S) (Panel 18). 
The PGI-S questionnaires will be completed at the trial site according to the schedule of trial 
procedures in Section 4. 
Panel 18: Patient Global Impression of Severity (PGI-S) questionnaires 
Itch PGI-S 
Pain PGI-S 
HESD PGI-S 
Please choose the response 
below that best describes the 
severity of any itch on your 
hands over the past week 
Please choose the response 
below that best describes the 
severity of any pain on your 
hands over the past week 
Please choose the response 
below that best describes the 
severity of your hand 
eczema signs and 
symptoms over the past 
week 
Response scale: 
□ None 
□ Mild 
□ Moderate 
□ Severe 
Response scale: 
□ None 
□ Mild 
□ Moderate 
□ Severe 
Response scale: 
□ None 
□ Mild 
□ Moderate 
□ Severe 
11.7.1.3 Patient Global Impression of Change (PGI-C) questionnaires 
The PGI-C is a 1-item questionnaire designed to assess the subject’s impression of changes 
(38). From 5 response options (‘much better’, ‘a little better’, ‘no change’, ‘a little worse’, or 
‘much worse’), the subjects have to select the one response that best describes the overall 
change in their itch, pain, or chronic hand eczema signs and symptoms since they started IMP 
treatment. 
The subjects will be asked to complete 3 PGI-C questionnaires, one each to assess the change 
in itch (Itch PGI-C), pain (Pain PGI-C), and their overall impression of their chronic hand 
eczema (HESD PGI-C) (Panel 19). 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 86 of 160 
 
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 
 
The PGI-C questionnaires will be completed at the trial site according to the schedule of trial 
procedures in Section 4. 
Panel 19: Patient Global Impression of Change (PGI-C) questionnaires 
Itch PGI-C 
Pain PGI-C 
HESD PGI-C 
Please choose the response 
below that best describes the 
overall change in any itch 
on your hands since you 
started taking the study 
medication 
Please choose the response 
below that best describes the 
overall change in any pain 
on your hands since you 
started taking the study 
medication 
Please choose the response 
below that best describes the 
overall change in your hand 
eczema signs and 
symptoms since you started 
taking the study medication 
Response scale: 
□ Much better 
□ A little better 
□ No change 
□ A little worse 
□ Much worse 
Response scale: 
□ Much better 
□ A little better 
□ No change 
□ A little worse 
□ Much worse 
Response scale: 
□ Much better 
□ A little better 
□ No change 
□ A little worse 
□ Much worse 
11.7.1.4 Hand Eczema Impact Scale (HEIS) 
The HEIS is an instrument used in the phase 2b trial with delgocitinib (LP0133-1273) and 
validated based on these data. HEIS includes  items addressing the subject’s perception of 
the impact of hand eczema on 
 
 over the past 7 days. Each item is scored on a 5-point scale (0=‘not 
at all’, 1=‘a little’, 2=‘moderately’, 3=‘a lot’, 4=‘extremely’). The HEIS score is the average 
of the  items. The highest possible score is 4, and a high score is indicative of a high impact. 
 domain scores can be calculated for HEIS: PDAL (average of  items), 
 
 
. The HEIS will be completed at the 
trial site according to the schedule of trial procedures in Section 4. 
11.7.1.5 Patient’s Global Assessment of disease severity (PaGA) 
Subjects will make a global assessment of the severity of their hand eczema. The assessment 
will be made using a 5-point scale (0=‘clear’, 1=‘almost clear’, 2=‘mild’, 3=‘moderate’, 
4=‘severe’) and will be based on the severity of their hand eczema at the time of the 
assessment (Panel 20). The PaGA will be completed by the subjects in an electronic device at 
the trial site according to the schedule of trial procedures in Section 4. 
TMF-000340756 - Version
5. 0
CCI
CCI
CCI
CCI
CCI
CCI
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 87 of 160 
 
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 
 
Panel 20: Patient’s Global Assessment of disease severity (PaGA) 
Rate the severity of your hand eczema right now. In making your rating you should think 
about the severity of any hand eczema symptoms you have right now, including scaling, 
blistering, cracking, swelling, redness, or thickening of the skin on your hands. 
□ Clear (No hand eczema symptoms) 
□ Almost clear (Only slight redness, no other hand eczema symptoms) 
□ Mild 
□ Moderate 
□ Severe 
 
11.7.1.6 Dermatology Life Quality Index (DLQI) 
The DLQI 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, daily activities, leisure, work or school, personal 
relationships, and the treatment (39). 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 DLQI score is the sum of the 
10 items (score ranging from 0 to 30); a high score is indicative of a poor quality of life. The 
DLQI will be completed at the trial site according to the schedule of trial procedures in 
Section 4. 
11.7.1.7 EuroQol 5-Dimension Health Questionnaire 5 Level (EQ-5D-5L) 
The EQ-5D-5L is a standardised measure of health status developed by the EuroQol group to 
provide a simple, generic measure of health for clinical and economic appraisal (40). The 
EQ-5D-5L is a self-administered questionnaire used to assess health status ‘today’ and is 
divided into 2 sections. 
The first section includes 5 dimensions (mobility, self-care, usual activity, pain/discomfort, 
and anxiety/depression). Each dimension will be assessed by the subject using a 5-point scale 
(‘no problems’, ‘slight problems’, ‘moderate problems’, ‘severe problems’, and ‘unable 
to/extreme problems’). The EQ-5D-5L index score is derived from the 5 dimensions and has 
been converted from the 5L system to the 3L system using the EQ-5D-5L crosswalk value set. 
The index score ranges from -0.594 to 1.0 (based on the UK country-specific value set), with 
a higher score indicating a better health status. 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 88 of 160 
 
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 
 
The second section consists of a vertical visual analogue scale anchored at 0 (‘the worst 
health you can imagine’) and 100 (‘the best health you can imagine’). The EQ-5D-5L will be 
completed at the trial site according to the schedule of trial procedures in Section 4. 
11.7.1.8 Work Productivity and Activity Impairment: Chronic Hand 
Eczema (WPAI:CHE) 
The impact of CHE on the subject’s ability to work and perform regular activities will be 
assessed by WPAI:CHE, which is an instrument to measure impairments in both paid work 
and unpaid work (41). The WPAI:CHE consists of 6 items, and scores can be calculated for 
4 domains, each reflecting the percentage impairment due to CHE during the past 7 days, with 
higher numbers indicating greater impairment and less productivity: 
• Absenteeism: percentage work time missed due to CHE for those who were currently 
employed. 
• Presenteeism: percentage impairment while working due to CHE for those who were 
currently employed and actually worked in the past 7 days. 
• Work productivity loss: percentage overall work impairment due to CHE for those who 
were currently employed. 
• Activity impairment: percentage activity impairment due to CHE for all respondents. 
The WPAI:CHE will be completed at the trial site according to the schedule of trial 
procedures in Section 4. 
11.7.2 Exit interviews (selected trial sites) 
Exit interviews will be conducted with a subgroup of approximately 40 native 
English-speaking subjects by a CRO. Participation in this component of the trial is voluntary 
and requires that the subject provides additional informed consent. The exit interviews will be 
qualitative, semi-structured interviews conducted by experienced qualitative interviewers. The 
exit interviews will be conducted in English with subjects from selected trial sites in Canada 
and UK. 
The exit interviews will be conducted by phone or using a video conferencing platform. A 
date and time for the exit interview will be agreed with the subject. The interviews will be 
scheduled to occur as soon as possible and within a maximum of 2 weeks after Week 16. 
Subjects at the selected sites will be given the opportunity to participate in the exit interviews 
on a first-come, first-served basis. Once approximately 40 subjects have completed exit 
interviews, sites will be advised that this assessment is closed. Subjects who discontinue IMP 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 89 of 160 
 
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 
 
or withdraw from the trial prior to Week 16 will not be invited to participate in the exit 
interviews. 
Each interview is expected to last approximately 60 minutes. A semi-structured interview 
guide will be used to explore the subjects’ experience of CHE, treatment experience, and 
changes in concepts assessed by PROs, including whether changes they have experienced 
were meaningful. 
Interviewers will use the semi-structured interview guide to guide the discussion, and the 
interviews will be audio-recorded and transcribed verbatim for the purpose of accurately 
capturing the subjects’ comments. Qualitative analysis of the verbatim transcripts will be 
performed using thematic analysis and ATLAS.ti software. The analysis of the exit interview 
data will be reported separately as an addendum to the CTR. The interviewers will be trained 
in capturing potential AEs and will report any potential AEs to the trial site for recording in 
the eCRF if applicable (Section 13.2). 
11.8 End of trial 
End-of-treatment form 
An end-of-treatment form will be completed in the eCRF for all randomised subjects exposed 
to IMP when they have had their last application 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 application 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 (for subjects not participating in the LTE trial) or attended the baseline visit 
for the LTE trial (for subjects participating in the LTE trial). 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.  
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 90 of 160 
 
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 
 
• 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, screen failure 
(failure to meet eligibility criteria), or other. 
• Was the reason for not completing the trial related to COVID-19? 
• Was the subject transferred to the extension trial (LP0133-1403)? 
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’ is selected, it will be recorded whether the subject withdrew informed 
consent or not. 
11.9 Estimate of total blood volume collected 
Blood samples will be drawn for haematology, biochemistry, and serology. The total volume 
of blood to be drawn is approximately 65 mL. If additional blood samples are required, the 
amount of blood drawn may be more than this stated value; however, the total volume of 
blood drawn will be less than that taken during a blood donation (approximately 500 mL). 
11.10 Storage of biological samples 
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. 
Tape strips (and/or material extracted from tape strips) will be retained for as long as the 
quality of the material permits evaluation but for no longer than 12 months after completion 
of the CTR unless specific additional consent has been obtained that allows storage for future 
research (see below). 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 91 of 160 
 
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 
 
Biobank 
This protocol includes the collection and analysis of different biological samples. If consent is 
given by the subject, LEO Pharma will store the collected tape strips and/or material extracted 
from these in a biobank established by LEO Pharma and hosted by Brooks Life Sciences 
(Germany), GmbH. The stored biological samples will be used for future research by LEO 
Pharma. Donation of the samples for future research is voluntary and subjects must give their 
separate written consent to confirm donation and storage and the terms associated herewith. 
The samples will be transferred from the relevant laboratory to the biobank. The samples will 
be labelled with the trial ID, subject ID, and the sample date to protect the privacy of the 
subjects and to allow continued blinding for future analyses. The samples from this trial will 
be stored in the biobank for as long as the quality of the material permits evaluation and will 
then be destroyed. 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 92 of 160 
 
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 
 
12 Scientific rationale for trial design and appropriateness of assessments 
12.1 Scientific rationale for trial design 
This is a randomised, double-blind, vehicle-controlled, parallel-group, multi-site trial, which 
will be conducted in accordance with the protocol, ICH GCP, and applicable regulatory 
requirements. The trial will be conducted at multiple trial sites located in Europe and North 
America. High-quality trial sites with shared standards of practice will be selected. 
Subjects with hand eczema represent a heterogeneous population as hand eczema 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. The randomisation 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) and region 
(Europe or North America). IGA-CHE severity is viewed as a strong prognostic factor while 
regional differences could occur given the heterogeneous population. 
The vehicle control group will serve as reference and has been added to establish the efficacy 
and safety of delgocitinib cream in a blinded trial design. The randomisation ratio of 2:1 
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. 
Eligible subjects who complete the Week 16 visit (and who do not permanently discontinue 
IMP prior to Week 16) will be invited to continue in the LTE trial (conducted under a separate 
clinical trial protocol). 
Topical application is considered the preferred route of administration for treatments for CHE, 
since CHE is a cutaneous disease characterised by few lesions affecting small 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. Furthermore, a patient insights meeting supports 
that topical treatment for CHE is preferred over systemic treatment from a patient point of 
view. 
The dose and treatment duration of delgocitinib cream are based on data from the phase 2b 
dose-ranging trial LP0133-1273, showing a clear 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. The 
IGA-CHE TS response rates at Week 16 were similar in the delgocitinib cream 8 mg/g and 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 93 of 160 
 
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 
 
20 mg/g groups (41.5% and 39.0%, vs. 10.5% in the cream vehicle group). The complete 
absence of safety concerns at both strengths 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. 
Thus, the 20 mg/g dose was selected. 
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. However, 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 endpoint at 
Week 16. 
The trial population is selected to reflect the general adult population with CHE to ensure that 
the trial results will be generalisable to the target population. No upper age limit is included, 
and 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 confirm the efficacy of delgocitinib in improving the 
severity and extent of CHE. 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 
score 1 adjustment as recommended by the FDA. The IGA-CHE was used in the phase 2b 
trial (LP0133-1273) and has been further revised for the current trial. HECSI is a validated 
measure used in clinical practice and clinical trials to assess the severity and extent of CHE 
(42). 
By validated PROs, this trial will also address the subjects’ perception of disease severity and 
the impact on health-related quality of life. 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 94 of 160 
 
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 
 
Standard/widely used non-invasive tape stripping is included to demonstrate the ability of 
delgocitinib to improve the skin barrier function. 
Safety will be assessed using standard clinical methods such as AE reporting, ECG, vital 
signs, and clinical laboratory measurements. 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 95 of 160 
 
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 
 
13 Adverse events 
13.1 Definition and classification of adverse events 
Adverse events (AEs) and serious adverse events (SAEs) are defined in Appendix 1. 
Classification of AEs in terms of severity, causality, and outcome is defined in Appendix 2. 
13.2 Collection of adverse event reports 
AE data must be collected from time of first trial-related activity after the subject has signed 
the ICF until end of trial (as defined in Section 7.3). For subjects participating in an exit 
interview, AEs may be reported retrospectively as exit interviews may be conducted after the 
end of trial for the individual subject. 
AEs must be assessed by a physician. 
At all visits, the subject will be asked a non-leading question by the investigator about AEs, 
e.g.: ‘How have you felt since I saw you last?’. Subject-reported local tolerability will be 
queried specifically (see Section 11.5.5) and reported as AE(s) if deemed relevant by the 
investigator. In case of suspected local skin reaction related to IMP application, the final 
diagnosis based on the IMP patch test result (see Section 11.5.5.1) must be recorded as an AE. 
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. 
To avoid duplicate reporting of AEs in the present trial and the LTE trial, any AE with onset 
before the baseline visit in the LTE trial should be recorded as an AE in the present trial. If 
ongoing at the screening or baseline visit in the LTE trial, the AE should also be recorded as 
medical history in the LTE trial. An AE with onset after the baseline visit in the LTE trial 
should be recorded as an AE in the LTE trial. 
Any potential AE reported by the subjects during an exit interview must be collected by the 
interviewer on the Potential Adverse Event Collection Form. The interviewer must forward 
the completed form to the investigator within 24 hours of the interview. The investigator must 
evaluate if the potential AEs are indeed to be considered as AEs and whether they were 
already recorded in the eCRF and date and sign their evaluation within 24 hours of receipt of 
the form. Interviewer and investigator should confirm to each other receipt of the form by the 
investigator within those 24 hours. If the confirmed AEs were not recorded in the eCRF, or if 
the investigator is in doubt, they must record the AEs in the eCRF. If considered relevant, the 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 96 of 160 
 
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 
 
investigator should follow up on the AEs with the subject at the safety follow-up visit. If a 
potential AE qualifies as an SAE, the SAE must be reported within 24 hours of receipt by the 
site/investigator as described in Section 13.4.1. 
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). 
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). 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 97 of 160 
 
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 
 
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 but not later than within U24 hours of first 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: 
Global Safety at LEO Pharma 
E-mail address: drug.safety@leo-pharma.com 
Fax number: +45 7226 3287 
If relevant, the investigator will enclose other information with the SAE form, such as 
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. 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 98 of 160 
 
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 
 
SAEs occurring after the completion of the clinical trial should not be routinely sought or 
recorded. However, such events should be reported to Global Safety at LEO Pharma (see 
contact details above) if the investigator becomes aware of them. 
13.4.2 LEO Pharma reporting responsibilities 
Global Safety at LEO Pharma is responsible for assessing whether an SAE is expected. The 
relevant reference safety information document for this clinical trial is: 
• For the IMP, the Investigator’s Brochure Section 7.3, edition 4.0 and subsequent updates 
must be used (31). 
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 (30), and which are 
unexpected (suspected, unexpected serious adverse reactions [SUSARs]), are subject to 
expedited reporting to regulatory authorities, and IEC(s)/IRB(s) according to the current 
applicable legislation in the concerned countries. Investigators will be notified of the evolving 
safety profile of the IMP on an ongoing basis. 
13.5 Other events that require expedited reporting 
13.5.1 Pregnancy 
Any pregnancy occurring after first exposure to IMP and until the subject has completed the 
trial must be reported to LEO Pharma within 24 hours of first knowledge using the (paper) 
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). 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 99 of 160 
 
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 
 
13.6 Reporting of other events 
13.6.1 Adverse events of special interest 
The events listed in Panel 21 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 21. 
Panel 21: 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) 
Deep vein 
thrombosis 
Risk factors: 
• Previous thromboembolism (record as medical history) 
• Family history of deep vein thrombosis/pulmonary embolism or other 
cardiovascular/blood-clotting disorders 
• Genetic disorders that might increase the risk for thrombosis (record as 
medical history) 
• History of cancer (record as medical history) 
• Recent venous catheter placement (record as medical history) 
• Current smoker (record as tobacco smoking history) 
• Hormonal contraception/hormonal replacement therapy (record as 
concomitant medication) 
• Trauma or surgery (record as per protocol) 
• Immobilisation (e.g. prolonged bed rest or sitting for long periods) 
Method of verification: 
• Clinical evaluation 
• Image-verified 
• Laboratory test(s) 
Pulmonary 
embolism 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 100 of 160 
 
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 
 
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 (including missed doses) where no clinical consequence occurred 
or could have occurred should not be recorded as medication errors. See Section 9.8.4 for 
recording of treatment compliance. 
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 defined in the protocol. 
Misuse refers to situations where the IMP is intentionally and inappropriately used for 
therapeutic purposes not in accordance with the protocol. 
Abuse refers to intentional use of an IMP for what could be considered desirable 
non-therapeutic effects (e.g. sedative, stimulant, euphoric effects). 
Misuse and abuse must be recorded on the 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). 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 101 of 160 
 
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 
 
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 the 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) until the subject’s last visit in the trial. For subjects completing the treatment period 
and not participating in the LTE trial, this will be the safety follow-up visit. For subjects 
prematurely discontinuing IMP prior to Week 16, the last visit will in most cases be the 
primary endpoint visit. For subjects who will participate in the LTE 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 in the present trial, or until the final 
outcome is determined, whichever comes first. This could be at a safety follow-up visit via 
phone or at an LTE trial site visit. 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 period, 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 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 102 of 160 
 
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 
 
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.” (43). 
If the investigator becomes aware of information that requires an immediate change in a 
clinical trial procedure or a temporary halt of the clinical trial to protect clinical trial subjects 
from any immediate hazard to their health and safety, the investigator can do so without prior 
approval from LEO Pharma, regulatory authorities, or IRBs/IECs. 
The investigator must immediately inform LEO Pharma – by contacting the clinical project 
manager or medical expert – of this change in a clinical trial procedure or of the temporary 
halt; the investigator will provide full details of the information and the decision-making 
process leading to the implementation of the urgent safety measure. 
LEO Pharma must act immediately upon receipt of the urgent safety measure notification in 
accordance with internal procedures and local legislation. 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 103 of 160 
 
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 
 
14 Statistical methods 
14.1 Sample size 
A total of 470 subjects will be randomised 2:1 to delgocitinib cream 20 mg/g or cream 
vehicle. The sample size is chosen to ensure that sufficient safety information including 
adequate long-term exposure data is collected. 
With a one-sided significance level of 2.5%, a sample size of 470 subjects randomised will 
provide at least 99% power for detecting a treatment difference for the primary endpoint, 
assuming an IGA-CHE TS response rate at Week 16 of 40% vs. 10% for delgocitinib cream 
20 mg/g and cream vehicle, respectively. The assumptions on response rates are based on 
results from the phase 2b dose-ranging trial (LP0133 1273). 
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 FAS and will be analysed 
based on the randomised treatment allocation. Exclusions from the FAS can be considered in 
special cases as described in ICH E9, Section 5.2.1, Full Analysis Set. If it is decided to 
exclude a subject from the FAS, a justification addressing ICH E9 will be given. 
A safety analysis set 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 Aspects related to the COVID-19 pandemic 
As the implications of the COVID-19 pandemic might, extraordinarily, influence trial events 
and data in manners not foreseen by the protocol, this section introduces the statistical 
considerations for handling of events related to the pandemic for primary and key secondary 
endpoints. 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 104 of 160 
 
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 
 
A supplementary estimand, ‘pandemic modified composite’, is introduced for analysis of the 
primary and key secondary endpoints. This estimand addresses permanent discontinuation of 
IMP related to the pandemic as an IE. Details are described in Section 14.3.6. 
Interruption of IMP during the treatment period is not expected as per protocol and hence not 
considered as an IE. This is supported by the assumption that LEO Pharma will secure 
availability of IMP at all times. In addition, as the IMP supply is secured, the IE initiation of 
rescue medication will be considered independent of the pandemic (see Appendix 7). 
The causal relationship of permanent discontinuation of IMP related to the pandemic will be 
recorded in the eCRF (see also Section 10.2). 
Missing or ‘treated as missing’ data related to the COVID-19 pandemic 
At scheduled visits, it will be recorded in the eCRF whether data are missing due to the 
pandemic. As a consequence of the pandemic and associated local preventive measures, 
subjects may miss an entire visit, or visits may be performed via phone or video, thereby only 
allowing for a subset of planned assessments to be collected. 
Observed data after permanent discontinuation of IMP related to the pandemic will be ‘treated 
as missing’ and imputed assuming MAR. Missing data related to the pandemic will be 
imputed assuming MAR. 
It should be noted that a subject may have missing data related to the pandemic, even though 
the subject has not experienced an IE related to the pandemic. 
An overview of how observed and missing data will be handled according to the IEs and their 
relatedness to the pandemic is presented in Panel 23 for the primary analysis for estimands. 
Details of the analysis are described in Section 14.3.6. 
14.3.2 Disposition of subjects 
The reasons for permanent discontinuation of IMP and for not completing the trial will be 
presented for all randomised subjects and by treatment group. 
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 FAS, permanently discontinuing IMP, and not completing the trial by 
treatment group and overall. 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 105 of 160 
 
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 
 
14.3.3 Demographics and other baseline characteristics 
Descriptive statistics of demographics and other baseline characteristics will be presented for 
all randomised subjects and by treatment group. 
Demographics include age, sex, ethnicity, and race. Other baseline characteristics include 
height, weight, body mass index, region, country, total IgE, Fitzpatrick skin type, CHE 
history, CHE treatment history, exogenous risk factors for CHE, 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. 
Baseline investigator efficacy assessments and baseline HESD assessments related to the 
primary and key secondary endpoints will be presented by region, baseline IGA-CHE score, 
and CHE subtype (main diagnosis). 
14.3.4 Exposure and treatment compliance 
The duration of exposure to treatment in a specific week interval will be calculated as the 
number of days from date of first 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 for each treatment group. 
14.3.5 Testing strategy 
For the primary and key secondary endpoints, confirmatory one-sided (superiority) 
hypotheses will be tested for delgocitinib cream 20 mg/g vs. cream vehicle based on the 
primary analysis for the primary estimand. Let the treatment effect be defined as 
μ = (delgocitinib cream 20 mg/g minus cream vehicle), then: 
• For binary endpoints: H0:μ ≤ 0 against Ha:μ > 0. 
• For continuous endpoints: H0:μ ≥ 0 against Ha:μ < 0. 
 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 106 of 160 
 
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 
 
A closed testing procedure with hierarchical tests, alpha splitting and alpha recycling will be 
used to control the overall type I error at a nominal one-sided 2.5% level. The statistical 
testing strategy is built on the principle that the IGA-CHE TS superiority at Week 16 will 
have to be established before testing for additional benefits (key secondary endpoints) related 
to efficacy and health-related quality of life. 
The first hypothesis to be tested is superiority of delgocitinib cream 20 mg/g in terms of 
IGA-CHE TS at Week 16. It will be tested at the overall one-sided significance level of 2.5%. 
In general, if a test is significant, the significance level will be reallocated according to the 
weight and the direction of the arrows as specified in Panel 22. Each of the following 
hypotheses will be tested at their local significance level (α-local). This process will be 
repeated until no further tests are significant.
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 107 of 160 
 
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 
 
Panel 22: Graphical display of closed testing procedure for primary and key secondary endpoints 
 
 
 
 
 
 
 
 
 
 
 
1) From baseline among subjects with a baseline HESD itch score (weekly average) ≥4 points. 
2) From baseline among subjects with a baseline HESD score (weekly average) of ≥4. 
3) From baseline among subjects with a baseline HESD pain score (weekly average) of ≥4. 
4) From baseline among subjects with a baseline DLQI score of ≥4. 
Abbreviations: DLQI = Dermatology Life Quality Index; 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; HEIS = Hand Eczema Impact Scale; HESD = Hand Eczema Symptom Diary; 
α=2.5% (one-sided) 
1. IGA-CHE TS at Week 8 
2. IGA-CHE TS at Week 4 
3. Reduction of HESD itch score (weekly average) of ≥4 points at Week 81 
4. Reduction of HESD itch score (weekly average) of ≥4 points at Week 41 
5. Reduction of HESD itch score (weekly average) of ≥4 points at Week 21 
6. Reduction of HESD score (weekly average) of ≥4 points at Week 82 
7. Reduction of HESD score (weekly average) of ≥4 points at Week 42 
8. Reduction of HESD pain score (weekly average) of ≥4 points at Week 163 
9. Reduction of HESD pain score (weekly average) of ≥4 points at Week 83 
10. Reduction of HESD pain score (weekly average) of ≥4 points at Week 43 
1/5 α 
4/5 α 
1. HECSI-90 at Week 16 
2. HECSI-75 at Week 16 
3. HECSI-75 at Week 8 
4. Percentage change in HECSI score from baseline to Week 16 
5. Change in DLQI score from baseline to Week 16 
6. Change in HESD score (weekly average) from baseline to Week 16 
7. Change in HESD itch score (weekly average) from baseline to Week 16 
8. Change in HESD pain score (weekly average) from baseline to Week 16 
9. Change in HEIS score from baseline to Week 16 
10. Change in HEIS PDAL score from baseline to Week 16 
11. Reduction of DLQI score of ≥4 points at Week 164 
IGA-CHE TS at Week 16 
Primary endpoint 
1 α 
1. Reduction of HESD itch score (weekly average) of ≥4 points at Week 161 
2. Reduction of HESD score (weekly average) of ≥4 points at Week 162 
4/5 α 
1/5 α 
Key secondary endpoints 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 108 of 160 
 
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 
 
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; PDAL = Proximal Daily Activity Limitations.
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 109 of 160 
 
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 
 
14.3.6 Estimand strategy 
14.3.6.1 Overview 
The analysis of endpoints related to efficacy and health-related quality of life will be based on 
the FAS. 
The following primary and supplementary estimands will be defined for binary and 
continuous endpoints (primary and key secondary endpoints). 
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 (see also Section 5.3). 
A first supplementary estimand will use a ‘pandemic modified composite’ strategy. The 
strategy follows a ‘composite’ strategy for IEs independent of the COVID-19 pandemic. 
However, data collected after the IE related to the pandemic will be ‘treated as missing’ and 
imputed assuming MAR. 
A second 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 (independent of the 
pandemic) occurred. Data collected after an IE related to the pandemic will be ‘treated as 
missing’ and imputed assuming MAR. This second supplementary estimand will be used for 
endpoints related to Week 16 (primary endpoint visit). 
For the ‘composite’ and ‘treatment policy’ estimands, pre-specified sensitivity analyses will 
be conducted to assess the robustness of the results with respect to the handling of missing 
data. 
The primary estimand for ‘time-to-event’ endpoints (exploratory endpoints) will use a ‘while 
on treatment’ strategy. Under the ‘while on treatment’ strategy, the actual duration of 
treatment is not important for determining treatment benefit. The interest lies in assessing the 
treatment response prior to the occurrence of IEs. This strategy will be implemented to handle 
IEs for time-to-event endpoints. 
Analysis to summarise and assess the effect of patterns of missing data related to the 
pandemic will be specified in the statistical analysis plan prior to breaking the randomisation 
code. 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 110 of 160 
 
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 
 
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, 
regardless of relatedness to the COVID-19 pandemic, 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). This IE is handled without assessing relatedness to the pandemic. 
• Permanent discontinuation of IMP independent of the COVID-19 pandemic: This IE 
occurs when a subject permanently discontinues IMP independent of the pandemic. This 
IE can occur at the subject's own initiative, at the discretion of the investigator or the 
sponsor, or if the subject is lost to follow-up. 
• Permanent discontinuation of IMP related to the COVID-19 pandemic: This IE 
occurs when a subject permanently discontinues IMP due to circumstances related to the 
pandemic; not attributed to lack of efficacy or randomised treatment features considered 
unacceptable by the subject. 
Panel 23 presents an overview of how observed and missing data will be handled according to 
the IEs for the primary analysis for estimands.
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 111 of 160 
 
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 
 
Panel 23: Handling of observed and missing data according to the intercurrent events for the primary analysis for estimands 
 
 
Estimand strategy for binary endpoints 
Estimand strategy for continuous endpoints 
Intercurrent event 
Data observed 
or missing 
Composite 
 
(Primary) 
Pandemic 
modified 
composite 
(First 
supplementary) 
Treatment policy 
 
(Second 
supplementary) 
Composite 
 
(Primary) 
Pandemic modified 
composite 
(First 
supplementary) 
Treatment policy 
 
(Second 
supplementary) 
Initiation of rescue 
treatment1 
Observed 
Non-response 
Non-response 
Value will be used 
as observed 
WOCF 
(including 
baseline value) 
WOCF (including 
baseline value) 
Value will be used as 
observed 
Missing 
Non-response 
Non-response 
MI (MAR) 
WOCF 
(including 
baseline value) 
WOCF (including 
baseline value) 
MI (MAR) 
Permanent 
discontinuation of 
IMP independent of 
the pandemic 
Observed 
Non-response 
Non-response 
Value will be used 
as observed 
WOCF 
(including 
baseline value) 
WOCF (including 
baseline value) 
Value will be used as 
observed 
Missing 
Non-response 
Non-response 
MI (MAR) 
WOCF 
(including 
baseline value) 
WOCF (including 
baseline value) 
MI (MAR) 
Permanent 
discontinuation of 
IMP related to the 
pandemic 
Observed 
Non-response 
Treated as 
missing, MI 
(MAR) 
Treated as 
missing, MI 
(MAR) 
WOCF 
(including 
baseline value) 
Treated as missing, 
MI (MAR) 
Treated as missing, 
MI (MAR) 
Missing 
Non-response 
MI (MAR) 
MI (MAR) 
WOCF 
(including 
baseline value) 
MI (MAR) 
MI (MAR) 
No intercurrent events 
Observed 
Value will be 
used as 
observed 
Value will be used 
as observed 
Value will be used 
as observed 
Value will be 
used as 
observed 
Value will be used 
as observed 
Value will be used as 
observed 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 112 of 160 
 
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 
 
 
 
Estimand strategy for binary endpoints 
Estimand strategy for continuous endpoints 
Intercurrent event 
Data observed 
or missing 
Composite 
 
(Primary) 
Pandemic 
modified 
composite 
(First 
supplementary) 
Treatment policy 
 
(Second 
supplementary) 
Composite 
 
(Primary) 
Pandemic modified 
composite 
(First 
supplementary) 
Treatment policy 
 
(Second 
supplementary) 
Missing 
independent 
of the 
pandemic 
Non-response 
Non-response 
MI (MAR) 
WOCF 
(including 
baseline 
value) 
WOCF (including 
baseline value) 
MI (MAR) 
Missing 
related to the 
pandemic 
Non-response 
MI (MAR) 
MI (MAR) 
WOCF 
(including 
baseline 
value) 
MI (MAR) 
MI (MAR) 
1) Initiation of rescue treatment is considered an intercurrent event regardless of the relatedness to the COVID-19 pandemic. 
Abbreviations: COVID-19 = coronavirus disease 2019; MAR = missing at random; MI = multiple imputation; WOCF = worst observation carried forward. 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 113 of 160 
 
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 
 
14.3.6.2 Estimand strategy for binary endpoints 
The population level summary will be the difference in response rates between delgocitinib 
cream 20 mg/g and cream vehicle. 
Primary estimand: ‘composite’ strategy 
This primary estimand evaluates the treatment effect in adult subjects 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. 
 
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 difference in response rates between the two treatment groups will be analysed using the 
CMH test stratified by region and baseline IGA-CHE score. The difference in response rates 
with 95% CI will be calculated by the Mantel-Haenszel method stratified by region and 
baseline IGA-CHE score. 
First 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 values 0.1 and 0.2. The same parameter p will be used for both treatment groups. 
The parameter values 0.1 and 0.2 are based on the response rates of IGA-CHE TS and HESD 
itch score (weekly average) ≥4 points, respectively, at Week 16 in the cream vehicle group in 
LP0133-1273 and will introduce uncertainty due to missing data. A MI procedure 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 114 of 160 
 
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 
 
(100 iterations) will be used for each value of p. For each of the 100 complete datasets, the 
difference in response rates will be analysed using a CMH test stratified by region and 
baseline IGA-CHE score. 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. 
Second sensitivity analysis for the primary estimand 
A tipping point analysis will be performed. Missing data at the endpoint of interest, for 
subjects who did not experience the IEs prior to that, will be handled as follows: 
• For subjects in the delgocitinib cream 20 mg/g group, missing data will be imputed as 
non-response. 
• For subjects in the cream vehicle group, missing data will be imputed from a Bernoulli 
distribution with parameter p (ranging from 0 to 1). By varying the parameter p, different 
percentages of subjects in the cream vehicle group will be assumed to be responders, 
deviating from the default zero percent used in the primary analysis. A MI procedure (100 
iterations) will be used for each value of p. 
 
For each of the 100 complete datasets, the difference in response rates will be analysed using 
a CMH test stratified by region and baseline IGA-CHE score. 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. 
The tipping point is then found as the value of p which changes the conclusion from 
statistically significant to non-significant and will be judged from a clinical perspective. 
First supplementary estimand: ‘pandemic modified composite’ strategy 
This first supplementary estimand evaluates the treatment effect in adult subjects with 
moderate to severe CHE, without initiation of rescue treatment or permanent discontinuation 
of IMP in a world without COVID-19 pandemic, where interest lies in the treatment effect as 
it would have been observed had the COVID-19 pandemic not happened. 
For subjects who experience IEs independent of the pandemic prior to the endpoint of 
interest, observed data after the IEs will be considered non-response. 
For subjects who experience an IE related to the pandemic prior to the endpoint of interest, 
observed data after the IE will be ‘treated as missing’ and imputed assuming MAR. 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 115 of 160 
 
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 
 
Primary analysis for the first supplementary estimand 
Missing data for subjects who do not attend the visit for the endpoint of interest and do not 
experience IEs prior to this visit will be imputed as non-response, unless data is missing due 
to the pandemic in which case it will be imputed assuming MAR. 
The procedure for imputing values will be implemented in a 2-step procedure, where all 
missing or ‘treated as missing’ data will be imputed using MI (100 iterations) assuming MAR 
within treatment groups. Once the 100 complete data sets have been generated by MI, 
non-responder imputation of relevant data points not affected by the pandemic will be applied 
according to the rules described above. 
For each of the 100 complete datasets, the difference in response rates will be analysed using 
the CMH test stratified by region and baseline IGA-CHE score. 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. 
Second supplementary estimand for endpoints at Week 16: ‘treatment policy’ strategy 
This supplementary estimand evaluates the treatment effect in adult subjects with moderate to 
severe CHE, regardless of initiation of rescue treatment or permanent discontinuation of IMP 
in a world without COVID-19 pandemic. 
Observed data will be used in the analysis, including the data observed after the occurrence of 
IEs independent of the pandemic. 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. 
For subjects who experience an IE related to the pandemic prior to Week 16, observed data at 
Week 16 will be ‘treated as missing’ and imputed assuming MAR. 
Primary analysis for the second supplementary estimand 
Missing data at Week 16 independent of the pandemic will be imputed using MI 
(100 iterations) assuming MAR within 4 groups defined according to treatment group and 
whether the subject has experienced an IE (independent of the pandemic). 
Missing data or ‘treated as missing’ data at Week 16 due to the pandemic will be imputed 
using MI assuming MAR within treatment group using data from subjects who have not 
experienced an IE. 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 116 of 160 
 
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 
 
For each of the 100 imputed datasets, the difference in response rates will be analysed using 
the CMH test stratified by region and baseline IGA-CHE score. 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. 
Sensitivity analysis for the second supplementary estimand 
Missing data at Week 16 will be imputed as non-response, unless data is missing or ‘treated as 
missing’ due to the pandemic in which case it will be imputed using MI (100 iterations) 
assuming MAR within treatment group using data from subjects who have not experienced an 
IE. 
The difference in response rates will be analysed as described above for the primary analysis 
for the second supplementary estimand. 
14.3.6.3 Estimand strategy for continuous endpoints 
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 adult subjects 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 by 
using WOCF (including the baseline value). 
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 WOCF (including the baseline value). 
The change (or percentage change) from baseline to the endpoint of interest will be analysed 
using an ANCOVA model with effects of treatment group, region, baseline IGA-CHE score, 
and baseline value (endpoint of interest). 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 117 of 160 
 
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 
 
Sensitivity analysis for the primary estimand 
Missing data at the endpoint of interest, for subjects who did not experience IEs prior to that, 
will be handled as follows: 
• For subjects in the delgocitinib cream 20 mg/g group, missing data will be imputed as 
WOCF (including the baseline value). 
• For subjects in the cream vehicle group, missing data will be imputed using MI 
(100 iterations) assuming MAR. 
 
For each of the 100 complete datasets, the change (or percentage change) from baseline to the 
endpoint of interest will be analysed using the ANCOVA model with effects of treatment, 
region, baseline IGA-CHE score, and baseline value. The estimates and standard errors from 
the analyses will be combined using Rubin’s rule to provide the estimate and associated 
standard error. 
First supplementary estimand: ‘pandemic modified composite’ strategy 
This first supplementary estimand evaluates the treatment effect in adult subjects with 
moderate to severe CHE, without initiation of rescue treatment or permanent discontinuation 
of IMP in a world without COVID-19 pandemic, where interest lies in the treatment effect as 
it would have been observed had the COVID-19 pandemic not happened. 
For subjects who experience IEs independent of the pandemic prior to the endpoint of 
interest, observed data after the IEs will be considered non-response by using WOCF 
(including the baseline value). 
For subjects who experience an IE related to the pandemic prior to the endpoint of interest, 
observed data after the IE will be ‘treated as missing’ and imputed assuming MAR. 
Primary analysis for the first supplementary estimand 
Missing data for subjects who do not attend the visit for the endpoint of interest and do not 
experience IEs prior to this visit will be imputed as WOCF (including the baseline value), 
unless data is missing due to the pandemic in which case it will be imputed assuming MAR. 
The procedure for imputing values will be implemented in a 2-step procedure, where all 
missing or ‘treated as missing’ data will be imputed using MI (100 iterations) assuming MAR 
within treatment groups. WOCF imputation of relevant data points not affected by the 
pandemic will be applied according to the rules described above. 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 118 of 160 
 
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 
 
For each of the 100 complete datasets, the change (or percentage change) from baseline to the 
endpoint of interest will be analysed using the ANCOVA model with effects of treatment, 
region, baseline IGA-CHE score, and baseline value. The estimates and standard errors from 
the analyses will be combined using Rubin’s rule to provide the estimate and associated 
standard error. 
Second supplementary estimand for endpoints at Week 16: ‘treatment policy’ strategy 
This supplementary estimand evaluates the treatment effect in adult subjects with moderate to 
severe CHE, regardless of initiation of rescue treatment or permanent discontinuation of IMP 
in a world without COVID-19 pandemic. 
Observed data will be used in the analysis, including the data observed after the occurrence of 
IEs independent of the pandemic. 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. 
For subjects who experience an IE related to the pandemic prior to Week 16, observed data at 
Week 16 will be ‘treated as missing’ and imputed assuming MAR. 
Primary analysis for the second supplementary estimand 
Missing data at Week 16 independent of the pandemic will be imputed using MI 
(100 iterations) assuming MAR within 4 groups defined according to treatment group and 
whether the subject has experienced an IE independent of the pandemic. 
Missing data or ‘treated as missing’ data at Week 16 due to the pandemic will be imputed 
using MI assuming MAR within treatment group using data from subjects who have not 
experienced an IE. 
For each of the 100 complete datasets, the change (or percentage change) from baseline to 
Week 16 will be analysed using an ANCOVA model with effects of treatment, region, baseline 
IGA-CHE score, and baseline value. The estimates and standard errors from the analyses will 
be combined using Rubin’s rule to provide the estimate and associated standard error. 
Sensitivity analysis for the second supplementary estimand 
Missing data at Week 16 independent of the pandemic will be imputed using a pattern-mixture 
model where data in the delgocitinib cream 20 mg/g group as well as the cream vehicle group 
will be imputed from the cream vehicle group (copy-reference approach). The data will be 
imputed using MI (100 iterations) assuming MAR within 2 groups: subjects in the cream 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 119 of 160 
 
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 
 
vehicle group who have experienced an IE independent of the pandemic, and subjects in the 
cream vehicle group who have not experienced an IE. 
Missing data or ‘treated as missing’ data at Week 16 due to the pandemic will be imputed 
using MI assuming MAR within treatment group using data from subjects who have not 
experienced an IE. 
For each of the 100 completed datasets, the change (or percentage change) from baseline to 
Week 16 will be analysed using an ANCOVA model with effects of treatment, region, baseline 
IGA-CHE score, and baseline value. The results of the analysis will be combined using 
Rubin’s rule to provide the estimate and associated standard error. 
14.3.6.4 Estimand strategy for time-to-event endpoints 
The difference in the estimates of the cumulative incidence functions for the event of interest 
between delgocitinib cream 20 mg/g and cream vehicle will be evaluated at Weeks 2, 4, and 8. 
Primary estimand: ‘while on treatment’ strategy 
With the ‘while on treatment’ strategy, response to treatment prior to the occurrence of the IEs 
is of interest. This strategy is chosen for the time-to-event endpoints with an expected early 
effect, e.g. reduction of HESD itch score (weekly average) of ≥4 points from baseline. 
Let T represent the time from randomisation to the time-to-event endpoint and TIE represent 
the time from randomisation to occurrence of the first IE. The ‘while on treatment’ estimand 
evaluates: 
 Pr(T < TIE ∧ 16) 
where TIE ∧ 16 is the minimum of TIE and the end of the treatment period (administrative 
censoring time), corresponding to Week 16 in this trial. Since interest lies in estimating the 
time to achieving the endpoint while remaining on the randomised treatment, the occurrence 
of the IEs can be accounted for through the formulation of a competing risks model. It is 
assumed that IEs indicate failure of the randomised treatment. 
Primary analysis for the primary estimand 
The null hypothesis, H0: λdelgo(t) = λvehicle(t), ∀ t ∈ (0,16), where λ(t) denotes the 
sub-distribution hazard rate associated with the time-to-event endpoint at time t (measured in 
weeks), will be tested against the alternative, Ha: λdelgo(t) ≠ λvehicle(t) based on Gray’s test. 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 120 of 160 
 
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 
 
To quantify the magnitude of the potential treatment effect, the estimated cumulative 
incidence functions for the competing risks model will be presented for the treatment groups, 
based on the Aalen-Johansen estimator, along with 95% CIs. 
Cause-specific hazard Cox regression models will be fit for the cause-specific hazard for the 
2 competing risks. The estimated cause-specific hazard ratios will be presented along with 
95% CIs. 
14.3.7 Analysis of primary endpoint 
The primary endpoint will be analysed as described in Sections 14.3.6.1 and 14.3.6.2. The 
confirmatory one-sided (superiority) hypothesis, described in Section 14.3.5, will be tested for 
delgocitinib cream 20 mg/g vs. cream vehicle based on the primary analysis for the primary 
estimand. 
14.3.8 Analysis of key secondary endpoints 
The confirmatory hypotheses for key secondary endpoints, presented in Sections 14.3.6.1 
and 14.3.5, will be tested based on the primary analyses for the primary estimand strategies 
described in Sections 14.3.6.2 and 14.3.6.3. 
Panel 24 provides an overview of the primary analysis of the key secondary endpoints related 
to the primary and supplementary estimands. For further details, including sensitivity 
analysis, refer to Section 14.3.6. 
 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 121 of 160 
 
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 
 
Panel 24: Overview of the primary analysis of the key secondary endpoints related to the primary and supplementary estimands 
Key secondary endpoint 
Type of 
endpoint 
Primary estimand 
First supplementary estimand 
Second supplementary estimand 
Strategy to 
handle IEs 
Handling of 
missing data 
and data 
collected 
after IE 
Strategy to 
handle IEs 
Handling of 
missing data and 
data collected after 
IE 
Strategy to 
handle IEs 
Handling of 
missing data and 
data collected 
after IE 
Reduction of HESD itch score 
(weekly average) of ≥4 points from 
baseline at Week 161 
Binary 
Composite 
 
Non-response 
imputation 
Pandemic 
modified 
composite 
Independent of the 
COVID-19 
pandemic: non-
response imputation 
 
Related to the 
COVID-19 
pandemic: MI 
assuming MAR 
within treatment 
group 
Treatment 
policy 
Independent of the 
COVID-19 
pandemic: MI 
assuming MAR 
within treatment 
group and 
occurrence of IEs 
 
Related to the 
COVID-19 
pandemic: MI 
assuming MAR 
within treatment 
group 
Reduction of HESD score (weekly 
average) of ≥4 points from baseline 
at Week 162 
IGA-CHE TS at Week 8 
Binary 
Composite 
 
Non-response 
imputation 
Pandemic 
modified 
composite 
Independent of the 
COVID-19 
pandemic: non-
response imputation 
 
Related to the 
COVID-19 
pandemic: MI 
assuming MAR 
within treatment 
group 
Not 
applicable 
Not applicable 
IGA-CHE TS at Week 4 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 122 of 160 
 
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 
 
Key secondary endpoint 
Type of 
endpoint 
Primary estimand 
First supplementary estimand 
Second supplementary estimand 
Strategy to 
handle IEs 
Handling of 
missing data 
and data 
collected 
after IE 
Strategy to 
handle IEs 
Handling of 
missing data and 
data collected after 
IE 
Strategy to 
handle IEs 
Handling of 
missing data and 
data collected 
after IE 
Reduction of HESD itch score 
(weekly average) of ≥4 points from 
baseline at Week 81 
Binary 
Composite 
 
Non-response 
imputation 
Pandemic 
modified 
composite 
Independent of the 
COVID-19 
pandemic: non-
response imputation 
 
Related to the 
COVID-19 
pandemic: MI 
assuming MAR 
within treatment 
group 
Not 
applicable 
Not applicable 
Reduction of HESD itch score 
(weekly average) of ≥4 points from 
baseline at Week 41 
Reduction of HESD itch score 
(weekly average) of ≥4 points from 
baseline at Week 21 
Reduction of HESD score (weekly 
average) of ≥4 points from baseline 
at Week 82 
Reduction of HESD score (weekly 
average) of ≥4 points from baseline 
at Week 42 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 123 of 160 
 
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 
 
Key secondary endpoint 
Type of 
endpoint 
Primary estimand 
First supplementary estimand 
Second supplementary estimand 
Strategy to 
handle IEs 
Handling of 
missing data 
and data 
collected 
after IE 
Strategy to 
handle IEs 
Handling of 
missing data and 
data collected after 
IE 
Strategy to 
handle IEs 
Handling of 
missing data and 
data collected 
after IE 
Reduction of HESD pain score 
(weekly average) of ≥4 points from 
baseline at Week 163 
Binary 
Composite 
Non-response 
imputation 
Pandemic 
modified 
composite 
Independent of the 
COVID-19 
pandemic: non-
response imputation 
 
Related to the 
COVID-19 
pandemic: MI 
assuming MAR 
within treatment 
group 
Treatment 
policy 
Independent of the 
COVID-19 
pandemic: MI 
assuming MAR 
within treatment 
group and 
occurrence of IEs 
 
Related to the 
COVID-19 
pandemic: MI 
assuming MAR 
within treatment 
group 
Reduction of HESD pain score 
(weekly average) of ≥4 points from 
baseline at Week 83 
Binary 
Composite 
 
Non-response 
imputation 
Pandemic 
modified 
composite 
Independent of the 
COVID-19 
pandemic: non-
response imputation 
 
Related to the 
COVID-19 
pandemic: MI 
assuming MAR 
within treatment 
group 
Not 
applicable 
Not applicable 
Reduction of HESD pain score 
(weekly average) of ≥4 points from 
baseline at Week 43 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 124 of 160 
 
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 
 
Key secondary endpoint 
Type of 
endpoint 
Primary estimand 
First supplementary estimand 
Second supplementary estimand 
Strategy to 
handle IEs 
Handling of 
missing data 
and data 
collected 
after IE 
Strategy to 
handle IEs 
Handling of 
missing data and 
data collected after 
IE 
Strategy to 
handle IEs 
Handling of 
missing data and 
data collected 
after IE 
HECSI-90 at Week 16 
Binary 
Composite 
 
Non-response 
imputation 
Pandemic 
modified 
composite 
Independent of the 
COVID-19 
pandemic: non-
response imputation 
 
Related to the 
COVID-19 
pandemic: MI 
assuming MAR 
within treatment 
group 
Treatment 
policy 
 
Independent of the 
COVID-19 
pandemic: MI 
assuming MAR 
within treatment 
group and 
occurrence of IEs 
 
Related to the 
COVID-19 
pandemic: MI 
assuming MAR 
within treatment 
group 
HECSI-75 at Week 16 
HECSI-75 at Week 8 
Binary 
Composite 
 
Non-response 
imputation 
Pandemic 
modified 
composite 
Independent of the 
COVID-19 
pandemic: non-
response imputation 
 
Related to the 
COVID-19 
pandemic: MI 
assuming MAR 
within treatment 
group 
Not 
applicable 
Not applicable 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 125 of 160 
 
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 
 
Key secondary endpoint 
Type of 
endpoint 
Primary estimand 
First supplementary estimand 
Second supplementary estimand 
Strategy to 
handle IEs 
Handling of 
missing data 
and data 
collected 
after IE 
Strategy to 
handle IEs 
Handling of 
missing data and 
data collected after 
IE 
Strategy to 
handle IEs 
Handling of 
missing data and 
data collected 
after IE 
Percentage change in HECSI score 
from baseline to Week 16 
Continuous Composite 
WOCF 
(including 
baseline 
value) 
Pandemic 
modified 
composite 
Independent of the 
COVID-19 
pandemic: WOCF 
(including baseline 
value) 
 
Related to the 
COVID-19 
pandemic: MI 
assuming MAR 
within treatment 
group 
Treatment 
policy 
Independent of the 
COVID-19 
pandemic: MI 
assuming MAR 
within treatment 
group and 
occurrence of IEs 
 
Related to the 
COVID-19 
pandemic: MI 
assuming MAR 
within treatment 
group 
Change in DLQI score from 
baseline to Week 16 
Change in HESD score (weekly 
average) from baseline to Week 16 
Change in HESD itch score (weekly 
average) from baseline to Week 16 
Change in HESD pain score 
(weekly average) from baseline to 
Week 16 
Change in HEIS score from baseline 
to Week 16 
Continuous 
Composite 
WOCF 
(including 
baseline 
value) 
Pandemic 
modified 
composite 
Independent of the 
COVID-19 
pandemic: WOCF 
(including baseline 
value) 
 
Related to the 
COVID-19 
pandemic: MI 
assuming MAR 
within treatment 
group 
Not 
applicable 
Not applicable 
Change in HEIS PDAL score from 
baseline to Week 16 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 126 of 160 
 
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 
 
Key secondary endpoint 
Type of 
endpoint 
Primary estimand 
First supplementary estimand 
Second supplementary estimand 
Strategy to 
handle IEs 
Handling of 
missing data 
and data 
collected 
after IE 
Strategy to 
handle IEs 
Handling of 
missing data and 
data collected after 
IE 
Strategy to 
handle IEs 
Handling of 
missing data and 
data collected 
after IE 
Reduction of DLQI score of 
≥4 points from baseline at Week 164 
Binary 
Composite 
Non-response 
imputation 
Pandemic 
modified 
composite 
Independent of the 
COVID-19 
pandemic: non-
response imputation 
 
Related to the 
COVID-19 
pandemic: MI 
assuming MAR 
within treatment 
group 
Treatment 
policy 
 
Independent of the 
COVID-19 
pandemic: MI 
assuming MAR 
within treatment 
group and 
occurrence of IEs 
 
Related to the 
COVID-19 
pandemic: MI 
assuming MAR 
within treatment 
group 
1) Among subjects with a baseline HESD itch score (weekly average) ≥4 points. 
2) Among subjects with a baseline HESD score (weekly average) of ≥4 points. 
3) Among subjects with a baseline HESD pain score (weekly average) of ≥4 points. 
4) Among subjects with a baseline DLQI score of ≥4 points. 
Abbreviations: COVID-19 = coronavirus disease 2019; DLQI = 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; HEIS = 
Hand Eczema Impact Scale; 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; IMP = investigational medicinal product; 
MAR = missing at random; MI = multiple imputation; PDAL = Proximal Daily Activity Limitations; WOCF = worst observation carried forward.
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 127 of 160 
 
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 
 
14.3.9 Analysis of exploratory endpoints 
The analysis of exploratory endpoints will be based on the FAS. 
The analysis of exploratory endpoints will resemble the primary analysis for the primary 
estimand related to a specific endpoint type: binary, continuous, or time to event. For details 
refer to Section 14.3.6 (for binary endpoints refer to Section 14.3.6.2, for continuous 
endpoints refer to Section 14.3.6.3, and for time-to-event endpoints refer to Section 14.3.6.4). 
Panel 25 provides an overview of the statistical analysis of the exploratory endpoints. 
Panel 25: Overview of the statistical analysis of exploratory endpoints 
Endpoints 
Type of endpoint 
Primary estimand 
Strategy to 
handle IEs 
Handling of 
missing data and 
data collected 
after IE 
Efficacy 
IGA-CHE TS at Weeks 1, 2, and 12 
Binary 
Composite 
Non-response 
imputation 
HECSI-75 at Weeks 1, 2, 4, and 12 
Binary 
Composite 
Non-response 
imputation 
HECSI-90 at Weeks 1, 2, 4, 8, and 12 
Binary 
Composite 
Non-response 
imputation 
Percentage change in HECSI score from 
baseline to Weeks 1, 2, 4, 8, and 12 
Continuous 
Composite 
WOCF (including 
baseline value) 
Reduction of HESD itch score (weekly average) 
of ≥4 points from baseline at Weeks 1 and 121 
Binary 
Composite 
Non-response 
imputation 
Reduction of HESD itch score (weekly average) 
of ≥3 points from baseline at Weeks 1, 2, 4, 8, 
12, and 162 
Binary 
Composite 
Non-response 
imputation 
Time to reduction of HESD itch score (weekly 
average) of ≥4 points1 
Time to event 
While on 
treatment 
Not applicable 
Change in HESD itch score (weekly average) 
from baseline to Weeks 1, 2, 4, 8, and 12 
Continuous 
Composite 
WOCF (including 
baseline value) 
Reduction of HESD score (weekly average) of 
≥4 points from baseline at Weeks 1, 2, and 123 
Binary 
Composite 
Non-response 
imputation 
Reduction of HESD score (weekly average) of 
≥3 points from baseline at Weeks 1, 2, 4, 8, 12, 
and 164 
Binary 
Composite 
Non-response 
imputation 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 128 of 160 
 
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 
 
Endpoints 
Type of endpoint 
Primary estimand 
Strategy to 
handle IEs 
Handling of 
missing data and 
data collected 
after IE 
Time to reduction of HESD score (weekly 
average) of ≥4 points3 
Time to event 
While on 
treatment 
Not applicable 
Change in HESD score (weekly average) from 
baseline to Weeks 1, 2, 4, 8, and 12 
Continuous 
Composite 
WOCF (including 
baseline value) 
Reduction of HESD pain score (weekly 
average) of ≥4 points from baseline at Weeks 1, 
2, and 125 
Binary 
Composite 
Non-response 
imputation 
Reduction of HESD pain score (weekly 
average) of ≥3 points from baseline at Weeks 1, 
2, 4, 8, 12, and 166 
Binary 
Composite 
Non-response 
imputation 
Time to reduction of HESD pain score (weekly 
average) of ≥4 points5 
Time to event 
While on 
treatment 
Not applicable 
Change in HESD pain score (weekly average) 
from baseline to Weeks 1, 2, 4, 8, and 12 
Continuous 
Composite 
WOCF (including 
baseline value) 
Change in HESD (weekly average for each 
individual symptom [excluding itch and pain]) 
score from baseline to Week 16 
Continuous 
Composite 
WOCF (including 
baseline value) 
Health-related quality of life and efficacy 
Change in HEIS score from baseline to 
Weeks 1, 2, 4, 8, and 12 
Continuous 
Composite 
WOCF (including 
baseline value) 
Reduction of HEIS score of ≥1.5 points at 
Weeks 1, 2, 4, 8, 12, and 167 
Binary 
Composite 
Non-response 
imputation 
Change in HEIS PDAL score from baseline to 
Weeks 1, 2, 4, 8, and 12 
Continuous 
Composite 
WOCF (including 
baseline value) 
Reduction of HEIS PDAL score of ≥1.5 points 
at Weeks 1, 2, 4, 8, 12, and 168 
Binary 
Composite 
Non-response 
imputation 
Change in HEIS (each individual domain 
[excluding PDAL]) score from baseline to 
Weeks 1, 2, 4, 8, 12, and 16 
Continuous 
Composite 
WOCF (including 
baseline value) 
Reduction in DLQI score of ≥4 points at 
Weeks 1, 4, 8, and 129 
Binary 
Composite 
Non-response 
imputation 
Change in DLQI score from baseline to 
Weeks 1, 4, 8, and 12 
Continuous 
Composite 
WOCF (including 
baseline value) 
Change in EQ-5D-5L index score from baseline 
to Weeks 1, 4, 8, 12, and 16 
Continuous 
Composite 
WOCF (including 
baseline value) 
Change in EQ-5D-5L visual analogue scale 
score from baseline to Weeks 1, 4, 8, 12, and 16 
Continuous 
Composite 
WOCF (including 
baseline value) 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 129 of 160 
 
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 
 
Endpoints 
Type of endpoint 
Primary estimand 
Strategy to 
handle IEs 
Handling of 
missing data and 
data collected 
after IE 
Change in WPAI:CHE absenteeism score from 
baseline to Week 4, 8, and 1610 
Continuous 
Composite 
WOCF (including 
baseline value) 
Change in WPAI:CHE presenteeism score from 
baseline to Week 4, 8, and 1610 
Continuous 
Composite 
WOCF (including 
baseline value) 
Change in WPAI:CHE work productivity loss 
score from baseline to Week 4, 8, and 1610 
Continuous 
Composite 
WOCF (including 
baseline value) 
Change in WPAI:CHE activity impairment 
score from baseline to Week 4, 8, and 16 
Continuous 
Composite 
WOCF (including 
baseline value) 
1) Among subjects with a baseline HESD itch score (weekly average) ≥4 points. 
2) Among subjects with a baseline HESD itch score (weekly average) ≥3 points. 
3) Among subjects with a baseline HESD score (weekly average) ≥4 points. 
4) Among subjects with a baseline HESD 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 HEIS score ≥1.5 points. 
8) Among subjects with a baseline HEIS PDAL score ≥1.5 points. 
9) Among subjects with a baseline DLQI score ≥4 points. 
10) Among subjects with paid work at baseline. 
Abbreviations: DLQI = 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; HEIS = Hand Eczema Impact Scale; 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; IMP = investigational medicinal product; MAR = missing at random; MI = multiple imputation; 
PDAL = Proximal Daily Activity Limitations; WOCF = worst observation carried forward; WPAI:CHE = 
Work Productivity and Activity Impairment: Chronic Hand Eczema. 
14.3.10 Analysis of patient-reported outcomes 
The 3 PGI-S scores (Itch PGI-S, Pain PGI-S, and HESD PGI-S), the 3 PGI-C scores (Itch 
PGI-C, Pain PGI-C, and HESD PGI-C), and PaGA score will be summarised by visit for each 
treatment group. 
14.3.11 Analysis of pharmacodynamics 
The analysis of pharmacodynamic endpoints will be documented in a separate biomarker 
statistical analysis plan before breaking the randomisation code. The pharmacodynamic 
results will be described in an addendum to the CTR. 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 130 of 160 
 
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 
 
14.3.12 Analysis of safety 
The analysis of safety will be based on the safety analysis set. 
14.3.12.1 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 dose 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. 
AEs will be summarised in terms of the number of subjects with at least 1 event, the 
percentage of subjects with at least 1 event, the number of events, and the event rate per 
100 person years of observation time. 
Related AEs are defined as AEs for which the investigator has not described the causal 
relationship to IMP as ‘not related’. 
An overall summary presenting any treatment-emergent AEs, deaths, SAEs, permanent 
discontinuations from IMP and/or withdrawals from the trial due to AEs, treatment-related 
AEs, and severe AEs will be presented. 
Tabulations by SOC and preferred term will be presented for all AEs, SAEs, related AEs, 
AESIs, AEs leading to withdrawal from trial, and AEs leading to permanent discontinuation 
of IMP. In addition, all AEs will be presented by severity and causal relationship to IMP, 
respectively. If an AE worsens in severity, the severity will be reported as the most severe 
recording for that AE. 
SAEs will be evaluated separately and a narrative will be given. 
AESIs will be listed by treatment group. No narratives will be given. 
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 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 131 of 160 
 
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 
 
the subject, treatment received at the time of AE onset, the AE preferred and reported terms, 
causality and severity of the AE, the action taken with the IMP, AE outcome, start and stop 
date of AE, duration of AE, and number of days since first and last IMP administration. No 
narratives will be given. 
Other events (medication error, misuse, and abuse of IMP) will be tabulated and listed. No 
narratives will be given. 
14.3.12.2  Vital signs and physical examination 
For vital signs (resting blood pressure, pulse, and body temperature), the absolute values at 
baseline and Week 16 as well as the change from baseline to Week 16 will be summarised for 
each treatment group. 
14.3.12.3 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). 
14.3.12.4 Assessment of local tolerability 
Assessment of local tolerability will be summarised by visit and treatment group. 
14.3.13 Interim analysis 
No interim analysis is planned. 
14.3.14 General principles 
Significance tests, for binary and continuous endpoints, will be one-sided using the 2.5% 
significance level. The Gray’s test, used for time-to-event endpoints, will be two-sided using a 
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). 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 132 of 160 
 
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 
 
Categorical data will be summarised using the number and percentage of subjects in each 
category. Continuous data will be summarised using the mean, median, SD, 1st quartile, 
3rd quartile, minimum, and maximum values. 
Baseline measurements will be defined as the latest available observation at or prior to the 
date of randomisation. 
All the analyses specified in the protocol will be reviewed in relation to the blinded data 
actually obtained, and the statistical analysis plan will be finalised before breaking the 
randomisation code. 
Any changes from the statistical analyses planned in this clinical trial protocol will be 
described and justified in a protocol amendment, the statistical analysis plan, and/or in the 
CTR, dependent on the type of change. 
14.3.15 Handling of missing values 
The methods for handling of missing values in the different analyses are described in 
Section 14.3.6. 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 133 of 160 
 
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 
 
15 References 
1. 
Diepgen TL, Andersen KE, Chosidow O, Coenraads PJ, Elsner P, English J, Fartasch 
M, Gimenez-Arnau A, Nixon R, Sasseville D, Agner T. Guidelines for diagnosis, 
prevention and treatment of hand eczema. J Dtsch Dermatol Ges. 2015;13(1):e1-22. 
 
2. 
Agner T, Aalto-Korte K, Andersen KE, Foti C, Gimenez-Arnau A, Goncalo M, 
Goossens A, Le Coz C, Diepgen TL. Classification of hand eczema. J Eur Acad 
Dermatol Venereol. 2015;29(12):2417-2422. 
 
3. 
Cronin E. Clinical patterns of hand eczema in women. Contact Dermatitis. 
1985;13(3):153-161. 
 
4. 
Johansen JD, Hald M, Andersen BL, Laurberg G, Danielsen A, Avnstorp C, Kristensen 
B, Kristensen O, Kaaber K, Thormann J, et al. Classification of hand eczema: clinical 
and aetiological types. Based on the guideline of the Danish Contact Dermatitis 
Group. Contact Dermatitis. 2011;65(1):13-21. 
 
5. 
Apfelbacher C, Molin S, Weisshaar E, Bauer A, Elsner P, Mahler V, Weiss M, Ruzicka 
T, Diepgen TL. Characteristics and provision of care in patients with chronic hand 
eczema: updated data from the CARPE registry. Acta Derm Venereol. 2014;94(2):163-
167. 
 
6. 
Thyssen JP, Johansen JD, Linneberg A, Menné T. The epidemiology of hand eczema 
in the general population--prevalence and main findings. Contact Dermatitis. 
2010;62(2):75-87. 
 
7. 
Thyssen JP, Carlsen BC, Menne T, Linneberg A, Nielsen NH, Meldgaard M, Szecsi 
PB, Stender S, Johansen JD. Filaggrin null mutations increase the risk and persistence 
of hand eczema in subjects with atopic dermatitis: results from a general population 
study. Br J Dermatol. 2010;163(1):115-120. 
 
8. 
Mortz CG, Bindslev-Jensen C, Andersen KE. Hand eczema in The Odense 
Adolescence Cohort Study on Atopic Diseases and Dermatitis (TOACS): prevalence, 
incidence and risk factors from adolescence to adulthood. Br J Dermatol. 
2014;171(2):313-323. 
 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 134 of 160 
 
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 
 
9. 
Anveden I, Wrangsjo K, Jarvholm B, Meding B. Self-reported skin exposure -- a 
population-based study. Contact Dermatitis. 2006;54(5):272-277. 
 
10. 
Hald M, Berg ND, Elberling J, Johansen JD. Medical consultations in relation to 
severity of hand eczema in the general population. Br J Dermatol. 2008;158(4):773-
777. 
 
11. 
Lind ML, Albin M, Brisman J, Kronholm Diab K, Lillienberg L, Mikoczy Z, Nielsen 
J, Rylander L, Toren K, Meding B. Incidence of hand eczema in female Swedish 
hairdressers. Occup Environ Med. 2007;64(3):191-195. 
 
12. 
Meding B, Jarvholm B. Incidence of hand eczema - a population-based retrospective 
study. J Invest Dermatol. 2004;122(4):873-877. 
 
13. 
Fowler JF, Ghosh A, Sung J, Emani S, Chang J, Den E, Thorn D, Person J, Duh MS. 
Impact of chronic hand dermatitis on quality of life, work productivity, activity 
impairment, and medical costs. J Am Acad Dermatol. 2006;54(3):448-457. 
 
14. 
Cortesi PA, Scalone L, Belisari A, Bonamonte D, Cannavo SP, Cristaudo A, De Pita O, 
Gallo R, Giannetti A, Gola M, et al. Cost and quality of life in patients with severe 
chronic hand eczema refractory to standard therapy with topical potent corticosteroids. 
Contact Dermatitis. 2014;70(3):158-168. 
 
15. 
Augustin M, Kuessner D, Purwins S, Hieke K, Posthumus J, Diepgen TL. Cost-of-
illness of patients with chronic hand eczema in routine care: results from a multicentre 
study in Germany. Br J Dermatol. 2011;165(4):845-851. 
 
16. 
van Gils RF, Bosmans JE, Boot CR, Rustemeyer T, van Mechelen W, van der Valk PG, 
Anema JR. Economic evaluation of an integrated care programme for patients with 
hand dermatitis. Contact Dermatitis. 2013;69(3):144-152. 
 
17. 
Cvetkovski RS, Rothman KJ, Olsen J, Mathiesen B, Iversen L, Johansen JD, Agner T. 
Relation between diagnoses on severity, sick leave and loss of job among patients with 
occupational hand eczema. Br J Dermatol. 2005;152(1):93-98. 
 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 135 of 160 
 
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 
 
18. 
Lerbaek A, Kyvik KO, Ravn H, Menne T, Agner T. Clinical characteristics and 
consequences of hand eczema - an 8-year follow-up study of a population-based twin 
cohort. Contact Dermatitis. 2008;58(4):210-216. 
 
19. 
Cazzaniga S, Apfelbacher C, Diepgen T, Ofenloch RF, Weisshaar E, Molin S, Bauer A, 
Mahler V, Elsner P, Schmitt J, et al. Patterns of chronic hand eczema: a semantic map 
analysis of the CARPE registry data. Br J Dermatol. 2018;178(1):229-237. 
 
20. 
Herschel S, Schmitt J, Bauer A. Satisfaction with medical treatment in patients with 
hand dermatitis - a cross-sectional study. J Dtsch Dermatol Ges. 2013;11(10):1007-
1013. 
 
21. 
Pedersen MB, Skov L, Menne T, Johansen JD, Olsen J. Gene expression time course 
in the human skin during elicitation of allergic contact dermatitis. J Invest Dermatol. 
2007;127(11):2585-2595. 
 
22. 
Brunner PM, Guttman-Yassky E, Leung DY. The immunology of atopic dermatitis and 
its reversibility with broad-spectrum and targeted therapies. J Allergy Clin Immunol. 
2017;139(4S):S65-S76. 
 
23. 
Gittler JK, Krueger JG, Guttman-Yassky E. Atopic dermatitis results in intrinsic 
barrier and immune abnormalities: implications for contact dermatitis. Journal of 
Allergy and Clinical Immunology. 2013;131(2):300-313. 
 
24. 
Stiefel. Toctino. Summary of Product Characteristics (SmPC). 2020. 
 
25. 
Christoffers WA, Coenraads PJ, Svensson Å, Diepgen TL, Dickinson‐Blok JL, Xia J, 
Williams HC. Interventions for hand eczema. Cochrane Database of Systematic 
Reviews. 2019;(4). 
 
26. 
Schwartz DM, Kanno Y, Villarino A, Ward M, Gadina M, O'Shea JJ. JAK inhibition as 
a therapeutic strategy for immune and inflammatory diseases. Nat Rev Drug Discov. 
2017;16(12):843-862. 
 
27. 
Amano W, Nakajima S, Kunugi H, Numata Y, Kitoh A, Egawa G, Dainichi T, Honda 
T, Otsuka A, Kimoto Y, et al. The Janus kinase inhibitor JTE-052 improves skin 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 136 of 160 
 
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 
 
barrier function through suppressing signal transducer and activator of transcription 3 
signaling. J Allergy Clin Immunol. 2015;136(3):667-677.e667. 
 
28. 
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. 
 
29. 
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. 
 
30. 
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. 
 
31. 
LEO Pharma. Delgocitinib cream Investigator's Brochure (IB) Edition 4.0. 2021. 
 
32. 
EMA. European Medicines Agency. Guidance on the Management of Clinical Trials 
during the COVID-19 (Coronavirus) Pandemic. Version 3. 2020. 
 
33. 
FDA. FDA Guidance on Conduct of Clinical Trials of Medical Products during 
COVID-19 Public Health Emergency. 2020. 
 
34. 
Schulz KF, Altman DG, Moher D. CONSORT 2010 Statement: updated guidelines for 
reporting parallel group randomised trials. BMC Med. 2010;8:18. 
 
35. 
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. 
 
36. 
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. 
 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 137 of 160 
 
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 
 
37. 
Johansen JD, Aalto-Korte K, Agner T, Andersen KE, Bircher A, Bruze M, Cannavó A, 
Giménez-Arnau A, Gonçalo M, Goossens A, et al. European Society of Contact 
Dermatitis guideline for diagnostic patch testing - recommendations on best practice. 
Contact Dermatitis. 2015;73(4):195-221. 
 
38. 
FDA. Food and Drug Administration. Methods to Identify What is Important to 
Patients & Select, Develop or Modify Fit-for-Purpose Clinical Outcomes Assessments. 
Attachment to Discussion Document for Patient-Focused Drug Development Public 
Workshop on Guidance 3. 2018. 
 
39. 
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. 
 
40. 
EuroQol--a new facility for the measurement of health-related quality of life. Health 
Policy. 1990;16(3):199-208. 
 
41. 
Reilly MC, Zbrozek AS, Dukes EM. The validity and reproducibility of a work 
productivity and activity impairment instrument. Pharmacoeconomics. 1993;4(5):353-
365. 
 
42. 
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. 
 
43. 
European Parliament Union, European CoT. Directive 2001/20/EC of the European 
Parliament 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. 
 
44. 
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. 
 
45. 
CIOMS. International Ethical Guidelines for Health-related Research Involving 
Humans. Council for International Organizations of Medical Sciences. 4th. Geneva. 
2016. 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 138 of 160 
 
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 
 
 
46. 
EFPIA. European Federation of Pharmaceutical Industries and Associations. 
Principles for Responsible Clinical Trial Data Sharing. 2013. 
 
 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 139 of 160 
 
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 
 
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 (44). 
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 11.5.4.2). 
Serious adverse event definition 
An SAE is any untoward medical occurrence that: 
• Results in death. 
• Is life-threatening – at risk of death at the time of the SAE (not an event that 
hypothetically might have caused death if more severe). 
• Requires in-patient hospitalisation or prolongation of existing hospitalisation*. 
• Results in persistent or significant disability or incapacity. 
• Is a congenital anomaly or birth defect. 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 140 of 160 
 
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 
 
• Is a medically important condition. Events that may not be immediately life-threatening or 
result in death or hospitalisation but may jeopardise the subject or may require 
intervention to prevent one of the other outcomes listed in the definition above. Examples 
are intensive treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias, and convulsions that do not result in hospitalisation, development of drug 
dependency, or drug abuse. 
 
*Hospitalisation for procedures or treatments planned prior to the subject consented to trial 
participation does not constitute an AE and should therefore not be reported as 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 concern 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. 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 141 of 160 
 
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 
 
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 severity change, should be recorded. However, if an AE with onset prior to 
initiation of IMP worsens after administration of IMP, 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. 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 142 of 160 
 
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 
 
Possibly 
related 
 
Follows a reasonable temporal sequence from the administration of the 
IMP. 
 
Could also be reasonably explained by the subject’s clinical state, 
environmental or toxic factors, or other therapies administered to the 
subject. 
 
Follows a known pattern of response to the IMP. 
Not related 
 
Does not follow a reasonable temporal sequence from administration of the 
IMP. 
 
Is better explained by other factors like the subject’s clinical state, 
environmental or toxic factors, or other therapies administered to the 
subject. 
 
Does not reappear or worsen upon re-challenge. 
 
Does not follow a known pattern of response to the IMP. 
 
Outcome 
The outcome of the event according to the investigator’s clinical judgement should be 
classified using the categories below. 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 143 of 160 
 
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 
 
Recovered/ 
resolved 
The event has stopped. The stop date of the event must be recorded. 
Recovering/ 
resolving 
The subject is clearly recovering from an event. The event is not yet 
completely resolved.  
Not 
recovered/ 
not resolved 
Event is still ongoing.  
Recovered/ 
resolved 
with 
sequelae 
The event has reached a state where no further changes are expected and the 
residual symptoms are assumed to persist. An example is hemiparesis after 
stroke. 
 
The stop date of the event must be recorded. In case of an SAE, the sequelae 
should be specified. 
Fatal 
The subject has died as a consequence of the event. Date of death is recorded 
as stop date for the AE. 
Unknown 
Unknown to investigator, e.g. subject lost to follow-up. 
 
LEO Pharma definitions versus CDISC definitions 
Note that as per the above definition, LEO Pharma uses ‘recovered/resolved’ only if an event 
has actually stopped. According to the CDISC definition, the category ‘recovered/resolved’ 
also includes events which have improved. However, following the LEO Pharma definitions 
above, such an improved event will instead be classified as ‘not recovered/not resolved’ or 
‘recovering/resolving’. 
Similarly, it should be noted that as per the above definition, LEO Pharma uses 
‘recovered/resolved with sequelae’ only if an event has reached a state where the residual 
symptoms are assumed to persist. According to CDISC, an event is considered ‘with 
sequelae’, if it has ‘retained pathological conditions’. Consequently, it is likely that some of 
the events classified by LEO Pharma with the outcome ‘recovered/resolved with sequelae’ 
could have been classified with the outcome ‘recovered/resolved’ according to the CDISC 
definition. 
In summary, the definitions used by LEO Pharma are more conservative than those used by 
CDISC. 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 144 of 160 
 
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 
 
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 (29) and Council for International Organizations of 
Medical Sciences (CIOMS) International Ethical Guidelines (45). 
• Current version of applicable International Council for Harmonisation Good Clinical 
Practice (ICH GCP) Guidelines (30). 
• 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 form(s), or advertisements) will be submitted to the IRB/IEC. These 
documents must be reviewed and approved by the IRB/IEC before the trial is initiated. 
Any amendments to the protocol must be approved by/receive favourable opinion from 
relevant regulatory authorities and IRBs/IECs, as required, prior to implementation. 
The principal investigator will be responsible for the following, if required by local 
legislation: 
• Providing written summaries of the status of the trial to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC. 
• Notifying the local IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures. 
• Providing oversight of the conduct of the trial at the trial site and ensuring adherence to 
applicable national and international legislation. 
Appendix 3B: Informed consent process 
Subjects will receive written and verbal information concerning the clinical trial. This 
information will emphasise that participation in the clinical trial is voluntary and that the 
subject may withdraw from the clinical trial at any time and for any reason. All subjects will 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 145 of 160 
 
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 
 
be given an opportunity to ask questions and will be given sufficient time to consider before 
consenting. 
The subject’s signed and dated informed consent to participate in the clinical trial will be 
obtained prior to any clinical trial-related procedure being carried out in accordance with 
ICH GCP and all applicable laws and regulations. The authorised person obtaining the 
informed consent must also sign the ICF. 
Subjects will be re-consented to the most current version of the ICF(s) during their 
participation in the trial, if required. 
A copy of the ICF(s) must be provided to the subject. 
Subject card 
At screening, subjects will be provided with a card stating that they are participating in a 
clinical trial and which contains contact address(es) and telephone number(s) of relevant trial 
site staff including the number for the investigator in case of emergency situations. The 
subject card also includes a local telephone number for the emergency unblinding CRO to be 
used if the investigator or delegated site staff cannot be reached or if unblinding in the IRT 
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. 
Trial subjects must be informed that their personal trial-related data will be used by LEO 
Pharma in accordance with local data protection law. 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 146 of 160 
 
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 
 
Trial subjects must be informed and consent to that their medical records may be examined by 
clinical quality assurance auditors or other authorised personnel appointed by LEO Pharma, 
by appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
Trial subjects must be informed that LEO Pharma might keep their trial-related data for as 
long as they are useful for developing treatments for the disease or other diseases and future 
research. 
Processing of personal data 
This protocol specifies the personal data on trial subjects (e.g. race, ethnicity, age, sex, health 
condition, medical history, test results, etc.) which shall be collected as part of the clinical trial 
and processed during and after trial completion. 
Personal data collected as part of the clinical trial will be transferred to/from the 
institution/investigator, LEO Pharma, and third parties acting on behalf of LEO Pharma. 
Processing of personal data on behalf of LEO Pharma requires a written agreement between 
LEO Pharma and the relevant party which covers collection, processing, and transfer of 
personal data in the clinical trial. In certain cases, an agreement on transfer of personal data 
may also be required. 
Investigators and LEO Pharma must ensure that collection, processing, and transfer of 
personal data are in compliance with applicable legislation on data protection and privacy, 
including but not limited to the EU General Data Privacy Regulation. 
Subjects must be asked to consent to the collection, processing, and transfer of their personal 
data to EU and non-EU countries for the purpose of conducting the clinical trial, research and 
development of new or existing products/services, improving existing products/services, 
applying for marketing authorisations for products/services, marketing of products/services, 
and other related activities. 
LEO Pharma has obtained the necessary authorisations for the processing of personal data 
collected in the trial. 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 147 of 160 
 
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 
 
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 generated by the site should as a general rule be recorded in the subject’s medical 
record or other defined document normally used at the trial site from which the data will be 
transcribed into the eCRF. 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 physicians. 
The date and time of 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 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 148 of 160 
 
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 
 
staff should be available for discussions at monitoring visits and between monitoring visits 
(e.g. by telephone). 
Protocol compliance 
Protocol deviations will be documented and notified to the investigator. Protocol deviations 
will be assessed by LEO Pharma and major 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 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. 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 149 of 160 
 
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 
 
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 30-Mar-2018 or newer was used for definition of 
controlled terminology used throughout this protocol. Standard data tabulation model 
(SDTM) version 1.4 will be used for data tabulations. 
Archiving of trial documentation 
The investigator at each trial site must make arrangements to store the essential trial 
documents, including the investigator trial file (30). 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. 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 150 of 160 
 
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 
 
For archiving purposes, each investigator will be supplied with an electronic copy of the 
eCRFs and ePRO data for all screened subjects at the trial site. This is done after completion 
of the trial and before access to the eCRF/ePRO is revoked. Audit trail information will be 
included. eCRFs and ePRO data must be available for inspection by authorised 
representatives from LEO Pharma, from regulatory authorities and/or IRBs/IECs. 
Appendix 3E: Registration, reporting, and publication policy 
Trial disclosure 
LEO Pharma is committed to be transparent with respect to its clinical trials. 
Basic information of this clinical trial will be registered in the global data registry, 
www.ClinicalTrials.gov. before the first subject enters the trial. The trial may also become 
registered in other online data registries, according to applicable law and regulations. 
Results of this clinical trial will be posted on leopharmatrials.com in accordance with our 
Position on Public Access to Clinical Trial Information within approximately 12 months of 
trial completion. Trial results may also become reported in www.ClinicalTrials.gov, 
www.clinicaltrialsregister.eu, and national data registries in accordance with applicable law 
and regulations after clinical trial completion or premature termination. 
Publications 
A publication can be a journal manuscript, an abstract, a poster/presentation for a congress, or 
any openly accessible material. 
A primary publication including the primary results of the trial (i.e. the results of the primary 
endpoint[s]) will be submitted for peer-reviewed publication within 12 months of database 
lock. LEO Pharma is responsible for this publication. All authors (trial responsible employees 
and/or applicable investigators and advisors) must fulfill the criteria for authorship from the 
International Committee of Medical Journal Editors (ICMJE). 
The investigators may reach out to LEO Pharma to publish results that are not included in the 
primary publication. The investigator and LEO Pharma should agree on terms for data sharing 
and collaboration on such publications, as well as timing for release of the publication(s). In 
all cases, LEO Pharma retains the right to review and comment on the draft publication in due 
time before submission, but the investigator is not required to revise the draft accordingly, 
unless it discloses company confidential information or protected personal information, or 
may compromise intellectual property rights of LEO Pharma. 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 151 of 160 
 
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 
 
LEO Pharma may give researchers outside LEO Pharma access to anonymised data from this 
trial for further research according to the principles outlined by the European Federation of 
Pharmaceutical Industries and Associations (EFPIA) (46). In that case, the researchers are 
obliged to attempt publication of the results obtained from their analyses. 
LEO Pharma complies with Good Publication Practice (GPP3) standards and the 
recommendations from ICMJE. 
Appendix 3F: Insurance 
LEO Pharma has taken out relevant insurances covering the subjects in the present clinical 
trial in accordance with applicable laws and regulations. 
Appendix 3G: Financial disclosure 
Investigators will provide LEO Pharma with sufficient, accurate financial information as 
requested to allow LEO Pharma to submit complete and accurate financial certification or 
disclosure statements to the appropriate regulatory authorities. Investigators are responsible 
for providing information on financial interests during the course of the clinical trial and for 
1 year after completion of the clinical trial, or for a longer period of time if required by local 
legislation. 
Appendix 3H: 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: 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 152 of 160 
 
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 
 
• Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, LEO Pharma procedures, or GCP guidelines. 
• Inadequate recruitment of subjects by the investigator. 
Completion of trial 
Investigators will be informed when subject recruitment is to cease. Screening activities will 
be stopped at a trial site when the total requested number of subjects for the clinical trial has 
been obtained, irrespective of the specific site’s planned inclusion number. 
Trial sites will be closed upon trial completion. LEO Pharma will undertake arrangements for 
the collection and disposal of any unused trial material that the investigator is not required to 
keep in his/her files. A trial site is considered closed when all required documents and trial 
supplies have been collected and a trial site closure visit has been performed. 
When the randomisation code has been broken, the investigators will receive information 
about the treatment allocation for the subjects randomised at their respective sites and will be 
asked to record this in the subject’s medical record. 
Appendix 3I: Responsibilities 
The signatory investigator is responsible for the approval of the clinical trial protocol and 
the CTR on behalf of all clinical trial investigators and as agreed to in a signatory investigator 
agreement. 
The national coordinating investigators are responsible for national issues relating to the 
clinical trial as agreed to in a national coordinating investigator agreement. 
Each participating investigator is responsible for all aspects of the clinical trial conduct at 
his/her trial site as agreed to in a clinical trial agreement. 
 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 153 of 160 
 
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 
 
Appendix 4: Country-specific requirements 
 
France 
This appendix describes requirements and procedures that are specific for France. The text 
from the protocol is presented in normal font. The specific country requirements or 
procedures are presented below in bold font. 
Section 8.3 Exclusion criteria 
Subjects are not eligible for the trial if they violate any of the following criteria:  
30. 
Subjects 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 25 years. 
 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 154 of 160 
 
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 
 
Appendix 5: Short version of eligibility criteria 
 
Inclusion criteria 
No. 
Short version 
1 
Signed and dated informed consent has been obtained prior to any protocol-related procedures. 
2 
Age 18 years or above at screening. 
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 
HESD itch score (weekly average) of ≥4 points at baseline. 
6 
Subjects who have a documented recent history of inadequate response to treatment with TCS or TCS treatment being medically inadvisable. 
7 
Subjects adherent to standard non-medicated skin care including avoidance of known and relevant irritants and allergens. 
8 
A woman of childbearing potential must use an acceptable form of birth control throughout the trial up until the last application of IMP. 
 
 
 
Exclusion criteria 
No. 
Short version 
1 
Concurrent skin diseases on the hands, e.g. tinea manuum.  
2 
Active AD requiring medical treatment in regions other than the hands and feet. 
3 
Active psoriasis on any part of the body. 
4 
Hyperkeratotic hand eczema in combination with a history of psoriasis on any part of the body. 
5 
Clinically significant infection (e.g. impetiginised hand eczema) on the hands. 
6 
Systemic treatment with immunosuppressive drugs, immunomodulating drugs, retinoids, or corticosteroids within 28 days prior to baseline. 
7 
Use of tanning beds, phototherapy (e.g. UVB, UVA1, PUVA), or bleach baths on the hands within 28 days prior to baseline. 
8 
Previous or current treatment with JAK inhibitors (including delgocitinib/LEO 124249), systemic or topical. 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 155 of 160 
 
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 
 
9 
Cutaneously applied treatment with immunomodulators (e.g. PDE-4 inhibitors, pimecrolimus, tacrolimus) or TCS on the hands within 
14 days prior to baseline. 
10 
Use of systemic antibiotics or cutaneously applied antibiotics on the hands within 14 days prior to baseline. 
11 
Other transdermal or cutaneously applied therapy on the hands (except for the use of subject’s own emollients) within 7 days prior to 
baseline. 
12 
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. 
13 
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. 
14 
Treatment with any non-marketed drug substance within the last 28 days prior to baseline or 5 half-lives, whichever is the longest. 
15 
Clinically significant infection (systemic infection or serious skin infection requiring parenteral treatment) within 28 days prior to baseline. 
16 
History of any known primary immunodeficiency disorder including a positive HIV test at screening, or the subject taking antiretroviral 
medications. 
17 
Major surgery within 8 weeks prior to screening, or planned in-patient surgery or hospitalisation during the trial period. 
18 
History of cancer. 
19 
Any disorder which is not stable and could affect the safety of the subject, influence the findings of the trial, or impede the subject’s ability to 
complete the trial. 
20 
Any abnormal finding which may put the subject at risk, influence the results of the trial, or influence the subject’s ability to complete the 
trial. 
21 
Positive hepatitis B surface antigen or hepatitis C virus antibody serology at screening. 
22 
ALT or AST level 2.0 times the ULN or more at screening. 
23 
Known or suspected hypersensitivity to any component(s) of the IMP. 
24 
Current participation in any other interventional clinical trial. 
25 
Previously randomised in this clinical trial.  
26 
Current or recent chronic alcohol or drug abuse, or any other condition associated with poor compliance as judged by the investigator. 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 156 of 160 
 
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 
 
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. 
 
 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 157 of 160 
 
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 
 
Appendix 6: Contact list 
Contact details for the clinical project manager, appointed CRA, and sponsor’s medical expert 
are provided to the trial sites as a separate contact list. 
Sponsor 
ULEO Pharma A/SU (referred to as ‘LEO Pharma’ or ‘the sponsor’ in this clinical trial protocol) 
is the sponsor of the clinical trial: 
LEO Pharma A/S  
Industriparken 55 
DK-2750 Ballerup 
Denmark 
International coordinating investigator 
Robert Bissonnette, MD, dermatologist 
Innovaderm Research Inc 
3530 St-Laurent - Suite 300 
Montreal (Quebec), H2X 2V1 Canada 
 
 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 158 of 160 
 
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 
 
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 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). 
• PROs (HEIS, PaGA, DLQI, EQ-5D-5L, WPAI:CHE). The subjects will receive a link to 
complete the PROs in a web browser from their own device. 
• 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. 
• Exit interviews, if applicable. 
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 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 159 of 160 
 
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 
 
site/depot. To ensure availability of IMP, the trial sites will dispense additional IMP if 
considered relevant (i.e. if local authority-issued preventive measures are to be expected at the 
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. 
 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0


Trial ID: LP0133-1401 
Date: 20-Aug-2021 
Version: 4.0, Final 
Page 160 of 160 
 
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 
 
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. 
 
TMF-000340756 - Version
5. 0
TMF-000864677 - Version 1.0