Clinical trial NCT05259722
Conditions: Chronic Hand Eczema
Sponsor: LEO Pharma
Start date: 2022-06-15; Completion date: 2023-12-05
Enrollment: 513 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a 24-week study in adult participants with severe chronic hand eczema (CHE) and with a documented inadequate response to treatment with topical corticosteroids (TCS) or for whom TCS are documented to be otherwise medically inadvisable. Eligible participants will be randomised to receive topical administration of delgocitinib cream 20 mg/g, twice-daily, or oral administration of alitretinoin capsules 30 mg (with an option to reduce to 10 mg during trial conduct), once-daily. The participants will visit 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 of this trial is to compare the efficacy, health-related quality of life, and safety of delgocitinib cream and alitretinoin capsules.

Detailed description:

Arms: arm 1: Twice-daily topical application for up to 24 weeks arm 2: 1 capsule per day for up to 24 weeks
Interventions: intervention 1: Delgocitinib intervention 2: Toctino
Intervention descriptions: intervention 1: Cream for topical application 20 mg/g intervention 2: 1 capsule toctino 30 mg per day; optional reduction to 10 mg per day in case unacceptable adverse reactions to the higher dose occur

Protocol documents:
Prot_SAP_000.pdf: 
Cover Page 
Study title: A 24-week, randomised, assessor-blinded, active-controlled, parallel-group, phase 3, 2-arm 
trial to compare the efficacy and safety of delgocitinib cream 20 mg/g twice-daily with alitretinoin 
capsules once-daily in adult participants with severe chronic hand eczema 
LEO Pharma number: LP0133-1528 
NCT number: NCT05259722 
Date: 29-Jun-2022


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Title Page 
Protocol Title: 
A 24-week, randomised, assessor-blinded, active-controlled, 
parallel-group, phase 3, 2-arm trial to compare the efficacy and 
safety of delgocitinib cream 20 mg/g twice-daily with alitretinoin 
capsules once-daily in adult participants with severe chronic hand 
eczema  
Brief Title: 
A 24-week trial to compare the efficacy and safety of delgocitinib 
cream 20 mg/g twice-daily with alitretinoin capsules once-daily in 
adult participants with severe chronic hand eczema 
Acronym 
DELTA FORCE 
Compound: 
Delgocitinib 
Indication: 
Chronic hand eczema 
Trial Sponsor: 
LEO Pharma A/S 
Industriparken 55, DK 2750 Ballerup, Denmark 
Protocol Number: 
LP0133-1528 
Trial Phase: 
Phase 3 
Regulatory Agency 
Identifying 
Number: 
EudraCT-2021-003543-16 
Version: 
Version 5.0 
Approval Date: 
Final, 29 Jun 2022 
Date and Version 
of Original 
Protocol: 
30 Sep 2021; Version 1.0 
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Approval Statement for Sponsor Signatories: 
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 
Biostatistics lead, Medical Sciences 
, MD 
Medical lead, Medical Sciences 
Clinical operations lead, Global Clinical Operations 
Approval Statement for International Coordinating Investigator: 
The international coordinating investigator approves the clinical trial protocol by manually 
signing the Investigator Agreement Page, which is provided as a separate document. 
The following person has approved this clinical trial protocol: 
, MD 
International coordinating investigator 
Medical Monitor Name and Contact Information: 
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PPD
PPD
PPD
PPD
PPD
PPD
C
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Protocol Amendment Summary of Changes Table 
 
DOCUMENT HISTORY 
Document 
Amendment Scope; 
Region/Country Identifier 
(if applicable) 
Protocol Version 
Date 
Amendment 4 
Global amendment 
5.0 
24 Jun 2022 
Amendment 3 
Global amendment 
4.0 
08 Apr 2022 
Amendment 2 
Country-specific; UK 
3.0 
25 Feb 2022 
Amendment 1 
Country-specific; CAN 
2.0 
21 Jan 2022 
Original Protocol 
Not Applicable 
1.0 
30 Sep 2021 
 
Amendment 4 (24 Jun 2022) 
Overall Rationale for the Amendment  
The protocol was amended in order to add the patient reported outcomes PGI-S and PGI-C. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 1.3: Schedule of 
Activities (SoA) 
Section 8.1.3.7: Patient 
Global Impression of 
Severity (PGI-S) 
questionnaires 
Section 8.1.3.8: Patient 
Global Impression of 
Change (PGI-C) 
questionnaires 
Section 9.3.10: Analysis of 
PGI-S and PGI-C 
Appendix 5: COVID 19 
Pandemic Contingency Plan 
Appendix 8: Abbreviations 
Patient reported outcomes 
PGI-S and PGI-C were added 
to the trial. 
To enable assessment of 
psychometric measurement 
properties of the HESD. 
Section 6.8.3: Prohibited 
medications and procedures 
Wash-out period for retinoids 
and vitamin A in Table 6-2 
was corrected. 
To avoid discrepancies. 
Section 1.3: Schedule of 
Activities 
Weight measurement was 
added at screening.  
Weight is required at 
screening to calculate renal 
insufficiency (Cockcroft-
Gault formula). 
Throughout the document 
Minor editorial revisions. 
Minor, have therefore not 
been summarized. 
 
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Table of Contents 
Title Page ........................................................................................................................................ 1 
Protocol Amendment Summary of Changes Table ......................................................................... 3 
Table of Contents ............................................................................................................................ 5 
List of Tables ................................................................................................................................... 9 
List of Figures ............................................................................................................................... 10 
1 
Protocol Summary ...................................................................................................................11 
1.1 
Synopsis ...............................................................................................................................11 
1.2 
Schema ............................................................................................................................... 15 
1.3 
Schedule of Activities (SoA) .............................................................................................. 16 
2 
Introduction............................................................................................................................. 21 
2.1 
Trial Rationale .................................................................................................................... 21 
2.2 
Background......................................................................................................................... 21 
2.2.1 
Chronic Hand Eczema .................................................................................................... 21 
2.2.2 
Delgocitinib Cream ........................................................................................................ 22 
2.3 
Benefit/Risk Assessment .................................................................................................... 23 
2.3.1 
Risk Assessment ............................................................................................................. 23 
2.3.2 
Benefit Assessment ......................................................................................................... 28 
2.3.3 
Overall Benefit/Risk Conclusion .................................................................................... 28 
3 
Objectives and Endpoints ....................................................................................................... 29 
4 
Trial Design ............................................................................................................................ 32 
4.1 
Overall Design .................................................................................................................... 32 
4.2 
Scientific Rationale for Trial Design .................................................................................. 33 
4.3 
Justification for Dose .......................................................................................................... 35 
4.4 
End of Trial Definition ....................................................................................................... 35 
5 
Trial Population ...................................................................................................................... 36 
5.1 
Inclusion Criteria ................................................................................................................ 36 
5.2 
Exclusion Criteria ............................................................................................................... 38 
5.3 
Lifestyle Considerations ..................................................................................................... 42 
5.3.1 
Skin Care ........................................................................................................................ 42 
5.3.2 
Meals and Dietary Restrictions ...................................................................................... 42 
5.4 
Screen Failures ................................................................................................................... 42 
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5.4.1 
Screening and Enrolment Log and Participant Identification Numbers ......................... 43 
6 
Trial Treatments and Concomitant Therapy ........................................................................... 44 
6.1 
Trial Treatments Administered ........................................................................................... 44 
6.2 
Preparation, Handling, Storage, and Accountability .......................................................... 44 
6.2.1 
Administration of Trial Treatment .................................................................................. 44 
6.2.1.1 
Delgocitinib Cream ..................................................................................................... 44 
6.2.1.2 
Alitretinoin Capsules .................................................................................................. 45 
6.2.2 
Handling, Storage, and Accountability ........................................................................... 46 
6.3 
Measures to Minimise Bias: Randomisation and Blinding ................................................ 47 
6.4 
Trial Treatment Compliance ............................................................................................... 48 
6.5 
Dose Modification .............................................................................................................. 48 
6.5.1 
Retreatment Criteria ....................................................................................................... 48 
6.6 
Continued Access to Trial Treatment After the End of the Trial ........................................ 49 
6.7 
Treatment of Overdose ....................................................................................................... 49 
6.8 
Concomitant Therapy ......................................................................................................... 49 
6.8.1 
Background Treatment ................................................................................................... 51 
6.8.2 
Rescue Medication ......................................................................................................... 51 
6.8.3 
Prohibited Medications and Procedures ......................................................................... 52 
7 
Discontinuation of Trial Treatment and Participant Discontinuation ..................................... 54 
7.1 
Discontinuation of Trial Treatment .................................................................................... 54 
7.2 
Participant Discontinuation/Withdrawal from the Trial ..................................................... 55 
7.3 
Loss to Follow-Up .............................................................................................................. 56 
8 
Trial Assessments and Procedures .......................................................................................... 57 
8.1 
Efficacy Assessments ......................................................................................................... 62 
8.1.1 
Hand Eczema Severity Index (HECSI) .......................................................................... 62 
8.1.2 
Investigator’s Global Assessment for Chronic Hand Eczema© (IGA-CHE).................. 63 
8.1.3 
Patient-reported Outcomes ............................................................................................. 64 
8.1.3.1 
eDiary Assessments .................................................................................................... 64 
8.1.3.2 
Dermatology Life Quality Index (DLQI) ................................................................... 65 
8.1.3.3 
Hand Eczema Impact Scale© (HEIS) .......................................................................... 65 
8.1.3.4 
EuroQol 5-Dimension Health Questionnaire 5 Level (EQ-5D-5L)............................ 66 
8.1.3.5 
Treatment Satisfaction Questionnaire for Medicine (TSQM) .................................... 66 
8.1.3.6 
Work Productivity and Activity Impairment – Chronic Hand Eczema (WPAI-CHE) 67 
8.1.3.7 
Patient Global Impression of Severity (PGI-S) questionnaires .................................. 67 
8.1.3.8 
Patient Global Impression of Change (PGI-C) questionnaires ................................... 68 
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8.1.4 
CHE Lesions Photography ............................................................................................. 69 
8.2 
Safety Assessments ............................................................................................................. 70 
8.2.1 
Physical Examinations .................................................................................................... 70 
8.2.2 
Vital Signs ...................................................................................................................... 70 
8.2.3 
Electrocardiograms ......................................................................................................... 71 
8.2.4 
Clinical Safety Laboratory Tests .................................................................................... 72 
8.2.5 
Pregnancy Testing ........................................................................................................... 73 
8.2.6 
Mental Health Monitoring .............................................................................................. 73 
8.2.7 
Local Tolerability ........................................................................................................... 74 
8.2.7.1 
Participant’s Assessment of Local Tolerability ........................................................... 74 
8.2.7.2 
Investigator’s Assessment of Local Tolerability ......................................................... 75 
8.3 
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other Safety Reporting ..... 76 
8.3.1 
Time Period and Frequency for Collecting AE and SAE Information ........................... 76 
8.3.2 
Method of Detecting AEs and SAEs .............................................................................. 76 
8.3.3 
Follow-up of AEs and SAEs ........................................................................................... 77 
8.3.4 
Regulatory Reporting Requirements for SAE ................................................................ 77 
8.3.5 
Pregnancy ....................................................................................................................... 78 
8.3.6 
Other Events ................................................................................................................... 79 
8.3.6.1 
AEs of Special Interest ............................................................................................... 79 
8.3.6.2 
Medication Errors ....................................................................................................... 79 
8.3.6.3 
Misuse or Abuse.......................................................................................................... 80 
8.3.7 
Handling of Urgent Safety Measures ............................................................................. 80 
8.4 
Pharmacokinetics ................................................................................................................ 81 
8.5 
Pharmacodynamics ............................................................................................................. 81 
8.6 
Genetics .............................................................................................................................. 81 
8.7 
Biomarkers ......................................................................................................................... 81 
8.8 
Immunogenicity Assessments ............................................................................................ 81 
8.9 
Medical Resource Utilisation and Health Economics ........................................................ 81 
8.10 End-of-trial Assessments .................................................................................................... 82 
8.10.1 
End-of-treatment Form ................................................................................................... 82 
8.10.2 
End-of-trial Form ............................................................................................................ 82 
9 
Statistical Considerations........................................................................................................ 83 
9.1 
Statistical Hypotheses ......................................................................................................... 83 
9.1.1 
Multiplicity Adjustment .................................................................................................. 83 
9.2 
Analysis Sets ...................................................................................................................... 85 
9.3 
Statistical Analyses ............................................................................................................. 85 
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9.3.1 
General Considerations .................................................................................................. 85 
9.3.2 
Aspects Related to the COVID-19 Pandemic ................................................................ 86 
9.3.3 
Disposition of Participants ............................................................................................. 87 
9.3.4 
Demographics and Other Baseline Characteristics ........................................................ 87 
9.3.5 
Exposure and Treatment Compliance ............................................................................. 87 
9.3.6 
Estimand Strategy ........................................................................................................... 87 
9.3.6.1 
General Considerations ............................................................................................... 87 
9.3.6.2 
Estimand Strategy for Continuous Endpoints ............................................................. 91 
9.3.6.3 
Estimand Strategy for Binary Endpoints .................................................................... 92 
9.3.6.4 
Estimand Strategy for AUC Endpoints ....................................................................... 94 
9.3.7 
Primary Endpoint(s) Analysis ......................................................................................... 95 
9.3.8 
Secondary Endpoint(s) Analysis ..................................................................................... 95 
9.3.9 
Exploratory Endpoints Analysis ..................................................................................... 98 
9.3.10 
Analysis of PGI-S and PGI-C ....................................................................................... 100 
9.3.11 
Safety Analyses ............................................................................................................ 100 
9.3.11.1 
Adverse Events ......................................................................................................... 100 
9.3.11.2 
Vital Signs and Physical Examination ...................................................................... 102 
9.3.11.3 
Clinical Laboratory Evaluation ................................................................................. 102 
9.3.11.4 
Participant’s and Investigator’s Assessment of Local Tolerability ........................... 102 
9.4 
Interim Analyses ............................................................................................................... 102 
9.5 
Sample Size Determination .............................................................................................. 102 
10 Supporting Documentation and Operational Considerations ............................................... 104 
10.1 Appendix 1: Regulatory, Ethical, and Trial Oversight Considerations ............................ 104 
10.1.1 
Regulatory and Ethical Considerations ........................................................................ 104 
10.1.2 
Financial Disclosure ..................................................................................................... 105 
10.1.3 
Informed Consent Process ............................................................................................ 105 
10.1.4 
Data Protection ............................................................................................................. 106 
10.1.5 
Dissemination of Clinical Trial Data ............................................................................ 106 
10.1.6 
Data Quality Assurance ................................................................................................ 106 
10.1.6.1 
Quality Tolerance Limits .......................................................................................... 107 
10.1.7 
Source Documents ........................................................................................................ 108 
10.1.8 
Trial and Site Start and Closure .................................................................................... 108 
10.1.9 
Publication Policy ......................................................................................................... 109 
10.1.10 Protocol Approval and Amendment ..............................................................................110 
10.1.11 Liability and Insurance ..................................................................................................110 
10.1.11.1 Access to Source Data ...............................................................................................110 
10.2 Appendix 2: Clinical Laboratory Tests ..............................................................................112 
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10.3 Appendix 3: AEs and SAEs: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ..................................................................................................114 
10.3.1 
Definition of AE ............................................................................................................114 
10.3.2 
Definition of SAE ..........................................................................................................114 
10.3.3 
Recording and Follow-up of AE and SAE ....................................................................115 
10.3.4 
Reporting of SAE ......................................................................................................... 120 
10.4 Appendix 4: Contraceptive and Barrier Guidance ........................................................... 122 
10.4.1 
Definitions .................................................................................................................... 122 
10.4.2 
Contraception Guidance ............................................................................................... 124 
10.5 Appendix 5: COVID-19 Pandemic Contingency Plan ..................................................... 126 
10.6 Appendix 6: Liver Safety: Suggested Actions and Follow-up Assessments .................... 128 
10.6.1 
Liver Chemistry Monitoring and Reporting ................................................................. 128 
10.6.2 
Discontinuation of IMP ................................................................................................ 128 
10.6.3 
Recommended Follow-up Assessments ....................................................................... 128 
10.7 Appendix 7 Country-specific requirements...................................................................... 130 
10.8 Appendix 8: Abbreviations ............................................................................................... 131 
10.9 Appendix 9: Amendments ................................................................................................ 134 
11 References............................................................................................................................. 139 
 
List of Tables 
Table 1–1 
Schedule of Activities (SoA) ................................................................................ 16 
Table 2–1 
Risk Assessment.................................................................................................... 24 
Table 3–1 
Primary Objective and Estimands for Primary Endpoint and Key Secondary 
Endpoints .............................................................................................................. 29 
Table 3–2 
Secondary and Exploratory Objectives and Endpoints ......................................... 29 
Table 6–1 
Trial Treatments Administered .............................................................................. 44 
Table 6–2 
Prohibited Medications and Procedures ................................................................ 52 
Table 8–1 
Fitzpatrick Skin Classification .............................................................................. 59 
Table 8–2 
Definition of Subtypes of Hand Eczema .............................................................. 61 
Table 8–3 
HECSI Severity Score Scale and Area Score Scale .............................................. 63 
Table 8–4 
Calculation of the Total HECSI Score .................................................................. 63 
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Table 8–5 
Investigator’s Global Assessment for Chronic Hand Eczema© (IGA-CHE) ........ 64 
Table 8–6 
Participant’s Assessment of Local Tolerability after Delgocitinib Cream 
Application ............................................................................................................ 74 
Table 8–7 
Berger and Bowman Scoring Scales if Investigator Suspects a Local Skin 
Reaction Related to Delgocitinib Application ...................................................... 75 
Table 8–8 
Adverse Events of Special Interest ....................................................................... 79 
Table 9–1 
Participant Analysis Sets ....................................................................................... 85 
Table 9–2 
Handling of Observed and Missing Data According to the Intercurrent Events for 
the Primary Analysis for Estimands ...................................................................... 90 
Table 9–3 
Overview of the Primary Statistical Analysis of the Key Secondary Efficacy 
Endpoints Related to the Primary and Supplementary Estimands ........................ 97 
Table 9–4 
Overview of the Statistical Analysis of Exploratory Endpoints ........................... 99 
Table 10–1 
Protocol-required Safety Laboratory Tests ..........................................................112 
 
List of Figures 
Figure 1–1 
Trial Design ........................................................................................................... 15 
Figure 8–1 
Sequence of Assessments ...................................................................................... 57 
Figure 9–1 
Graphical Display of Closed Testing Procedure for Primary and Key Secondary 
Endpoints .............................................................................................................. 84 
 
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1 Protocol Summary 
1.1 Synopsis 
Protocol Title: A 24-week, randomised, assessor-blinded, active-controlled, parallel-group, 
phase 3, 2-arm trial to compare the efficacy and safety of delgocitinib cream 20 mg/g twice-daily 
with alitretinoin capsules once-daily in adult participants with severe chronic hand eczema  
Brief Title: A 24-week trial to compare the efficacy and safety of delgocitinib cream 20 mg/g 
twice-daily with alitretinoin capsules once-daily in adult participants with severe chronic hand 
eczema 
Sponsor Protocol No.: LP0133-1528 
Trial Phase: Phase 3 
Sponsor: LEO Pharma A/S 
Rationale: There is a clear unmet need for long-term treatment options for patients suffering 
from moderate to severe chronic hand eczema (CHE). Alitretinoin is the only approved product 
specifically indicated for treatment of CHE, but it is only indicated for severe CHE and only 
approved in few countries worldwide. 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 purpose of this 24-week trial is to compare efficacy, health-related 
quality of life, and safety of delgocitinib cream and alitretinoin capsules in participants 
diagnosed with severe CHE. 
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Objectives and Endpoints and/or Estimands: 
Primary Objective 
Objectives 
Estimand type and strategy 
Endpoints 
Primary objective:  
To compare the efficacy and 
health-related quality of life 
of twice-daily topical 
application of delgocitinib 
cream with once-daily oral 
administration of alitretinoin 
capsules in the treatment of 
patients with severe CHE. 
Primary. ‘Composite’ strategy. 
First supplementary. 
‘Pandemic modified composite’ 
strategy. 
Second supplementary (for 
endpoints at Week 12 and 
Week 24). ‘Treatment policy’ 
strategy. 
Primary endpoint:  
• 
Change in HECSI score from baseline to 
Week 12. 
Key secondary endpoints: 
• 
HECSI-90 at Week 12. 
• 
IGA-CHE TS at Week 12. 
• 
Change in HESD itch score (weekly 
average) from baseline to Week 12. 
• 
Change in HESD pain score (weekly 
average) from baseline to Week 12. 
• 
AUC of HECSI-90 from baseline up to 
Week 24. 
• 
AUC of change from baseline in DLQI 
score up to Week 24. 
• 
Change in HECSI score from baseline to 
Week 24. 
Abbreviations: AUC=area under the curve; CHE=chronic hand eczema; DLQI=Dermatology Life Quality Index; 
HECSI=Hand Eczema Severity Index; HECSI-90=at least 90% improvement in HECSI score from baseline; 
HESD=Hand Eczema Symptom Diary©; IGA-CHE=Investigator’s Global Assessment for chronic hand 
eczema©; IGA-CHE TS=IGA-CHE treatment success. 
 
Secondary Objective 
Objectives 
Endpoints 
Secondary objective: 
To compare the safety of twice-daily topical 
application of delgocitinib cream with once-daily 
oral administration of alitretinoin capsules in the 
treatment of patients with severe CHE. 
Secondary endpoints: 
• 
Number of treatment-emergent AEs from baseline up 
to Week 26. 
• 
Number of treatment-emergent SAEs from baseline 
up to Week 26. 
• 
Number of AEs leading to IMP discontinuation up to 
Week 24. 
Abbreviations: AE=adverse event; CHE=chronic hand eczema, IMP=investigational medicinal product, 
SAE=serious adverse event. 
 
Exploratory objectives 
Exploratory objectives are described in Section 3. 
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Overall Design: 
• This is a phase 3, randomised, assessor-blinded, active-controlled, parallel-group, multi-site, 
24-week trial. 
• The trial population will consist of adult participants with severe CHE and with a 
documented inadequate response to treatment with topical corticosteroids (TCS) or for whom 
TCS are documented to be otherwise medically inadvisable. The trial will include a 
maximum of 20% of participants with hyperkeratotic subtype.  
• Eligible participants will be randomised to receive topical administration of delgocitinib 
cream 20 mg/g, twice-daily, or oral administration of alitretinoin capsules 30 mg (with an 
option to reduce to 10 mg during trial conduct), once-daily. Randomisation will be stratified 
by subtype (hyperkeratotic/non-hyperkeratotic) and region (North America/Europe). 
• Participants are not blinded to treatment assignment, but efficacy (Investigator’s Global 
Assessment for chronic hand eczema© [IGA-CHE©, hereafter referred to IGA-CHE] and 
Hand Eczema Severity Index [HECSI]) will be evaluated by an assessor blinded to treatment 
assignment. Other assessments will be performed by an unblinded investigator and treatment 
decisions will be made by the unblinded investigator following the recommendation from the 
blinded assessor. 
• Certain Contract Research Organisation (CRO) and sponsor staff will also be blinded to 
ensure the integrity of the trial. 
Brief Summary: 
The purpose of this trial is to compare the efficacy, health-related quality of life, and safety of 
delgocitinib cream 20 mg/g twice-daily with alitretinoin capsules 30 mg (with an option to 
reduce to 10 mg during trial conduct) once-daily in adult patients with severe CHE. The trial 
duration will be up to 33 weeks. The treatment duration will be up to 24 weeks. The visit 
frequency will be weekly for the first 3 weeks of treatment and every 4 weeks from Week 4 to 
the end of treatment. 
Number of Participants: 
Approximately 510 participants will be randomly assigned to trial treatment in a 1:1 ratio, with 
255 evaluable participants per treatment group. Approximately 660 participants will be screened 
to achieve this target. 
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Intervention Groups and Duration: 
For each participant, the trial will last at least 25 weeks and up to 33 weeks, including:  
• a screening period of 1 to 4 weeks (at least 1 visit) 
• a treatment period of 24 weeks (9 visits) 
• a safety follow-up period of 2 to 5 weeks (1 visit for all participants 2 weeks after the last 
investigational medicinal product [IMP] dose, plus a pregnancy follow-up visit for woman of 
childbearing potential [WOCBP] treated with alitretinoin 5 weeks after the last IMP dose) 
Eligible participants will be randomised in a 1:1 ratio to receive 1 of the following treatments: 
• Topical administration of delgocitinib cream 20 mg/g, twice-daily until Week 16, which may 
continue up to Week 24 depending on clearance status (i.e. IGA-CHE score) and clinical 
benefit. 
• Oral administration of alitretinoin capsules 30 mg (with an option to reduce to 10 mg during 
trial conduct), once-daily until Week 12, which may continue up to Week 24 depending on 
clearance status (i.e. IGA-CHE score) and clinical benefit. 
Data Monitoring/Other Committee: No
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1.2 Schema 
Figure 1–1 
Trial Design 
 
1. For participants treated with medications requiring a 28-day washout period prior to baseline (see Table 6-2), the duration of the screening period may be 
extended up to 31 days to ensure appropriate washout. 
Abbreviations: HECSI=Hand Eczema Severity Index; IGA-CHE=Investigator’s Global Assessment for chronic hand eczema©. 
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1.3 Schedule of Activities (SoA) 
Table 1-1 
Schedule of Activities (SoA) 
 
Screen-
ing 
Treatment period 
 
Follow-
up 2 
Pregnancy 
follow-up 3 
Primary 
endpoint 
visit at 
Week 12, if 
applicable4 
Nominal 
Week 24 
visit, if 
applicabl
e4 
Unscheduled 
visit, if 
applicable 5 
Protocol 
section 
EOT/ 
ET 1 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
Week 
-4 to -1 
0 
1 
2 
4 
8 
12 
16 
20 
24 
2 weeks 
after 
last 
dose 
5 weeks 
after last 
dose 
Day 
-28 6  
to -7 
1 
8 
15 
29 
57 
85 
113 141 
169 
Visit window (days)  
- 
- 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
+6 
Eligibility / baseline assessments 
 
Informed consent(s)  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10.1.3 
Participant eligibility 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.1, 5.2 
Demographics  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8 
Fitzpatrick skin type 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8, Table 8-1 
Medical history (including 
CHE treatment history) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8 
Classification of CHE  
(including patch test 7) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
(X) 7 
8, Table 8-2 
Height  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
8 
Weight 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
8 
Treatments and randomisation 
 
Randomisation 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.3 
Instruction for use of IMP 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.2.1 
Dispensing of IMP 
 
X 
 
 
X 
X 
(X) 
(X) 
(X) 
 
 
 
 
 
(X) 
6.1 
Determination of affected 
area(s) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
(X) 
6.2.1 
New CHE lesions 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
6.2.1 
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Screen-
ing 
Treatment period 
 
Follow-
up 2 
Pregnancy 
follow-up 3 
Primary 
endpoint 
visit at 
Week 12, if 
applicable4 
Nominal 
Week 24 
visit, if 
applicabl
e4 
Unscheduled 
visit, if 
applicable 5 
Protocol 
section 
EOT/ 
ET 1 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
Week 
-4 to -1 
0 
1 
2 
4 
8 
12 
16 
20 
24 
2 weeks 
after 
last 
dose 
5 weeks 
after last 
dose 
Day 
-28 6  
to -7 
1 
8 
15 
29 
57 
85 
113 141 
169 
Visit window (days)  
- 
- 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
+6 
Delgocitinib cream topical 
application 
 
Twice-daily for 16 weeks 
Stop/restart  
as necessary 
 
 
 
 
 
6.2.1.1 
Alitretinoin capsules oral 
administration 
 
Once-daily for 12 weeks 
Stop/restart  
as necessary 
 
 
 
 
 
6.2.1.2 
Treatment compliance 
(eDiary) 
 
Daily 8 
 
 
 
 
 
6.4 
Return of treatment and 
accountability  
 
 
 
 
X 
X 
X 
(X) 
(X) 
(X) 
 
 
 
 
(X) 
6.4 
Concomitant medication and 
concurrent procedures  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
6.8 
Blinded assessor assessment of efficacy 
 
HECSI 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
(X) 
8.1.1 
IGA-CHE 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
(X) 
8.1.2 
Participant assessments of efficacy at home 
 
eDiary handout/training 8 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.1.3.1 
HESD 
Daily 8 
 
 
Daily 8 
Daily 8 
 
8.1.3.1 
Return of eDiary 
 
 
 
 
 
 
 
 
 
X 9 
 
 
 
X 9 
 
8.1.3.1 
Participant assessments of efficacy and health-related quality of life during trial visits 
 
HEIS 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
 
8.1.3.3 
DLQI 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
 
8.1.3.2 
EQ-5D-5L 
 
X 
 
 
X 
X 
X 
X 
 
X 
 
 
X 
X 
 
8.1.3.4 
TSQM 
 
 
 
 
X 
 
X 
 
 
X 
 
 
X 
X 
 
8.1.3.5 
WPAI-CHE 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
X 
X 
 
8.1.3.6 
PGI-S10 
 
X 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
8.1.3.7 
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Screen-
ing 
Treatment period 
 
Follow-
up 2 
Pregnancy 
follow-up 3 
Primary 
endpoint 
visit at 
Week 12, if 
applicable4 
Nominal 
Week 24 
visit, if 
applicabl
e4 
Unscheduled 
visit, if 
applicable 5 
Protocol 
section 
EOT/ 
ET 1 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
Week 
-4 to -1 
0 
1 
2 
4 
8 
12 
16 
20 
24 
2 weeks 
after 
last 
dose 
5 weeks 
after last 
dose 
Day 
-28 6  
to -7 
1 
8 
15 
29 
57 
85 
113 141 
169 
Visit window (days)  
- 
- 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
+6 
PGI-C11 
 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
8.1.3.8 
Participant assessment of safety 
Participant assessment of 
local tolerability (delgocitinib 
group only) 
 
Weekly while on treatment12 
X 
 
 
 
 
 
8.2.7.1 
Unblinded investigator assessments of safety 
 
Physical examination 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
(X) 
8.2.1 
Vital signs 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
(X) 
8.2.2 
ECG 
X 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
(X) 
8.2.3 
Fasting 13 triglycerides and 
cholesterol (central 
laboratory) 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
(X) 
8.2.4, 10.2 
Chemistry, haematology 
(central laboratory) 13 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
(X) 
8.2.4, 10.2 
Serology, total IgE (central 
laboratory) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.2.4, 10.2 
Urinalysis (urine dipstick) 
X 
X 
 
 
 
X 
X 
X 
 
X 
 
 
 
 
(X) 
8.2.4, 10.2 
Urine pregnancy test 
(WOCBP only) 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 14 
X 3 
X 
X 
(X) 
8.2.5, 10.2 
Check contraception 
compliance (alitretinoin group 
only) 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(X) 
8.2.5 
Mental health interview15  
X 
X 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
(X) 
8.2.6 
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Screen-
ing 
Treatment period 
 
Follow-
up 2 
Pregnancy 
follow-up 3 
Primary 
endpoint 
visit at 
Week 12, if 
applicable4 
Nominal 
Week 24 
visit, if 
applicabl
e4 
Unscheduled 
visit, if 
applicable 5 
Protocol 
section 
EOT/ 
ET 1 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
Week 
-4 to -1 
0 
1 
2 
4 
8 
12 
16 
20 
24 
2 weeks 
after 
last 
dose 
5 weeks 
after last 
dose 
Day 
-28 6  
to -7 
1 
8 
15 
29 
57 
85 
113 141 
169 
Visit window (days)  
- 
- 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
+6 
Local tolerability according to 
investigator (delgocitinib 
group only) 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
(X) 
8.2.7.2 
AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
8.3, 10.3 
Optional assessments (at selected sites only) 
 
 
 
 
 
 
 
 
 
 
 
Photography of both hands 
back and front including the 
wrist 16 
 
X 
 
 
 
 
X 
X 
 
X 
 
 
 
 
 
8.1.4 
End of treatment/trial 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
End-of-treatment form 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
8.10.1 
End-of-trial form 17 
 
 
 
 
 
 
 
 
 
(X) 
X 
X 
 
(X) 
(X) 
8.10.2 
1. End-of-treatment assessments will be conducted at Week 24. Participants who permanently discontinue the IMP or who withdraw from the trial prior to 
Week 24 will be asked to return to the trial site for an ET visit as soon as possible after the last dose for completion of all trial procedures scheduled for the 
visit at Week 24. 
2. All participants will be asked to return to the trial site approximately 2 weeks after the last dose of IMP for assessment of safety at a follow-up visit. 
3. For WOCBP treated with alitretinoin, only. 
4. Participants who permanently discontinue the IMP prior to Week 12 will be asked to return to the trial site at Week 12 for a primary endpoint visit and at 
Week 24 for a nominal Week 24 visit. Participants who permanently discontinue the IMP between Week 12 and Week 24 will be asked to return to the trial 
site for a nominal Week 24 visit. 
5. Unscheduled visits occur if participants need to make a visit in between the scheduled visit dates, e.g. for reading of a patch test, 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 unblinded investigator. 
6. For participants treated with medications requiring a 28-day washout period prior to baseline (see Table 6-2), the duration of the screening period may be 
extended up to 31 days to ensure appropriate washout. For WOCBP the duration of the screening period may be extended up to 42 days to ensure 
compliance with contraceptive and pregnancy prevention programme requirements. 
7. For participants who have not had a patch test within 3 years prior to screening, the patch test should be completed so results are available prior to baseline 
assessments (Day 1).  
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8. Completion of the HESD component of the eDiary will be initiated at least 1 week prior to baseline (Day 1), but preferably from the date the participants 
receive the eDiary. Compliance with the eDiary completion will be reviewed by the trial site staff throughout the trial. Participants who permanently 
discontinue the IMP but remain in the trial will continue completing the eDiary until the nominal Week 24 visit. 
9. Not applicable at the ET visit if the participant does not withdraw from the trial, as participants who discontinue IMP but remain in the trial will continue 
completing the eDiary until the nominal Week 24 visit. 
10. Includes Itch PGI-S, Pain PGI-S, and HESD PGI-S. 
11. Includes Itch PGI-C, Pain PGI-C, and HESD PGI-C. 
12. While on treatment with delgocitinib cream 20 mg/g, local tolerability will be evaluated weekly by the participants in the eDiary from Day 7 onwards up to 
End of Treatment/Early Termination visit. 
13. Participants should be fasting for at least 8 hours prior to collection of laboratory samples. 
14. For WOCBP treated with delgocitinib, only. 
15. After baseline, mental health interview is required only for the alitretinoin group. 
16. Photography will require additional informed consent. If deemed necessary (e.g. in case of poor quality), photographs can be retaken at the next visit. 
17. An end-of-trial form must be completed for all screened participants at the participant’s last trial visit. For participants who discontinue IMP prematurely, the 
end-of-trial form will be completed at the nominal Week 24 visit, if this visit occurs after Visit 11 or Visit 12 (if applicable). For WOCBP treated with 
alitretinoin, the end-of-trial form must be completed at Visit 12 (pregnancy follow-up). For all other participants, the end-of-trial form must be completed at 
Visit 11 (follow-up).  
Abbreviations: AE=adverse event; CHE=chronic hand eczema; DLQI=Dermatology Life Quality Index: ECG=electrocardiogram; eDiary=electronic diary; 
EQ-5D-5L=EuroQoL 5-Dimension Health Questionnaire 5-Level; EOT= end-of-treatment; ET=early termination; HECSI=Hand Eczema Severity Index; 
HEIS=Hand Eczema Impact Scale©; HESD=Hand Eczema Symptom Diary©; IGA-CHE=Investigator’s Global Assessment for chronic hand eczema©; 
IgE=immunoglobulin E; IMP=investigational medicinal product; PGI-C = Patient Global Impression of Change; PGI-S = Patient Global Impression of 
Severity; TSQM=Treatment Satisfaction Questionnaire for Medicine; WOCBP=woman of childbearing potential; WPAI-CHE=Work Productivity and 
Activity Impairment – Chronic Hand Eczema. 
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2 Introduction 
Delgocitinib is a pan-Janus kinase (JAK) inhibitor that is being developed as a cream for the 
treatment of inflammatory skin disorders, such as CHE. 
2.1 Trial Rationale 
There is a clear unmet need for new long-term treatment options for patients suffering from 
moderate to severe CHE. Alitretinoin is the only approved product specifically indicated for 
treatment of CHE, but it is only indicated for severe CHE and only approved in few countries 
worldwide.  
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 purpose of this 24-week trial is to compare efficacy, health-related quality of life, and safety 
of delgocitinib cream and alitretinoin capsules in participants diagnosed with severe CHE. 
2.2 Background 
2.2.1 
Chronic Hand Eczema 
CHE refers to hand eczema that persists for more than 3 months or returns twice or more often 
within 12 months (Diepgen et al, 2015). 
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 characterised 
by chronic relapses and a poor prognosis.  
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 (Diepgen et al, 2015). 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 
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effect, TCS remain the mainstay of 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 is the only 
approved product specifically indicated for treatment of CHE, but it is only indicated for severe 
CHE and only approved in few countries worldwide. Significant safety precautions apply to 
alitretinoin. Alitretinoin is highly teratogenic and is strictly contraindicated in pregnant women 
and in women of childbearing potential unless all of the conditions of a Pregnancy Prevention 
Programme are met. Furthermore, alitretinoin is contraindicated in nursing mothers. Alitretinoin 
is also contraindicated in patients with hepatic insufficiency, severe or end-stage renal 
insufficiency, uncontrolled hypercholesterolemia, uncontrolled hypertriglyceridemia, 
uncontrolled hypothyroidism, and hypervitaminosis A. In addition, alitretinoin contains soya oil 
and sorbitol, and therefore patients who are allergic to peanut, soya, or with rare hereditary 
fructose intolerance should not use this product. 
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. 
As the currently available treatment options either lack documented treatment effect or are 
limited by restrictions of long-term use due to safety concerns (Diepgen et al, 2015; Christoffers 
et al, 2019), there is a high unmet medical need for new topical treatments 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.  
2.2.2 
Delgocitinib Cream 
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 (Delgocitinib cream 
IB, 2022).  
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 
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administration of delgocitinib was also shown to improve the impaired skin barrier function in 
mouse models and in human skin (Amano et al, 2015). 
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 both trials, delgocitinib was 
well-tolerated, and a low systemic exposure to delgocitinib was observed. Two ongoing pivotal 
vehicle-controlled phase 3 trials (trial LP0133-1401 and trial LP0133-1402) are confirming the 
efficacy and evaluating the safety of delgocitinib cream 20 mg/g twice-daily for 16 weeks in 
patients with moderate to severe CHE (followed by 36-week safety evaluation in a long-term 
extension trial, trial LP0133-1403). 
A detailed description of the chemistry, pharmacology, efficacy, and safety of delgocitinib is 
provided in the Investigator’s Brochure (IB). 
2.3 Benefit/Risk Assessment 
More detailed information about the known and expected benefits and risks of delgocitinib and 
alitretinoin may be found in the IB of delgocitinib cream and the local product information of 
alitretinoin. 
2.3.1 
Risk Assessment 
Delgocitinib cream is a topically applied JAK inhibitor. Oral JAK inhibitors are associated with 
potential safety concerns of serious infections, all-cause mortalities, major adverse 
cardiovascular events, malignancies, thrombosis, lipid elevations and low blood cell counts. 
These risks are not considered relevant for delgocitinib cream due to the low systemic exposure 
observed in previous trials with topically applied delgocitinib in CHE patients. 
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 nonclinical and clinical data on delgocitinib is 
available in the IB. 
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Table 2-1 
Risk Assessment 
Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for 
Risk 
Mitigation Strategy 
Delgocitinib 
Lymphocytopenia 
Lymphocytopenia was observed 
in oral nonclinical toxicity studies 
and is considered a potential 
clinical consequence of systemic 
levels of delgocitinib. 
Lymphocytopenia is therefore 
considered an important potential 
risk for delgocitinib cream (see IB 
Section 5.4 and Section 7.2.2). 
Haematology parameters including WBC count 
(with differential count) will be monitored during 
the trial (see Section 8.2.4). 
Local skin infection 
and acneiform 
eruptions 
Potential risks that could arise 
from use of delgocitinib cream 
are local skin infection and 
acneiform eruptions, which have 
been reported in clinical trials, 
studying a different formulation 
(delgocitinib ointment) in atopic 
dermatitis (see IB Section 7.2.3). 
Patients with clinically significant infections on the 
hands (exclusion criterion 5), a serious skin 
infection requiring parenteral antibiotics (exclusion 
criterion 7.b) will be excluded from the trial. 
During the trial, eczema herpeticum will be 
monitored as an AESI (see Section 8.3.6). 
Physical examination including whole body 
inspection of the skin will be performed at 
screening and the end of treatment and during any 
trial visit or unscheduled visits if necessary. 
Use during 
pregnancy or 
lactation 
No data are available about the 
use of delgocitinib cream in 
pregnant or breastfeeding women. 
In oral animal studies, 
delgocitinib was not teratogenic, 
but increased post-implantation 
loss was observed (see IB 
Section 5.6 and 7.4.6). 
Women must agree to use highly effective 
contraception during the trial (inclusion criterion 6). 
Pregnant or breastfeeding women are excluded 
from the trial (exclusion criterion 30). 
Pregnancy tests will be performed for WOCBP 
prior to the first dose (screening and Day 1), every 
4 weeks during the treatment period, and 2 weeks 
after the last dose of delgocitinib. 
Female participants will be instructed to discontinue 
the IMP immediately in case of pregnancy. 
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Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for 
Risk 
Mitigation Strategy 
Alitretinoin 
Teratogenicity 
Alitretinoin is a powerful human 
teratogen inducing a high 
frequency of severe and 
life-threatening birth defects. 
It is strictly contraindicated in 
pregnant women and women of 
childbearing potential (unless 
specific pregnancy prevention 
program is followed).  
Refer to alitretinoin product 
information. 
Women will be informed of the teratogenicity of 
alitretinoin and must agree to use highly effective 
contraception 1 month before treatment, throughout 
treatment period, including participants with 
amenorrhea. Contraception must additionally be 
used for 1 month after the end of treatment with 
alitretinoin (inclusion criterion 6). If local 
guidelines for contraception have stricter 
requirements, then local guidelines should be 
followed. Pregnant or breastfeeding women are 
excluded from the trial (exclusion criterion 30). 
Pregnancy tests will be performed prior to the first 
dose (screening and Day 1), every 4 weeks during 
the treatment period, and 5 weeks after the last dose 
of alitretinoin. 
Female participants will be instructed to discontinue 
the IMP immediately in case of pregnancy. 
Participants must not donate blood during and for 
1 month after treatment with alitretinoin, as there is 
a potential risk to the foetus in pregnant women 
receiving such a blood transfusion. This will not be 
monitored in this trial, however, it will be stated in 
the ICF to ensure participant’s consent to these 
instructions. 
Phototoxicity 
Refer to alitretinoin product 
information. 
Participants will be instructed to avoid excessive 
exposure to sunlight or sunlamps and to use sun 
protection (see Section 5.3.1). 
The use of tanning bed and phototherapy is 
forbidden at least 28 days before the first dose and 
until the end of the trial (see Section 6.8.3). 
Psychiatric disorders 
Refer to alitretinoin product 
information. 
Patients with psychiatric disorders within the last 
year or current self-reported depression or mood 
disturbance will be excluded from the trial 
(exclusion criterion 11). 
Mental health will be monitored during the 
treatment period (see Section 8.2.6) and a specific 
discontinuation criterion is defined in case of 
mental health issues (see Section 7.1). 
Lipid metabolism 
Refer to alitretinoin product 
information. 
Participants with uncontrolled hypercholesterolemia 
and hypertriglyceridemia will not be enrolled in the 
trial. (exclusion criteria 6.c and 6.d) 
Fasting triglycerides and cholesterol parameters 
will be monitored every 4 weeks during treatment 
and 2 weeks after the last dose (see Section 8.2.4) 
and participants with increased lipids that cannot be 
controlled at an acceptable level are required to 
discontinue alitretinoin (see Section 7.1). 
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Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for 
Risk 
Mitigation Strategy 
Male fertility 
Based on non-clinical findings, 
the male fertility may be 
compromised by treatment with 
alitretinoin. 
No effects on male or female 
reproductive parameters were 
observed at the highest dose 
tested which reached similar 
plasma concentrations as those 
observed in humans. 
As with other retinoids, reversible 
effects on male reproductive 
organs were observed in 
experimental animals in the form 
of disturbed spermatogenesis and 
associated degenerative lesions of 
the testes. The safety margin in 
dogs with regard to the no-effect 
level of toxicity to male 
reproductive organs was 1-6 for a 
human dose of 30 mg 
If a male is planning to reproduce during the 
treatment, he should be made aware that his fertility 
could potentially be reversibly compromised during 
the treatment period. 
The information should be given prior to enrolment 
and stated in the ICF. 
Ability to drive and 
use machinery 
Impaired night vision has been 
observed during treatment with 
alitretinoin and other retinoids. 
Participants will be informed of this potential 
problem and urged to exercise appropriate caution 
when driving or operating machinery in the dark. 
These effects usually resolve after discontinuation 
of treatment. 
Other risks related to 
alitretinoin 
Refer to alitretinoin product 
information. 
Participants with any contraindications to 
alitretinoin will be excluded from the trial 
(exclusion criterion 6) and participants with any 
symptoms requiring treatment discontinuation per 
local product information are required to 
discontinue alitretinoin (see Section 7.1). 
The most important risks will be stated in the ICF. 
For information on other side effects the 
participants should be informed according to the 
alitretinoin product information. 
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Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for 
Risk 
Mitigation Strategy 
Other 
COVID-19 
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 participants 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 participants 
may enter public areas (e.g. 
commute to the trial site) and 
have additional human contact 
(e.g. with trial site staff). It is 
unknown whether treatment with 
delgocitinib cream 20 mg/g may 
predispose to COVID-19. 
Alitretinoin is not considered to 
increase the risk of COVID-19 
infection. 
Appropriate risk assessments and mitigation 
measures must be considered to protect the 
participants and trial site staff and to ensure the 
integrity of the trial data. If on-site visits are not 
possible, the affected site will postpone screening 
and randomisation of new participants until on-site 
visits can be conducted. For already randomised 
participants, post-baseline visits can be done 
remotely via phone or video (see Section 10.5 for 
details). 
During the trial, safety monitoring will ensure that 
all AEs are continuously monitored. 
 
The risk of the concomitant use of 
COVID-19 vaccine and 
delgocitinib was assessed and it is 
considered that, for topical 
delgocitinib, COVID-19 
vaccination does not require 
pausing or discontinuing 
delgocitinib administration. 
Alitretinoin product information 
does not include any instruction 
or recommendation in relation to 
vaccination in general. 
Assessment of the benefit-risk of 
the concomitant use of 
COVID-19 vaccine and 
alitretinoin was performed and it 
was considered that, for oral 
alitretinoin, COVID-19 
vaccination does not require 
pausing or discontinuing 
alitretinoin administration. 
COVID-19 vaccines are allowed during the trial 
and should be recorded as a concomitant 
medication. 
AESI=adverse event of special interest; COVID-19=coronavirus disease 2019; IB=Investigator’s Brochure; 
ICF=informed consent form; SARS-CoV-2=severe acute respiratory syndrome coronavirus 2; WBC=white 
blood cell; WOCBP=woman of childbearing potential. 
 
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2.3.2 
Benefit Assessment 
Participants randomised in the trial will receive either delgocitinib cream or alitretinoin capsules 
for the treatment of their severe CHE: 
• The efficacy of delgocitinib in CHE was 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 both trials, delgocitinib was well tolerated, and a 
low systemic exposure to delgocitinib was observed.  
• Alitretinoin capsules are the only approved treatment for severe CHE.  
2.3.3 
Overall Benefit/Risk Conclusion 
Taking into account the measures taken to minimise risk for the trial participants, the potential 
risks identified in association with delgocitinib and alitretinoin are justified by the anticipated 
benefits that may be afforded to participants with severe CHE, and more generally the potential 
benefits to patients with moderate to severe CHE in the future. 
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3 Objectives and Endpoints 
Table 3-1 
Primary Objective and Estimands for Primary Endpoint and Key 
Secondary Endpoints 
Objectives 
Estimand type and strategy 
Endpoints 
Primary objective:  
To compare the efficacy and 
health-related quality of life 
of twice-daily topical 
application of delgocitinib 
cream with once-daily oral 
administration of alitretinoin 
capsules in the treatment of 
patients with severe CHE. 
Primary. ‘Composite’ strategy. 
First supplementary. 
‘Pandemic modified composite’ 
strategy. 
Second supplementary (for 
endpoints at Week 12 and 
Week 24). ‘Treatment policy’ 
strategy. 
Primary endpoint:  
• 
Change in HECSI score from baseline to 
Week 12. 
Key secondary endpoints: 
• 
HECSI-90 at Week 12. 
• 
IGA-CHE TS at Week 12. 
• 
Change in HESD itch score (weekly 
average) from baseline to Week 12. 
• 
Change in HESD pain score (weekly 
average) from baseline to Week 12. 
• 
AUC of HECSI-90 from baseline up to 
Week 24. 
• 
AUC of change from baseline in DLQI 
score up to Week 24. 
• 
Change in HECSI score from baseline to 
Week 24. 
Abbreviations: AUC=area under the curve; CHE=chronic hand eczema; DLQI=Dermatology Life Quality Index; 
HECSI=Hand Eczema Severity Index; HECSI-90=at least 90% improvement in HECSI score from baseline; 
HESD=Hand Eczema Symptom Diary©; IGA-CHE=Investigator’s Global Assessment for chronic hand 
eczema©; IGA-CHE TS=IGA-CHE treatment success. 
Table 3-2 
Secondary and Exploratory Objectives and Endpoints 
Objectives 
Endpoints 
Secondary objective: 
To compare the safety of twice-daily topical 
application of delgocitinib cream with once-daily 
oral administration of alitretinoin capsules in the 
treatment of patients with severe CHE. 
Secondary endpoints: 
• 
Number of treatment-emergent AEs from baseline up to 
Week 26. 
• 
Number of treatment-emergent SAEs from baseline up 
to Week 26. 
• 
Number of AEs leading to IMP discontinuation up to 
Week 24. 
Exploratory objectives: 
Exploratory endpoints: 
To compare the efficacy and health-related 
quality of life of twice-daily topical application of 
delgocitinib cream with once-daily oral 
administration of alitretinoin capsules in the 
treatment of patients with severe CHE. 
Efficacy:  
• 
IGA-CHE TS at Week 24. 
• 
HECSI-75 at Week 12 and Week 24. 
• 
HECSI-90 at Week 24. 
• 
Change in HESD itch score (weekly average) from 
baseline to Week 24. 
• 
Reduction of HESD itch score (weekly average) of 
≥3 points 1 at Week 12 and Week 24 
• 
AUC from baseline to Week 24 of reduction of HESD 
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Objectives 
Endpoints 
itch score (weekly average) of ≥3 points 1. 
• 
Reduction of HESD itch score (weekly average) of 
≥4 points 2 at Week 12 and Week 24 
• 
AUC from baseline to Week 24 of reduction of HESD 
itch score (weekly average) of ≥4 points 2. 
• 
Change in HESD pain score (weekly average) from 
baseline to Week 24.  
• 
Reduction of HESD pain score (weekly average) of 
≥3 points 3 at Week 12 and Week 24. 
• 
AUC from baseline to Week 24 of reduction of HESD 
pain score (weekly average) of ≥3 points 3.  
• 
Reduction of HESD pain score (weekly average) of 
≥4 points 4 at Week 12 and Week 24. 
• 
AUC from baseline to Week 24 of reduction of HESD 
pain score (weekly average) of ≥4 points 4.  
• 
Change in HESD score (weekly average) from baseline 
to Week 12 and Week 24.  
• 
Reduction of HESD score (weekly average) of 
≥3 points 5 at Week 12 and Week 24.  
• 
Reduction of HESD score (weekly average) of 
≥4 points 6 at Week 12 and Week 24.  
Health-related quality of life:  
• 
Change in DLQI score from baseline to Week 12 and 
Week 24.  
• 
Reduction of DLQI score of ≥4 points 7 at Week 12 and 
Week 24.  
• 
DLQI score of 0 or 1 at Week 12 and Week 24. 
• 
Change in HEIS (individual domains and total score) 
from baseline to Week 12 and Week 24. 
• 
Change in EQ-5D-5L index score from baseline to 
Week 12 and Week 24. 
• 
Change in EQ-5D-5L visual analogue scale score from 
baseline to Week 12 and Week 24. 
To evaluate the effect of twice-daily topical 
application of delgocitinib cream on treatment 
satisfaction and work productivity compared with 
once-daily oral administration of alitretinoin 
capsules in the treatment of patients with severe 
CHE. 
• 
TSQM at Week 12 and at Week 24. 
• 
Change in WPAI-CHE (each individual domain) score 
from baseline to Week 12 and Week 24 8. 
To compare the safety of twice-daily topical 
application of delgocitinib cream with once-daily 
oral administration of alitretinoin capsules in the 
treatment of patients with severe CHE. 
• 
Number of events of increased levels of triglycerides 
>3.42 mmol/L (fasted state) up to Week 26. 
• 
Number of AEs of hypertriglyceridaemia up to 
Week 26. 
• 
Number of events of increased levels of 
cholesterol >7.75 mmol/L (fasted state) up to Week 26. 
• 
Number of AEs of hypercholesterolaemia up to 
Week 26. 
• 
Number of AEs of headache up to Week 26. 
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Objectives 
Endpoints 
• 
Number of AEs of liver toxicity up to Week 26. 
• 
Number of events of increased levels of ALT and/or 
AST >3×ULN (or >3×baseline if baseline was abnormal 
but <2×ULN) up to Week 26. 
• 
Number of events of increased levels of 
ALP >2.5×ULN up to Week 26. 
• 
Number of events of increased levels of 
bilirubin >1.5×ULN up to Week 26. 
1. Among participants with a baseline HESD itch score (weekly average) ≥3 points. 
2. Among participants with a baseline HESD itch score (weekly average) ≥4 points. 
3. Among participants with a baseline HESD pain score (weekly average) ≥3 points.  
4. Among participants with a baseline HESD pain score (weekly average) ≥4 points.  
5. Among participants with a baseline HESD score (weekly average) ≥3 points. 
6. Among participants with a baseline HESD score (weekly average) ≥4 points. 
7. Among participants with a baseline DLQI score ≥4 points. 
8. Among participants with paid work at baseline. 
Abbreviations: AE=adverse event; ALT=alanine aminotransferase; AST=aspartate aminotransferase; AUC=area 
under the curve; 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; SAE=serious adverse event; TSQM=Treatment Satisfaction Questionnaire for Medicine; ULN=upper 
limit of normal; WPAI-CHE=Work Productivity and Activity Impairment – Chronic Hand Eczema. 
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4 Trial Design 
4.1 Overall Design 
This phase 3, randomised, assessor-blinded, active-controlled, parallel-group, multi-site, 
24-week trial will compare the efficacy, health-related quality of life, and safety of delgocitinib 
cream 20 mg/g twice-daily with alitretinoin capsules 30 mg (with an option to reduce to 10 mg 
during trial conduct) once-daily in adult patients with severe CHE. 
The trial will be conducted in approximately 80 sites in European countries and Canada. 
For each participant, the trial will last at least 25 weeks and up to 33 weeks, including:  
• a screening period of 1 to 4 weeks (at least 1 visit) 
• a treatment period of 24 weeks (9 visits) 
• a safety follow-up period of 2 to 5 weeks (1 visit for all participants 2 weeks after the last 
IMP dose, plus a pregnancy follow-up visit for WOCBP treated with alitretinoin 5 weeks 
after the last IMP dose) 
Screening: During the screening visit, after checking eligibility criteria, participants will be 
dispensed with an eDiary and provided training and instructions to complete the eDiary at home. 
Participants will be asked to start completing the Hand Eczema Symptom Diary© (HESD©, 
hereafter referred to as HESD) component of eDiary at least 1 week prior to baseline (Day 1), 
but preferably from the date the participants receive the eDiary. 
Treatment period: On Day 1, eligible participants will be randomised in a 1:1 ratio to receive 
1 of the following treatments: 
• Topical administration of delgocitinib cream 20 mg/g, twice-daily until Week 16, which may 
continue up to Week 24 depending on clearance status (i.e. IGA-CHE score) and clinical 
benefit. 
• Oral administration of alitretinoin capsules 30 mg (with an option to reduce to 10 mg during 
trial conduct), once-daily until Week 12, which may continue up to Week 24 depending on 
clearance status (i.e. IGA-CHE score) and clinical benefit. 
Randomisation will be stratified by subtype (hyperkeratotic/non-hyperkeratotic) and region 
(North America/Europe). 
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Efficacy (HECSI and IGA-CHE) will be evaluated by an assessor blinded to treatment 
assignment (hereinafter referred to as ‘blinded assessor’). Based on the efficacy assessments, the 
blinded assessor will make recommendations for the following: 
• Treatment discontinuation to initiate rescue medication due to lack of efficacy (Sections 6.8.2 
and 7.1). 
• To continue, stop or restart treatment from Week 12 and onwards for alitretinoin 
(Section 6.5.1). 
Safety assessments, adverse events, and treatment decisions will be made by the unblinded 
investigator to allow for: 
• Dose reductions for participants treated with alitretinoin (Section 6.5). 
• Permanent IMP discontinuation (Section 7.1). 
• Decisions to continue, stop or restart the IMP from Week 16 for delgocitinib or Week 12 for 
alitretinoin (Section 6.5.1). 
Participants will stop the IMP if they achieve an IGA-CHE score of 0 (clear) or 1 (almost clear) 
after 16 weeks of delgocitinib treatment or 12 weeks of alitretinoin treatment. Participants who 
discontinued delgocitinib treatment due to IGA-CHE score of 0 or 1 must restart treatment if 
they relapse to an IGA-CHE score of ≥2. These participants will continue attending the treatment 
period visits as planned until Week 24. 
Participants who permanently discontinue the IMP will attend an ET visit, they will stop 
attending the treatment period visits and will only be asked to return to the trial site at Week 12 
for a primary endpoint visit and at Week 24 for a nominal Week 24 visit.  
Follow-up period: Approximately 2 weeks after the last dose of IMP, participants will attend a 
follow-up visit for safety assessments. Women of childbearing potential treated with alitretinoin 
will attend an additional follow-up visit for a pregnancy test, 5 weeks after the last dose of 
alitretinoin. 
Refer to Section 10.5 for coronavirus disease 2019 (COVID-19) pandemic contingency plan. 
4.2 Scientific Rationale for Trial Design 
This is a randomised, assessor-blinded, active-controlled, parallel-group, multi-site trial, which 
will be conducted in accordance with the protocol, International Council for Harmonisation of 
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Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice 
(GCP), and applicable regulatory requirements. 
Patients with hand eczema represent a heterogeneous population as hand eczema is associated 
with different aetiologies and morphologies. To mitigate any potential difference in trial outcome 
based on baseline characteristics, the trial participants 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 subtype 
(hyperkeratotic/non-hyperkeratotic) and region. 
The trial will include a maximum of 20% of participants with hyperkeratotic subtype. Based on 
data from the phase 2b trial and the CARPE registry (Apfelbacher et al, 2014), the proportion of 
patients with hyperkeratotic subtype in the CHE background population is 20%, when calculated 
based on the aetiology of irritant and atopic CHE prevailing over the hyperkeratotic diagnosis. 
As there was a clear overrepresentation of participants with hyperkeratotic subtype in previous 
trials with alitretinoin (Ruzicka et al, 2008; Ruzicka et al, 2004), the rationale for limiting the 
proportion of participants with a hyperkeratotic subtype in this trial is to ensure a representative 
proportion of participants with this particular subtype. 
As no topical treatment is approved for moderate to severe CHE, delgocitinib cream will be 
compared with alitretinoin capsules. Due to the different administration routes for delgocitinib 
and the active comparator (alitretinoin), participants and investigators will not be blinded to 
treatment assignment. However, the evaluation of efficacy (IGA-CHE and HECSI) will be 
performed by a blinded assessor (see Section 6.3). Certain CRO and sponsor staff will also be 
blinded to ensure the integrity of the trial. 
Participants randomised to the alitretinoin arm will not receive delgocitinib vehicle cream 
because the vehicle cream may influence both the physician’s clinical evaluation and 
patient-reported outcomes (PROs). Both arms are allowed to use their normal and preferred 
emollient throughout the trial in line with standard care of CHE. 
Two ongoing pivotal vehicle-controlled phase 3 trials (trial LP0133-1401 and trial 
LP0133-1402) are confirming the efficacy and evaluating the safety of delgocitinib cream 
20 mg/g twice-daily for 16 weeks in patients with moderate to severe CHE (plus 36-week safety 
evaluation in a long-term extension trial, trial LP0133-1403). The current trial enrols patients 
with severe CHE only, because alitretinoin is only approved for the treatment of severe CHE. 
In the 2 vehicle-controlled trials, the primary endpoint is assessed at Week 16. However, the 
recommended continuous treatment with alitretinoin is 12 weeks with a label recommendation to 
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discontinue treatment in patients who have achieved an IGA-CHE score of 0 (clear) or 1 (almost 
clear) after 12 weeks and earlier than 24 weeks, and with an option to restart treatment in case of 
worsening. To ensure comparable evaluation in the 2 arms, the primary endpoint in this trial will 
be assessed at Week 12. After Week 12, alitretinoin will be used as per label with a 
recommendation to discontinue treatment if participants achieve an IGA-CHE score of 0 (clear) 
or 1 (almost clear) at the investigator’s discretion. Delgocitinib treatment will be continuous until 
Week 16 as in the pivotal phase 3 trials and based on data from the phase 2b dose ranging trial 
LP0133-1273. After Week 16, it will be recommended to discontinue treatment with delgocitinib 
if the participants achieve an IGA-CHE score of 0 (clear) or 1 (almost clear), at the investigator’s 
discretion, with an option to restart treatment in case of worsening. 
Participants who stop treatment with delgocitinib or alitretinoin because they achieve an 
IGA-CHE score of 0 or 1 will continue to attend the treatment period visits as planned. The 
protocol requires that participants who relapse (defined as an IGA-CHE score of ≥2) after 
stopping treatment must restart treatment, as this is expected to mimic clinical practice. 
The trial endpoints were selected to compare the efficacy of delgocitinib and alitretinoin in 
improving the extent and severity of CHE. Both the HECSI and the IGA-CHE will be used in 
this clinical trial as investigator-rated assessments of disease severity. The HECSI is an 
instrument used to score both the extent and the severity of the disease. The IGA-CHE is an 
assessment of the participant’s global CHE severity at a given timepoint and is based on a 
5-point scale ranging the severity of the disease from 0 (clear) to 4 (severe). The primary 
endpoint of the trial is change in HECSI score from baseline to Week 12. 
The trial endpoints will also address the impact on health-related quality of life, work 
productivity, and treatment satisfaction.  
AEs selected as exploratory endpoints (headache, hypertriglyceridaemia, hypercholesterolaemia, 
and liver toxicity) are based on the current knowledge of the safety profile of alitretinoin. 
4.3 Justification for Dose 
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 adults with mild to severe CHE.  
4.4 End of Trial Definition 
The end of the trial is defined as the date of the last visit of the last participant in the trial. 
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A participant is considered to have completed the trial if he/she has completed all periods of the 
trial including the last follow-up visit. 
5 Trial Population 
Prospective approval of protocol deviations to eligibility criteria, also known as protocol waivers 
or exemptions, is not permitted. 
The trial population will consist of adult participants with severe CHE and with a documented 
inadequate response to treatment with TCS or for whom TCS are documented to be otherwise 
medically inadvisable. The trial will include a maximum of 20% of participants with 
hyperkeratotic subtype.  
Participants must be able to provide written consent and meet all the inclusion criteria and none 
of the exclusion criteria. 
It will be recorded in the electronic case report form (eCRF) if the participant has met all the 
inclusion criteria and none of the exclusion criteria. 
5.1 Inclusion Criteria 
Participants are eligible to be included in the trial only if all of the following criteria apply: 
Age 
1. Participant must be at least 18 years of age inclusive, at the time of signing the informed 
consent. 
Type of Participant and Disease Characteristics 
2. 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. 
3. Disease severity graded as severe at screening and baseline according to IGA-CHE (i.e. an 
IGA-CHE score of 4). 
4. 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). 
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a.
Inadequate response is defined as a history of failure to achieve and maintain a low
disease activity state (comparable to an IGA-CHE score ≤2) despite treatment with a
daily regimen of TCS of III-IV (potent to very potent) for the European Union (EU)
and 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.
b.
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.
5. Participant is adherent to standard non-medicated skin care including avoidance of known
and relevant irritants and allergens.
Contraceptive/Barrier Requirements 
6. Contraceptive use must be consistent with local regulations (if they are stricter than the
protocol requirements) regarding the methods of contraception for those participating in
clinical studies.
For female participants: 
•
A female participant is eligible to participate if she is not pregnant (see Appendix 4), not
breastfeeding, and 1 of the following conditions applies:
o
Not a WOCBP as defined in Appendix 4.
OR
o
Women of childbearing potential must use at least one highly reliable method of
contraception (i.e., a user-independent method) or two complementary user-dependent
methods of contraception (see Appendix 4). Contraception must be used 1 month before
treatment and throughout treatment period, including participants with amenorrhea.
Contraception must additionally be used for 1 month after the end of treatment with
alitretinoin. If local guidelines for contraception have stricter requirements, then local
guidelines should be followed.
Informed Consent 
7. Participant is capable of giving signed informed consent as described in Appendix 1,
Section 10.1.3 which includes compliance with the requirements and restrictions listed in the
ICF and in this protocol.
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5.2 Exclusion Criteria 
Participants are excluded from the trial if any of the following criteria apply: 
Diagnostic Assessments 
1. Concurrent skin diseases on the hands (e.g. tinea manuum). 
2. Active atopic dermatitis 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. 
Medical Conditions 
6. Participants who cannot receive alitretinoin for any of the following reasons: 
a. 
Hepatic impairment, defined as alanine aminotransferase (ALT) and/or aspartate 
aminotransferase (AST) values >2×ULN, and/or prothrombin international normalised 
ratio (INR) >1.5×ULN. 
b. 
Renal insufficiency, defined as creatinine clearance <60 mL/min calculated by use of 
the Cockcroft-Gault formula. 
c. 
Uncontrolled hypercholesterolemia, defined as fasting cholesterol >1.5×ULN and/or 
fasting low-density lipoprotein (LDL) cholesterol >1.5×ULN. 
d. 
Uncontrolled hypertriglyceridemia, defined as fasting triglyceridaemia 1.5×ULN. 
e. 
Uncontrolled hypothyroidism, defined as thyroid-stimulating hormone >1×ULN 
and/or thyroxine <1×lower limits of normal. 
f. 
Hypervitaminosis A, defined as retinol levels >1×ULN (e.g. due to the use of vitamin 
A supplements containing >2000 IU). 
g. 
Known or suspected hypersensitivity either to alitretinoin, to other retinoids or to any 
of the excipients listed in the applicable alitretinoin label, in particular allergies to 
peanut or soya, or intolerance to sorbitol or fructose.  
h. 
Any other contraindication to receive alitretinoin according to the investigator’s 
judgement. 
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7. Clinically significant infection within 28 days prior to baseline which, in the opinion of the 
investigator, may compromise the safety of the participant in the trial, interfere with the 
evaluation of the IMP, or reduce the participant’s ability to participate in the trial. Clinically 
significant infections are defined as: 
a. 
A systemic infection. 
b. 
A serious skin infection requiring parenteral (intravenous or intramuscular) antibiotics, 
antiviral, or antifungal medication. 
8. History of any known primary immunodeficiency disorder including a positive human 
immunodeficiency virus (HIV) test at screening, or the participant taking antiretroviral 
medications as determined by medical history and/or participant’s verbal report. 
9. Major surgery within 8 weeks prior to baseline, or planned in-patient surgery or 
hospitalisation during the trial period. 
10. History of cancer except the following: 
a. 
Participants 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 participant is 
in remission and curative therapy was completed at least 12 months prior to screening. 
b. 
Participants who have had other malignancies are eligible provided that the participant 
is in remission and curative therapy was completed at least 5 years prior to screening. 
11. Psychiatric disorders within the last year (e.g. depression, depression aggravated, anxiety, 
aggressive tendencies, mood alterations, psychotic symptoms, suicidal ideation, suicide 
attempts) or current self-reported depression or mood disturbance. 
12. Any disorder that is not stable and could: 
a. 
Affect the safety of the participant throughout the trial. 
b. 
Impede the participant’s ability to complete the trial. 
Examples include but are not limited to cardiovascular, gastrointestinal, hepatic, renal, 
neurological, musculoskeletal, infectious, endocrine, metabolic, haematological, and 
immunological disorders, and major physical impairment. 
13. Any abnormal finding that may: 
a. 
Put the participant at risk because of their participation in the trial. 
b. 
Influence the participant’s ability to complete the trial. 
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The abnormal finding must be clinically significant and observed during the screening 
period. Examples include abnormal findings in physical examination, vital signs, 
electrocardiogram (ECG), haematology, clinical chemistry, or urinalysis. 
14. Positive hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV) antibody serology 
at screening. 
15. Current or recent history of chronic alcohol or drug abuse or any condition associated with 
poor compliance as judged by the investigator. 
Prior/Concomitant Therapy 
16. Systemic treatment with immunosuppressive drugs (e.g. methotrexate, cyclosporine, 
azathioprine), immunomodulating drugs, retinoids, potent CYP3A4 inducers (only for 
WOCBP who take hormonal contraceptives), 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). 
17. Use of tanning beds, phototherapy (e.g. UVB, UVA1, PUVA), or bleach baths on the hands 
within 28 days prior to baseline. 
18. Previous or current treatment with JAK inhibitors (including delgocitinib/LEO 124249), 
systemic or topical. 
19. Cutaneously applied treatment with immunomodulators (e.g. PDE-4 inhibitors, 
pimecrolimus, tacrolimus) or TCS on the hands within 14 days prior to baseline. 
20. Use of systemic antibiotics or cutaneously applied antibiotics on the hands within 14 days 
prior to baseline. 
21. Other transdermal and cutaneously applied therapy on the hands (except for the use of 
participant’s own emollients) within 7 days prior to baseline. 
22. 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. 
23. Treatment with any marketed biological therapy or investigational biologic agents 
(including immunoglobulin, anti-IgE, and dupilumab), except vaccines: 
a. 
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. 
b. 
Other biologics: within 3 months or 5 half-lives, whichever is longer, prior to baseline. 
24. Treatment with CYP3A4 inhibitors (e.g. ketoconazole), potent CYP2C9 inhibitors (e.g. 
fluconazole, miconazole, oxandrolone), or potent CYP2C8 inhibitors (e.g. gemfibrozil), 
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CYP2C8 substrates (e.g. amiodarone, paclitaxel, rosiglitazone, repaglinide), simvastatin, or 
tetracyclines within 7 days prior to screening. Topical treatment with CYP2C9 inhibitors 
(e.g. fluconazole, miconazole, oxandrolone) on areas of the body other than hands is 
allowed. 
25. Treatment with any marketed therapy that may interfere with the trial objective. 
Prior/Concurrent Clinical Trial Experience 
26. Previously used alitretinoin or participated in a clinical trial with alitretinoin or 
delgocitinib. 
27. 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. 
28. Current participation in any other interventional clinical trial. 
Other Exclusions 
29. Known or suspected hypersensitivity to any component(s) of the IMPs, including allergies 
to peanut or soya. 
30. Women who are pregnant or lactating. 
31. 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. 
32. Participants who are legally institutionalised. 
33. Previously randomised in this clinical trial. 
 
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5.3 Lifestyle Considerations 
5.3.1 
Skin Care 
• Participants should adhere to standard non-medicated skin care including avoidance of 
known and relevant irritants and allergens. 
• Participants should not change their usual skin care routine of the hands regarding use of 
emollients during the trial. However, emollients should preferably not be used on the affected 
areas within 2 hours before and after application of delgocitinib. Furthermore, emollients 
must not be used on the hands and wrists in both treatment groups for at least 2 hours prior to 
trial visits. Participants are allowed to apply other skin treatments/products to other areas of 
the body for other skin conditions (including topical miconazole for foot dermatitis) during 
the trial, as long as this does not interfere with the trial (i.e. participants 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 delgocitinib.  
• Use of cosmetic body care products (e.g. body lotion, shampoo, bath oil), which are routinely 
used by the participants, 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 delgocitinib application or alternatively performed using disposable gloves. 
• Excessive exposure to sunlight and sunlamps should be avoided. Sunscreen products on the 
body and protective gloves on the hands are recommended when exposure cannot be 
avoided. 
5.3.2 
Meals and Dietary Restrictions 
• Participants should be fasting for at least 8 hours prior to collection of laboratory samples to 
allow for analysis of fasting values of triglycerides and cholesterol (LDL, HDL, and total 
cholesterol), at the visits specified in the SoA (Table 1-1). 
• Alitretinoin capsules should be taken with a main meal, preferentially at the same time each 
day. 
5.4 Screen Failures 
A screen failure occurs when a participant who consents to participate in the clinical trial is not 
subsequently randomly assigned to trial treatment. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the Consolidated 
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Standards of Reporting Trials (CONSORT) publishing requirements 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 serious adverse events (SAEs). 
In case of any SAEs, these must be followed up as described in Section 10.3.3. 
Individuals who do not meet the criteria for participation in this trial (screen failure) may not be 
rescreened. However, if the reason for screen failure is not due to the participant 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. Rescreened participants should be assigned a new participant number for every 
screening/rescreening event. 
5.4.1 
Screening and Enrolment Log and Participant Identification Numbers 
The investigator will maintain a log of all patients considered for screening, whether they have 
provided written informed consent or not (prescreening log). This log will be anonymous and 
will include the reason(s) for not entering the trial, if applicable, or the allocated participant 
identification number. For patients not willing to consent, the main reason will be collected on 
the prescreening log (e.g. time constraint, due to side effect profile of alitretinoin, other safety 
concerns, number of blood samples). 
Upon enrolment, each participant will receive a unique participant identification number. 
Participant numbers must not be re-used for different participants.  
The investigator will maintain a log of all consented participants at the trial site (participant 
identification list). This log will include each participant’s identity, date of consent, and 
corresponding participant identification number, so that any participant may be identified if 
required for any reason. The log must not be copied or retained by LEO Pharma. 
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6 Trial Treatments and Concomitant Therapy 
Trial treatment is defined as any investigational treatment or marketed product, intended to be 
administered to a trial participant according to the trial protocol. 
6.1 Trial Treatments Administered 
Table 6-1 
Trial Treatments Administered 
Treatment Name 
Delgocitinib 
Alitretinoin 
Type 
Drug 
Drug 
Dosage Formulation 
Cream 
Soft capsule 
Unit Dose Strength(s) 
20 mg/g  
101 or 30 mg per capsule 
Dosage Level(s) 
1 application twice-daily  
1 capsule per day 
Route of 
Administration 
Topical (application of a thin layer on 
affected areas) 
Oral 
Use 
Experimental 
Active Comparator 
IMP or NIMP 
IMP 
IMP 
Sourcing 
Provided centrally by the sponsor 
Provided centrally by the sponsor 
Packaging and 
Labelling 
Delgocitinib will be provided in a tube 
containing 30 g of cream. Each tube will 
be labelled as required per each country.  
Alitretinoin will be provided in 
aluminium blisters, containing 
30 capsules. Each blister will be labelled 
as required per each country. 
Current/Former 
Name(s) or Alias(es) 
LEO 124249 
Toctino® (commercial name) 
Abbreviations: IMP= investigational medicinal product; NIMP=non-investigational medicinal product. 
1. 10 mg will only be used in participants with unacceptable adverse reactions after the dose of 30 mg (see 
Section 6.5). 
 
6.2 Preparation, Handling, Storage, and Accountability 
6.2.1 
Administration of Trial Treatment 
6.2.1.1 
Delgocitinib Cream 
Delgocitinib cream 20 mg/g will be applied as a twice-daily topical application for up to 
24 weeks. The applications will be performed approximately 12 hours apart. Instructions for use 
will be provided. 
Delgocitinib will be applied to clean, dry hands, fingers, fingertips, and wrists in a thin layer 
covering the affected area(s). The amount of delgocitinib to be used depends on the size of the 
affected area(s) and the size of the hands, fingers, fingertips, and wrists. 1 tube of 
30 g delgocitinib cream is considered sufficient for treatment of the whole surface of hands, 
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fingers, fingertips, and wrists twice-daily for 2 weeks; however, a few participants may need 
more (based on experience from the LP0133-1273 trial), which will be allowed at the discretion 
of the unblinded investigator. 
The first application of delgocitinib will occur at the trial site under supervision of the unblinded 
investigator or delegate. Prior to the first application of delgocitinib cream, the participant will be 
instructed how much cream to apply and which area(s) to treat. 
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 participant. If new CHE lesions occur, the scheme will be updated to 
document these. 
Only the affected area(s) on the hands, fingers, fingertips, and wrists will be treated. If new 
lesions occur on initially untreated area(s) of the hands, fingers, fingertips, and wrists, these new 
lesions will be treated with delgocitinib as well. The participants will be advised to contact the 
unblinded investigator before initiating treatment of new lesions. 
Delgocitinib application on initially affected area(s) and new lesions will continue until Week 16 
regardless of clearance status. Participants with an IGA-CHE score ≥2 may continue with 
treatment up until Week 24 if, in the opinion of the unblinded investigator, they may benefit 
from continued treatment. After Week 16, it is recommended to discontinue delgocitinib if 
IGA-CHE is 0 (clear) or 1 (almost clear). Participants who discontinued delgocitinib treatment 
due to IGA-CHE score of 0 or 1 must restart treatment if they relapse to an IGA-CHE score of 
≥2. These participants will remain on continuous treatment until Week 24. Treatment with 
delgocitinib should be discontinued if participants still have an IGA-CHE score of 4 (severe) 
after the initial 16 weeks of treatment. 
Prior to each trial visit, application of delgocitinib cream will occur at the participant’s home at 
least 2 hours prior to the trial visit. 
6.2.1.2 
Alitretinoin Capsules 
Alitretinoin capsules 30 mg will be taken once-daily for up to 24 weeks with an option to reduce 
to 10 mg during trial conduct (see Section 6.5). 
Alitretinoin should be taken with a main meal, preferably at the same time each day. The 
capsules should be swallowed whole and not chewed. A missed dose should be taken as soon as 
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possible, unless it is close to the time for the next dose, in which case the missed dose should be 
skipped. It is not allowed to take a double dose to make up for a forgotten capsule. 
The first dose of alitretinoin will be taken at the trial site with a meal, under the supervision of 
the unblinded investigator or delegate.  
Treatment with alitretinoin will continue until Week 12 regardless of clearance status, according 
to the alitretinoin label, unless safety issues arise. After Week 12, it is up to the unblinded 
investigator’s judgement whether the participant would benefit from continuing the treatment. 
Participants with an IGA-CHE score ≥2 may continue with treatment up until Week 24 if, in the 
opinion of the unblinded investigator, they may benefit from continued treatment. After 
Week 12, it is recommended to discontinue alitretinoin if IGA-CHE is 0 (clear) or 1 (almost 
clear). Participants who discontinued alitretinoin treatment due to IGA-CHE score of 0 or 1 must 
restart treatment if they relapse to an IGA-CHE score of ≥2. These participants will remain on 
continuous treatment until Week 24. It should be considered to discontinue treatment with 
alitretinoin for participants who still have an IGA-CHE score of 4 (severe) after the initial 
12 weeks of treatment. 
Local safety requirements for the use of alitretinoin should be followed, and educational material 
about alitretinoin should be discussed and handed out to the patients at inclusion (a sample of 
this information should be available in the trial master file [TMF] at each site). 
Patients should stop alitretinoin if they develop depression, mood disturbance, psychosis, or 
aggression. Patients should be monitored until these symptoms resolve. Discontinuation of 
alitretinoin may be insufficient to alleviate symptoms and therefore further psychiatric evaluation 
may be necessary. 
Alitretinoin capsules are approved in all countries participating in this trial. Alitretinoin is 
sourced from Almac UK (Toctino®). The UK SmPC for Toctino® has been chosen as the 
representative drug label for Canada and the UK. For the EU countries, the German SmPC for 
Toctino® has been chosen as the representative drug label to align with the requirements of EU 
legislation. The UK and German SmPC are equivalent. The sponsor will monitor the SmPC 
regulatory and inform agencies immediately should there be any divergence. 
6.2.2 
Handling, Storage, and Accountability 
The investigator or designee must maintain a log to confirm appropriate temperature conditions 
have been maintained during transit for all IMPs received, and any discrepancies are reported 
and resolved before use of the IMP. 
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Only participants randomised in the trial may receive the IMP, and only authorised site staff may 
supply or administer the IMP. All IMPs must be stored in a secure, environmentally controlled, 
and monitored (manual or automated) area in accordance with the labelled storage conditions 
with access limited to the investigator and authorised site staff. 
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for IMP accountability, reconciliation, and record maintenance (e.g. receipt, 
reconciliation, and final disposition records). 
Further guidance and information for the final disposition of unused IMP are provided in the 
Investigator’s Manual. 
6.3 Measures to Minimise Bias: Randomisation and Blinding 
Due to the different administration routes for the 2 IMPs, participants are not blinded to 
treatment assignment. A double-dummy design is not considered feasible since addition of the 
cream vehicle to alitretinoin-treated participants may increase the clinical effect in the 
alitretinoin arm. To ensure unbiased clinical assessments, efficacy (IGA-CHE and HECSI) will 
be evaluated by a blinded assessor. Each site will have at least 1 dermatologist or allergist and 
1 physician to allow for both an unblinded investigator and a blinded assessor. The sponsor will 
ensure appropriate measures are in place to keep information about treatment assignment 
segregated from the blinded assessor. Such measures will include training of site personnel and 
participants, as well as separate systems access and source documentation.  
In addition, to minimise the risk of potential bias into final analyses, a blinding maintenance plan 
will be implemented by the sponsor and by the CRO to maintain the integrity of the trial data for 
the decision making at the final analyses. The details regarding access to blinded or unblinded 
data by the site, CRO and sponsor staff, as well as blinding procedures, will be outlined in the 
blinding maintenance plan. The blinding maintenance plan will be finalised prior to the first 
participant first visit. Although the trial is not double-blinded, the specific treatment to be taken 
by a participant will be randomly assigned using interactive response technology (IRT). The site 
will contact the IRT prior to the start of IMP administration for each participant. The site will 
record the treatment assignment on the applicable eCRF, if required.  
Trial treatment will be administered/dispensed at the trial visits as summarised in the SoA 
(Table 1-1). Returned IMP should not be re-dispensed to the participants. 
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6.4 Trial Treatment Compliance 
Treatment days will be recorded by the participants in the eDiary, the participant will be asked to 
confirm treatment administration once-daily. 
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 participant of the 
importance of following the instructions given. 
At baseline, the date of first dose of IMP will be recorded in the eCRF.  
Delgocitinib: The first application of delgocitinib cream will occur at the trial site with clear 
instructions from the site staff on which areas of the hands, fingers, fingertips, and wrists the 
cream must be applied and which amount of cream to be used per application. Returned, opened 
delgocitinib tubes will be weighed at the trial site to determine the amount of delgocitinib cream 
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). 
Alitretinoin: Returned alitretinoin capsules will be counted to assess treatment compliance. The 
number of returned capsules will be recorded in the individual drug accountability form and in 
the eCRF. 
6.5 Dose Modification 
Delgocitinib: Dose modifications are not possible with the delgocitinib cream, but the amount of 
cream applied to the hands may be increased, if new lesions appear, at the discretion of the 
unblinded investigator (see Section 6.2.1.1).  
Alitretinoin: The dose of alitretinoin may be reduced from 30 mg to 10 mg in participants with 
unacceptable adverse reactions. If the dose is decreased, it will not be permitted to increase the 
dose at a later point during the trial. Alitretinoin dose reductions and the reason for dose 
reduction will be reported in the eCRF. 
6.5.1 
Retreatment Criteria 
For participants who achieve an IGA-CHE score of 0 or 1 after 16 weeks of delgocitinib 
treatment or 12 weeks of alitretinoin treatment, it is recommended to discontinue treatment.  
However, these participants must restart treatment if they relapse to an IGA-CHE score of ≥2 
and will remain on continuous treatment until Week 24. 
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6.6 Continued Access to Trial Treatment After the End of the Trial 
After the end of the trial, participants will be treated at the investigator’s discretion or referred to 
other physician(s) according to standard practice. 
6.7 Treatment of Overdose 
For this trial, the following will be considered an overdose: 
• More than 1 alitretinoin capsule per day. 
Alitretinoin: Alitretinoin has been administered in oncological clinical studies at dosages of 
more than 10-times of the therapeutic dosage given for CHE. The adverse effects observed were 
consistent with retinoid toxicity, and included severe headache, diarrhoea, facial flushing, 
hypertriglyceridemia. These effects were reversible. 
In the event of an overdose, the investigator should: 
• Closely monitor the participant for any AE/SAE or laboratory abnormalities. 
• Report any clinically relevant findings.  
• Use clinical judgement to treat any symptoms connected with an overdose. 
6.8 Concomitant Therapy 
Any medication or vaccine (including over-the-counter or prescription medicines, recreational 
drugs, vitamins, and/or herbal supplements) that the participant is receiving at the time of 
enrolment or receives during the trial must be recorded along with: 
• Medication name or therapy. 
• Primary indication. 
• Whether the medication or therapy is a rescue treatment for CHE (yes, no), see Section 6.8.2. 
• 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. 
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• For cutaneous treatment, it must also be recorded if the treatment is within 5 cm 
(approximately 2 inches) of the borders of CHE lesions. 
Similarly, any concurrent procedure must also be recorded in the participant’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 Table 6-2. As described in 
Section 6.8.2, prohibited medications used as rescue treatment for intolerable CHE symptoms are 
allowed, but participants using rescue treatment must discontinue IMP immediately and will not 
be allowed to restart treatment with IMP. The medical monitor should be contacted if there are 
any questions regarding concomitant or prior therapy. 
Prior and Concomitant Medications Review 
The investigator or qualified designee will review prior medication use and record prior 
medications taken by the participant within 3 months prior to screening. 
Previous treatments for CHE (name and type of treatment, rationale for discontinuation of 
treatment) will be collected. 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. 
The following information will also be collected in the eCRF for prior 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 participant specifically on inclusion criterion 4: 
o 
Has the participant fulfilled the trial inclusion criterion 4.a based on having inadequate 
response to treatment with TCS during the last 12 months? (yes, no). 
o 
Has the participant fulfilled the trial inclusion criterion 4.b based on TCS being 
medically inadvisable for the participant? (yes, no). 
- 
If yes: reason for TCS use being medically inadvisable. 
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The investigator or qualified designee will record medication, if any, taken by the participant 
during the trial through the last visit. Concomitant medications will be recorded for 14 days after 
the last dose of IMP (or longer if related to an SAE). 
6.8.1 
Background Treatment 
No background treatment is required in this trial. Participants should adhere to standard 
non-medicated skin care, as described in Section 5.3. 
Of note, emollients are not considered concomitant medication and should not be recorded as 
such. 
6.8.2 
Rescue Medication 
If medically necessary (i.e. to control intolerable CHE symptoms), rescue treatment for CHE 
may be prescribed to the participant. Following the assessment of efficacy (IGA-CHE and 
HECSI), the blinded assessor will recommend whether rescue medication should be initiated. 
The unblinded investigator will select and initiate the rescue medication.  
Alitretinoin cannot be used as rescue treatment. The investigator should make every attempt to 
ensure that efficacy and safety assessments (e.g. disease severity scores, safety laboratory 
assessments) are conducted immediately before administering any rescue treatment. If rescue 
treatment is initiated, the participant must stop the IMP immediately and will not be allowed to 
restart the IMP.  
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. 
The date and time of rescue medication administration as well as the name and dosage regimen 
of the rescue medication must be recorded. 
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6.8.3 
Prohibited Medications and Procedures 
Medications and procedures listed in Table 6-2 are prohibited during the trial. All prohibited 
medications must be recorded as concomitant medication. 
Table 6-2 
Prohibited Medications and Procedures 
Medication/procedure 
Prohibited from 
Prohibited to 
Systemic immunosuppressive/immunomodulating drugs (e.g. 
methotrexate, cyclosporine, azathioprine), retinoids (other than the 
IMP), or corticosteroids (steroid eye drops 1 and inhaled or intranasal 
steroids corresponding to up to 1 mg prednisolone for allergic 
conjunctivitis, asthma, or rhinitis are allowed). 
28 days prior to baseline. 
End of trial. 
JAK inhibitors, systemic or topical (other than the IMP). 
Participant’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 and cutaneously applied therapy on the hands 
(except for the IMP and the participant’s own emollient). 
7 days prior to baseline. 
End of trial. 
Cutaneously applied treatments in regions other than the hands that 
could interfere with clinical trial evaluations or pose a safety 
concern.  2 
7 days prior to baseline. 
End of trial. 
Any marketed biological therapy or investigational biologic agents 
(including immunoglobulin, anti-IgE, and dupilumab), except 
vaccines: 
 
 
• 
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 that 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. 
CYP3A4 inhibitors (e.g. ketoconazole), potent CYP2C9 inhibitors 
(e.g. fluconazole, miconazole, oxandrolone), or potent CYP2C8 
inhibitors (e.g. gemfibrozil). 
7 days prior to baseline 
End of trial. 
CYP2C8 substrates (e.g. amiodarone, paclitaxel, rosiglitazone, 
repaglinide). 
7 days prior to baseline 
End of trial. 
Potent CYP3A4 inducers. 3 
28 days prior to baseline 
End of trial. 
Simvastatin. 
7 days prior to baseline 
End of trial. 
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Medication/procedure 
Prohibited from 
Prohibited to 
Systemic tetracyclines. 
7 days prior to baseline 
End of trial. 
Systemic vitamin A. 
Baseline. 
End of trial. 
1. 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 participants 
need to use gloves when applying treatment). 
3. Only applies for WOCBP who take hormonal contraceptives. 
Abbreviations: CYP=cytochrome P450; IgE=immunoglobulin E; IMP=investigational medicinal product; 
JAK=Janus kinase; PDE-4=phosphodiesterase-4; PUVA=psoralen ultraviolet A; TCS=topical corticosteroid; 
UVA1=ultraviolet A1; UVB=ultraviolet B; WOCBP=women of childbearing potential. 
 
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7 Discontinuation of Trial Treatment and Participant Discontinuation 
Discontinuation of specific sites or of the trial as a whole are handled as part of the appendix on 
Governance, Appendix 1, Section 10.1.8. 
7.1 Discontinuation of Trial Treatment 
It may be necessary for a participant to permanently discontinue the IMP. If the IMP is 
permanently discontinued, the participant will remain in the trial and attend an early termination 
visit, a follow-up visit 2 weeks after the last administration of IMP, the primary endpoint visit at 
Week 12 (for participants who discontinue the IMP prior to Week 12), and the nominal Week 24 
visit. Female participants on alitretinoin treatment should have a pregnancy test performed 
5 weeks after the last IMP administration. See the SoA (Table 1-1) for data to be collected at the 
time of IMP discontinuation and follow-up and for any further evaluations that need to be 
completed. 
IMP must be discontinued permanently in case of the following: 
1. An AE that, in the opinion of the investigator or sponsor’s medical expert, contraindicates 
further dosing. 
2. Evidence of pregnancy. 
3. Intolerable CHE symptoms requiring the initiation of rescue medication (see Section 6.8.2). 
4. Symptoms or AEs requiring treatment with prohibited medication or procedure (see 
Section 6.8.3). 
5. Clinically important laboratory abnormalities in liver chemistry (see Appendix 6): 
a. ALT and/or AST values >3×ULN with total bilirubin >2×ULN (unless elevated bilirubin 
is related to Gilbert Meulengracht Syndrome). 
b. ALT and/or AST values >3×ULN with prothrombin INR >1.5×ULN. 
c. Confirmed ALT and/or AST values >5×ULN (for more than 2 weeks). 
6. For alitretinoin only, if participant develops depression, mood disturbance, psychosis, or 
aggression. Participant should be referred immediately to a mental health care professional 
for further assessment. 
7. For alitretinoin only, if participant develops any symptoms requiring treatment 
discontinuation per local product information (e.g. signs of benign intracranial hypertension, 
increased lipids that cannot be controlled at an acceptable level, symptoms of pancreatitis, 
severe diarrhoea). 
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Trial treatments should be discontinued permanently in case of the following: 
8. An IGA-CHE score of 4 (severe) after receiving 12 weeks of alitretinoin treatment or 
16 weeks of delgocitinib treatment. 
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 participant. 
• 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. 
7.2 Participant Discontinuation/Withdrawal from the Trial 
A participant may withdraw from the trial at any time at their own request or may be withdrawn 
at any time at the discretion of the investigator for safety, behavioural, or compliance reasons. 
The participant will be permanently discontinued from the IMP and the trial at that time. 
If the participant withdraws consent for disclosure of future information, the sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. 
If a participant withdraws from the trial, he/she may request destruction of any samples taken 
and not tested, and the investigator must document this in the site trial records. 
At the time of discontinuing from the trial, if possible, an early discontinuation visit should be 
conducted, as shown in the SoA (Table 1-1). Refer to the SoA for data to be collected at the time 
of trial discontinuation and follow-up and for any further evaluations that need to be completed. 
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7.3 Loss to Follow-Up 
A participant will be considered lost to follow-up if they repeatedly fail to return for scheduled 
visits and are unable to be contacted by the trial site. 
The following actions must be taken if a participant fails to return to the clinic for a required trial 
visit: 
• The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible (and within the visit window, where one is defined), counsel the participant on the 
importance of maintaining the assigned visit schedule, and ascertain whether the participant 
wishes to and/or should continue in the trial. 
• In cases in which the participant is deemed lost to follow-up, the investigator or designee 
must make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing address or 
local equivalent methods). These contact attempts should be documented in the participant’s 
medical record/CRF. 
• Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the trial. 
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8 Trial Assessments and Procedures 
Trial procedures and their timing are summarised in the SoA (Table 1-1). Protocol waivers or 
exemptions are not allowed. 
Assessments and procedures at each trial visit should be performed in the order shown in 
Figure 8–1. 
Figure 8–1 
Sequence of Assessments 
 
Abbreviations: HECSI=Hand Eczema Severity Index; IGA-CHE=Investigator’s Global Assessment for chronic hand 
eczema©; IMP=investigational medicinal product; PRO=patient-reported outcome. 
 
Trial participants 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 a physician. 
AEs must be assessed by a physician (Section 8.3). 
Immediate safety concerns should be discussed with the sponsor immediately upon occurrence or 
awareness to determine if the participant should continue or discontinue the IMP. 
Adherence to the trial design requirements, including those specified in the SoA, is essential and 
required for trial conduct. 
Clinical safety laboratory tests
PROs 
IGA-CHE and HECSI
(assessed by the blinded assessor)
Safety assessments
Application of IMP
(baseline visit and delgocitinib group, only) 
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All screening evaluations must be completed and reviewed to confirm that potential participants 
meet all eligibility criteria. The investigator will maintain a screening log to record details of all 
participants screened and to confirm eligibility or record reasons for screening failure, as 
applicable. 
The maximum amount of blood collected from each participant over the duration of the trial, 
including any extra assessments that may be required, will not exceed 180 mL. 
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the 
samples. 
Participant Identification Card 
All participants will be given a participant identification card identifying them as participants in 
a research trial. The card will contain trial site contact information (including direct telephone 
numbers) to be used in the event of an emergency. The investigator or qualified designee will 
provide the participant with a participant identification card immediately after the participant 
provides written informed consent. At the time of treatment allocation/randomisation, site 
personnel will add the treatment/randomisation number to the participant identification card. 
The participant identification card also contains information about the IMP. 
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 participant’s age. 
•  Sex: female, male. 
• Ethnic origin (self-reported by the participant): ‘Hispanic or Latino’, ‘not Hispanic or 
Latino’. 
• Race (self-reported by the participant): 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 participant in 
the eCRF. 
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Height and Weight 
The participant’s height (without shoes) will be measured; the participant’s weight (in indoor 
clothing and without shoes) will be measured. 
Fitzpatrick Skin Type 
The participant’s skin type will be recorded using the Fitzpatrick skin classification (Table 8-1). 
Table 8-1 
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. 
 
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 participant’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 5.2). 
Medical history related to CHE will include the following information: 
• Date of diagnosis of CHE. 
• Number and duration of flares experienced during the past year. 
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• Results of relevant previous diagnostic procedures other than diagnostic patch testing (e.g. 
prick test). 
• Presence of atopy. 
• Presence of atopy in the participant’s family history. 
The following exogenous risk factors for CHE will also be reported: 
• Environmental trigger factors (yes, no, unknown). 
o 
If yes: Occupational relevance (yes, no, unknown). 
o 
If yes: Name of trigger (name or unknown). 
o 
If yes: Type of trigger (allergen, irritant, unknown). 
o 
If yes: Has the trigger been avoided (yes, no, not applicable). 
o 
If yes: Has it been possible to avoid the trigger (yes, no, not applicable). 
• 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 1 option applies, the status that the participant had for the 
longest period during the past year should be captured. 
o 
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]). 
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o 
If current smoker: Type of tobacco (cigarettes, other). 
o 
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. 
Classification of CHE 
The investigator will determine the CHE subtype(s) according to the definitions in Table 8-2.  
Table 8-2 
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 Diepgen et al, 2015. Note that the terms eczema and dermatitis are used 
interchangeably in the referenced publication. 
Abbreviations: IgE=immunoglobulin E. 
 
The classification of CHE will be done according to standard clinical practice including 
mandatory diagnostic patch testing with at least a relevant baseline series including the most 
important contact allergens relevant to the locality of the site. For participants 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 participants who have not had a patch test within 
3 years prior to screening, a patch test will be performed. The patch test should be completed so 
results are available prior to baseline assessments (Day 1). 
The diagnostic patch test is done by applying patches containing standardised samples of 
allergens to the participants’ upper back. The patches will stay in place for approximately 
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48 hours under occlusion, after which they are removed during a visit at the trial site. The 
participants will return to the trial site for assessment of patch test reactions according to 
standard clinical practice at the trial site. 
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. 
8.1 Efficacy Assessments 
Planned timepoints for all efficacy assessments are provided in the SoA (Table 1-1). 
8.1.1 
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 (Held et al, 2005). 
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) (Table 8-3). 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) (Table 8-3). For each of the hand regions, the 
region score will be calculated by adding up the severity scores for the 6 clinical signs of hand 
eczema and multiplying with the area score (Table 8-4). 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 SoA (Table 1-1). 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 will be included in the assessment. The HECSI score will be 
recorded in the eCRF. 
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Table 8-3 
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. 
Table 8-4 
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. 
 
8.1.2 
Investigator’s Global Assessment for Chronic Hand Eczema© 
(IGA-CHE) 
The IGA-CHE is an instrument used in clinical trials to rate the severity of the participant’s 
global disease and is based on a 5-point scale ranging from 0 (clear) to 4 (severe) (Table 8-5). 
The IGA-CHE score will be assessed according to the SoA (Table 1-1). 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 will be included in the assessment. The IGA-CHE score will be 
recorded in the eCRF. 
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Table 8-5 
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 1: 
• 
Slight but definite erythema (pink) 
• 
Slight but definite scaling (mostly fine scales) 
• 
Slight but definite hyperkeratosis/lichenification 
and at least 1: 
• 
Scattered vesicles, without erosion 
• 
Barely palpable oedema 
• 
Superficial fissures 
Moderate 
3 
At least 1: 
• 
Clearly perceptible erythema (dull red) 
• 
Clearly perceptible scaling (coarse scales) 
• 
Clearly perceptible hyperkeratosis/lichenification 
and at least 1: 
• 
Clustered vesicles, without visible erosion 
• 
Definite oedema 
• 
Definite fissures 
Severe 
4 
At least 1: 
• 
Marked erythema (deep or bright red) 
• 
Marked and thick scaling 
• 
Marked hyperkeratosis/lichenification 
and at least 1: 
• 
High density of vesicles with erosions 
• 
Marked oedema 
• 
1 or more deep fissures 
Abbreviations: IGA-CHE=Investigator’s Global Assessment for chronic hand eczema©  
 
8.1.3 
Patient-reported Outcomes 
8.1.3.1 
eDiary Assessments 
At the screening visit, participants will be dispensed with the eDiary device and will receive 
training on how to fill out the eDiary. Participants will complete the eDiary daily at home and 
will return the eDiary device to the trial site, as outlined in the SoA (Table 1-1). 
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Participants will complete the following assessments in the eDiary as outlined in the SoA 
(Table 1-1), in the listed order: 
• Daily: HESD. 
• Daily: treatment compliance (see Section 6.4). 
• Weekly: Participant’s assessment of local tolerability (see Section 8.2.7). 
Hand Eczema Symptom Diary© (HESD) 
The HESD is a 6-item PRO instrument designed to assess severity of CHE signs and symptoms. 
Participants will assess the worst severity of 6 signs and symptoms of CHE (itch, pain, cracking, 
redness, dryness, and flaking) over the past 24 hours using an 0-10 numeric rating scale with 
anchors of 0=‘no (symptom)’ and 10=‘severe (symptom)’. 
The HESD score is derived as an average of the 6 items.  
8.1.3.2 
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 participant’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 (Finlay et al, 1994). Each item is scored on a 4-point Likert scale (0=‘not at 
all⁄not relevant’; 1=‘a little’; 2=‘a lot’; 3=‘very much’). The 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. 
8.1.3.3 
Hand Eczema Impact Scale© (HEIS) 
The Hand Eczema Impact Scale© (HEIS©, hereafter referred to as HEIS) is an instrument that 
includes 9 items addressing the participant’s perception over the past 7 days within the following 
domains: Proximal Daily Activity Limitations (PDAL), embarrassment with the appearance of 
the hands, frustration with CHE, sleep, work, and physical functioning. 
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 9 items. The highest possible score is 4, 
and a high score is indicative of a high impact. In addition, 6 domain scores can be calculated for 
HEIS: PDAL (average of 3 items), embarrassment with the appearance of the hands (average of 
2 items), frustration with CHE (1 item), sleep (1 item), work (1 item), and physical functioning 
(1 item). 
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8.1.3.4 
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 (EuroQoL 
Group, 1990). 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 participant 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. 
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’).  
8.1.3.5 
Treatment Satisfaction Questionnaire for Medicine (TSQM) 
The TSQM v.II is a generic questionnaire assessing participant’s satisfaction with the treatment 
(Atkinson et al, 2004).  
The tool consists of 11 items addressing 4 domains (effectiveness, side effects, convenience and 
overall satisfaction): 
• 7 items (in the domains of effectiveness, convenience and overall satisfaction) will be 
assessed by the participant using a 7-category scale (score) (‘extremely dissatisfied’=1, ‘very 
dissatisfied’=2, ‘dissatisfied’=3, ‘somewhat satisfied’=4, ‘satisfied’=5, ‘very satisfied’=6, 
and ‘extremely satisfied’=7). 
• 3 items (in the domain of side effects) will be assessed by the participants using a 6-category 
scale (score) (‘extremely dissatisfied’=1, ‘very dissatisfied’=2, ‘somewhat dissatisfied’=3, 
‘slightly dissatisfied’=4, ‘not at all dissatisfied’=5, ‘not applicable’=5). 
• 1 item (item 3 in the domain of side effects) will be assessed using a 2-category scale (score) 
(‘yes’=1, ‘no’=0). 
The scores for each of the 4 domains ranges from 0 to 100 with higher scores indicating higher 
satisfaction. 
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The TSQM contains specific questions on side effects. If the participant answers ‘yes’ for item 3, 
and/or tick anything but ‘not applicable’ for items 4, 5 or 6, the investigator must follow-up with 
the participant to ensure AEs are appropriately recorded (see Section 8.3.2). 
8.1.3.6 
Work Productivity and Activity Impairment – Chronic Hand 
Eczema (WPAI-CHE) 
The impact of CHE on the participant’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 (Reilly et al, 1993). 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. 
8.1.3.7 
Patient Global Impression of Severity (PGI-S) questionnaires 
The PGI-S is a 1-item questionnaire designed to assess the participant’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 participants 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) (Table 8-6). 
The PGI-S questionnaires will be completed at the trial site according to the schedule of trial 
procedures in Section 1.3. 
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Table 8-6 
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 
 
8.1.3.8 
Patient Global Impression of Change (PGI-C) questionnaires 
The PGI-C is a 1-item questionnaire designed to assess the participant’s impression of changes. 
From 5 response options (‘much better’, ‘a little better’, ‘no change’, ‘a little worse’, or ‘much 
worse’), the participants 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 participants 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) (Table 8-7). 
The PGI-C questionnaires will be completed at the trial site according to the schedule of trial 
procedures in Section 1.3. 
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Table 8-7 
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 
 
8.1.4 
CHE Lesions Photography 
Participant at selected trial sites will be asked to participate in an optional photography 
component of the trial which involves digital photography assessments to show disease status 
over time. Participation in this optional photography component requires that the participant 
provides additional informed consent with the possibility to choose for which purpose (scientific 
and/or commercial) the photographs can be used. 
Digital colour photographs will be taken of both hands-back and front, including wrist on both 
sides according the SoA (Table 1-1). It will be recorded in the eCRF if the photo(s) was taken; if 
not, a reason should be provided. If deemed necessary (e.g. in case of poor quality), photographs 
can be retaken at the next visit. 
Photography equipment, standards, and procedures are provided to the trial sites by the central 
photography vendor. Instructions for photography will be provided to the sites in a photography 
manual. 
The photographs will have no other participant identifier than the participant ID, year of birth, 
visit number, and date, and will be transmitted electronically to the photography vendor using a 
secure file transfer protocol. 
The photographs must be included as part of the individual participant source documentation. 
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Depending on the participant’s consent, LEO Pharma may use the photographs in publications, 
posters, and similar types of information material or media targeting patients and healthcare 
professionals. The photographs may also be part of training material used for training and 
educational purposes. Steps will be taken to ensure that the identity of the participant is protected 
to the extent possible. 
8.2 Safety Assessments 
Planned timepoints for all safety assessments are provided in the SoA (Table 1-1). 
8.2.1 
Physical Examinations 
A complete physical examination of the participant including whole body inspection of the skin, 
auscultation of heart, lungs, and abdomen, palpation of the abdominal organs, and basic 
neurological status will be performed. Presence of foot dermatitis will be documented. The 
investigator should perform the same examinations as in clinical practice as a minimum. 
If CHE is the only finding, the physical examination should be considered normal. 
8.2.2 
Vital Signs 
Vital signs (resting blood pressure, pulse, and body temperature) will be assessed. 
Blood pressure and pulse measurements will be assessed in a sitting position with a completely 
automated device. Manual techniques will be used only if an automated device is not available. 
Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest for the 
participant in a quiet setting without distractions (e.g. television, cell phones). 
Vital signs will consist of 1 pulse and 3 blood pressure measurements (after the participant has 
been sitting for 5 minutes, 3 consecutive blood pressure readings will be recorded at intervals of 
at least 1 minute). The average of the 3 blood pressure readings will be recorded. 
In case of an abnormal finding, the 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. 
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In case of clinically significant abnormality at screening, exclusion criterion 13 will be assessed 
at the discretion of the investigator.  
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 (see Section 10.3.3). 
8.2.3 
Electrocardiograms 
Single 12-lead digital ECGs will be recorded as outlined in the SoA (Table 1-1), after at least 
5 minutes of rest in a supine position. 
A pre-evaluation of the ECGs will be performed by the investigators to evaluate immediate 
safety of the participant. As a minimum, the date of ECG recording will be documented in the 
source. 
The ECG recordings 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. 
In case of clinically significant abnormality at screening, exclusion criterion 13 will be assessed 
at the discretion of the investigator.  
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. 
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8.2.4 
Clinical Safety Laboratory Tests 
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and the SoA 
(Table 1-1) for the timing and frequency. All protocol-required laboratory tests, as defined in 
Appendix 2, must be conducted in accordance with the laboratory manual. 
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 participant should be excluded from the trial per 
exclusion criterion 13. Participants should also be excluded if their screening laboratory results 
meet exclusion criteria 6.a, 6.b, 6.c, 6.d, 6.e, or 6.f. 
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 SoA (Table 1-1). It will be at the 
investigator’s discretion to decide whether a urine sample should be sent to the central laboratory 
for further analysis. 
 
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 
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sent to the central laboratory. If the urine sample was not tested with a dipstick, a reason will be 
provided. The investigator’s assessment of the urine dipstick results (‘normal’, ‘abnormal’) will 
be recorded in the eCRF. In case urinalysis is performed, the investigator’s assessment of the 
results (‘normal’, ‘abnormal, not clinically significant’, ‘abnormal, clinically significant’) will be 
recorded in the eCRF. 
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 (see Section 10.3.3). 
8.2.5 
Pregnancy Testing 
Alitretinoin is teratogenic, and there remains a risk of severe and serious malformation of the 
foetus in case of pregnancy even after stopping treatment. Thus, negative urine pregnancy test 
results must be obtained for WOCBP at screening and at baseline prior to randomisation, 
monthly during the trial, and 5 weeks after the last dose of alitretinoin, as shown in the SoA 
(Table 1-1). 
For WOCBP randomised to alitretinoin, the investigator must confirm compliance to acceptable 
method(s) of contraception, as shown in the SoA (Table 1-1). 
Similarly, for women treated with delgocitinib, negative urine pregnancy test results must be 
obtained for WOCBP at screening and at baseline prior to randomisation, monthly during the 
trial, but the last pregnancy test will occur 2 weeks after the last dose of delgocitinib, as shown in 
the SoA (Table 1-1). 
If pregnancy occurs during the trial, treatment must be discontinued immediately, and 
participants treated with alitretinoin capsules should be referred to a physician specialised or 
experienced in teratology for evaluation and advice.  
It will be recorded in the eCRF if the participant is a WOCBP 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’). 
8.2.6 
Mental Health Monitoring 
Depression, depression aggravated, anxiety, aggressive tendencies, mood alterations, psychotic 
symptoms, and very rarely, suicidal ideation, suicide attempts and suicide have been reported in 
patients treated with systemic retinoids, including alitretinoin. 
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All participants treated with alitretinoin should be monitored for signs of depression and referred 
for appropriate treatment if necessary.  
Prior to initiation of alitretinoin and at each visit during treatment, participants should be asked 
about any psychiatric disorder, depression, or mood disturbance in a mental health interview, as 
outlined in the SoA (Table 1-1). 
Participants should stop alitretinoin if they develop depression, mood disturbance, psychosis, or 
aggression, as described in Section 7.1. However, discontinuation of alitretinoin may be 
insufficient to alleviate symptoms and therefore further psychiatric or psychological evaluation 
may be necessary. Awareness by family or friends may be useful to detect mental health 
deterioration. 
8.2.7 
Local Tolerability 
For participants receiving delgocitinib cream only, an assessment of local tolerability will be 
provided by the participant and by the investigator, according to the SoA (Table 1-1). 
8.2.7.1 
Participant’s Assessment of Local Tolerability 
The participant will complete a weekly assessment of stinging/burning in connection with the 
delgocitinib cream applications in the eDiary. The participant will be asked to retrospectively 
assess the worst stinging/burning in connection with the delgocitinib cream application during 
the last week. In addition, the participant will be asked by the unblinded investigator at the End 
of Treatment/Early Termination visit to assess the local tolerability during the last week (see 
Section 1.3). The assessment will be done using the 4-point scale shown in Table 8-8. 
Table 8-8 
Participant’s Assessment of Local Tolerability after Delgocitinib 
Cream 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. 
 
The participant’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 the 
application of delgocitinib cream (reporting of e.g. pain or stinging/burning by the participant). 
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For the participant’s assessment of local tolerability at the EOT/ET visit, the highest (worst) skin 
reaction score across treatment area(s) will be recorded in the eCRF. 
8.2.7.2 
Investigator’s Assessment of Local Tolerability 
The investigator will assess whether he/she suspects a local skin reaction related to application of 
the delgocitinib cream. If the investigator suspects a local skin reaction related to application of 
the delgocitinib cream, the skin reaction will be scored according to the Berger and Bowman 
scales in Table 8-9. The scoring should only assess skin signs suspected to be related to 
application of the delgocitinib cream and not signs or symptoms related to the participant’s CHE. 
Table 8-9 
Berger and Bowman Scoring Scales if Investigator Suspects a Local 
Skin Reaction Related to Delgocitinib 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 1 score) if a local skin reaction is suspected to be related to application of 
delgocitinib cream. 
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. 
 
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 delgocitinib (yes, no). If 
the investigator suspects a local skin reaction to be related to application of delgocitinib, the 
scores in Table 8-9 (1 score for Scale 1; and 0, 1, or multiple scores for Scale 2) will be recorded 
in the eCRF.  
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8.3 Adverse Events (AEs), Serious Adverse Events (SAEs), and Other Safety 
Reporting 
The definitions of AEs and SAEs can be found in Appendix 3. 
AEs reported by the participants or observed by the investigator must be recorded on the AE 
form of the eCRF (see Section 8.3.2). 
The investigator and any qualified designees are responsible for detecting, documenting, and 
reporting events that meet the definition of an AE or SAE and remain responsible for following 
up all AEs (see Section 8.3.3). The method of recording, evaluating, and assessing causality of 
AEs and SAEs and the procedures for completing and transmitting SAE reports are provided in 
Appendix 3. 
8.3.1 
Time Period and Frequency for Collecting AE and SAE Information 
All AEs and SAEs will be collected from the signing of the ICF until the end of trial (defined as 
attending the last visit in the trial [the ET visit, the nominal Week 24 visit, or the last follow-up 
visit, whichever comes last]), at the timepoints specified in the SoA (Table 1-1). 
It will be recorded in the eCRF if the AE started prior to first administration of IMP. 
All SAEs will be recorded and reported to the sponsor immediately without undue delay but no 
later than within 24 hours of awareness, as indicated in Appendix 3. The investigator will submit 
any updated SAE data to the sponsor within 24 hours of it being available. 
Investigators are not obliged to actively seek information on new AEs or SAEs after the 
conclusion of trial participation. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the trial, and he/she considers the 
event to be reasonably related to the IMP or trial participation, the investigator must promptly 
notify the sponsor. 
8.3.2 
Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrence. 
At all visits, participants will be asked a non-leading question by the investigator about AEs, 
e.g.: ‘How have you felt since I saw you last?’. Participant-reported local tolerability will be 
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queried specifically (see Section 8.2.7.1) and reported as AE(s) if deemed relevant by the 
investigator.  
When completing the TSQM PRO questionnaire, participants will be asked direct questions 
about side effects. If the participant answers ‘yes’ for item 3, and/or tick anything but ‘not 
applicable’ for items 4, 5 or 6 (see Section 8.1.3.5), the investigator must follow-up with the 
participant to ensure AEs are appropriately recorded. 
If the AE qualifies as an SAE, expedited reporting is required (see Section 10.3.4). It is important 
that the investigator also observes the participant for any changes not reported by the participant 
and records these changes. 
8.3.3 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow-up with the 
participant at subsequent visits/contacts. All SAEs will be followed until resolution, stabilisation, 
until the event is otherwise explained, or the participant is lost to follow-up (as defined in 
Section 7.3). Further information on follow-up procedures is given in Appendix 3. 
8.3.4 
Regulatory Reporting Requirements for SAE 
Prompt notification (within 24 hours, see Appendix 3) by the investigator to the sponsor of an 
SAE is essential so that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a trial treatment under clinical investigation are met. 
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a trial treatment under clinical investigation. The sponsor 
will comply with country-specific regulatory requirements relating to safety reporting to the 
regulatory authority, Institutional Review Board (IRB)/Independent Ethics Committee (IEC), 
and investigators. 
An investigator who receives an Investigator Safety Report describing an SAE or other specific 
safety information (e.g. summary or listing of SAEs) from the sponsor will review and then file it 
along with the IB of delgocitinib cream and the product information of alitretinoin capsules, and 
will notify the IRB/IEC, if appropriate according to local requirements. 
All SAEs that occur during the trial, and all SAEs occurring until the safety follow-up visit, 
whether considered to be associated with the IMP or not, must be reported to the sponsor on the 
(paper) SAE form immediately, without undue delay and no later than within 24 hours of 
obtaining knowledge. The completed SAE forms must be faxed or scanned and e-mailed to 
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Global Safety at LEO Pharma. Contact details are given as described in Appendix 3 
(Section 10.3.4). 
Investigators will be notified of the evolving safety profile of the IMP on an ongoing basis. 
8.3.5 
Pregnancy 
Details of all pregnancies in female participants will be collected after the start of IMP and until 
2 weeks after the last dose of delgocitinib or 5 weeks after the last dose of alitretinoin. 
Any pregnancy occurring after first exposure to IMP and until the participant has completed the 
trial must be reported to the sponsor 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 Appendix 3 (Section 10.3.4). 
Pregnant participants must immediately discontinue IMP permanently (see Section 7.1). 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy for medical reasons will be reported as an AE or SAE. 
Abnormal pregnancy outcomes (e.g. spontaneous abortion, foetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered to be SAEs and will be reported as such. 
The participant will be followed to determine the outcome of the pregnancy. The investigator 
will collect follow-up information on the participant and the neonate and the information will be 
forwarded to the sponsor. 
Any post-trial pregnancy-related SAE considered reasonably related to the IMP by the 
investigator will be reported to the sponsor as described in Section 8.3.4. While the investigator 
is not obligated to actively seek this information in former trial participants, he or she may learn 
of an SAE through spontaneous reporting. 
Any woman who becomes pregnant while participating in the trial will discontinue the IMP 
immediately and participants treated with alitretinoin capsules should be referred to a physician 
specialised or experienced in teratology for evaluation and advice. 
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8.3.6 
Other Events 
8.3.6.1 
AEs of Special Interest 
The events listed in Table 8-10 are considered AEs of special interest (AESIs) in this trial and 
will require additional details to be recorded. The sponsor 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 8.3.4 in addition to 
the requirements specified in Table 8-10. 
Table 8-10 
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 / 
Pulmonary embolism 
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) 
8.3.6.2 
Medication Errors 
Medication error refers to any unintentional error in the dispensing or administration of an IMP. 
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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 6.4 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 (see Section 10.3.4). 
8.3.6.3 
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 (see Section 10.3.4). 
8.3.7 
Handling of Urgent Safety Measures 
An urgent safety measure is a measure taken to implement an action/protocol deviation under an 
emergency. This is defined as “…the occurrence of any new event relating to the conduct of the 
trial or the development of the investigational medicinal product where that new event is likely 
to affect the safety of the participants, the sponsor and the investigator shall take appropriate 
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urgent safety measures to protect the participants against any immediate hazard.” (EU Directive 
2001/20/EC). 
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 participants from 
any immediate hazard to their health and safety, the investigator can do so without prior approval 
from the sponsor, regulatory authorities, or IRBs/IECs. 
The investigator must immediately inform the sponsor – 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. 
The sponsor must act immediately upon receipt of the urgent safety measure notification in 
accordance with internal procedures and local legislation. 
8.4 Pharmacokinetics 
Pharmacokinetic parameters are not evaluated in this trial. 
8.5 Pharmacodynamics 
Pharmacodynamic parameters are not evaluated in this trial. 
8.6 Genetics 
Genetics are not evaluated in this trial. 
8.7 Biomarkers 
Biomarkers are not evaluated in this trial. 
8.8 Immunogenicity Assessments 
Immunogenicity is not evaluated in this trial. 
8.9 Medical Resource Utilisation and Health Economics 
Medical resource utilisation and health economics parameters are not evaluated in this trial. 
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8.10 End-of-trial Assessments 
8.10.1 End-of-treatment Form 
An end-of-treatment form will be completed in the eCRF for all randomised participants exposed 
to IMP when they have had their last administration of IMP. This form will also be completed 
for participants who permanently discontinue IMP prior to Week 24 and participants who 
withdraw from trial, unless they were never exposed to IMP (see Section 7). 
The date of last administration of IMP will be recorded on the end-of-treatment form. It will also 
be recorded if the participant completed the treatment (i.e. did not discontinue IMP prior to 
Week 24, unless they achieved good clearance), and, if not, whether the reason for not 
completing the treatment period was related to COVID-19. If the participant did not complete the 
treatment, the primary reason for permanent discontinuation of IMP must be recorded (see 
Section 7.1). 
8.10.2 End-of-trial Form 
An end-of-trial form must be completed in the eCRF for all screened participants when they have 
had their last visit. The following data will be collected: 
• Date of last contact. 
• Did the participant complete the trial? Refer to Section 4.4 for a definition of trial 
completion. 
• Primary reason for not completing the trial based on the following categories: death, AE, lack 
of efficacy, lost to follow-up, withdrawal by participant, screen failure (failure to meet 
eligibility criteria), or other. 
• Whether the reason for not completing the trial was related to COVID-19. 
If ‘adverse event’ is selected, the AE in question will be linked to the non-completion of the trial. 
If ‘other’ is selected as a reason, a specification must be provided in the eCRF. If ‘withdrawal by 
participant is selected, it will be recorded whether the participant withdrew informed consent or 
not. 
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9 Statistical Considerations 
The statistical analysis plan (SAP) will be finalised prior to first participant’s first visit and if 
revisions are necessary the revised SAP will be finalised prior to database lock (DBL). The SAP 
will include a more technical and detailed description of the statistical analyses described in this 
section. This section is a summary of the planned statistical analyses of the most important 
endpoints including primary and key secondary endpoints.  
Any changes from the statistical analyses planned in this clinical trial protocol will be described 
and justified in a protocol amendment, the SAP, and/or in the clinical trial report, dependent on 
the type of change. 
9.1 Statistical Hypotheses 
For the primary and key secondary endpoints, confirmatory 1-sided (superiority) hypotheses will 
be tested for delgocitinib cream versus alitretinoin capsules, except for the key secondary 
endpoint ‘change in HECSI score from baseline to Week 24’ that will initially be evaluated for 
non-inferiority (at margin M) and subsequently for superiority.  
Let the treatment effect be defined as μ=(delgocitinib cream minus alitretinoin capsules), then: 
• For binary endpoints or area under the curve (AUC): H0: µ ≤0 against Ha: µ > 0. 
• For continuous endpoints (superiority): H0: µ ≥0 against Ha: µ < 0.  
• For continuous endpoints (non-inferiority): H0: µ ≥M against Ha: µ < M. 
9.1.1 
Multiplicity Adjustment 
A closed testing procedure with hierarchical tests will be used to control the overall type I error 
at a nominal 1-sided 2.5% level. The statistical testing strategy is built on the principle that 
superiority of change in HECSI score from baseline to Week 12 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 in terms of change in HECSI 
score from baseline to Week 12. It will be tested at the overall 1-sided significance level of 2.5%.  
The endpoints will be tested according to the fixed sequence specified in Figure 9–1. If a test is 
significant, the significance level will be reallocated to the next hypothesis. Each of the 
following hypotheses will be tested at a significance level of 2.5%. This process will be repeated 
until no further tests are significant. 
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The last hypothesis to be tested is the non-inferiority of delgocitinib cream in terms of change in 
HECSI score from baseline to Week 24 using a non-inferiority margin of 10 (i.e. M=10). The 
margin is based on a conservative choice (<½ minimal important difference) of what was found 
to be the minimal important difference between groups obtained from psychometric analyses of 
HECSI based on data from the moderate-to-severe population in the LP0133-1273 trial. If non-
inferiority is statistically significant, superiority is then evaluated. 
Figure 9–1 
Graphical Display of Closed Testing Procedure for Primary and Key 
Secondary Endpoints 
 
Abbreviations: AUC=area under the curve; DLQI=Dermatology Life Quality Index; HECSI=Hand Eczema Severity 
Index; HECSI-90=at least 90% improvement in HECSI score from baseline; HESD=Hand Eczema Symptom 
Diary©; IGA-CHE=Investigator’s Global Assessment for chronic hand eczema©; IGA-CHE TS=IGA-CHE 
treatment success, i.e. an IGA-CHE score of 0 (clear) or 1 (almost clear) with a ≥2-step improvement from 
baseline; TS=treatment success. 
 
α=2.5% (1-sided) 
Change in HECSI score from baseline to Week 12 
Primary endpoint 
1 α 
1. HECSI-90 at Week 12. 
2. IGA-CHE TS at Week 12. 
3. Change in HESD itch score (weekly average) from baseline to Week 12. 
4. Change in HESD pain score (weekly average) from baseline to Week 12. 
5. AUC of HECSI-90 from baseline up to Week 24. 
6. AUC of change from baseline in DLQI score up to Week 24. 
7. Change in HECSI score from baseline to Week 24  
(non-inferiority test with margin of 10, followed by superiority test). 
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9.2 Analysis Sets 
For purposes of analysis, the following analysis sets are defined: 
Table 9-1 
Participant Analysis Sets 
Participant Analysis Set 
Description 
Full analysis set 
All randomised participants. Participants will be included in the analyses according 
to randomised treatment allocation. Exclusions from the FAS can be considered in 
special cases, as described in Section 5.2.1 (Full Analysis Set) of ICH E9 guidelines.  
If a participant is excluded from the FAS, a justification per ICH E9 guidelines will 
be given. 
Safety analysis set 
All participants who are exposed to the IMP. Participants will be analysed according 
to the treatment they actually received. 
Abbreviations: FAS=full analysis set; IMP=investigational medicinal product. 
 
The full analysis set (FAS) is used to analyse endpoints related to the efficacy objectives and the 
safety analysis set is used to analyse the endpoints and assessments related to safety. 
The decisions regarding inclusion/exclusion of participants or participant data from the analysis 
sets will be documented in the analysis set definition document before DBL. 
9.3 Statistical Analyses 
9.3.1 
General Considerations 
Significance tests will be 1-sided using the 2.5% significance level. All confidence intervals will 
be presented with 95% degree of confidence, unless otherwise specified. 
An observed-cases approach will be used for tabulations of data by visit (that is, involving only 
those participants who attended each specific visit). 
Categorical data will be summarised using the number and percentage of participants 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. 
The statistical analyses were performed using SAS software (SAS Institute, Cary NC), 
version 9.3 or later. 
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9.3.2 
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 COVID-19 pandemic for primary and key secondary 
endpoints. 
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 COVID-19 pandemic as an intercurrent event (IE). Details are described in 
Section 9.3.6. 
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 COVID-19 pandemic (see 
Section 10.5). 
The causal relationship of permanent discontinuation of IMP related to the COVID-19 pandemic 
will be recorded in the eCRF (see Section 10.5). 
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 
COVID-19 pandemic. As a consequence of the COVID-19 pandemic and associated local 
preventive measures, participants 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 COVID-19 pandemic will 
be ‘treated as missing’ and imputed assuming missing at random (MAR). Missing data related to 
the COVID-19 pandemic will be imputed assuming MAR (Section 9.3.6). 
It should be noted that a participant may have missing data related to the COVID-19 pandemic, 
even though the participant has not experienced an IE related to the COVID-19 pandemic. 
An overview of how observed and missing data will be handled according to the IEs and their 
relatedness to the COVID-19 pandemic is presented in Table 9-2 for the primary analysis for 
estimands. Details of the analysis are described in Section 9.3.6. 
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9.3.3 
Disposition of Participants 
The reasons for permanent discontinuation of IMP and for not completing the trial will be 
presented for all randomised participants and by treatment group. 
An overall summary of participant disposition will be presented for all randomised participants. 
The disposition summary will include information on the number of randomised, exposed, 
included in the FAS, permanently discontinuing IMP, restarting after response, and not 
completing the trial by treatment group and overall. 
9.3.4 
Demographics and Other Baseline Characteristics 
Descriptive statistics of demographics and other baseline characteristics will be presented for all 
randomised participants 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. 
9.3.5 
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 administration of IMP in that period to the date of last 
administration 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. 
For delgocitinib only, the average weekly and total amount of IMP used will be presented for the 
safety analysis set for each visit interval and for the total treatment period. 
Treatment compliance will be presented for the safety analysis set for each treatment group. 
9.3.6 
Estimand Strategy 
9.3.6.1 
General Considerations 
The analysis of endpoints related to efficacy and health-related quality of life will be based on 
the FAS. 
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The following primary and supplementary estimands will be defined for binary, continuous, and 
AUC 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 IEs is a component of the endpoint. The occurrence of any IE 
will lead to assume failure of the randomised treatment. For continuous endpoints, observed 
data after the IEs will be imputed as non-response by using WOCF (including baseline value) 
which is considered an extremely unfavourable value. 
• 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 COVID-19 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. This policy 
reflects the intention‑to‑treat (ITT) principle and is intended to measure the effectiveness of 
the treatment under conditions closer to ‘real world’ conditions where patients will not adhere 
perfectly to the protocol when taking medication. Data collected for the endpoint of interest 
are used regardless of whether an IE occurred, except for the occurrence permanent 
discontinuation of IMP related to the COVID-19 pandemic data which will be assumed MAR 
and imputed.  
To support the ‘treatment policy’ strategy, participants who experience IEs prior to Week 12 
will be asked to attend the primary endpoint visit at Week 12 and nominal visit at Week 24 
for collection of data. Participants who experience IEs between Week 12 and Week 24 will be 
asked to attend the nominal visit at Week 24 for collection of data. 
For primary and key secondary endpoints only, pre-specified sensitivity analyses will also be 
conducted for selected combinations of endpoints and estimands to assess the robustness of the 
results with respect to the handling of missing data. 
Analysis to summarise and assess the effect of patterns of missing data related to the COVID-19 
pandemic will be specified in the SAP prior to DBL. 
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The following IEs are considered to affect the interpretation of the estimated treatment effects:  
• Initiation of rescue treatment: This IE occurs when a participant 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 participant must stop treatment 
with the IMP immediately and will not be allowed to restart treatment with the IMP (refer to 
Sections 6.8.2 and 7.1 for details). This IE is handled without assessing relatedness to the 
COVID-19 pandemic. 
• Permanent discontinuation of IMP independent of the COVID-19 pandemic: This IE 
occurs when a participant permanently discontinues the IMP independent of the COVID-19 
pandemic. This IE can occur at the participant's own initiative, at the discretion of the 
investigator or the sponsor, or if the participant is lost to follow-up. 
• Permanent discontinuation of IMP related to the COVID-19 pandemic: This IE occurs 
when a participant permanently discontinues the IMP due to circumstances related to the 
COVID-19 pandemic; not attributed to lack of efficacy or randomised treatment features 
considered unacceptable by the participant. 
The occurrence of IEs will be listed and summarised by treatment group. Table 9-2 presents an 
overview of how observed and missing data will be handled according to the IEs for the primary 
analysis for estimands.  
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Table 9-2 
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 
treatment 
Observed 
Non-response 
Non-response 
Value will be 
used as observed 
WOCF 
WOCF 
Value will be 
used as observed 
Missing 
Non-response 
Non-response 
MI (MAR) 
WOCF 
WOCF 
MI (MAR) 
Permanent 
discontinuation of 
IMP independent of 
the COVID-19 
pandemic 
Observed 
Non-response 
Non-response 
Value will be 
used as observed 
WOCF 
WOCF 
Value will be 
used as observed 
Missing 
Non-response 
Non-response 
MI (MAR) 
WOCF 
WOCF 
MI (MAR) 
Permanent 
discontinuation of 
IMP related to the 
COVID-19 
pandemic 
Observed 
Non-response 
MI (MAR) 
MI (MAR) 
WOCF 
MI (MAR) 
MI (MAR) 
Missing 
Non-response 
MI (MAR) 
MI (MAR) 
WOCF 
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 
Missing 
independent 
of the 
COVID-19 
pandemic 
Non-response 
Non-response 
MI (MAR) 
WOCF 
WOCF 
MI (MAR) 
Missing 
related to the 
COVID-19 
pandemic 
Non-response 
MI (MAR) 
MI (MAR) 
WOCF 
MI (MAR) 
MI (MAR) 
IMP=investigational medicinal product; MAR=missing at random; MI=multiple imputation; WOCF=worst observation carried forward (including baseline 
value). 
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9.3.6.2 
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 and alitretinoin capsules. 
The change (or percentage change) from baseline to the endpoint of interest will be analysed 
using an analysis of covariance (ANCOVA) model with effects of treatment group, region, 
hyperkeratotic/non-hyperkeratotic subtype, and baseline value (of the measure of interest). 
When analyses require multiple imputation (MI) procedures of data, 100 complete datasets will 
be sampled. For each dataset, the ANCOVA model will be fitted. The estimates and standard 
errors from the analyses will be combined using Rubin’s rule to provide the estimate and 
associated standard error. 
Primary Estimand: ‘Composite’ Strategy 
For the primary analysis, observed and missing data will be handled according to the IEs, as 
described in Table 9-2. 
For the sensitivity analysis, which is rather conservative against the delgocitinib group, missing 
data at the endpoint of interest, for participants who did not experience IEs prior to that, will be 
handled as follows: 
• For participants in the delgocitinib cream group, missing data will be imputed as WOCF 
(including baseline value). 
• For participants in the alitretinoin capsules group, missing data will be imputed using MI 
assuming MAR. 
First Supplementary Estimand: ‘Pandemic Modified Composite’ Strategy 
Observed and missing data will be handled according to the IE, as described in Table 9-2. 
All missing or ‘treated as missing’ data will be imputed using MI assuming MAR within 
treatment groups. The WOCF imputation of relevant data points not affected by the COVID-19 
pandemic will be applied. 
Second Supplementary Estimand: ‘Treatment Policy’ Strategy 
Observed data and missing data will be handled according to the IEs, as described in Table 9-2. 
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Missing data at Week 12 and Week 24, independent of the COVID-19 pandemic, will be imputed 
using MI assuming MAR within 4 groups defined according to treatment group and whether the 
participant has experienced an IE (independent of the COVID-19 pandemic). For imputation 
purposes, data available from all participants will be used.  
For the endpoint of interest, missing data or ‘treated as missing’ data due to the COVID-19 
pandemic will be imputed using MI assuming MAR within treatment group using data from 
participants who have not experienced an IE. 
9.3.6.3 
Estimand Strategy for Binary Endpoints 
The population level summary will be the difference in response rates between delgocitinib 
cream and alitretinoin capsules. 
The difference in response rates between the 2 treatment groups with the 95% CI will be 
calculated using the Cochran-Mantel-Haenszel (CMH) test stratified by region and 
hyperkeratotic/non-hyperkeratotic subtype. 
When analyses require MI procedures of data, 100 complete datasets will be sampled. For each 
dataset, the difference in response rates will be analysed using the CMH test stratified by region 
and hyperkeratotic/non-hyperkeratotic subtype. 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. 
Primary Estimand: ‘Composite’ Strategy 
For the primary analysis, observed data and missing data will be handled according to the IEs, as 
described in Table 9-2. 
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For the sensitivity analysis, which is rather conservative against the delgocitinib group, missing 
data at the endpoint of interest for participants who did not experience IEs prior to that will be 
handled as follows: 
• For participants in the delgocitinib cream group, missing data will be imputed as 
non-response. 
• For participants in the alitretinoin capsules group, missing data will be imputed using MI 
(100 iterations) assuming MAR. Binary response/non-response will be determined after 
imputation of the original raw continuous values when binary variable is obtained by 
derivation (e.g. for the HECSI-90 from baseline up to Week 24, the percentage of reduction 
from baseline will be derived from imputed values). 
First Supplementary Estimand: ‘Pandemic Modified Composite’ Strategy 
Observed data and missing data will be handled according to the IEs, as described in Table 9-2. 
All missing or ‘treated as missing’ data will be imputed using MI 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 COVID-19 pandemic will be applied. 
Second Supplementary Estimand: ‘Treatment Policy’ Strategy 
For the primary analysis, observed data and missing data will be handled according to the IEs, as 
described in Table 9-2. 
Missing data at Week 12 and Week 24 independent of the COVID-19 pandemic will be imputed 
using MI assuming MAR within 4 groups defined according to treatment group and whether the 
participant has experienced an IE (independent of the COVID-19 pandemic). 
Missing data or ‘treated as missing’ data at Week 12 and Week 24 due to the COVID-19 
pandemic will be imputed using MI assuming MAR within treatment group using data from 
participants who have not experienced an IE. 
For the sensitivity analysis, missing data at Week 12 and Week 24 will be imputed as 
non-response, unless data is missing or ‘treated as missing’ due to the COVID-19 pandemic in 
which case it will be imputed using MI assuming MAR within treatment group using data from 
participants who have not experienced an IE. 
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9.3.6.4 
Estimand Strategy for AUC Endpoints 
The population level summary will be the difference in estimated mean AUC from baseline to 
the endpoint of interest between delgocitinib cream and alitretinoin capsules. The AUC 
endpoints are based on curves that will be fitted on values determined for the corresponding 
continuous and binary endpoints, as presented in Table 9-2.  
Once points have been identified in accordance with estimands strategies, a piecewise line 
function will be drawn to connects points (𝑓(𝑡), where 𝑡 is the time in days from baseline). 
Baseline value will be set at 0 (zero). For each participant, the area under piecewise line will be 
determined integrating 𝑓(𝑡), as follows: 
𝐴𝑈𝐶=
∫
𝑓(𝑡)∆𝑡
𝑡=𝑊𝑒𝑒𝑘 24 
𝑡=0
   
The integral will be approximated by the trapezoidal rule. 
The differences between treatment group will be analysed using robust ANCOVA model with 
the AUC or related transformation as dependent variable, and treatment, region, 
hyperkeratotic/non-hyperkeratotic subtype and baseline value (of the measure of interest), as 
covariates. Details on robust ANCOVA model will be described in the SAP. 
The AUC at participant level (to be implemented as dependent variable in the ANCOVA model) 
will be determined in accordance with nature of the endpoint of interest, as follows: 
• AUC derived from binary endpoints, such as the AUC of HECSI-90 from baseline up to 
Week 24: 1 will be assigned when response is observed and 0 otherwise. The AUC is 
interpreted as number of days with 90% reduction in HECSI score until Week 24. 
• AUC derived from continuous endpoints, such as the AUC of change from baseline in 
DLQI score up to Week 24: For the sake of interpretability, differences will be analysed with 
opposite sign to interpret positive area as improvement in scores and negative area as 
worsening.  
When analyses require MI procedures of data, 100 complete datasets will be sampled. For each 
dataset, piecewise line function will be drawn to connects points and the AUC will be 
determined. ANCOVA model will be fitted for each dataset with treatment, region, 
hyperkeratotic/non-hyperkeratotic subtype as covariates. The estimates and standard errors from 
the analyses will be combined using Rubin’s rule to provide the estimate and associated standard 
error.  
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Primary Estimand: ‘Composite’ Strategy 
For the primary analysis, observed data and missing data will be handled according to the IEs, as 
described in Table 9-2. 
First Supplementary Estimand: ‘Pandemic Modified Composite’ Strategy 
Observed data and missing data of the corresponding continuous or binary endpoint will be 
handled according to the IEs, as described in Table 9-2. 
All missing or ‘treated as missing’ data will be imputed using MI assuming MAR within 
treatment groups. The WOCF or non-response imputation of relevant data points not affected by 
the COVID-19 pandemic will be applied. 
Second Supplementary Estimand: ‘Treatment Policy’ Strategy 
Observed data and missing data of the corresponding continuous or binary endpoint will be 
handled according to the IEs, as described in Table 9-2. 
Missing data at Week 12 and Week 24, independent of the COVID-19 pandemic, will be 
imputed using MI assuming MAR within 4 groups defined according to treatment group and 
whether the participant has experienced an IE (independent of the COVID-19 pandemic). For 
imputation purposes, data available from all participants will be used. 
For the endpoint of interest, missing data or ‘treated as missing’ data due to the COVID-19 
pandemic will be imputed using MI assuming MAR within treatment group using data from 
participants who have not experienced an IE. 
9.3.7 
Primary Endpoint(s) Analysis 
The primary endpoint will be analysed following the estimands strategy for continuous endpoints 
described in Section 9.3.6.2. The confirmatory 1-sided (superiority) hypothesis, described in 
Section 9.1, will be tested for delgocitinib cream versus alitretinoin capsules based on the 
primary analysis for the primary estimand. 
9.3.8 
Secondary Endpoint(s) Analysis 
The confirmatory hypotheses for key secondary endpoints, presented in Section 9.1. will be 
tested based on the primary analyses for the primary estimand strategies described in 
Sections 9.3.6.2, 9.3.6.3, and 9.3.6.4.  
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Table 9-3 provides an overview of the primary statistical analysis of the key secondary efficacy 
endpoints related to the primary and supplementary estimands. For further details, including 
sensitivity analysis, refer to Section 9.3.6. 
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Table 9-3 
Overview of the Primary Statistical Analysis of the Key Secondary Efficacy Endpoints Related to the 
Primary and Supplementary Estimands 
Key secondary 
endpoints 
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 
Strategy 
to handle 
IEs 
Handling of missing data 
HECSI-90 at Week 12 
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 
IGA-CHE TS at Week 12 
AUC of HECSI-90 from 
baseline up to Week 24  
AUC 
(derived 
from 
binary) 
Change in HECSI score 
from baseline to Week 24 
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 HESD itch score 
(weekly average) from 
baseline to Week 12 
Change in HESD pain score 
(weekly average) from 
baseline to Week 12 
AUC of change from 
baseline in DLQI score up to 
Week 24 
AUC 
(derived 
from 
continuous) 
AUC=area under the curve; COVID-19=coronavirus disease 2019; DLQI=Dermatology Life Quality Index; HECSI=Hand Eczema Severity Index; HECSI-90=at 
least 90% improvement in HECSI from baseline; HESD=Hand Eczema Symptom Diary©; IE=intercurrent event; IGA-CHE=Investigator’s Global Assessment 
for chronic hand eczema©; IGA-CHE TS=IGA-CHE treatment success, i.e. an IGA-CHE score of 0 (clear) or 1 (almost clear) with a ≥2 step improvement from 
baseline; MAR=missing at random; MI=multiple imputation; TS=treatment success; WOCF=worst observation carried forward (including baseline value). 
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9.3.9 
Exploratory Endpoints Analysis 
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 AUC. For details refer to 
Section 9.3.6. 
Table 9-4 provides an overview of the statistical analysis of the exploratory endpoints. 
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Table 9-4 
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 Week 24. 
Binary 
Composite 
Non-response imputation 
HECSI-75 at Week 12 and Week 24. 
HECSI-90 at Week 24. 
Reduction of HESD itch score (weekly average) of ≥3 
points 1 at Week 12 and Week 24. 
Reduction of HESD itch score (weekly average) of ≥4 
points 2 at Week 12 and Week 24. 
Reduction of HESD pain score (weekly average) of ≥3 
points 3 at Week 12 and Week 24. 
Reduction of HESD pain score (weekly average) of ≥4 
points 4 at Week 12 and Week 24. 
Reduction of HESD score (weekly average) of ≥3 points 
5 at Week 12 and Week 24. 
Reduction of HESD score (weekly average) of ≥4 points 
6 at Week 12 and Week 24. 
Change in HESD itch score (weekly average) from 
baseline to Week 24. 
Continuous 
Composite 
WOCF (including 
baseline value) 
Change in HESD pain score (weekly average) from 
baseline to Week 24. 
Change in HESD score (weekly average) from baseline 
to Week 12 and Week 24. 
AUC from baseline to Week 24 of reduction of HESD 
itch score (weekly average) of ≥3 points 1 
AUC 
(derived 
from 
binary) 
Composite 
Non-response imputation 
AUC from baseline to Week 24 of reduction of HESD 
itch score (weekly average) of ≥4 points 2 
AUC from baseline to Week 24 of reduction of HESD 
pain score (weekly average) of ≥3 points 3 
AUC from baseline to Week 24 of reduction of HESD 
pain score (weekly average) of ≥4 points 4 
Health-related quality of life 
Change in DLQI score from baseline to Week 12 and 
Week 24. 
Continuous 
Composite 
WOCF (including 
baseline value) 
Change in HEIS (individual domains and total score) 
from baseline to Week 12 and Week 24. 
Change in EQ-5D-5L index score from baseline to Week 
12 and Week 24. 
Change in EQ-5D-5L visual analogue scale score from 
baseline to Week 12 and Week 24. 
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Endpoints 
Type of 
endpoint 
Primary estimand 
Strategy 
to handle 
IEs 
Handling of missing 
data and data collected 
after IE 
Reduction of DLQI score of ≥4 points7 at Week 12 and 
Week 24. 
Binary 
Composite 
Non-response imputation 
DLQI score of 0 or 1 at Week 12 and Week 24. 
Treatment satisfaction and work productivity 
Change in WPAI-CHE (each individual domain) score 
from baseline to Week 12 and Week 24. 
Continuous 
Composite 
WOCF (including 
baseline value) 
TSQM at Week 12 and at Week 24. 
WOCF 
1. Among participants with a baseline HESD itch score (weekly average) ≥3 points. 
2. Among participants with a baseline HESD itch score (weekly average) ≥4 points. 
3. Among participants with a baseline HESD pain score (weekly average) ≥3 points. 
4. Among participants with a baseline HESD pain score (weekly average) ≥4 points. 
5. Among participants with a baseline HESD score (weekly average) ≥3 points. 
6. Among participants with a baseline HESD score (weekly average) ≥4 points. 
7. Among participants with a baseline DLQI score ≥4 points. 
Abbreviations: AE=adverse event; ALT=alanine aminotransferase; AST=aspartate aminotransferase; 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; SAE=serious adverse event; TSQM=Treatment 
Satisfaction Questionnaire for Medicine; ULN=upper limit of normal; WOCF=Worst Observation Carried 
Forward; WPAI-CHE=Work Productivity and Activity Impairment – Chronic Hand Eczema. 
 
9.3.10 Analysis of PGI-S and PGI-C 
The 3 PGI-S scores (Itch PGI-S, Pain PGI-S, and HESD PGI-S) and the 3 PGI-C scores (Itch 
PGI-C, Pain PGI-C, and HESD PGI-C) will be summarised by visit for each treatment group. 
9.3.11 Safety Analyses 
All safety analyses will be made on the safety analysis set. 
9.3.11.1 Adverse Events 
AEs will be coded during the course of the trial according to the 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 participant data listings. An event will be considered 
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treatment-emergent if it started after the first administration of IMP or if it started before the first 
administration of IMP and worsened in severity after the first administration 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 participants with at least 1 event, the 
percentage of participants with at least 1 event, the number of events, and the event rate per 
100 patient years of observation time.  
Related AEs are defined as AEs for which the investigator has not described the causal 
relationship to the 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 and AEs leading to permanent discontinuation of IMP will 
be listed. The detailed listing will provide an overview of the individual cases and include the 
age and sex of the participant, treatment received at the time of AE onset, the AE preferred and 
reported terms, causality and severity of the AE, the action taken with the IMP, AE outcome, 
start and stop date of AE, duration of AE, and number of days since first and last IMP 
administration. No narratives will be given. 
Specific summaries presenting AEs of hypertriglyceridaemia, hypercholesterolaemia, headache, 
liver toxicity will be prepared. The MedDRA search terms for these AEs will provided in the 
SAP. 
Other events (medication error, misuse, and abuse of IMP) will be tabulated and listed. No 
narratives will be given. 
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9.3.11.2 Vital Signs and Physical Examination 
For vital signs (resting blood pressure, pulse, and body temperature), the absolute values at 
baseline and EOT/ET as well as the change from baseline to EOT/ET will be summarised for 
each treatment group. 
9.3.11.3 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 each post-baseline visit. 
For participants with post-baseline values, the number of events reported up to Week 26 will be 
summarised. For the following laboratory abnormalities endpoints, binary estimand strategy will 
be applied, as described in Section 9.3.6.3: 
• Increased levels of triglycerides >3.42 mmol/L (fasted state). 
• Increased levels of cholesterol >7.75 mmol/L (fasted state). 
• Increased levels of ALT and/or AST >3×ULN (or >3×baseline if baseline was abnormal but 
<2×ULN). 
• Increased levels of ALP >2.5×ULN. 
• Increased levels of bilirubin >1.5×ULN up to Week 26. 
9.3.11.4 Participant’s and Investigator’s Assessment of Local Tolerability 
Participant’s and investigator’s assessment of local tolerability for delgocitinib cream will be 
summarised by visit. 
9.4 Interim Analyses 
No interim analysis is planned during the trial. 
9.5 Sample Size Determination 
Approximately 510 participants will be randomly assigned to trial treatment in a 1:1 ratio, with 
255 evaluable participants per treatment group. Approximately 660 participants will be screened 
to achieve this target. 
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With 510 participants randomised, the trial will provide 80% power to establish superiority of 
delgocitinib cream with regard to change from baseline to Week 12 in HECSI based on a 1-sided 
hypothesis test at a 2.5% significance level, assuming a difference in the mean change from 
baseline to Week 12 in HECSI of 7.5 (with a standard deviation of 30) between the 2 treatment 
arms (Ruzicka et al, 2008). Since there is limited published data on alitretinoin in terms of 
HECSI, anticipated treatment difference between delgocitinib and alitretinoin has been set using 
IGA scales as a surrogate endpoint (LP0133-1273 trial). Expected standard deviation is based on 
data observed in LP0133-1273 trial. 
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10 Supporting Documentation and Operational Considerations 
10.1 Appendix 1: Regulatory, Ethical, and Trial Oversight Considerations 
10.1.1 Regulatory and Ethical Considerations 
This trial will be conducted in accordance with the protocol and with: 
• Consensus ethical principles derived from international guidelines including the Declaration 
of Helsinki and Council for International Organizations of Medical Sciences (CIOMS) 
international ethical guidelines. 
• Applicable ICH GCP guidelines. 
• Applicable laws and regulations. 
The protocol, protocol amendments, ICF, IB, and other relevant documents (e.g. advertisements) 
must be submitted to an IRB/IEC by the investigator and reviewed and approved by the IRB/IEC 
before the trial is initiated. 
Any amendments to the protocol will require IEC/IRB approval before implementation of 
changes made to the trial design, except for changes necessary to eliminate an immediate hazard 
to trial participants. 
Protocols and any substantial amendments to the protocol will require health authority approval 
prior to initiation except for changes necessary to eliminate an immediate hazard to trial 
participants. 
The investigator will be responsible for the following: 
• 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/EC. 
• Notifying the IRB/IEC of SAE or other significant safety findings as required by IRB/IEC 
procedures. 
• Overall conduct of the trial at the site and adherence to requirements of 21 CFR, ICH GCP 
guidelines, the IRB/IEC, European regulation 536/2014 for clinical studies (if applicable), 
European Medical Device Regulation 2017/745 for clinical device research (if applicable), 
and all other applicable local regulations. 
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10.1.2 Financial Disclosure 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information in accordance with local regulations to allow the sponsor 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 trial and for 1 year after completion of the trial. 
10.1.3 Informed Consent Process 
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 for treatments listed as exclusion 
criteria. 
The investigator or their representative will explain the nature of the trial, including the risks and 
benefits, to the participant and answer all questions regarding the trial. 
Participants must be informed that their participation is voluntary. Participants will be required to 
sign a statement of informed consent that meets the requirements of 21 CFR 50, local 
regulations, ICH guidelines, privacy and data protection requirements, where applicable, and the 
IRB/IEC or trial site. 
The medical record must include a statement that written informed consent was obtained before 
the participant was enrolled in the trial and the date the written consent was obtained. The 
authorised person obtaining the informed consent must also sign the ICF. 
Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the trial. 
A copy of the ICF(s) must be provided to the participant. 
Participants who are rescreened are required to sign a new ICF. 
If a protocol amendment is required, the ICF may need to be revised to reflect the changes to the 
protocol. If the ICF is revised, it must be reviewed and approved by the appropriate IEC/IRB and 
signed by all participants subsequently enrolled in the trial as well as those currently enrolled in 
the trial. 
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10.1.4 Data Protection 
Participants will be assigned a unique identifier by the sponsor. Any participant records or 
datasets that are transferred to the sponsor will contain the identifier only; participant names or 
any information which would make the participant identifiable will not be transferred. 
The participant must be informed that their personal trial-related data will be used by the sponsor 
in accordance with local data protection law. The level of disclosure must also be explained to 
the participant who will be required to give consent for their data to be used as described in the 
informed consent. 
The participant must be informed that their medical records may be examined by Clinical 
Quality Assurance auditors or other authorised personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
10.1.5 Dissemination of Clinical Trial Data 
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 participant 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. 
10.1.6 Data Quality Assurance 
All participant data relating to the trial will be recorded on printed or electronic CRFs unless 
transmitted to the sponsor or designee electronically (e.g. laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or electronically 
signing the CRF. 
Guidance on completion of CRFs will be provided in the CRF Completion Guidelines. 
The investigator must permit trial-related monitoring, audits, IRB/IEC review, and Regulatory 
Agency inspections and provide direct access to source data documents. 
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Monitoring details describing strategies, including definition of trial critical data items and 
processes (e.g. risk-based initiatives in operations and quality such as risk management and 
mitigation strategies and analytical risk-based monitoring), methods, responsibilities and 
requirements, including handling of non-compliance issues and monitoring techniques (central, 
remote, or on-site monitoring) are provided in the Monitoring Plan. 
The sponsor or designee is responsible for the data management of this trial including quality 
checking of the data. 
The sponsor assumes accountability for actions delegated to other individuals (e.g. contract 
research organisations). 
Records and documents, including signed ICF, pertaining to the conduct of this trial must be 
retained by the investigator for 25 years after trial completion unless otherwise required by local 
regulations or institutional policies. No records may be destroyed during the retention period 
without the written approval of the sponsor. No records may be transferred to another location or 
party without written notification to the sponsor. 
All data generated by the site personnel will be captured electronically at each trial site using 
eCRFs. Data from external sources (such as laboratory data) will be imported into the database. 
Once the eCRF clinical data have been submitted to the central server at the independent data 
site, corrections to the data fields will be captured in an audit trail. The reason for change, the 
name of the person who performed the change, together with the time and date will be logged to 
provide an audit trail. 
If additional corrections are needed, the responsible monitor or data manager will raise a query in 
the electronic data capture (EDC) application. The appropriate staff at the trial site will answer 
queries sent to the investigator. The name of the staff member responding to the query, and time 
and date stamp will be captured to provide an audit trail. Once all source data verification is 
complete and all queries are closed, the monitor will freeze the eCRF page. 
The specific procedures to be used for data entry and query resolution using the EDC 
system/eCRF will be provided to trial sites in a training manual. In addition, site personnel will 
receive training on the EDC system/eCRF. 
10.1.6.1 Quality Tolerance Limits 
Quality Tolerance Limits will be defined in the Data Surveillance Plan.  
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10.1.7 Source Documents 
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site. 
Data reported in the eCRF that are transcribed from source documents must be consistent with 
the source documents or the discrepancies must be explained. The investigator may need to 
request previous medical records or transfer records, depending on the trial. Also, current 
medical records must be available. 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
Trial monitors will perform ongoing source data verification to confirm that data entered into the 
eCRF by authorised site personnel are accurate, complete, and verifiable from source documents; 
that the safety and rights of participants are being protected; and that the trial is being conducted 
in accordance with the currently approved protocol and any other trial agreements, ICH GCP, 
and all applicable regulatory requirements. 
10.1.8 Trial and Site Start and Closure 
First Act of Recruitment 
The trial start date is the date on which the clinical trial will be open for recruitment of 
participants. 
The first act of recruitment is the first participant’s first visit and will be the trial start date. 
Trial/Site Termination 
The sponsor or designee reserves the right to close the trial site or terminate the trial at any time 
for any reason at the sole discretion of the sponsor. Trial sites will be closed upon trial 
completion. 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. 
The investigator may initiate trial site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a trial site by the sponsor or investigator may include but are not 
limited to: 
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For trial termination: 
• Discontinuation of further IMP development. 
For site termination: 
• Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC or 
local health authorities, the sponsor's procedures, or GCP guidelines. 
• Inadequate or no recruitment (evaluated after a reasonable amount of time) of participants by 
the investigator. 
• Total number of participants included earlier than expected. 
If the trial is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research organisation(s) 
used in the trial of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up. 
10.1.9 Publication Policy 
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 DBL. The 
sponsor is responsible for this publication. All authors (trial responsible employees and/or 
applicable investigators and advisers) must fulfil the criteria for authorship from the International 
Committee of Medical Journal Editors (ICMJE). 
The investigators may reach out to the sponsor to publish results that are not included in the 
primary publication. The investigator and the sponsor 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, 
the sponsor 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 the sponsor. 
The sponsor 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 
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Pharmaceutical Industries and Associations (EFPIA) (48). In that case, the researchers are 
obliged to attempt publication of the results obtained from their analyses. 
The sponsor complies with Good Publication Practice (GPP3) standards and the 
recommendations from ICMJE. 
10.1.10 Protocol Approval and Amendment 
Before the start of the trial, the trial protocol and/or other relevant documents will be approved 
by the IEC/IRB/Competent Authorities, in accordance with local legal requirements. The 
sponsor must ensure that all ethical and legal requirements have been met before the first patient 
is enrolled in the trial. 
This protocol is to be followed exactly. To alter the protocol, amendments must be written, 
receive approval from the appropriate personnel, and receive IRB/IEC/Competent Authority 
approval prior to implementation (if appropriate).  
Administrative changes (not affecting the participant benefit/risk ratio) may be made without the 
need for a formal amendment. All amendments will be distributed to all protocol recipients, with 
appropriate instructions. 
10.1.11 Liability and Insurance 
The sponsor will take out reasonable third-party liability insurance cover in accordance with all 
legal requirements. The civil liability of the investigator, the persons instructed by him or her and 
the hospital, practice, or institute in which they are employed and the liability of the sponsor with 
respect to financial loss due to personal injury and other damage that may arise as a result of the 
carrying out of this trial are governed by the applicable law. 
The sponsor will arrange for patients participating in this trial to be insured against financial loss 
due to personal injury caused by the pharmaceutical products being tested or by medical steps 
taken in the course of the trial. 
10.1.11.1 Access to Source Data 
During the trial, a monitor will make site visits to review protocol compliance, compare eCRF 
entries and individual participant’s medical records, assess drug accountability, and ensure that 
the trial is being conducted according to pertinent regulatory requirements. eCRF entries will be 
verified with source documentation. The review of medical records will be performed in a 
manner to ensure that participant confidentiality is maintained. 
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Checking of the eCRF entries for completeness and clarity, and cross-checking with source 
documents, will be required to monitor the progress of the trial. Moreover, regulatory authorities 
of certain countries, IRBs, IECs, and/or the sponsor’s Clinical Quality Assurance Group may 
wish to carry out such source data checks and/or on-site audit inspections. Direct access to 
source data will be required for these inspections and audits; they will be carried out giving due 
consideration to data protection and medical confidentiality. The investigator assures the 
sponsor, and Parexel if involved in monitoring/data management, of the necessary support at all 
times. 
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10.2 Appendix 2: Clinical Laboratory Tests 
The tests detailed in Table 10-1 will be performed by a central laboratory. 
Local laboratory results are only required in the event that the central laboratory results are not 
available in time for either IMP administration and/or response evaluation. If a local sample is 
required, it is important that the sample for central analysis is obtained at the same time. 
Additionally, if the local laboratory results are used to make either an IMP decision or response 
evaluation, the results must be recorded. 
Protocol-specific requirements for inclusion or exclusion of participants are detailed in Section 5 
of the protocol. 
Additional tests may be performed at any time during the trial as determined necessary by the 
investigator or required by local regulations. 
Investigators must document their review of each laboratory safety report. 
Table 10-1 
Protocol-required Safety Laboratory Tests 
Laboratory Tests 
Parameters 
Haematology 
Thrombocytes 
Erythrocytes 
Haemoglobin 
Haematocrit 
Erythrocyte indices: 
• 
Erythrocyte mean corpuscular volume 
(MCV) 
• 
Erythrocyte mean corpuscular haemoglobin 
(MCH) 
• 
% Reticulocytes 
Leukocytes with differential count: 
• 
Neutrophils 
• 
Lymphocytes 
• 
Monocytes 
• 
Eosinophils 
• 
Basophils 
Clinical chemistry  
Urea nitrogen 
Potassium 
Creatinine 
Sodium 
Glucose fasting 1 
Calcium  
Cholesterol (LDL, HDL total) fasting 1 
Triglycerides fasting 1 
AST/SGOT 2 
Total and direct bilirubin 2 
ALT/SGPT 2 
Prothrombin INR 2 
Protein 
Alkaline phosphatase 3 
Gamma glutamyl transferase 
Lactate dehydrogenase 
Albumin 
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Laboratory Tests 
Parameters 
Routine urinalysis 
Specific gravity 
Glucose, protein, occult blood, ketones, nitrite, leukocytes by dipstick 
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). 
Pregnancy testing 
(WOCBP only) 
Highly sensitive urine hCG pregnancy test (as needed for women of childbearing 
potential) at timepoints detailed in Section 8.3.5. 4 
Other screening tests 
Follicle-stimulating hormone and oestradiol (as needed in women of non-childbearing 
potential only) 
Serology (HIV-1 antibody, HIV-2 antibody, HBsAg, HCV antibody) 
Immunoglobulin E 
Thyroid-stimulating hormone, thyroxine 
Retinol 
1. Participants should be fasting for at least 8 hours prior to the collection of samples for analysis of fasting values 
of triglycerides, cholesterol, and glucose. Participants will be reminded of fasting requirement the day before 
the visit. If they do not follow fasting requirements on the visit day, they will be asked to return to the site in 
fasting conditions (within the visit time window), so fasting blood samples can be collected. 
2. Details of liver chemistry stopping criteria and required actions and follow-up are given in Section 7.1 and 
Appendix 6. All events of concurrent measurements of ALT and/or AST ≥3×ULN with total bilirubin ≥2×ULN 
or prothrombin INR >1.5, which may indicate severe liver injury (possible Hy's Law), should be reported as an 
SAE without undue delay and no later than within 24 hours (see Section 10.3.4  for reporting of SAEs).  
3. If alkaline phosphatase is elevated, consider fractionating. 
4. Local urine testing will be standard for the protocol unless serum testing is required by local regulation or 
IRB/IEC. The test should have a minimum sensitivity of 25 mIU/mL. 
Abbreviations: ALT= alanine aminotransferase; AST=aspartate aminotransferase; BUN=blood urea nitrogen; 
HBsAg=hepatitis B virus surface antigen hCG=human chorionic gonadotropin; HCV=hepatitis C virus; 
HDL=high-density lipoprotein; IEC=independent ethics committee; INR=international normalised ratio; 
IRB=institutional review board; LDL=low-density lipoprotein; RBC=red blood cell; SGOT=serum glutamic-
oxaloacetic transaminase; SGPT=serum glutamic-pyruvic transaminase; WBC=white blood cell; 
WOCBP=woman of childbearing potential. 
 
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10.3 Appendix 3: AEs and SAEs: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting 
10.3.1 Definition of AE 
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
participant administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavourable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product (ICH E2A guidelines). 
This definition includes: 
• Accidental injuries. 
• Events related to trial procedures. 
• Reasons for any unfavourable and unplanned change in medication (drug and/or dose). 
• Clinically significant worsening of pre-existing conditions. 
• Reasons for admission to hospital or surgical procedures unless these were planned before 
the participant consented to trial participation.  
• AEs commonly observed and AEs anticipated based on the pharmacological effect of the 
IMP.  
• Any laboratory abnormality assessed as clinically significant by the investigator (see 
Section 8.2.4). 
10.3.2 Definition of SAE 
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). 
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• Requires in-patient hospitalisation or prolongation of existing hospitalisation. 
Notes:  
- 
Hospitalisation for procedures or treatments planned prior to the participant 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 participant 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 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 purpose does not constitute an AE and should 
therefore not be reported as an AE or SAE. 
- 
Complications that occur during hospitalisation are AEs. If a complication prolongs 
hospitalisation, the event is an SAE.  
- 
When in doubt as to whether hospitalisation occurred, the AE should be considered 
serious. 
• Results in persistent or significant disability or incapacity. 
• Is a congenital anomaly or birth defect. 
• Is a medically important condition. Events that may not be immediately life-threatening or 
result in death or hospitalisation but may jeopardise the participant 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. 
Additionally, all malignancies, including skin malignancies, should be reported as SAEs. 
10.3.3 Recording and Follow-up of AE and SAE 
AE and SAE Recording 
AEs must be assessed by a physician. 
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When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g. hospital progress notes, laboratory, and diagnostics reports) related to the 
event. 
AEs reported by the participant 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 participant). 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, for participants treated 
with delgocitinib cream, the location should be described using the following terminology: 
• Lesional/perilesional (≤2 cm from the border of lesion(s) treated with IMP). 
• Distant (>2 cm from the 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 
provided below. 
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). 
 
Assessment of 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 
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date of worsening, should be recorded. However, if an AE with onset prior to IMP initiation 
worsens after IMP administration, a new AE should be recorded: 
Mild: An AE that is usually transient and may require only minimal treatment or therapeutic 
intervention. The event does not generally interfere with usual activities of daily living. 
Moderate: An AE that is usually alleviated with additional specific therapeutic intervention. 
The event interferes with usual activities of daily living, causing discomfort, but poses no 
significant or permanent risk of harm to the participant. 
Severe: An AE that interrupts usual activities of daily living, or significantly affects clinical 
status, or may require intensive therapeutic intervention. An event is defined as ‘serious’ when 
it meets at least 1 of the predefined outcomes as described in the definition of an SAE, NOT 
when it is rated as severe. 
 
Assessment of Causality 
The investigator is obligated to assess the relationship between trial treatment and each 
occurrence of each AE/SAE. The investigator will use clinical judgement to determine the 
relationship. 
A reasonable possibility of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, 
as well as the temporal relationship of the event to trial treatment administration will be 
considered and investigated. 
The investigator will also consult the delgocitinib IB or the SmPC for alitretinoin (Toctino®) in 
their assessment. 
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
There may be situations in which an SAE has occurred, and the investigator has minimal 
information to include in the initial report in the EDC tool. However, it is very important 
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that the investigator always make an assessment of causality for every event before the 
initial recording of the SAE data in the EDC tool. 
The investigator may change their opinion of causality in light of follow-up information and 
send an SAE follow-up report with the updated causality assessment. 
The following decision choices will be used by the investigator to describe the causality 
assessment: 
Probably related: 
• Follows a reasonable temporal sequence from administration of the IMP. 
• Could not be reasonably explained by the participant’s clinical state, environmental or 
toxic factors, or other therapies administered to the participant. 
• Follows a known pattern of response to the IMP. 
• Disappears or decreases on cessation or reduction in dose of the IMP. 
• Reappears or worsens upon re-challenge. 
 
Possibly related: 
• Follows a reasonable temporal sequence from the administration of the IMP. 
• Could also be reasonably explained by the participant’s clinical state, environmental or 
toxic factors, or other therapies administered to the participant. 
• 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 participant’s clinical state, environmental or 
toxic factors, or other therapies administered to the participant. 
• Does not reappear or worsen upon re-challenge. 
• Does not follow a known pattern of response to the IMP. 
 
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
 
Assessment of Outcome 
The outcome of the event according to the investigator’s clinical judgement should be 
classified using the categories below. 
Recovered/resolved: The event has stopped. The stop date of the event must be recorded. 
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Recovering/resolving: The participant 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 participant 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. participant lost to follow-up. 
The sponsor’s definitions versus Clinical Data Interchange Standards Consortium 
(CDISC) definitions: Note that as per the above definition, the sponsor 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 sponsor’s 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, the sponsor 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 the sponsor 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 the sponsor are more conservative than those used by 
CDISC. 
 
Follow-up of AE and SAE 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may include 
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additional laboratory tests or investigations, histopathological examinations, or consultation 
with other health care professionals. 
If a participant dies during participation in the trial or during a recognised follow-up period, 
the investigator will provide the sponsor with a copy of any post-mortem findings including 
histopathology. 
New or updated information will be recorded in the originally completed form. 
The investigator will submit any updated SAE data to the sponsor within 24 hours of receipt of 
the information. 
10.3.4 Reporting of SAE 
Investigator Reporting Responsibilities 
Any SAE must be reported to the sponsor on the (paper) SAE form immediately, without 
undue delay but not later than within 24 hours of obtaining knowledge. This report should 
contain among 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 6910 2468 
If relevant, the investigator will enclose other information with the SAE form, such as 
anonymised reports of diagnostic procedures, hospital records, autopsy reports, etc. 
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Additionally, Global Safety at LEO Pharma may request further information in order to fully 
assess the SAE. The investigator must forward such information to LEO Pharma upon request 
by fax or e-mail (see contact details above). 
The investigator must notify the local IRB(s)/IEC(s) of SAEs, as required by current 
applicable legislation for the concerned country. 
SAEs occurring after the completion of the clinical trial should not be routinely sought or 
recorded. However, such events should be reported to Global Safety at LEO Pharma (see 
contact details above) if the investigator becomes aware of them. 
Sponsor Reporting Responsibilities 
Global Safety at LEO Pharma is responsible for assessing whether an SAE is expected. The 
relevant reference safety information documents for this clinical trial are: 
• For delgocitinib, the IB Section 7.3 for delgocitinib cream, edition 5.0 (Delgocitinib cream 
IB, 2022) and subsequent updates must be used. 
• For alitretinoin (Toctino®), the latest version of the SmPC must be used (Toctino® SmPC, 
UK). 
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. 
The following reporting requirements apply: all SAEs which are assessed as causally related to 
the IMP(s) by either the investigator or the sponsor, and which are unexpected (i.e. 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. 
 
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10.4 Appendix 4: Contraceptive and Barrier Guidance 
10.4.1 Definitions 
Woman of Childbearing Potential (WOCBP) 
Women in the following categories are considered WOCBP (fertile): 
1. Following menarche 
2. From the time of menarche until becoming postmenopausal unless permanently sterile (see 
below) 
• A postmenopausal state is defined as no menses for 24 months without an alternative 
medical cause. 
o A high follicle-stimulating hormone (FSH) level in the postmenopausal range may be 
used to confirm a postmenopausal state in women not using hormonal contraception 
or hormonal replacement therapy (HRT). However, in the absence of 24 months of 
amenorrhea, confirmation with more than 1 FSH measurement is required.  
o Females on HRT and whose menopausal status is in doubt will be required to use 1 of 
the non-oestrogen hormonal highly effective contraception methods if they wish to 
continue their HRT during the trial. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before randomisation. 
• Permanent sterilisation methods (for the purpose of this trial) include: 
o Documented hysterectomy 
o Documented bilateral salpingectomy 
o Documented bilateral oophorectomy 
o For individuals with permanent infertility due to an alternate medical cause other than 
the above, (e.g. Mullerian agenesis, androgen insensitivity, gonadal dysgenesis), 
investigator discretion should be applied to determining trial entry. 
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview. 
• If fertility is unclear (e.g. amenorrhea in adolescents or athletes) and a menstrual cycle 
cannot be confirmed before first dose of trial treatment, additional evaluation should be 
considered. 
Woman of Nonchildbearing Potential (WONCBP) 
Women in the following categories are considered WONCBP: 
1. Premenopausal woman with permanent infertility due to 1 of the following: 
a. Documented hysterectomy 
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b. Documented bilateral salpingectomy 
c. Documented bilateral oophorectomy 
d. For individuals with permanent infertility due to an alternate medical cause other than 
the above, (e.g. Mullerian agenesis, androgen insensitivity, gonadal dysgenesis), 
investigator discretion should be applied to determining trial entry. 
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview. 
2. Postmenopausal woman 
a. A postmenopausal state is defined as no menses for 24 months without an alternative 
medical cause. 
i. A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or HRT. 
However, in the absence of 24 months of amenorrhea, confirmation with more 
than 1 FSH measurement is required. 
ii. Women on HRT and whose menopausal status is in doubt must discontinue HRT 
to allow confirmation of postmenopausal status before randomisation. 
 
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10.4.2 Contraception Guidance 
Women of childbearing potential must use at least one highly reliable method of contraception 
(i.e., a user-independent method) or two complementary user-dependent methods of 
contraception. Contraception must be used 1 month before treatment and throughout the 
treatment period, including participants with amenorrhea. Contraception must additionally be 
used for 1 month after the end of treatment with alitretinoin. If local guidelines have stricter 
requirements, then local guidelines should be followed. 
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CONTRACEPTIVES a ALLOWED DURING THE TRIAL INCLUDE: 
Highly Effective Methodsb That Have Low User Dependency  
Failure rate of < 1% per year when used consistently and correctly. 
Implantable progestogen-only hormone contraception associated with inhibition of ovulationc. 
Intrauterine device (IUD). 
Intrauterine hormone-releasing system (IUS)c. 
Bilateral tubal occlusion. 
Azoospermic partner (vasectomised or due to a to medical cause) 
Azoospermia is a highly effective contraceptive method provided that the partner is the sole sexual partner of the 
WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method of 
contraception should be used. Spermatogenesis cycle is approximately 90 days. 
Note: documentation of azoospermia for a male participant can come from the site personnel’s review of the 
participant’s medical records, medical examination, or medical history interview. 
Highly Effective Methodsb That Are User Dependent  
Failure rate of <1% per year when used consistently and correctly. 
Combined (oestrogen- and progestogen-containing) hormonal contraception associated with inhibition of 
ovulationc 
oral 
intravaginal 
transdermal 
injectable 
Progestogen-only hormone contraception associated with inhibition of ovulationc 
oral 
injectable 
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the IMP. The reliability of sexual abstinence needs to 
be evaluated in relation to the duration of the trial and the preferred and usual lifestyle of the participant) 
a) 
Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for those participating in clinical studies. 
b) 
Failure rate of < 1% per year when used consistently and correctly. Typical use failure rates differ from 
those when used consistently and correctly. 
c)  
Male condoms must be used in addition to hormonal contraception. If locally required, in accordance 
with Clinical Trial Facilitation Group guidelines, acceptable contraceptive methods are limited to those which 
inhibit ovulation as the primary mode of action. 
Note: Periodic abstinence (e.g. calendar, symptothermal, post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and lactational amenorrhoea method are not acceptable methods of contraception. 
Male condom and female condom should not be used together (due to risk of failure with friction). 
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10.5 Appendix 5: COVID-19 Pandemic Contingency Plan 
Without compromising the safety of participants and trial integrity, it is expected that efforts are 
made to secure attendance at sites for all visits, ensuring important efficacy and safety 
assessments for the trial. 
If on-site visits are not possible due to local authority-issued preventive measures, the affected 
site will postpone screening and randomisation of new participants until on-site visits can be 
conducted. For already randomised participants, 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 SoA (Table 1-1): 
• AE reporting. 
• Treatment compliance (daily completion in the eDiary). 
• Concomitant medication and concurrent procedures. 
• HESD (daily completion in the eDiary). 
• Participant assessment of local tolerability (weekly completion in the eDiary). 
• PROs (DLQI, HEIS, EQ-5D-5L, TSQM, WPAI-CHE, PGI-S, and PGI-C). The participants 
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 participant will perform the test at home and inform the investigator 
about the result via phone and to send a picture of the test to the site or show it via video. 
Additional urine pregnancy tests can be shipped to the participant’s home together with IMP 
(see below) if needed. 
• For participants treated with alitretinoin: 
o Serum cholesterol and serum triglycerides (fasting values) should continue to be 
monitored by a local laboratory, at the timepoints outlined in the SoA (Table 1-1). 
o Remote consultation to allow for adequate monitoring of mental health should be 
maintained at the timepoints outlined in the SoA (Table 1-1). The potential for psychiatric 
disorders may be increased by COVID-19 isolation measures and this may complicate the 
clinical picture. 
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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 COVID-19 pandemic. 
It will be at the discretion of the investigator to decide whether clinical laboratory samples are 
considered necessary to ensure participant safety in periods when on-site visits are not possible. 
If possible, a home visit can be arranged for a healthcare professional to collect relevant clinical 
laboratory samples. 
Contingency plans due to COVID-19 must follow the authorities’ COVID-19 guidelines and 
local requirements. Written procedures describing the contingency plan must be in place at site 
and 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 participants to continue IMP although they are not able to go to 
the trial site. If a participant will not be able to attend on-site visits due to the COVID-19 
pandemic before running out of IMP, the trial site will ensure shipping of IMP to the 
participant’s home. As the participants’ IMP supply is secured, the IE of initiation of rescue 
treatment will be considered independent of the COVID-19 pandemic in the statistical analysis. 
If a participant is tested positive for COVID-19, the investigator will evaluate whether this is an 
AE that contraindicates further dosing, in which case the participant will permanently 
discontinue IMP as described in Section 7.1. 
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10.6 Appendix 6: Liver Safety: Suggested Actions and Follow-up Assessments 
10.6.1 Liver Chemistry Monitoring and Reporting 
In case of an increase of ALT and/or AST ≥5×ULN, re-sampling for ALP, ALT, AST, bilirubin, 
and prothrombin INR should be done immediately, without undue delay and no later than within 
72 hours from initial sampling time to confirm abnormalities. Re-sampling may be relevant at 
lower levels at the discretion of the investigator. Participant should be monitored weekly until 
liver chemistry test abnormalities resolve, stabilise, or return to baseline. 
In case of abnormal liver function tests of concurrent measurements of ALT and/or 
AST ≥3×ULN with total bilirubin ≥2×ULN or prothrombin INR ≥1.5×ULN, re-sampling for 
ALP, ALT, AST, bilirubin, and prothrombin INR should be done immediately, without undue 
delay and no later than within 24 hours from initial sampling time and the abnormality should be 
should be reported as an SAE (see Section 10.3.4 for reporting of SAEs). Participants should be 
monitored twice weekly until liver function test abnormalities resolve, stabilise, or return to 
baseline. 
10.6.2 Discontinuation of IMP 
As described in Section 7.1, the IMP should be discontinued permanently in case of: 
• ALT and/or AST values >3×ULN with total bilirubin >2×ULN (unless elevated bilirubin is 
related to Gilbert Meulengracht Syndrome). 
• ALT and/or AST values >3×ULN with prothrombinINR >1.5×ULN. 
• Confirmed ALT and/or AST values >5×ULN (for more than 2 weeks). 
10.6.3 Recommended Follow-up Assessments 
• Viral hepatitis serology, including hepatitis A immunoglobulin M (IgM) antibody; HBsAg 
and hepatitis C core antibody (HBcAb); hepatitis C ribonucleic acid (RNA); cytomegalovirus 
IgM antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, heterophile 
antibody or monospot testing); and hepatitis E IgM antibody. In those with underlying 
chronic hepatitis B at trial entry (identified by positive HBsAg) quantitative hepatitis B 
desoxyribonucleic acid (DNA) and hepatitis delta antibody. If hepatitis delta antibody assay 
cannot be performed, it can be replaced with a polymerase chain reaction (PCR) of hepatitis 
D RNA virus (where needed) (Le Gal et al, 2005). 
• Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH) 
• Fractionate bilirubin, if total bilirubin > 2×ULN 
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• Complete blood count with differential to assess eosinophilia 
• Record the following: 
o Appearance or worsening of clinical symptoms of liver injury, or hypersensitivity. 
o Use of concomitant medications (including acetaminophen, herbal remedies, recreational 
drugs and other over-the-counter medications). 
o Alcohol use. 
• If ALT and/or AST > 3×ULN and total bilirubin > 2×ULN or prothrombin INR > 1.5, the 
following assessments may be obtained (in addition to the assessments listed above): 
o Antinuclear antibody, anti-smooth muscle antibody, Type 1 anti-liver kidney microsomal 
antibodies, and quantitative total immunoglobulin G (IgG) or gamma globulins. 
o Serum acetaminophen adduct, when available, assay to assess potential acetaminophen 
contribution to liver injury in participants with definite or likely acetaminophen use in the 
preceding week. 
o Liver imaging (ultrasound, magnetic resonance, or computerised tomography) to evaluate 
liver disease. 
o Liver biopsy may be discussed with local specialist if available, for instance: 
▪ 
In participants when serology raises the possibility of autoimmune hepatitis (AIH). 
▪ 
In participants when suspected drug-induced liver injury (DILI) progresses or fails 
to resolve on withdrawal of trial intervention. 
▪ 
In participants with acute or chronic atypical presentation: hepatic vascular 
disorder, chronic hepatitis fibrosis, micro vesicular steatosis. 
 
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10.7 Appendix 7 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 5.2 
Exclusion criteria 
Participants are excluded from the trial if any of the following criteria apply:  
34. 
Participants not affiliated with or not a beneficiary of a social security scheme. 
 
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10.8 Appendix 8: Abbreviations 
Abbreviation 
Description 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AS 
area score 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
BfArM 
Federal Institute for Drugs and Medical Devices 
CDISC 
Clinical Data Interchange Standards Consortium 
CHE 
chronic hand eczema 
CIOMS 
Council for International Organizations of Medical Sciences 
CMH 
Cochran-Mantel-Haenszel 
CONSORT 
Consolidated Standards of Reporting Trials 
COVID-19 
coronavirus disease 2019 
CRF 
case report form(s) (paper or electronic as appropriate for this trial) 
CRO 
Contract Research Organisation 
DBL 
database lock 
DLQI 
Dermatology Life Quality Index 
DNA 
deoxyribonucleic acid 
ECG 
electrocardiogram 
EDC 
electronic data collection 
ET 
early termination 
EU 
European Union 
EudraCT 
European Clinical Trials Database 
FAS 
full analysis set 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
HBsAg 
hepatitis B surface antigen 
HBcAb 
hepatitis C core antibody 
HCV 
hepatitis C virus 
HDL 
high-density lipoprotein 
HECSI 
Hand Eczema Severity Index 
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HEIS / HEIS© 
Hand Eczema Impact Scale© 
HESD / 
HESD© 
Hand Eczema Symptom Diary© 
HIV 
human immunodeficiency virus 
HRT 
hormonal replacement therapy 
IB  
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
ICMJE 
International Committee of Medical Journal Editors 
IE 
intercurrent event 
IEC 
Independent Ethics Committee 
IGA-CHE / 
IGA-CHE© 
Investigator’s Global Assessment for chronic hand eczema© 
IgE 
immunoglobulin E 
IMP 
investigational medicinal product 
INR 
international normalised ratio 
IRB 
Institutional Review Board 
IRT 
interactive response technology 
JAK 
Janus kinase 
LDL 
low-density lipoprotein 
MAR 
missing at random 
MI 
multiple imputation 
PCR 
polymerase chain reaction 
PDAL 
Proximal Daily Activity Limitations 
PGI-C 
Patient Global Impression of Change 
PGI-S 
Patient Global Impression of Severity 
PRO 
patient-reported outcome 
RBC 
red blood cell 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SGOT 
serum glutamic-oxaloacetic transaminase 
SGPT 
serum glutamic-pyruvic transaminase 
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SmPC 
Summary of Product Characteristics 
SoA 
schedule of activities 
SOC 
system organ class 
SUSAR 
suspected unexpected serious adverse reaction 
TCS 
topical corticosteroid(s) 
TMF 
trial master file 
WBC 
white blood cell 
WOCBP 
woman of childbearing potential 
WOCF 
worst observation carried forward 
 
 
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10.9 Appendix 9: Amendments 
Amendment 3 (08 Apr 2022) 
Overall Rationale for the Amendment  
The protocol was amended in order to implement changes from local amendments (UK and 
Canada). 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.3: Schedule of 
Activities (SoA) 
Table 1-1 was updated to 
include the check of 
contraception compliance in 
the alitretinoin group only at 
all study visits (except at 
Day 8 and Day 15). 
A typo was corrected in 
footnote number 13. 
Sub header “Participant 
assessment of safety” was 
added. 
“Weekly” changed to 
“Weekly while on treatment” 
as many participants will not 
be on Delgocitinib treatment 
at visit 9 and 10. Footnote 
added to clarify this 
difference. 
This was updated to address 
questions from Health 
Canada. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 1.3: Schedule of 
Activities (SoA) 
Section 8.2.7.1: Pregnancy 
Testing 
Assessment added under 
sub-header “Participant 
assessments of efficacy and 
health-related quality of life 
during trial visits” to indicate 
an additional local 
tolerability assessment during 
visits. 
Addition of Participant 
assessment of local 
tolerability at End of 
Treatment and Early 
Termination visit. 
Only weekly assessment of 
local tolerability is collected 
in the eDiary. Participant 
assessment of local 
tolerability is added to the 
End of Treatment and Early 
Termination visit in eCRF to 
ensure that participant 
assessment of local 
tolerability data is collected 
at these visits. 
Section 1.3: Schedule of 
Activities (SoA) 
Section 2.3.1: Risk 
Assessment (Table 2-1) 
Section 5.1: Inclusion 
Criteria 
Section 10.4.2: 
Contraception Guidance 
Additional information for 
footnote 6 to accommodate 
for the extension of the 
screening period for WOCBP 
on contraception. 
Text amended to clarify 
contraception requirements. 
To ensure compliance with 
pregnancy prevention 
program for WOCBP. 
Section 1.3: Schedule of 
Activities (SoA) 
The text “alitretinoin group 
only” removed from mental 
health interview. 
Footnote added to Table 1-1 
for clarification. 
To clarify that the metal 
health interview is applicable 
for both treatment groups at 
Screening and Baseline. 
Section 2.3.1: Risk 
Assessment 
Text was added to report on 
the safety concerns for oral 
JAK inhibitors. 
This was updated according 
to the latest edition of the IB. 
Section 5.2: Exclusion 
Criteria 
Exclusion criterion 
number 16 was updated to 
include potent CYP3A4 
inducers to the list of drugs. 
This was updated to address 
questions from Health 
Canada. 
Section 6.2.1.2: Alitretinoin 
Capsules 
Section 10.3.4: Reporting of 
SAE 
Text added to specify the 
representative drug label to 
be used for Canada, the UK 
and EU countries. 
Added as per request from 
BfArM. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 6.8.3: Prohibited 
Medications and Procedures 
Table 6-2 was updated to 
include the prohibition period 
for potent CYP3A4 inducers 
(from 28 days prior to 
baseline to end of the trial). 
Footnote added to Table 6-2 
for clarification.  
This was updated to address 
questions from Health 
Canada. 
Section 8: Trial 
Assessments and Procedures 
The maximum amount of 
blood collected from each 
participant over the duration 
of the trial was changed from 
100 mL to 180 mL. 
It was identified that the 
previously indicated blood 
volume was lower than the 
amount required for the 
sampling specified in the 
protocol. 
Section 8.1.1: Hand Eczema 
Severity Index (HECSI) 
Section 8.1.2: Investigator’s 
Global Assessment for 
Chronic Hand Eczema© 
(IGA-CHE) 
Text amended to clarify the 
assessment of new lesions by 
blinded assessor. 
This was updated to address 
the comments of the Italian 
Regulatory Authority. 
Section 8.2.5: Pregnancy 
Testing 
A statement was added to 
mention that for women of 
childbearing potential 
randomized to alitretinoin, 
the investigator must confirm 
compliance to acceptable 
method(s) of contraception, 
as shown in the schedule of 
activities.  
This was updated to address 
questions from Health 
Canada. 
Section 10.9: Appendix 9: 
Amendments 
Addition of previous 
amendments under 
Appendix 9.  
Included to reflect the 
different amendments of the 
document. 
Section 11: References 
Reference added for the 
German Toctino® Summary 
of Product Characteristics 
(SmPC). 
Added as per request from 
BfArM. 
Throughout the document 
Addition of BfArM in the 
abbreviations list. 
Updating IB edition and year. 
Minor editorial and document 
formatting revisions. 
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Amendment 2 (25 Feb 2022) 
Overall Rational for the Amendment  
The protocol was amended in order to address feedback from the Federal Institute for Drugs and 
Medical Devices (BfArM) while allowing for a factual correction relating to blood sample 
volume that was identified in review. 
Section # and Name 
Description of Change 
Brief Rationale 
Section 5.1: Inclusion 
Criteria 
Section 10.4.2: 
Contraception Guidance 
Text amended to clarify 
contraception requirements. 
Added as per request from 
BfArM. 
 
Section 8: Trial 
Assessments and Procedures 
The maximum amount of 
blood collected from each 
participant over the duration 
of the trial was changed from 
100 mL to 180 mL. 
It was identified that the 
previously indicated blood 
volume was lower than the 
amount required for the 
sampling specified in the 
protocol. 
 
Amendment 1 (21 Jan 2022) 
Overall Rationale for the Amendment: 
The protocol was amended in order to address feedback from Health Canada while allowing for 
a factual correction relating to blood sample volume that was identified in review. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 1.3 Schedule of 
Activities (SoA) 
Table 1-1 was updated to 
include the check of 
contraception compliance 
in the alitretinoin group 
only at all study visits 
(except at Day 8 and 
Day 15). 
 
A typo was corrected in 
footnote number 13. 
This was updated to address 
questions from Health Canada. 
Section 5.2 Exclusion 
Criteria 
Exclusion criterion 
number 16 was updated to 
include potent CYP3A4 
inducers to the list of 
drugs. 
This was updated to address 
questions from Health Canada. 
Section 6.8.3 Prohibited 
Medications and 
Procedures 
Table 6-2 was updated to 
include the prohibition 
period for potent CYP3A4 
inducers (from 28 days 
prior to baseline to end of 
the trial). 
This was updated to align with the 
change done to the exclusion 
criterion number 16. 
Section 8 Trial 
Assessments and 
Procedures 
The maximum amount of 
blood collected from each 
participant over the 
duration of the trial was 
changed from 100 mL to 
180 mL. 
It was identified that the previously 
indicated blood volume was lower 
than the amount required for the 
sampling specified in the protocol. 
Section 8.2.5 Pregnancy 
Testing 
A statement was added to 
mention that for women of 
childbearing potential 
randomized to alitretinoin, 
the investigator must 
confirm compliance to 
acceptable method(s) of 
contraception, as shown in 
the schedule of activities.  
This was updated to align with the 
change done to the schedule of 
activities. 
 
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