Clinical trial NCT05919082
Conditions: Stable Plaque Psoriasis
Keywords: Stable plaque psoriasis Vitamin D analogue Native Chinese subjects
Sponsor: LEO Pharma
Start date: 2023-06-21; Completion date: 2024-03-05
Enrollment: 604 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is conducted to assess the efficacy and safety of LEO 90100 when used on the body for the treatment of stable plaque psoriasis in native adult Chinese subjects, compared to Daivobet® ointment.

Detailed description:
This study is phase 3, randomised, prospective, investigator-blinded, active-controlled, parallel group, multicentre trial to evaluate the efficacy and safety of 4 weeks treatment with LEO 90100 compared with Daivobet® ointment. Eligible participants will be randomised in a 1:1 ratio to either LEO 90100 or Daivobet® ointment treatment.

The trial will last for 6 weeks to 10 weeks for each participant, which includes wash out period and treatment period of up to 4 weeks and a safety follow up period of 2 weeks.

Arms: arm 1: The subjects will receive LEO 90100 foam once daily for 4 weeks. arm 2: The subjects will receive Daivobet® ointment once daily for 4 weeks.
Interventions: intervention 1: LEO 90100 intervention 2: Daivobet® ointment
Intervention descriptions: intervention 1: Subjects will apply LEO 90100 topically; up to 15 g per day (or 105 g per week). intervention 2: Subjects will apply Daivobet® ointment topically; up to 15 g per day (or 105 g per week).

Protocol documents:
Prot_000.pdf: 
 
 
 
 
 
 
 
 
 
 
Cover Page 
 
 
Study title: A Phase 3, Randomised, Investigator-blind, Active-controlled, Parallel Group, Multicentre 
Trial Comparing the Efficacy and Safety of 4-weeks Treatment With LEO 90100 and Daivobet® Oint-
ment in Adult Chinese Subjects With Stable Plaque Psoriasis 
LEO Pharma number: LP0053-2277 
NCT number: NCT05919082 
Date: 09-Nov-2022 
 


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Title Page
Protocol Title:
A phase 3, randomised, investigator-blind, active-controlled, 
parallel group, multicentre trial comparing the efficacy and safety 
of 4 weeks treatment with LEO 90100 and Daivobet® ointment in
adult Chinese subjects with stable plaque psoriasis
Brief Title: 
A study to investigate efficacy and safety with LEO 90100 
compared with Daivobet® ointment in adult Chinese subjects with 
stable plaque psoriasis
Compound:
LEO 90100
Trade Name:
Enstilar®
Indication:
Stable plaque psoriasis
Sponsor:
LEO Pharma A/S
Industriparken 55, DK-2750 Ballerup, Denmark
Protocol Number:
LP0053-2277
Study Phase:
Phase 3
Version:
Version 3.0
Approval Date:
Final, 09 Nov 2022


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Sponsor Signatory: For information about the sponsor signatory refer to Appendix 6: 
Protocol Elements for Redaction, Section 10.7.










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Table of Contents
Title Page ........................................................................................................................................ 1 
Table of Contents ............................................................................................................................ 7 
List of Tables................................................................................................................................. 10 
List of Figures................................................................................................................................11 
Abbreviations and Definitions...................................................................................................... 12 
1 
Protocol Summary .................................................................................................................. 13 
1.1 
Synopsis.............................................................................................................................. 13 
1.2 
Schema ............................................................................................................................... 17 
1.3 
Schedule of Activities (SoA).............................................................................................. 18 
2 
Introduction............................................................................................................................. 21 
2.1 
Trial Rationale .................................................................................................................... 21 
2.2 
Background......................................................................................................................... 21 
2.2.1 
Plaque Psoriasis.............................................................................................................. 21 
2.2.2 
LEO 90100 ..................................................................................................................... 21 
2.3 
Ethical Considerations........................................................................................................ 22 
2.4 
Benefit/Risk Assessment .................................................................................................... 23 
3 
Objectives, Endpoints and Estimands .................................................................................... 25 
4 
Trial Design ............................................................................................................................ 27 
4.1 
Overall Design.................................................................................................................... 27 
4.2 
Scientific Rationale for Study Design ................................................................................ 28 
4.3 
Justification for Dose.......................................................................................................... 30 
4.4 
End-of-Trial Definition....................................................................................................... 30 
5 
Trial Population ...................................................................................................................... 31 
5.1 
Inclusion Criteria................................................................................................................ 31 
5.2 
Exclusion Criteria............................................................................................................... 32 
5.3 
Lifestyle Considerations..................................................................................................... 34 
5.4 
Screen Failures ................................................................................................................... 34 
5.4.1 
Screening and Enrollment Log and Subject Identification Numbers............................. 35 
6 
Trial Treatment(s) and Concomitant Therapy......................................................................... 35 
6.1 
Trial Treatment(s) Administered ........................................................................................ 36 


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6.1.1 
Administration of Trial Treatment.................................................................................. 36 
6.2 
Preparation, Handling, Storage and Accountability ........................................................... 37 
6.3 
Treatment Assignment........................................................................................................ 39 
6.3.1 
Randomisation Code List ............................................................................................... 39 
6.4 
Blinding.............................................................................................................................. 39 
6.4.1 
Breaking the Randomisation Code................................................................................. 40 
6.5 
Treatment Compliance ....................................................................................................... 40 
6.6 
Dose Modification.............................................................................................................. 40 
6.7 
Continued Access to Trial Treatment After the End of the Trial ........................................ 40 
6.8 
Treatment of Overdose ....................................................................................................... 41 
6.9 
Prior and Concomitant Therapy ......................................................................................... 41 
6.9.1 
Concomitant Medication and Concurrent Procedures.................................................... 41 
6.9.2 
Rescue Treatment ........................................................................................................... 42 
6.9.3 
Prohibited Medication and Procedures........................................................................... 43 
7 
Discontinuation of Trial Treatment and Subject Discontinuation .......................................... 44 
7.1 
Discontinuation of Trial Treatment .................................................................................... 44 
7.2 
Subject Discontinuation/Withdrawal from the Study......................................................... 46 
7.3 
Loss to Follow-Up.............................................................................................................. 46 
8 
Study Assessments and Procedures ........................................................................................ 47 
8.1 
Administrative and Baseline Procedures............................................................................ 48 
8.2 
Efficacy Assessments ......................................................................................................... 49 
8.2.1 
Investigator Assessments................................................................................................ 49 
8.2.1.1 
PGA ............................................................................................................................ 49 
8.2.1.2 
............................................................................................................................. 50 
8.2.1.3 
mPASI......................................................................................................................... 50 
8.2.2 
....................................................................................... 52 
8.2.2.1 
............................................................................................................................ 53 
8.2.2.2 
........................................................................................................................... 53 
8.2.2.3 
............................................................................................................................... 53 
8.3 
Safety Assessments............................................................................................................. 54 
8.3.1 
Physical Examinations.................................................................................................... 54 
8.3.2 
Clinical Safety Laboratory Tests .................................................................................... 54 
8.3.3 
Pregnancy Testing........................................................................................................... 55 
8.4 
AEs, SAEs and Other Safety Reporting............................................................................. 55 
8.4.1 
Time Period and Frequency for Collecting AE and SAE Information........................... 55 
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8.4.2 
Method of Detecting AEs and SAEs .............................................................................. 56 
8.4.3 
Follow-up of AEs and SAEs........................................................................................... 56 
8.4.4 
Regulatory Reporting Requirements for SAE................................................................ 57 
8.4.5 
Pregnancy ....................................................................................................................... 57 
8.4.6 
Other Events ................................................................................................................... 58 
8.4.6.1 
Medication Errors ....................................................................................................... 58 
8.4.6.2 
Misuse or Abuse.......................................................................................................... 59 
8.4.7 
Handling of Urgent Safety Measures ............................................................................. 59 
8.5 
Pharmacokinetics................................................................................................................ 60 
8.6 
Pharmacodynamics............................................................................................................. 60 
8.7 
Genetics .............................................................................................................................. 60 
8.8 
Biomarkers ......................................................................................................................... 60 
8.9 
Immunogenicity Assessments ............................................................................................ 60 
8.10 Storage and Future Use of Biological Samples.................................................................. 60 
8.11 Medical Resource Utilisation and Health Economics........................................................ 60 
9 
Statistical Considerations........................................................................................................ 60 
9.1 
Statistical Hypotheses......................................................................................................... 61 
9.1.1 
Multiplicity Adjustment.................................................................................................. 61 
9.2 
Analysis Sets ...................................................................................................................... 62 
9.3 
Statistical Analyses............................................................................................................. 63 
9.3.1 
General Considerations .................................................................................................. 63 
9.3.2 
Disposition of Subjects................................................................................................... 64 
9.3.3 
Demographic and Other Baseline Characteristics.......................................................... 64 
9.3.4 
Exposure and Treatment Compliance............................................................................. 64 
9.3.5 
Estimand Strategy........................................................................................................... 65 
9.3.5.1 
General Considerations............................................................................................... 65 
9.3.5.2 
Estimand Strategy for Binary Endpoints .................................................................... 69 
9.3.5.3 
Estimand Strategy for Continuous Endpoints............................................................. 72 
9.3.6 
Primary Endpoint Analysis............................................................................................. 73 
9.3.7 
Secondary Endpoints Analysis ....................................................................................... 73 
9.3.8 
..................................................................................... 73 
9.3.9 
Safety Analyses .............................................................................................................. 73 
9.3.9.1 
AEs.............................................................................................................................. 73 
9.3.9.2 
Physical Examination ................................................................................................. 74 
9.3.9.3 
Clinical Safety Laboratory Tests................................................................................. 74 
9.4 
Interim Analyses................................................................................................................. 75 
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9.5 
Sample Size Determination................................................................................................ 75 
10 Supporting Documentation and Operational Considerations ................................................. 77 
10.1 Appendix 1: Regulatory, Ethical and Study Oversight Considerations ............................. 77 
10.1.1 
Regulatory and Ethical Considerations .......................................................................... 77 
10.1.2 
Financial Disclosure ....................................................................................................... 78 
10.1.3 
Informed Consent Process.............................................................................................. 78 
10.1.4 
Data Protection ............................................................................................................... 79 
10.1.5 
Dissemination of Clinical Study Data ............................................................................ 79 
10.1.6 
Data Quality Assurance .................................................................................................. 79 
10.1.6.1 
Quality Tolerance Limits ............................................................................................ 80 
10.1.7 
Source Documents.......................................................................................................... 81 
10.1.8 
Study and Site Start and Closure.................................................................................... 81 
10.1.9 
Publication Policy........................................................................................................... 82 
10.1.10 Protocol Approval and Amendment ............................................................................... 83 
10.1.11 Liability and Insurance................................................................................................... 83 
10.1.11.1 Access to Source Data ................................................................................................ 83 
10.2 Appendix 2: Clinical Laboratory Tests............................................................................... 85 
10.3 Appendix 3: AEs and SAEs: Definitions and Procedures for Recording, Evaluating, 
Follow-up and Reporting.................................................................................................... 86 
10.3.1 
Definition of AE ............................................................................................................. 86 
10.3.2 
Definition of SAE........................................................................................................... 86 
10.3.3 
Recording and Follow-up of AE and SAE ..................................................................... 87 
10.3.4 
Reporting of SAE ........................................................................................................... 92 
10.4 Appendix 4: Contraceptive and Barrier Guidance ............................................................. 94 
10.4.1 
Definitions ...................................................................................................................... 94 
10.4.2 
Contraception Guidance ................................................................................................. 96 
10.5 Appendix 5: COVID-19 Pandemic Contingency Plan....................................................... 98 
10.6 Appendix 6: Protocol Amendment History...................................................................... 100 
10.7 Appendix 6: Protocol Elements for Redaction................................................................. 102 
10.7.1 
Information About Sponsor Signatory.......................................................................... 102 
11 References............................................................................................................................. 103 
Investigator Agreement Page ...................................................................................................... 106 
List of Tables
Table 1–1 
Schedule of Activities (SoA) ................................................................................ 18 


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Table 3–1 
Primary Objective, Related Endpoints and Primary Estimands ........................... 25 
Table 3–2 
Secondary and 
 Objectives and Endpoints......................................... 26 
Table 6–1 
Trial Treatment(s) Administered........................................................................... 36 
Table 6–2 
Permitted Concomitant Anti-psoriatic Treatment ................................................. 42 
Table 6–3 
Prohibited Medications and Procedures................................................................ 43 
Table 8–1 
Fitzpatrick Skin Classification.............................................................................. 48 
Table 8–2 
Physician’s Global Assessment of Disease Severity ............................................ 50 
Table 8–3 
Scale for Disease Severity .................................................................................... 52 
Table 8–4 
Disease Severity Grading for Subject’s Assessment ............................................ 53 
Table 9–1 
Subject Analysis Sets............................................................................................ 63 
Table 9–2 
Handling of Observed and Missing Data According to the IEs for the Primary 
Analysis for Estimands ......................................................................................... 68 
Table 9–3 
Hypothetical Strategy for Addressing Permanent Discontinuation of IMP Due to 
Pandemic Restrictions and Handling of Missing Data in the Primary Analysis of 
the Primary Estimand............................................................................................ 71 
Table 9–4 
Hypothetical Strategy for Addressing Permanent Discontinuation of IMP Due to 
Pandemic Restrictions and Handling of Missing Data in the Primary Analysis of 
the Primary Estimand for Continuous Secondary Endpoints ............................... 72 
Table 9–5 
EU SmPC Trial Result .......................................................................................... 75 
Table 9–6 
Simulated Power................................................................................................... 76 
Table 10–1 
Protocol-required Safety Laboratory Tests ........................................................... 85 
List of Figures
Figure 1–1 
Trial Design........................................................................................................... 17 
Figure 9–1 
Graphical Display of Closed Testing Procedure for Primary, Key Secondary and 
Secondary Endpoints ............................................................................................ 62 
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1
Protocol Summary
1.1
Synopsis
Protocol Title: A phase 3, randomised, investigator-blind, active controlled, parallel group, 
multi-centre trial comparing the efficacy and safety of 4 weeks treatment with LEO 90100 and 
Daivobet® ointment in adult Chinese subjects with stable plaque psoriasis
Brief Title: A study to investigate efficacy and safety with LEO 90100 compared with 
Daivobet® ointment in adult Chinese subjects with stable plaque psoriasis
Sponsor Protocol No.: LP0053-2277
Study Phase: Phase 3
Sponsor: LEO Pharma A/S
Rationale:
LEO 90100 (Enstilar® Foam) is a fixed combination product containing calcipotriol 
monohydrate, a vitamin D analogue, and betamethasone dipropionate, a potent steroid that is
approved for topical treatment of stable plaque psoriasis in many countries. This trial is 
conducted to assess the efficacy and safety of LEO 90100 when used on the body for the 
treatment of stable plaque psoriasis in adult Chinese subjects, compared to Daivobet® ointment,
which is approved in China for the treatment of stable plaque psoriasis on the body.






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psoriasis. For each subject, the trial duration will be up to 10 weeks. The treatment duration will 
be up to 4 weeks. The visit frequency will be bi-weekly from the treatment period to the end of 
the follow-up period.
Number of Subjects:
Approximately 600 trial subjects will be randomised in a 1:1 ratio to either LEO 90100 or 
Daivobet® ointment treatment, with 300 evaluable subjects per treatment group.
Trial Arms and Duration:
For each subject, the trial will last 6 weeks to 10 weeks, including:
x
A washout/screening period of up to 4 weeks (at least 1 visit).
x
A treatment period up to 4 weeks (3 visits).
x
A safety follow-up period of 2 weeks (1 visit for all subjects 2 weeks after the last IMP 
administration).
Eligible subjects will be randomised in a 1:1 ratio to receive 1 of the following treatments:
x
Topical administration of LEO 90100 once daily (up to 15 g per day) until Week 4.
x
Topical administration of Daivobet® ointment once daily (up to 15 g per day) until Week 4.
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1.2
Schema
Figure 1–1
Trial Design
Abbreviations: N=number of subjects; No.=number; w=weeks.






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2
Assessments to be performed at unscheduled visits will be at the discretion of the investigator. The subject will be asked about AEs by the investigator.
3
Subjects who permanently discontinue IMP or withdraw from the trial will be asked to come for the primary endpoint visit and will be followed up 
(Section 7.1).
4
The ICF must be signed prior to performing any protocol-related procedures, including but not limited to screening evaluations and washout of prohibited 
medications. Screening evaluations can be either on the same date the ICF was signed or at a later date.
5
In case medical history is incomplete at screening visit, missing data will be retrieved at Day 1 (baseline).
6
To supplement the compliance check made at Visits 3 and 4, a subject diary should be completed daily during the treatment period.
7
Treatment compliance includes recording the number of applications missed by each subject (Section 6.5).
8
The body areas to be assessed are the trunk (including the neck) and the limbs, i.e., arms (including hands) and legs (including feet and buttocks). The 
face, scalp, genitals and skin folds (i.e., the axillae, the inguinal folds, the inter-gluteal folds and the infra-mammary folds) are not to be treated with the 
IMP or assessed as part of the efficacy analysis.
9
An end-of-treatment form (Section 7.1) and end-of-trial form (Section 4.4) must be completed in the eCRF for all subjects assigned to treatment.


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2
Introduction
LEO 90100 (Enstilar® Foam) is a fixed combination product containing calcipotriol 
monohydrate, a vitamin D analogue, and betamethasone dipropionate, a potent steroid that is
approved for topical treatment of stable plaque psoriasis in many countries.
2.1
Trial Rationale
This trial is conducted to assess efficacy and safety of LEO 90100 when used on the body for the 
treatment of stable plaque psoriasis in adult Chinese subjects, compared to Daivobet® ointment,
which is approved in China for the treatment of stable plaque psoriasis on the body.
2.2
Background
2.2.1
Plaque Psoriasis
Plaque psoriasis is a chronic, immune-mediated, inflammatory skin disease affecting up to 3% of 
the global population1, 2, 3. In China, the prevalence of psoriasis is 0.47%4. In addition to skin 
manifestations, psoriasis is associated with multiple co-morbidities such as arthritis and 
cardiovascular disease5, 6. The hallmark of psoriasis is inflammation of the skin. In the majority 
of subjects, psoriasis manifests as plaque type psoriasis, clinically seen as sharply demarcated, 
elevated, scaling and erythematous plaques located predominantly on the scalp, extensor sides of 
elbows and knees and the sacral region6, 7, 8. Skin lesions can be painful and pruritic and may 
cause significant emotional and physical discomfort9, 10.
The majority of affected subjects have mild-to-moderate disease and can be treated with topical 
therapies11. In the group of subjects with moderate-to-severe psoriasis, topical therapies are also 
appropriate as an adjunct to either phototherapy or systemic therapy, including biological 
agents11,12. One of the advantages of topical therapies is a reduced risk of systemic toxicity 
compared with other treatment modalities.
2.2.2
 LEO 90100
LEO 90100 (Enstilar® Foam) is a fixed combination product containing calcipotriol 
monohydrate, a vitamin D analogue, and betamethasone dipropionate, a potent steroid. 
LEO 90100 is approved for topical treatment of stable plaque psoriasis in many countries. The 
first authorisation was received in the United States (US) in 2015, where LEO 90100 was
approved for topical treatment of stable plaque psoriasis (plaque psoriasis) in subjects 18 years of 
age and older. The indication was extended to subjects 12 years of age and older with stable 
plaque psoriasis in July 2019. The marketing authorisation in Europe was achieved in 2016, 
where LEO 90100 was approved for topical treatment of stable plaque psoriasis in subjects 18 


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years and older. To date, LEO 90100 is approved in more than 40 markets worldwide, including 
Hong Kong (China). LEO 90100 is launched under the trademarks Enstilar®, Enstilum® and 
Dovobet® Foam. The recommended treatment duration is once daily for up to 4 weeks, and long-
term maintenance is also approved in several countries.
Daivobet® ointment and Xamiol® gel contain the same 2 active pharmaceutical ingredients 
(calcipotriol monohydrate and betamethasone dipropionate), at the same concentration as 
LEO 90100, and are approved for topical treatment of stable plaque psoriasis in China since
2008 and 2013 respectively. LEO 90100 therefore represents a new formulation of a 
well-established combination with which Chinese physicians have gained much experience. 
Based on data from global trials, it is hypothesised that LEO90100 will have an advantage over 
Daivobet® ointment in terms of improved efficacy in the Chinese population.
Up until 30-Nov-2021, 797,227 treatment courses of Daivobet® ointment and 171,316 treatment 
courses of Xamiol® gel have been prescribed in China.
A detailed description of the chemistry, pharmacology, efficacy and safety of LEO 90100 is
provided in the investigator’s brochure (IB) and Summary of Product Characteristics (SmPC)13,
14.
2.3
Ethical Considerations
This trial will be conducted in accordance with the ethical principles that have their origins in 
International Council for Harmonisation (ICH) Good Clinical Practice (GCP) guidelines and in 
compliance with the approved protocol and applicable regulatory requirements.
Trial subjects will be under careful supervision of dermatologists and physicians experienced in 
GCP clinical trials and in the handling of plaque psoriasis. During the entire course of the trial, 
subjects will be required to attend planned trial visits every 2 weeks. At either their own or the 
physician’s discretion, subjects may be withdrawn from the trial at any time. In case of lack of 
efficacy of the investigational medicinal product (IMP), it will be at the discretion of the trial site 
physician whether the subject needs rescue treatment or discontinuation from the trial. This is 
further described in Section 6.9.2 and Section 7.
No children or other vulnerable subjects incapable of giving informed consent will be included in 
this clinical trial. Pregnant or breastfeeding women and women trying to conceive will not be 
included in the trial. Woman of childbearing potential (WOCBP) must agree to use an adequate 
method of contraception to prevent pregnancy during the clinical trial and until end-of-treatment
of IMP and for at least 8 weeks after last administration of the IMP. In addition, all WOCBP will 


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have a pregnancy test performed before and after study treatment to minimise the risk of foetuses 
being exposed to the IMP.
The trial design chosen for this efficacy and safety trial is regarded as ethically justified and 
adherent with ethical requirements. All subjects will receive active treatment for their plaque 
psoriasis during the treatment period.
2.4
Benefit/Risk Assessment
To date, 16 clinical trials with LEO 90100 have been completed. These trials included in total 
over 2000 subjects with stable plaque psoriasis and approximately 334 healthy subjects. 
Available clinical data do not indicate any specific safety or tolerability concerns with 
LEO 90100 formulation in adult subjects. More detailed information about the known and 
expected benefits and risks and reasonably expected adverse events (AEs) of LEO 90100 and 
Daivobet® ointment may be found in the IB and SmPC of Enstilar® Foam and the SmPC of 
Daivobet® ointment13, 14, 15.
In this trial, all subjects will be treated with LEO 90100 or Daivobet® ointment. Both IMPs will 
be applied to psoriasis lesions on the following body areas: the trunk (including the neck) and the 
limbs (such as arms [including hands] and legs [including feet and buttocks]). The face, scalp, 
genitals and skin folds (i.e., the axillae, the inguinal folds, the inter-gluteal folds and the infra-
mammary folds) are not to be treated with the IMPs or assessed as part of the efficacy analysis.
Permitted concomitant anti-psoriatic treatment for the scalp, trunk and limbs and face and 
sensitive areas (i.e., armpits, groin, under the breasts and in other skin folds around the genitals 
and buttocks) are specified in Section 6.9.1.
Overdose with calcipotriol may be associated with hypercalcaemia (although unlikely to occur if 
used within the limits of 105 g of LEO 90100 or Daivobet® ointment per week). Clinically 
important hypercalcaemia will be managed at the investigator’s discretion with rehydration, 
bisphosphonate administration or according to local standard of care. Hypercalcaemia should 
rapidly subside when treatment is discontinued.
Overdose with corticosteroid containing products (although unlikely to occur if used within the 
limits of 105 g of LEO 90100 or Daivobet® ointment per week) may result in suppression of 
adrenal function which is usually reversible. In such cases, symptomatic treatment is indicated. 
In case of chronic toxicity, corticosteroid treatment must be discontinued gradually.
Subjects may face discomfort and might have to discontinue ongoing treatment during the 
washout phase. However, once the subjects enter the trial, they will be under close supervision of 
a dermatologist and will be provided with LEO 90100 or Daivobet® ointment for treatment of 


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psoriasis. LEO 90100 and Daivobet® ointment have been shown to be effective and safe when 
used for up to 4 weeks and for long-term maintenance (trial LP0052-1004).
Participation in clinical trials may currently be associated with increased risk and added 
challenges due to the coronavirus disease 2019 (COVID-19) pandemic caused by severe acute 
respiratory syndrome coronavirus 2 (SARS-CoV-2). The proposed trial is not believed to put 
subjects with plaque psoriasis at an increased risk for viral infections including SARS-CoV-2.
However, a risk of exposure to infected people cannot be excluded as the trial subjects may enter 
public areas (e.g., commute to the trial site) and have additional human contact (e.g., with trial 
site staff). Appropriate risk assessments and mitigation measures must be considered to protect 
the subjects and trial site staff and to ensure the integrity of the trial data. If on-site visits are not 
possible, the affected site will postpone screening and randomisation of new subjects until 
on-site visits can be conducted. For already randomised subjects, post-baseline visits can be done 
remotely via phone or video (see Section 10.5 for details). During the trial, safety monitoring 
will ensure that all AEs are continuously monitored. COVID-19 vaccines are allowed during the
trial and should be recorded as a concomitant medication.
Details regarding justification of exclusion criteria for safety reasons can be referenced from 
Section 4.2.
Taking into account the measures taken to minimise risk for the trial subjects, the potential risks 
identified in association with LEO 90100 and Daivobet® ointment are justified by the anticipated 
benefits that may be afforded to adult Chinese subjects with stable plaque psoriasis.






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4
Trial Design
4.1
Overall Design
This phase 3, randomised, prospective, investigator-blinded, active-controlled, parallel group, 
multicentre trial will evaluate the efficacy and safety of 4 weeks treatment with LEO 90100 
compared with Daivobet® ointment in native Chinese subjects (aged ≥18 years) with at least 
mild stable plaque psoriasis.
600 trial subjects are planned to be randomised in a 1:1 ratio to either LEO 90100 or Daivobet®
ointment treatment. Randomisation will be stratified by Physician’s Global Assessment of 
disease severity (PGA) at baseline (mild [PGA=2], moderate [PGA=3] or severe [PGA=4]).
For each subject, the trial will last 6 weeks to 10 weeks, including:
x
A washout/screening period up to 4 weeks (at least 1 visit);
x
A treatment period up to 4 weeks (3 visits);
x
A safety follow-up period of 2 weeks (1 visit for all subjects 2 weeks after the last IMP 
administration).
The subjects will provide written consent according to national laws and regulations before any 
trial-related activities are carried out.
Washout/Screening Period
For subjects who have been receiving prohibited medications (see Section 6.9) prior to 
screening, the screening period may be extended up to 4 weeks to ensure they complete the 
required washout period before they start receiving the IMP. On completion of the washout 
period, confirmation of the subject’s ongoing eligibility for the trial will be made at Day 1 
(baseline). However, if no washout is needed the subject will enter Day 1 (baseline) directly.
Treatment Period
The treatment period will last for up to 4 weeks and includes 3 visits: Visit 2 (Day 1), Visit 3 
(Week 2) and Visit 4 (Week 4). The start of IMP treatment will be at Day 1 and this visit will be 
considered as baseline. The first application of the IMP will be made at site under supervision 
and instruction of an un-blinded member of the trial staff (not the investigator, as this is an 
investigator-blinded trial) at the Day 1 visit. The subjects also have the option to apply the first 
IMP at home after the instruction has been given at the site. Refer to Section 6.1 for further 
details on the treatment principles applied.


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Follow-up Period
The follow-up visit (Visit 5) will be performed at Week 6, which is 2 weeks after the last visit in 
the treatment period.
The trial design is illustrated in Figure 1–1 and visit schedule is provided in Table 1–1.
Refer to Section 10.5 for the COVID-19 pandemic contingency plan.
4.2
Scientific Rationale for Study Design
Treatment Duration and Comparator
As part of the registration process for LEO 90100 in China, this trial is being conducted to 
provide efficacy and safety data in the Chinese population. The treatment regimen of once daily 
for a duration of 4 weeks is consistent with the current approved label in Europe and the US. The 
comparator, Daivobet® ointment, is a well-established treatment of stable plaque psoriasis in
China.
Trial Population
The current indication of LEO 90100 in Europe is topical treatment of stable plaque psoriasis in
adults. The inclusion and exclusion criteria are set to include the target population for 
LEO 90100 in China, namely native Chinese subjects aged ≥ 18 years with stable plaque 
psoriasis.
Inclusion criteria 2 to 4 are set to ensure that subjects have a stable and correct diagnosis of 
stable plaque psoriasis, and to comply with the reference safety information:
Exclusion criteria 1, 2, 3 and 14 to 16 are set to exclude subject conditions that may interfere 
with safety endpoint assessment.
Exclusion criterion 4 is set to minimise the risk of serious allergic reactions.
Exclusion criteria 5 to 12 are set to exclude subject conditions that may interfere with clinical 
and safety endpoint assessment.
Exclusion criterion 17 is set to ensure that subjects can tolerate the washout period.
Exclusion criteria 13 and 18 are set to exclude subject conditions that may interfere with clinical 
endpoint assessment.


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Exclusion criterion 19 is set to ensure subjects are mentally stable, able to comprehend the 
consent process, follow the protocol and maximise safety of patients.
Exclusion criterion 20 is set to avoid biases.
Exclusion criterion 21 is set as there is currently no (adequate) safety data on the use of IMPs
during pregnancy or lactation.
Trial Endpoints
The PGA scale, the modified Psoriasis Area and Severity Index (mPASI) and 
measurements will be used to determine the severity of psoriasis among subjects
entering the trial. The trial will be investigator-blinded to avoid bias from knowing the type of 
IMP on efficacy assessments.
The PGA is an instrument used in clinical trials to rate the severity of psoriasis. It is a 5-point 
scale measurement ranging from 0 (clear) to 4 (severe) based on degree of plaque thickening, 
scaling and erythema (Section 8.2.1). The PGA score will be assessed by the investigator 
according to the Schedule of Activities (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.
The mPASI score will be assessed according to the SoA (Table 1–1). The investigator will make 
assessments of the extent and severity of clinical signs of the subject’s psoriasis 
(Section 8.2.1.3). Assessment is not made for the face, scalp, genitals and skin folds (i.e., the 
axillae, the inguinal folds, the inter-gluteal folds and the infra-mammary folds). Hence, this PASI 
assessment is modified to exclude the aforementioned areas.
The investigator will assess the total psoriatic involvement on the trunk (including the neck) and 
the limbs (such as arms [including hands] and legs [including feet and buttocks]) as a percentage 
of the 
; any involvement on face, scalp, skin folds and genitals will be excluded. The 
purpose of this assessment is to obtain an estimate of the total area to be treated with the IMP. As 
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Trial-specific Laboratory Measurements
Laboratory evidence of adrenal insufficiency due to the use of topical corticosteroid treatment 
has been reported17. Any systemic absorption of betamethasone and potential effect on the 
adrenal function will be evaluated by measuring the serum cortisol concentration at baseline and 
at the end-of-treatment at Week 4.
Overdosage with topical calcipotriol, a vitamin D analogue, may cause hypercalcaemia due to 
the systemic absorption of calcipotriol18. Any systemic absorption of calcipotriol will be 
evaluated by measurement of serum calcium, urinary calcium excretion and the urinary 
calcium/creatinine ratio. Albumin-corrected serum calcium concentration is the most clinically 
relevant assessment for assessing calcium metabolism, but urinary assessment of calcium 
concentrations is more sensitive to identify small changes; therefore, both assessments will be 
included in this trial.
4.3
Justification for Dose
The strengths of LEO 90100 and Daivobet® ointment planned for the trial (up to 15 g per day, 
once daily for up to 4 weeks) follow the current approved label in Europe and the US.
4.4
End-of-Trial Definition
The end of the trial is defined as the date of the last visit of the last subject in the trial.
A subject is considered to have completed the trial if he/she has completed all periods of the trial 
including the last follow-up visit.
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End-of-trial Form
An end-of-trial form must be completed in the electronic case report form (eCRF) for all subjects
assigned to treatment when they have had their last visit (that is, the follow-up visit at Week 6 or 
early termination visit). The following data will be collected:
x
Date of last contact.
x
Did the subject complete the trial?
x
Primary reason for not completing the trial based on the following categories: death, AE, lack 
of efficacy, lost to follow-up, withdrawal by subject, screen failure (failure to meet eligibility 
criteria) or other.
x
Whether the reason for not completing the trial was related to COVID-19.
If ‘AE’ is selected, the AE in question will be linked to the non-completion of the trial. If ‘other’ 
is selected as a reason, a specification must be provided in the eCRF. If ‘withdrawal by subject is
selected, it will be recorded whether the subject withdrew informed consent or not.
For end-of-treatment form, please referred to Section 7.1.
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 subjects who are native Chinese subjects aged ≥ 18 years with 
stable plaque psoriasis. Subjects 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 eCRF if the subject has met all the inclusion criteria and none of the 
exclusion criteria.
5.1
Inclusion Criteria
Subjects are eligible to be included in the study only if all of the following criteria apply:
Age
1. Subject of either gender aged 18 years or above.


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Type of Subject and Disease Characteristics
2. A clinical diagnosis of stable plaque psoriasis for at least 6 months, which can be controlled 
by treatment with a maximum of 105 g of LEO 90100 per week, in the investigator's opinion.
3. Stable plaque psoriasis on the trunk and/or limbs (excluding psoriasis on the face, scalp, 
genitals, and skin folds) involving 2-30% of the 
at Day 1 (Visit 2).
4. A PGA of at least ‘mild’ at Day 1 (Visit 2).
5. An mPASI score of at least 2 on the trunk and/or limbs at Day 1 (Visit 2).
Contraceptive/Barrier Requirements
6. Female subjects of childbearing potential* must use an adequate form of birth control 
throughout the trial and for at least 8 weeks after last administration of IMP.
* A woman is defined as not being of childbearing potential if she is postmenopausal (at least 
12 months with no menses without an alternative medical cause prior to screening) or 
surgically sterile (hysterectomy, bilateral salpingectomy or bilateral oophorectomy).
7. Male subjects with a female partner of childbearing potential must use adequate 
contraceptive methods (adequate contraceptive measures as required by local regulation or 
practice).
Informed Consent
8. Signed and dated informed consent has been obtained prior to any protocol-related 
procedures.
Others
9. Subject is native Chinese.
5.2
Exclusion Criteria
Subjects are excluded from the study if any of the following criteria apply:
Medical Conditions
1. Known or suspected renal insufficiency, hepatic disorders or severe heart disease.
2. Clinical signs or symptoms of Cushing’s disease or Addison’s disease.
3. Hypercalcaemia or abnormal calcium metabolism.
4. Known or suspected hypersensitivity to any component(s) of the IMP.
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Prior/Concomitant Therapy
5. Systemic treatment with biological therapies, whether marketed or not, with a possible effect 
on plaque psoriasis within the following time periods:
a. Etanercept (Yisaipu®), within 4 weeks prior to treatment assignment;
b. Adalimumab (Humira®), Infliximab (Remicade®) or Brodalumab (Kyntheum®), within 
8 weeks prior to treatment assignment;
c. Ustekinumab (Stelara®), within 16 weeks prior to treatment assignment;
d. Secukinumab (Cosentyx®), within 12 weeks prior to treatment assignment;
e. Other products, within 4 weeks/5 half-lives (whichever is longer) prior to treatment 
assignment.
6. Systemic treatment with a possible effect on plaque psoriasis (e.g., corticosteroids, retinoids, 
methotrexate, ciclosporin and other immunosuppressants, traditional Chinese medicine) 
within 4 weeks prior to treatment assignment.
7. Systemic treatment with Apremilast within 4 weeks prior to treatment assignment.
8. Psoralen combined with ultraviolet A therapy (PUVA) within 4 weeks prior to treatment 
assignment.
9. Ultraviolet B (UVB) therapy within 2 weeks prior to treatment assignment.
10. Topical treatment of psoriasis with very potent (World Health Organization [WHO] classes 
IV and stronger) corticosteroids within 2 weeks prior to treatment assignment.
11. Topical treatment of psoriasis with traditional Chinese medicine within 2 weeks prior to 
treatment assignment.
12. Treatment with any non-marketed drug substance (that is, an agent which has not yet been 
made available for clinical use following registration) within 4 weeks/5 half-lives (whichever 
is longer) prior to treatment assignment.
13. Any topical treatment that could affect plaque psoriasis within 2 weeks prior to treatment 
assignment.
Prior/Concurrent Clinical Study Experience
14. Current participation in any other interventional clinical trial.
15. Previously screened in this clinical trial.
16. Previously participated in a clinical trial within 4 weeks prior to treatment assignment.


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Diagnostic Assessments
17. Current diagnosis of guttate, erythrodermic, exfoliative, pustular or unstable (psoriasis is 
getting worse quickly and may become erythrodermic) psoriasis.
18. Subjects with any of the following conditions present on any skin area: viral lesions, fungal 
and bacterial skin infections, parasitic infections, skin manifestations in relation to syphilis or 
tuberculosis, rosacea, acne vulgaris, acne rosacea, atrophic skin, striae atrophicae, fragility of 
skin veins, ichthyosis, ulcers and wounds.
Other Exclusion Criteria
19. History of chronic alcohol or drug abuse within 12 months prior to screening, or any 
condition associated with poor compliance as judged by the investigator.
20. 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.
21. Women who are pregnant, lactating, or of childbearing potential and wish to become 
pregnant during the trial.
5.3
Lifestyle Considerations
Detailed instructions on permitted concomitant anti-psoriatic treatment, prohibited medication
and procedures and contraception are provided in Section 6.9.1, Section 6.9.3 and Appendix 4:
Contraceptive and Barrier Guidance, respectively.
5.4
Screen Failures
A screen failure occurs when a subject who has consented to participate in the clinical study is
not subsequently randomly assigned to treatment. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure subjects to meet the Consolidated 
Standards of Reporting Trials (CONSORT) publishing requirements and to respond to queries 
from regulatory authorities. Minimal information includes demography, reason for screen failure 
(i.e., eligibility requirements failed) and documentation of any medical occurrences that qualify 
as serious adverse events (SAEs).
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 subject failing to meet the 
eligibility criteria but is administrative (e.g., delayed test results or temporary site closure due to 
the COVID-19 pandemic), re-screening may be permitted. This will require approval by the
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LEO Pharma A/S. Rescreened subjects should be assigned a new subject number for every 
screening/rescreening event.
5.4.1
Screening and Enrollment Log and Subject Identification Numbers
The investigator will maintain a log of all subjects considered for screening, whether they have 
provided written informed consent or not (pre-screening log). This log will be anonymous and 
will include the reason(s) for not entering the trial, if applicable, or the allocated subject
identification number. For subjects not willing to consent, the main reason will be collected on 
the pre-screening log (e.g., time constraint, other safety concerns, number of blood samples).
Upon enrollment, each subject will receive a unique subject identification number. Subject
numbers must not be re-used for different subjects.
The investigator will maintain a log of all consented subjects at the trial site (subject
identification list). This log will include each subject’s identity, date of consent and 
corresponding subject identification number, so that any subject may be identified if required for 
any reason. The log must not be copied or retained by LEO Pharma A/S and the designated 
CRO.
6
Trial Treatment(s) and Concomitant Therapy
Trial treatments are all pre-specified, investigational and non-IMPs, intended to be administered 
to the study subjects during the trial conduct.


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6.1
Trial Treatment(s) Administered
Table 6–1
Trial Treatment(s) Administered
Treatment Name
LEO 90100
Daivobet® ointment
Active Ingredient 
and Concentration
Calcipotriol 50 mcg/g (as 
monohydrate) and betamethasone 
0.5 mg/g (as dipropionate)
Calcipotriol 50 mcg/g (as 
monohydrate) and betamethasone 
0.5 mg/g (as dipropionate)
Type
Drug
Drug
Dosage Formulation
Foam
Ointment
Dosage Level(s)
Once daily for 4 weeks; up to 15 g per 
day (or 105 g per week)
Once daily for 4 weeks; up to 15 g 
per day (or 105 g per week)
Route of 
Administration
Topical
Topical
Use
Experimental
Experimental
IMP or NIMP
IMP
IMP 
Sourcing
Provided centrally by LEO Pharma 
A/S.
Provided centrally by LEO Pharma 
A/S.
Packaging and 
Labelling
LEO 90100 will be provided in an
aluminum can, which is pre-filled 
and subsequently administered 
through a continuous valve. 240 g of 
IMP will be dispensed every second 
week to subjects. Each can will be 
labelled as required per China
requirement. 
Daivobet® will be provided in a tube.
240 g of IMP will be dispensed every 
second week to subjects. Each tube 
will be labelled as required per China
requirement.
Abbreviations: IMP= investigational medicinal product; NIMP=non-investigational medicinal product.
6.1.1
Administration of Trial Treatment
Dosing visits are shown in the SoA (Table 1–1). Subjects will be asked to use the assigned IMP
once daily (up to 15 g per day) on skin affected by psoriasis on trunk and limbs, at no specific 
time of the day, for the duration of the 4 weeks treatment period, starting on Day 1.
At Visit 2 (Day 1) the subject will be given a treatment instruction sheet, and the subject will 
receive verbal instruction about how to apply the IMP. The first application of the IMP should be 
made either under supervision and instruction of an un-blinded member of the trial staff (not the 
investigator) or at home the same day the subject attended the Day 1 visit. The IMP will be 
dispensed by a designated un-blinded person (different from the investigator). The dispenser 
should ensure that the subject is familiar with the procedures for IMP administration, including 
instructions to return all dispensed cans/tubes, whether used or not, at the following visit. All 
returned IMP should be stored in the kit outer box.
Dispensing of IMP is described in Section 6.2.


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6.2
Preparation, Handling, Storage and Accountability
Dispensation of IMP
All kits will contain 240 g of IMP.
IMP will be supplied at the dispensing visits listed in the SoA (Table 1–1). Each kit will contain 
the necessary amount of IMP to treat a subject between 2 visits in the treatment period.
The subject may use up to a maximum of 15 g per day (or 105 g per week), and 240 g of IMP 
will be dispensed every second week.
Storage of IMP
All LEO Pharma A/S supplied IMP must be stored in a secure, environmentally controlled and 
monitored (manual or automated) area under the conditions specified on the label and remain in 
the original container until dispensed, with access limited to the authorised site staff (different 
from the investigator).
The investigator or designee (e.g., hospital pharmacy) must maintain a log to confirm appropriate 
conditions (e.g., temperature) have been maintained during transit for all IMP received, and any 
discrepancies are reported and resolved before use of the IMP. Damaged IMP should be 
documented and may not be used. Storage facilities should be checked at least every working 
day.
The following storage conditions and handling precautions should be observed for LEO 90100:
x
Store below 30°C. Do not freeze.
x
Extremely flammable aerosol.
x
Pressurised container: May burst if heated.
x
Protect from sunlight.
x
Do not expose to temperatures exceeding 50°C.
x
Do not pierce or burn, even after use.
x
Do not spray on an open flame or other ignition source.
x
Keep away from sparks, open flames and other ignition sources.
x
No smoking.
x
Keep out of the reach of children.


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The following storage conditions and handling precautions should be observed for Daivobet®
ointment:
x
Do not store above 25°C. Do not refrigerate.
x
Keep the tube in the outer carton and way from sunlight.
x
Keep out of the reach of children.
Only subjects randomised in the study may receive IMP, and only authorised site staff (different 
from the investigator) may supply, prepare or administer IMP.
Accountability of IMP
The investigator is fully responsible for the IMP accountability, reconciliation and record 
maintenance (e.g., receipt, reconciliation and final disposition records). However, the 
aforementioned tasks will be delegated to an un-blinded person as the investigator needs to stay
blinded from the IMP type.
Management of IMP may be delegated (e.g., to a hospital pharmacy) as locally applicable.
Documentation of drug accountability must be kept of the IMP administered to each individual 
subject in the trial. This documentation must be available during monitoring visits and will be 
checked by the monitor to verify correct dispensing of the IMP.
The subject will return used, partly used and unused IMP (including packaging material) at the 
visits specified in the SoA (Table 1–1).
Returned IMP (used, partly used and unused [including packaging material]) can be stored under 
condition as described above and must be stored separately from non-allocated IMP.
All unused IMP (including packaging material) supplied by the contract manufacturing 
organisation (CMO) on behalf of LEO Pharma A/S will be returned to the CMO or local depot. 
Prior to their return, the IMP must be fully accounted for by the monitor with the help of site 
staff responsible for dispensing the IMP.
IMP Destruction
Used and unused IMP will be destroyed by the CMO or local depot according to approved 
procedures and/or local requirements.


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6.3
Treatment Assignment
Subjects will be randomly assigned to one of the following IMP, via a central interactive web 
response system (IWRS) in accordance with a computer-generated randomisation schedule in a 
1:1 ratio:
x
LEO 90100
x
Daivobet® ointment
Randomisation will be stratified by baseline disease severity determined by the PGA (mild 
[PGA=2], moderate [PGA=3] or severe [PGA=4]).
At Visit 2, after confirmation of eligibility, the subject randomisation number will be generated 
by the IWRS. The IWRS will assign treatment for each subject and will provide a kit number. 
Likewise, at the subsequent dispensing visits, the site personnel (different from the investigator) 
will access the IWRS to be informed of the kits to assign to the subject.
IMP will be administered/dispensed at the study visits as summarised in the SoA (Table 1–1).
Returned IMP should not be re-dispensed to the subjects.
6.3.1
Randomisation Code List
The randomisation code lists will be generated by the IWRS of the designated CRO. These files 
will be stored securely by the CRO, inaccessible to staff involved with the conduct and 
administration of the clinical trial until the clinical trial data base is declared clean and released 
to the trial statistician.
These files are only shared with un-blinded LEO Pharma A/S representatives Clinical Trial 
Supplies (CTS), Global Safety or the CMO as required.
6.4
Blinding
The trial is investigator-blinded.
As LEO 90100 and Daivobet® ointment are provided in different containers (LEO 90100 is in a 
can and Daivobet® ointment is in a tube), the subject will know which IMP he/she is receiving.
To ensure that the investigator’s assessment of efficacy and safety is not influenced or biased, the 
investigator will stay blinded throughout the trial. It is important that the investigator does not 
see or get information about which IMP the subject is receiving. The IMP will be handed out to 
the subjects by a designated person so the investigator will not know which IMP the subject has 


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received. Subjects will be instructed/reminded not to reveal the form of the IMP that they are 
dispensed to the investigator each time product is dispensed.
In addition, to minimise the risk of potential bias, a measure of artificial blinding will be 
implemented to preserve the integrity of the trial data. Detailed strategies on artificial blinding 
and a study team list specifying blinded and unblinded functions will be described in a blinding 
plan.
6.4.1
Breaking the Randomisation Code
Un-blinding of Individual Subject Treatment
Un-blinding of individual subject treatment is not considered necessary as the ingredients in the 
2 IMPs are the same.
Un-blinding of the Clinical Trial
The clinical trial will be un-blinded when a final validated database has been produced, the 
statistical analysis specified in this protocol has been reviewed in relation to the blinded data 
actually obtained and the Statistical Analysis Plan (SAP) Update has been approved.
6.5
Treatment Compliance
Subjects will be provided with a paper diary to record adherence to the once daily treatment 
regimen during the treatment period. The diary should be returned to the site staff at the 
subsequent trial visit.
The investigator (or designee) should review the compliance data recorded by subjects in the 
paper diary before each visit. In case of non-compliance, the investigator should remind the 
subject of the importance of following the instructions given. Compliance/non-compliance and 
the reason for it must be recorded in the eCRF.
6.6
Dose Modification
Not applicable
6.7
Continued Access to Trial Treatment After the End of the Trial
After the end of the trial, subjects will be treated at the investigator’s discretion or referred to 
other physician(s) according to standard practice.


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6.8
Treatment of Overdose
For this study, any dose of LEO 90100 and Daivobet® ointment greater than 105 g within one 
week will be considered an overdose.
Overdose with calcipotriol may be associated with hypercalcaemia. Clinically important 
hypercalcaemia will be managed at the investigator’s discretion with rehydration, 
bisphosphonate administration or according to local standard of care. Hypercalcaemia should 
rapidly subside when treatment is discontinued.
Overdose with corticosteroid containing products may result in suppression of adrenal function,
which is usually reversible. In such cases, symptomatic treatment is indicated. In case of chronic 
toxicity, corticosteroid treatment must be discontinued gradually.
6.9
Prior and Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, recreational 
drugs, vitamins and/or herbal supplements) that the subject is receiving at the time of enrollment 
or receives during the trial must be recorded along with:
x
Reason for use.
x
Dates of administration including start and end dates.
x
Dosage information including dose and frequency.
x
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 and record prior medication use taken by the 
subject within at least 16 weeks prior to treatment assignment or longer if required to washout 
other products per exclusion criterion 5.
The investigator or qualified designee will record medication, if any, taken by the subject during 
the study through the last visit. Concomitant medications will be recorded for 14 days after the 
last IMP administration (or longer if related to an SAE).
6.9.1
Concomitant Medication and Concurrent Procedures
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x
An AE that, in the opinion of the investigator or medical monitor of the designated CRO, 
contraindicates further dosing. The decision made by the designated CRO will need to be 
confirmed by LEO Pharma A/S;
x
Evidence of pregnancy;
x
Subject decides to discontinue voluntarily;
x
Lack of efficacy defined as at least a 
 in mPASI score from baseline until 
Week 2 or unscheduled visits thereafter and where the investigator sees a need for rescue 
therapy.
End-of-treatment Form
An end-of-treatment form will be completed in the eCRF for all subjects exposed to IMP when 
they have had their last IMP administration. This form will also be completed for subjects who 
permanently discontinue IMP prior to Week 4 and subjects who withdraw from the trial, unless 
they were never exposed to IMP (see Table 1–1 for early termination assessments).
The date and time of last IMP administration and time of permanent discontinuation of IMP will 
be recorded on the end-of-treatment form. It will also be recorded if the subject completed the 
IMP treatment (i.e., did not discontinue IMP prior to Week 4). If not, the primary reason for 
permanent IMP discontinuation must be recorded in the medical records and on the 
end-of-treatment form in the eCRF where the following options are available:
x
AE;
x
Death;
x
Lost to follow-up;
x
Pregnancy;
x
Withdrawal by subject;
x
Lack of efficacy;
x
Pandemic restrictions as defined in Section 9.3.5.1;
x
Other.
If ‘AE’ is selected, the AE in question will be linked to the IMP discontinuation. If ‘other’ is 
selected as a reason, a specification must be provided in the eCRF.
It will also be recorded whether the IMP discontinuation was related to the COVID-19 pandemic 
to support the statistical analysis.
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7.2
Subject Discontinuation/Withdrawal from the Study
A subject may withdraw from the study at any time at their own request or for any reason (or 
without providing any reason). A subject may be withdrawn at any time at the discretion of the 
investigator for safety, behavioral or compliance reasons. The subject will be permanently 
discontinued from the IMP and the trial at that time.
If the subject withdraws consent for disclosure of future information, the investigator must 
document this in the site study records; data collected before a withdrawal of consent may be 
retained and used.
If a subject withdraws from the trial, he/she may request destruction of any samples taken and 
not tested, and the investigator must document this in the site study records.
At the time of discontinuing from the study, 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 study discontinuation and follow-up and for any further evaluations that need to be completed.
In order to ensure appropriate treatment of the subjects after they have discontinued IMP or 
withdrawn from the trial, the subjects will be treated at the investigator’s discretion.
7.3
Loss to Follow-Up
A subject will be considered lost to follow-up if the subject repeatedly fails to return for 
scheduled visits and are unable to be contacted by the trial site.
The following actions must be taken if a subject fails to return to the clinic for a required study 
visit:
x
The site must attempt to contact the subject and reschedule the missed visit as soon as 
possible (and within the visit window, where one is defined), counsel the subject on the 
importance of maintaining the assigned visit schedule, and ascertain whether the subject 
wishes to and/or should continue in the trial.
x
In cases in which the subject is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the subject (where possible, 3 telephone calls and, if 
necessary, a certified letter to the subject’s last known mailing address or local equivalent 
methods). These contact attempts should be documented in the subject’s medical 
record/eCRF.
x
Should the subject continue to be unreachable, the subject will be considered to have 
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8
Study Assessments and Procedures
Study procedures and their timing are summarised in the SoA (Table 1–1). Protocol waivers or 
exemptions are not allowed. The IMP will be administered after subject and investigator 
assessments.
Trial subjects will be under careful supervision by the principal investigator who must be a 
dermatologist. Investigators must be physicians who are experienced in treating psoriasis, have 
documented experience and have received the training for the use of the assessments required by 
the protocol.
AEs must be assessed by a physician (Section 8.4).
Immediate safety concerns should be discussed with LEO Pharma A/S immediately upon 
occurrence or awareness to determine if the subject should continue or discontinue the IMP.
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct.
All screening evaluations must be completed and reviewed to confirm that potential subjects
meet all eligibility criteria. The investigator will maintain a screening log to record details of all 
subjects screened and to confirm eligibility or record reasons for screening failure, as applicable.
In the event of a significant study-continuity issue (e.g., caused by a pandemic), alternate 
strategies for subject visits, assessments, medication distribution and monitoring may be 
implemented by LEO Pharma A/S or the investigator, as per local health authority/ethics 
requirements.
Blood and urine samples will be drawn for biochemistry assessments and pregnancy tests (for 
WOCBP only). The maximum amount of blood collected from each subject over the duration of 
the trial, including any extra assessments that may be required, will not exceed 100 mL, which is 
less than the volume of blood taken during a blood donation (which is approximately 500 mL).
The total volume of urine needed is approximately 300 mL.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the 
samples.
Subject Identification Card
All subjects will be given a subject identification card identifying them as subjects in a research 
study. The card will contain trial site contact information (including direct telephone numbers) to 




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(i.e., other locations of psoriasis, previous anti-psoriatic therapy, last anti-psoriatic therapy) will 
be collected from the subject’s date of birth. For each condition, diagnosis or surgical procedure, 
the start date and stop date or whether it is ongoing will be recorded.
x
Other locations of psoriasis: The presence of psoriasis affecting regions of the body not 
considered to be part of the treatment area (i.e., face, scalp, skin folds and genitals) will be 
recorded.
x
Previous anti-psoriatic therapy: All previous anti-psoriatic treatment (systemic and topical 
medications and light therapy) used by the subject to treat their plaque psoriasis will be 
recorded by pre-defined category.
x
Last anti-psoriatic therapy: Last anti-psoriatic treatment (systemic and topical medications 
and light therapy) used by the subject to treat their plaque psoriasis will be recorded.
Height and Weight
The subject’s height (without shoes) in ‘cm’ will be measured; the subject’s weight (in indoor 
clothing and without shoes) in ‘kg’ will be measured.
8.2
Efficacy Assessments
Planned timepoints for all efficacy assessments are provided in the SoA (Table 1–1).
8.2.1
Investigator Assessments
The body areas to be assessed are the trunk (including the neck) and the limbs, i.e., arms 
(including hands) and legs (including feet and buttocks). The face, scalp, genitals and skin folds 
(i.e., the axillae, the inguinal folds, the inter-gluteal folds and the infra-mammary folds) are not 
to be treated with the IMP or assessed as part of the efficacy analysis.
8.2.1.1
PGA
The PGA is an instrument used in clinical trials to rate the severity of psoriasis. It is a 5-point 
scale measurement ranging from 0 (clear) to 4 (severe) based on degree of plaque thickening, 
scaling and erythema (Table 8–2). The PGA 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.




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The extent of psoriatic involvement will be recorded for each of the areas (trunk [including the 
neck] and the limbs [such as arms and legs]; excluding any involvement on face, scalp, genitals 
and skin folds) using the following scale:
x
0=no involvement
x
1=< 10%
x
2=10%-29%
x
3=30%-49%
x
4=50%-69%
x
5=70%-89%
x
6=90%-100%
This assessment of extent is the percentage of that body area that is affected, and not the
percentage 
 (see Section 8.2.1.2). For example, if one arm was totally 
affected, and the other arm was totally unaffected, the extent assessment for the arms would be
50% (half of the arms affected).
The severity of the psoriatic lesions in each of the areas will be recorded for each of the clinical 
signs of redness, thickness and scaliness. For each clinical sign, a single score, reflecting the 
average severity of all psoriatic lesions on the given body region, will be determined according 
to Table 8–3.
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8.2.2.1
8.2.2.2
 
8.2.2.3
 
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Site staff will train the subject on the proper reporting at Day 1 (baseline) visit.
8.3
Safety Assessments
Planned timepoints for all safety assessments are provided in the SoA (Table 1–1).
8.3.1
Physical Examinations
An abbreviated physical examination of the subject, including assessment of the skin, lungs, 
cardiovascular system and abdomen (liver and spleen), must be performed according to the SoA 
(Table 1–1). Abnormal findings may preclude subject eligibility for the trial or where the subject
remains eligible despite the finding, they may be documented as concurrent diagnoses.
8.3.2
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 and urinalysis 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 and the results must be reported as an (S)AE 
as defined in Appendix 3.
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 pregnancy test will be performed according to the SoA (Table 1–1).
At each visit, the site staff will record in the eCRF if a blood and/or urine sample was taken. If 
not, a reason should be provided. The investigator’s assessment of the results (‘normal’, 


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‘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 8.4).
8.3.3
Pregnancy Testing
For WOCBP, serum and/or urine pregnancy tests will be performed as shown in the SoA 
(Table 1–1). Negative pregnancy test results must be obtained at screening and at baseline prior 
to randomisation.
If the subject becomes pregnant during the trial, IMP must be discontinued immediately.
It will be recorded in the eCRF if the subject is a WOCBP and if a serum and/or urine pregnancy 
test was performed. If not, a reason should be provided. Also, the date and the outcome of the 
pregnancy test will be recorded in the eCRF (‘positive’, ‘negative’).
8.4
AEs, SAEs and Other Safety Reporting
The definitions of AEs and SAEs can be found in Appendix 3.
AEs reported by the subjects or observed by the investigator must be recorded on the AE form of 
the eCRF (see Section 8.4.2).
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 of AEs and SAEs as described in Section 8.4.3.
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.
8.4.1
Time Period and Frequency for Collecting AE and SAE Information
All AEs and SAEs will be collected from the signing of informed consent form (ICF) until the
end-of-trial (defined as attending the last visit in the trial [the early termination visit or the last 
follow-up visit (Visit 5), whichever comes last]), at the timepoints specified in the SoA (Table 1–
1).
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All SAEs will be recorded and reported to LEO Pharma A/S 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 LEO Pharma A/S within 24 hours of it being available.
Investigators are not obliged to actively seek information on 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 subject has been discharged from the trial, and the investigator considers the event to be 
reasonably related to the IMP or trial participation, the investigator must promptly notify LEO 
Pharma A/S.
8.4.2
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 subject is the preferred method to inquire about 
AE occurrence.
At all visits, subjects will be asked a non-leading question by the investigator about AEs, e.g.,
‘How have you felt since I saw you last?’.
If the AE qualifies as an SAE, expedited reporting is required (see Appendix 3). It is important 
that the investigator also observes the subject for any changes not reported by the subject and 
records these changes.
8.4.3
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each subject at 
subsequent visits/contacts.
During the trial, the investigator should follow-up for final outcome on all AEs (including 
SAEs). Once a subject leaves the clinical trial, the investigator should follow-up on the outcome 
of all non-serious AEs classified as of possibly or probably related to the IMP for 2 weeks or 
until the final outcome is determined, whichever comes first.
SAEs must be followed up until a final outcome has been established, that is, the follow-up may 
continue beyond the end of the clinical trial. For SAEs which have stabilised and from which the 
subject cannot be expected to recover during the trial or the safety follow-up periods, for 
example chronic or stabilised conditions, the final outcome should be reported as ‘not 
recovered’. In addition, a statement that the SAE has stabilised or is chronic should be added to 
the narrative description of the SAE on the SAE form.
Further information on follow-up procedures is given in Appendix 3.


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8.4.4
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours, see Appendix 3) by the investigator to LEO Pharma A/S of
an SAE is essential so that legal obligations and ethical responsibilities towards the safety of 
subjects and the safety of a trial treatment under clinical investigation are met.
LEO Pharma A/S 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. LEO Pharma 
A/S 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 LEO Pharma A/S will review and 
then file it along with the IB and SmPC of LEO 90100 and the SmPC of Daivobet® ointment,
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 LEO Pharma A/S
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 
Global Safety at LEO Pharma A/S. Contact details are given as described in Appendix 3.
Investigators will be notified of the evolving safety profile of the IMP on an ongoing basis.
8.4.5
Pregnancy
Details of all pregnancies in female subjects and partners of male subjects will be collected after 
the start of IMP and until 7 days after the last dose of IMP (or longer if appropriate according to 
local requirements) for partners of male subjects and 8 weeks after the last dose of IMP for 
female subjects.
Any pregnancy occurring after first exposure to IMP and until the subject has completed the trial 
must be reported to LEO Pharma A/S 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 A/S. Contact details are given in Appendix 3.


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Pregnant subjects 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., maternal serious complications, therapeutic abortion, 
spontaneous abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are 
considered to be SAEs and will be reported as such.
The subject/pregnant partner will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on the subject/pregnant partner and the neonate 
and the information will be forwarded to LEO Pharma A/S.
Any post-trial pregnancy-related SAE considered reasonably related to the IMP by the 
investigator will be reported to LEO Pharma A/S as described in Section 8.4.4. While the
investigator is not obligated to actively seek this information in former trial subjects/pregnant 
partners, he or she may learn of an SAE through spontaneous reporting.
Any female subject who becomes pregnant while participating in the study will discontinue IMP.
8.4.6
Other Events
8.4.6.1
Medication Errors
Medication error refers to any unintentional error in the dispensing or administration of an IMP.
Medication errors include accidental overdose or underdose, inappropriate schedule of product 
administration, incorrect route of product administration, wrong product administered and 
expired product administered.
Accidental overdose or underdose where a clinical consequence occurred or could have occurred 
should be recorded based on investigator judgement.
Inappropriate schedule of product administration where a clinical consequence occurred or could 
have occurred should be recorded based on investigator judgement.
Treatment non-compliance (including missed doses) where no clinical consequence occurred or 
could have occurred should not be recorded as medication errors. See Section 6.5 for recording 
of treatment compliance.
Medication error must be recorded on the other event involving IMP form in the eCRF. In 
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the AE form. If the AE originating from the medication error qualifies as an SAE, expedited 
reporting is required (see Appendix 3).
8.4.6.2
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 Appendix 3).
8.4.7
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 IMP where that new event is likely to affect the safety of the 
subjects, LEO Pharma A/S and the investigator shall take appropriate urgent safety measures to 
protect the subjects against any immediate hazard.” 21.
If the investigator becomes aware of information that requires an immediate change in a clinical 
trial procedure or a temporary halt of the clinical trial to protect clinical trial subjects from any
immediate hazard to their health and safety, the investigator can do so without prior approval 
from LEO Pharma A/S, regulatory authorities or IRBs/IECs.
The investigator must immediately inform the clinical project manager or medical monitor of the
designated CRO of this change in a clinical trial procedure or of the temporary halt; the 
investigator will provide full details of the information and the decision-making process leading 
to the implementation of the urgent safety measure.
LEO Pharma A/S must act immediately upon receipt of the urgent safety measure notification in 
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8.5
Pharmacokinetics
Pharmacokinetic parameters are not evaluated in this trial.
8.6
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this trial.
8.7
Genetics
Genetics are not evaluated in this trial.
8.8
Biomarkers
Biomarkers are not evaluated in this trial.
8.9
Immunogenicity Assessments
Immunogenicity is not evaluated in this trial.
8.10 Storage and Future Use of Biological Samples
Blood and urine samples are collected only for clinical laboratory tests in the trial (chemistry and 
urinalysis). The storage and destruction of these biological samples will therefore follow the 
standard operating procedures at the sites and laboratories where the tests are conducted.
8.11 Medical Resource Utilisation and Health Economics
Medical resource utilisation and health economics parameters are not evaluated in this trial.
9
Statistical Considerations
The SAP will be finalised as per ICH E9 requirements22. The SAP will include a more technical 
and detailed description of the statistical analyses described in this section. This section describes
the planned statistical analyses of the most important endpoints including primary, key 
secondary, secondary and 
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, depend on the 
type of change.
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9.1
Statistical Hypotheses
For the primary, key secondary and one secondary endpoints, superiority 2-sided hypotheses will 
be tested for LEO 90100 versus Daivobet® ointment, except for the primary endpoint “having 
PGA score of 0 (clear) or 1 (almost clear) at Day 29, with at least a 2-point reduction from 
baseline”, that will first be evaluated for non-inferiority (at threshold T= 
) and subsequently 
for superiority.
Let the treatment effect defined as odds ratio (OR), then:
x
For binary endpoints (non-inferiority): Ͳǣ൑ against ǣ൐.
x
For binary endpoints (superiority): Ͳǣ൑ͳ against ǣ൐ͳ.
9.1.1
Multiplicity Adjustment
The primary endpoint, the key secondary endpoint and the other secondary endpoint are included 
in a closing testing procedure with hierarchical tests will be used to control the overall type I 
error at nominal 2-sided 5% level. The hypothesis relating to a specific endpoint cannot be 
rejected unless all hypotheses earlier in the hierarchy are also rejected.
The confirmatory conclusions from the confirmatory testing strategy will be based on the results 
from the primary analyses of the primary estimands. The primary endpoint will first be evaluated
for non-inferiority and if the 95% confidence interval (CI) for the treatment effect (on the OR
scale) not only lies entirely above the non-inferiority threshold (T=
) but also above 1 then 
there is evidence of superiority in terms of statistical significance at the 2-sided 5% level.
In this case, it is acceptable to calculate the p-value associated with a test of superiority and 
evaluate whether this is sufficiently small (two-sided p-value<0.05) to reject the hypothesis of no 
difference. In the switch from non-inferiority to superiority there is no multiplicity argument that 
affects the interpretation because, in statistical terms, it corresponds to a simple closed test 
procedure.
The complete superiority testing scheme is described below and illustrated in Figure 9–1. If 
non-inferiority is confirmed the following 3 hypotheses will be tested sequentially:
x
No difference in the proportion of subjects with at least a 2-point PGA reduction from 
baseline having PGA score of 0 (clear) or 1 (almost clear) at Day 29 between LEO 90100 and 
Daivobet® ointment treatment.
x
No difference in the proportion of subjects having mPASI-75 at Day 29 between LEO 90100 
and Daivobet® ointment treatment.
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x
No difference in the proportion of subjects having mPASI-90 at Day 29 between LEO 90100 
and Daivobet® ointment treatment.
The trial is considered a success if non-inferiority is confirmed for the primary endpoint. The 
non-inferiority margin of 10% on the OR scale, is equivalent to a non-inferiority threshold of 
T=
.
Justification for non-inferiority margin of
 on the odds-ratio scale.
There is no guidelines nor meta-analysis that suggest non-inferiority margins when assessing 
PGA 0/1 or mPASI in the population to be studied in this trial. Therefore, the non-inferiority 
margin has been set based on the following general principles:
x
The non-inferiority margin should be on the same scale as the primary analysis 
(Odds-ratio).
x
The non-inferiority margin should not be too large. Here 
 is chosen as a conservative 
margin. The justification for 
 being conservative is that
o
For bioequivalence trials margins of 0.8-1.25 is usually applied.
o
Reaching the non-inferiority margin of 
 in example means: for LEO 90100 
having 170 responders in 300 subjects =56.7% and 154 in 300 subjects =51.3% 
for Daivobet ointment gives a crude odds-ratio of 1.23 with 95% CI of [
;1.7]. 
Therefore, on a population basis the difference in proportion of responders is in 
the neighborhood of 56.7% - 51.3% =5.3%, so approximately 10% relative to 
Daivobet ointment – but still with an odds-ratio of 1.23 in favor of LEO 90100.
Figure 9–1
Graphical Display of Closed Testing Procedure for Primary, Key 
Secondary and Secondary Endpoints
Abbreviations: mPASI=modified Psoriasis Area and Severity Index; PG=Physician’s Global Assessment.
9.2
Analysis Sets
For purposes of analyses, the following analysis sets are defined:
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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.
9.3.2
Disposition of Subjects
The reasons for permanent IMP discontinuation and for not completing the trial will be presented 
for all randomised subjects and by treatment group.
An overall summary of subject disposition will be presented for all randomised subjects. The 
disposition summary will include information on the number of randomised, exposed, included 
in the FAS, permanently discontinuing IMP and not completing the trial by treatment group and 
overall.
9.3.3
Demographic and Other Baseline Characteristics
Descriptive statistics of demographics and other baseline characteristics will be presented for all 
randomised subjects and by treatment group.
Demographics include age and sex. Other baseline characteristics include height, weight, body 
mass index, Fitzpatrick skin type, washout period, past and current medical history and prior and 
concomitant medication. In addition, the baseline scores, utilised to derive efficacy variables for 
the primary, key secondary and secondary endpoints will be summarised.
9.3.4
Exposure and Treatment Compliance
The duration of exposure to IMP in a specific week interval will be calculated as the number of 
days from date of first IMP administration in that period to the date of last IMP administration in 
that period, both days included.
Exposure to IMP will be presented for the safety analysis set as days of exposure per treatment
group.
The average weekly and total amount of IMP used will be presented for the safety analysis set
for each visit interval and for the total treatment period.
Treatment compliance will be presented for the safety analysis set for each treatment group.


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9.3.5
Estimand Strategy
9.3.5.1
General Considerations
The analysis of endpoints related to efficacy will be based on the FAS.
An intercurrent event (IE) refers to a post-randomisation event that affects either the 
interpretation or the existence of the measurements of an endpoint. For the purposes of this trial, 
the following 2 IEs are defined:
x
Permanent discontinuation of IMP not due to pandemic restrictions: This IE occurs 
when a subject permanently discontinues IMP for reasons not related to pandemic 
restrictions. This event can occur either at the subject’s own initiative or at the investigator or 
sponsor’s discretion. The timing of the event will be defined in the SAP. Permanent
discontinuation of IMP due to sickness with COVID-19 (an AE) will be interpreted as 
permanent discontinuation of IMP not due to pandemic restrictions.
x
Permanent discontinuation of IMP due to pandemic restrictions: This IE occurs when a 
subject permanently discontinues IMP for reasons related to pandemic restrictions. Examples 
of permanent discontinuation of IMP due to pandemic restrictions are quarantines (i.e., 
subjects who have or have a suspicion they have COVID-19 and are not allowed on to site 
for visits due to quarantine measures imposed), travel limitations, subject being unable or 
unwilling to travel to site due to personal pandemic-related reasons, site closures, reduced 
availability of site staff and interruptions to the supply chain of IMP. The timing of the event 
will be defined in the SAP. Permanent discontinuation of IMP due to sickness with 
COVID-19 (an AE) will not be interpreted as permanent discontinuation of IMP due to 
pandemic restrictions, unless caused by quarantine measures.
Note, there is a distinction between permanent discontinuation of IMP (an IE) and withdrawal 
from trial and/or lost to follow-up. Withdrawal from trial and lost to follow-up, which are not 
IEs, will be addressed when specifying methods and/or assumptions for handling missing data. If 
the withdrawal from trial is related to the pandemic restrictions, missing data will be handled as 
missing data related to the pandemic restrictions.
The death of a subject has not been described above as an IE since occurrences of this event is 
considered unlikely in the setting of this trial. Should it happen that a subject dies, then analyses 
will handle this using the same strategy as described below for addressing permanent 
discontinuation of IMP due to pandemic restrictions.


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The following strategies will be implemented for handling the IEs (ICH E9 [R1] guidelines23):
x
The ‘hypothetical’ strategy attempts to quantify the effect of treatment in the hypothetical 
situation where IEs do not occur.
x
The ‘treatment policy’ strategy attempts to quantify the effect of the decision to treat subjects
with the randomised treatment, thus ignoring the occurrence of IEs.
x
The ‘composite’ strategy accounts for the occurrence of IEs, through the definition of a 
suitable composite endpoint, whose components include the aforementioned IEs, as well as 
the endpoint of interest.
Depending on the strategy selected, the occurrence of an IE may lead to the exclusion of data 
observed after the occurrence of the event, be ignored, be accounted for in the definition of a 
composite endpoint or restrict the relevant observation window to the time prior to the 
occurrence of the IE.
For each efficacy endpoint associated with a trial objective, a primary estimand will be 
pre-specified. For the binary endpoints a secondary estimand will be used to further aid in the 
interpretation of the results (see Section 9.3.5.2 and Section 9.3.5.3).
The following primary and secondary estimands will be defined:
x
The primary estimand for binary endpoints will use a ‘composite’ strategy to handle IEs for 
subjects who have permanently discontinued IMP independently of pandemic restrictions 
prior to the Week 4 visit (Visit 4). Subjects will be imputed as non-responders, reflecting an 
assumption that permanent discontinuation of IMP independent of pandemic restrictions 
indicates failure of the randomised treatment to achieve response. A ‘hypothetical’ strategy, 
in the form of a multiple imputation method, will be used to address permanent 
discontinuation of IMP due to pandemic restrictions. For subjects who have permanently 
discontinued IMP due to pandemic restrictions prior to Week 4 (Visit 4) data collected after 
permanent discontinuation of IMP will be replaced by model-based predictions.
x
Differently from the primary estimand for the binary endpoints, the secondary estimand for 
binary endpoints will use “treatment policy” strategy to handle IEs for subjects who have 
permanently discontinued treatment independently of pandemic restrictions prior to the 
Week 4 visit (Visit 4). Data will be used as observed.
x
The primary estimand for continuous endpoints will use the same strategies applied for the 
secondary estimand for binary variables.


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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 
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9.3.5.2
Estimand Strategy for Binary Endpoints
Evaluation of non-inferiority as well as test of the null hypothesis that the response rate for the 
LEO 90100 arm is less than or equal to the rate for the Daivobet® ointment arm, against the 
alternative that LEO 90100 is superior to Daivobet® ointment, will be based on the Wald-type 
test statistic for the estimated treatment effect from a logistic regression model, adjusted for 
baseline PGA.
The main analysis is based on the following assumptions:
1. Missing data will be handled according to Table 9–2.
2. Use of prohibited medication and procedures will be assumed to have no influence on the 
endpoint of interest among subjects not discontinuing IMP.
For each of the imputed datasets, estimates of the treatment effect along with the associated 
standard errors will be kept on the log-scale. The pooled estimate of risk difference and OR at 
Week 4, along with the associated 95% CIs and nominal p-values will be presented based on 
applying Rubin’s rules to the estimates and standard errors from the logistic regression of the 
imputed data sets and transforming to the odds-scale. Details for multiple imputation and pooling 
methods will be described in the SAP.
Primary Analysis of the Primary Estimand
The purpose of ‘hypothetical’ strategy is to predict what value the estimands variable would take 
if the given subject would not permanently discontinue IMP due to pandemic restrictions, 
assuming a similar course of events as experienced by subjects from the same treatment arm who 
have not permanently discontinued IMP due to pandemic restrictions. With this purpose in mind 
2 questions naturally arise because of the composite strategy used to address permanent 
discontinuation of IMP independent of pandemic restrictions:
1. Would the subject still have been on treatment at Week 4 as opposed to having permanently 
discontinued IMP independently of pandemic restrictions beforehand?
2. If yes, would the subject have had binary response (0/1) with a 2-point reduction from 
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In practice, both of these hypothetical questions will be addressed, although in reverse order, by 
carrying out the following steps:
1. Under missing at random (MAR) assumption within treatment arm, binary response at 
Week 4 (or Week 2) will be imputed for subjects who have permanently discontinued IMP 
due to pandemic restrictions prior to Week 4 (or Week 2) and for subjects who have not 
permanently discontinued IMP prior to Week 4 (or Week 2) and whose score at Week 4 (or 
Week 2) is missing due to pandemic restrictions. Fully conditional specification (FCS) 
method will be implemented to impute missing binary responses by implementing logistic or 
regression methods (number of imputed datasets = 1000; seed = 2)24. FCS logistic regression 
will be implemented for the binary PGA and 
. FCS linear regression will be 
utilised to impute the mPASI score. Binary mPASI-75 and mPASI-90 will be derived from 
the imputed score. Response at Week 4 (or Week 2) will be imputed using the stratification 
PGA, the value baseline score value (not for PGA as it coincides with the randomisation 
strata) and response at the Week 2 visit (not applicable when imputing data for Week 2) as 
covariates.
2. Non-responder imputation will be applied for subjects who have not permanently 
discontinued IMP prior to Week 4 (or Week 2) and whose binary response at Week 4 (or 
Week 2) is missing for reasons other than pandemic restrictions.
3.  A logistic regression model will be implemented to estimate each subject’s probability of 
permanent discontinuation of IMP not due to pandemic restrictions up until Week 4 (Day 29) 
among subjects who permanently discontinued IMP due to pandemic restrictions. 
Stratification PGA, sex and age will be utilised as covariates. Using the subject predicted 
probability (pi) of discontinuation, the following steps will be followed to derive the 
treatment adherence variable:
a. For each imputed dataset, a value from the exponential distribution with rate piwill be 
drawn and multiplied with 29 to obtain days (starting seed = 3)
b. Person-days already spent in the trial will be added to the drawn number
c. Derive the treatment adherence variable with the following categorisation:
-
Days <15: subject discontinued before Week 2
-
15 ≤ Days < 29: subject discontinued after Week 2 and before Week 4
-
Days ≥ 29: the subject did not discontinue.
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rules to the estimates and standard errors from the ANCOVA analyses of the imputed data sets. 
Details for multiple imputation and pooling methods will be described in the SAP.
9.3.6
Primary Endpoint Analysis
The primary endpoint will be analysed following the estimand strategy for binary endpoints 
described in Section 9.3.5.2. The non-inferiority and superiority 2-sided hypothesis, described in 
Section 9.3.1, will be tested for LEO 90100 vs Daivobet® ointment based on the primary analysis 
for the primary estimand.
9.3.7
Secondary Endpoints Analysis
The binary key secondary and secondary endpoint will be analysed following the estimand 
strategy for binary endpoints described in Section 9.3.5.2. The superiority 2-sided hypothesis, 
described in Section 9.3.1, will be tested for LEO 90100 vs Daivobet® ointment based on the 
primary analysis for the primary estimand. Continuous secondary endpoints will be analysed 
following the estimand strategy for the continuous endpoints, as per Section 9.3.5.3.
9.3.8
The binary 
 (binary) will be analysed following the primary estimand 
strategy for binary endpoints described in Section 9.3.5.2. Continuous secondary endpoints will 
be analysed following the estimand strategy for the continuous endpoints, as per Section 9.3.5.3.
9.3.9
Safety Analyses
All safety analyses will be made on the safety analysis set.
9.3.9.1
AEs
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 subject data listings. An event will be considered treatment-emergent 
if it started after the first IMP administration or if it started before the first IMP administration 
and worsened in severity after the first IMP administration. 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.
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AEs will be summarised in terms of the number of subjects with at least 1 event, the percentage 
of subjects with at least 1 event, the number of events and the event rate per 100 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, AEs 
leading to withdrawal from trial and AEs leading to permanent IMP discontinuation. 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.
AEs leading to withdrawal from trial and AEs leading to permanent IMP discontinuation will be 
listed. The detailed listing will provide an overview of the individual cases and include the age 
and sex of the subject, treatment received at the time of AE onset, the AE preferred and reported 
terms, causality and severity of the AE, the action taken with the IMP, AE outcome, start and 
stop date of AE, duration of AE and number of days since first and last IMP administration. No 
narratives will be given.
The MedDRA search terms for AEs will be provided in the SAP.
Other events (medication error, misuse and abuse of IMP) will be tabulated and listed. No 
narratives will be given.
9.3.9.2
Physical Examination
For physical examination, abnormalities at baseline and end-of-treatment (or early termination)
as well as the transition from baseline to end-of-treatment (or early termination) will be 
summarised for each treatment group.
9.3.9.3
Clinical Safety Laboratory Tests
For laboratory parameters, the absolute values as well as the changes from baseline will be 
summarised by visit for each treatment group.


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A shift table will be produced for relevant parameters showing the categories at baseline against 
those at each post-baseline visit.
For subjects with post-baseline values, out of reference range events reported up to Week 6 will 
be summarised.
9.4
Interim Analyses
No interim analysis is planned during the trial.
9.5
Sample Size Determination
Data from the EU SmPC is used for the sample size calculation14. Table 9–5 shows results from 
a historical comparative trial on the “Percentage of subjects with 'treatment success' according to 
the PGA of the body at Week 4 (PGA 0/1)”. These data from the SmPC give a relative risk of 
1.27 and a crude OR of 1.59 in favour of LEO 90100.
Table 9–5
EU SmPC Trial Result
Data from SmPC
LEO 90100
Daivobet® ointment
Trial Three
(N=141) 54.6%
(N=135) 43.0%
Abbreviations: SmPC=Summary of Product Characteristics.
Table 9–6 illustrates the power with 600 subjects randomised 1:1. The probability of superiority 
and non-inferiority is found by running 10,000 simulations using the data from the EU SmPC. 
The responder probabilities are used in a binomial sampling of the number of subjects with 
treatment success. For each of the simulations, the OR with 95% CI limits is calculated using 
Fisher’s exact test and the lower 95% boundary is used to evaluate superiority and 
non-inferiority at the thresholds 1 and 
 respectively.
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Table 9–6
Simulated Power
Endpoint
Proportion 
responders for 
Daivobet®
ointment
Proportion 
responders for 
LEO 90100
Probability of 
superiority
Probability of 
non-inferiority 
with a NI 
margin OR=
Probability of 
point estimate 
for LEO 90100 
exceeds 
Daivobet®
ointment 
(OR > 1)
PGA 0/1 at 
Day 29
43.0%
54.6%
0.799
0.9198
0.9975
Abbreviations: NI=non-inferiority; OR=odds ratio; PGA=Physician’s Global Assessment of disease severity.
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10 Supporting Documentation and Operational Considerations
10.1 Appendix 1: Regulatory, Ethical and Study Oversight Considerations
10.1.1 Regulatory and Ethical Considerations
This trial will be conducted in accordance with the protocol and with:
x
Consensus ethical principles derived from international guidelines including the Declaration 
of Helsinki and Council for International Organizations of Medical Sciences (CIOMS) 
international ethical guidelines.
x
Applicable ICH GCP guidelines.
x
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 study 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 subjects.
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 study 
subjects.
The investigator will be responsible for the following, as applicable:
x
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.
x
Notifying the IRB/IEC of SAE or other significant safety findings as required by IRB/IEC 
procedures.
x
Overall conduct of the study at the site and adherence to requirements of the Code of Federal 
Regulations (CFR) Title 21, 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 LEO Pharma A/S with sufficient, accurate 
financial information in accordance with local regulations to allow LEO Pharma A/S 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 study 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 washout 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 subject and answer all questions regarding the trial.
Potential subjects must be informed that their participation is voluntary. Subject 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 subject 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.
Subjects must be re-consented to the most current version of the ICF(s) during their participation 
in the study.
A copy of the ICF(s) must be provided to the subject.
Subjects 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 subjects subsequently enrolled in the trial as well as those currently enrolled in the 
trial.


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10.1.4 Data Protection
Subjects will be assigned a unique identifier by LEO Pharma A/S. Any subject records or 
datasets that are transferred to LEO Pharma A/S will contain the identifier only; subject names or 
any information which would make the subject identifiable will not be transferred.
The subject must be informed that their personal study-related data will be used by LEO Pharma 
A/S in accordance with local data protection law. The level of disclosure must also be explained 
to the subject who will be required to give consent for their data to be used as described in the 
informed consent.
The subject must be informed that their medical records may be examined by Clinical Quality 
Assurance auditors or other authorised personnel appointed by LEO Pharma A/S, by appropriate 
IRB/IEC members and by inspectors from regulatory authorities.
10.1.5 Dissemination of Clinical Study Data
LEO Pharma A/S is committed to be transparent with respect to its clinical trials.
Basic information of this clinical trial will be registered in the global data registry, 
www.ClinicalTrials.gov. before the first subject enters the trial. The trial may also become 
registered in other online data registries, according to applicable law and regulations.
Results of this clinical trial will be posted on leopharmatrials.com in accordance with LEO 
Pharma A/S 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 subject data relating to the study will be recorded on printed or electronic CRFs unless
transmitted to LEO Pharma A/S 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 eCRFs will be provided in the eCRF Completion Guidelines.
The investigator must permit trial-related monitoring, audits, IRB/IEC review and Regulatory
Agency inspections and provide direct access to source documents.


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Monitoring details describing strategies, including definition of study 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.
LEO Pharma A/S or designee is responsible for the data management of this trial including 
quality checking of the data.
LEO Pharma A/S assumes accountability for actions delegated to other individuals (e.g., CROs).
Records and documents, including signed ICF, pertaining to the conduct of this study must be 
retained by the investigator for 25 years after trial completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during the 
retention period without the written approval of LEO Pharma A/S. No records may be 
transferred to another location or party without written notification to LEO Pharma A/S.
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 collection (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
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10.1.7 Source Documents
Source documents provide evidence for the existence of the subject 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 subjects 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 Study and Site Start and Closure
The trial start date is the date of the first subject’s first visit.
Trial/Site Termination
LEO Pharma A/S 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 LEO Pharma A/S. 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 LEO Pharma A/S or investigator may include but 
are not limited to:
For trial termination:
x
Discontinuation of further IMP development.
For site termination:


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x
Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC or 
local health authorities, the procedures of LEO Pharma A/S or GCP guidelines.
x
Inadequate or no recruitment (evaluated after a reasonable amount of time) of subjects by the 
investigator.
x
Total number of subjects included earlier than expected.
If the trial is prematurely terminated or suspended, LEO Pharma A/S shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities and any CRO(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 subject and should assure appropriate subject 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 database lock
(DBL). LEO Pharma A/S 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 LEO Pharma A/S to publish results that are not included in 
the primary publication. The investigator and LEO Pharma A/S should agree on terms for data 
sharing and collaboration on such publications, as well as timing for release of the publication(s). 
In all cases, LEO Pharma A/S retains the right to review and comment on the draft publication in 
due time before submission, but the investigator is not required to revise the draft accordingly, 
unless it discloses company confidential information or protected personal information, or may 
compromise intellectual property rights of LEO Pharma A/S.
LEO Pharma A/S may give researchers outside LEO Pharma A/S access to anonymised data 
from this trial for further research according to the principles outlined by the European 
Federation of Pharmaceutical Industries and Associations (EFPIA). In that case, the researchers 
are obliged to attempt publication of the results obtained from their analyses.
LEO Pharma A/S complies with Good Publication Practice (GPP3) standards and the 
recommendations from ICMJE.


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10.1.10Protocol 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. LEO 
Pharma A/S must ensure that all ethical and legal requirements have been met before the first 
subject 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 subject 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.
10.1.11Liability and Insurance
LEO Pharma A/S 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 LEO 
Pharma A/S 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.
LEO Pharma A/S 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.
10.1.11.1Access to Source Data
During the trial, a monitor will make site visits to review protocol compliance, compare eCRF 
entries and individual subject’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 subject confidentiality is maintained.
Checking 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 Clinical Quality Assurance group of LEO Pharma A/S 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 LEO 


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Pharma A/S, and Parexel if involved in monitoring/data management, of the necessary support at 
all times.




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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
AE Definition
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavourable and unintended sign 
(including an abnormal laboratory finding), symptom or disease temporally associated with the 
use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product (ICH E2A guidelines25).
This definition includes:
x
Accidental injuries.
x
Events related to trial procedures.
x
Reasons for any unfavourable and unplanned change in medication (drug and/or dose).
x
Clinically significant worsening of pre-existing conditions.
x
Reasons for admission to hospital or surgical procedures unless these were planned before 
the subject consented to trial participation.
x
AEs commonly observed and AEs anticipated based on the pharmacological effect of the 
IMP.
x
Any laboratory abnormality assessed as clinically significant by the investigator (see 
Section 8.3.2).
10.3.2 Definition of SAE
An SAE is any untoward medical occurrence that:
x
Results in death.
x
Is life-threatening, that is at risk of death at the time of the SAE (not an event that 
hypothetically might have caused death if more severe).
x
Requires in-patient hospitalisation or prolongation of existing hospitalisation*.
x
Results in persistent or significant disability or incapacity.


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x
Is a congenital anomaly or birth defect.
x
Is a medically important condition. Events that may not be immediately life-threatening or 
result in death or hospitalisation but may jeopardise the subject or may require treatment 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.
*Notes:
-
Hospitalisation for procedures or treatments planned prior to the subject consented to 
trial participation does not constitute an AE and should therefore not be reported as an 
AE or SAE.
-
Hospitalisation for elective treatment of a pre-existing condition which did not worsen 
from the subject is not considered an AE and should therefore not be reported as an AE 
or SAE, even if not planned before consent to trial participation.
-
Hospitalisation for routine scheduled treatment or monitoring of the studies indication 
not associated with any aggravation of the condition does not constitute an AE and 
should therefore not be reported as an AE or SAE.
-
Hospitalisation for administrative, trial-related or social purpose does not constitute an 
AE and should therefore not be reported as an AE or SAE.
-
Complications that occur during hospitalisation are (S)AEs. If a complication prolongs 
hospitalisation, the event is an SAE.
-
When in doubt as to whether hospitalisation occurred or was necessary, the AE should be 
considered serious.
Additionally, all malignancies, 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.
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 subject or observed by the investigator must be recorded on the AE form of 
the eCRF and should be described in the following manner:


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The AE term must be in precise English medical terminology (that is, not necessarily the exact 
words used by the subject). Whenever possible, a specific diagnosis should be stated (e.g.,
‘allergic contact dermatitis’).
For cutaneous AEs, the location must be part of the AE description and may be described as 
(e.g., the face, scalp, back, chest, arm, leg, trunk or limb). Additionally, the location should be 
described using the following terminology:
x
Lesional/perilesional (≤ 2 cm from the border of lesion [s] treated with the IMP).
x
Distant (> 2 cm from the border of lesions [s] treatment with the 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 IMP administration.
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 Intensity
The severity of the AE should be described in terms of mild, moderate or severe according to the 
investigator's clinical judgement. If the AE worsens in severity, the new severity including date 
of worsening, should be recorded. However, if an AE with onset prior to IMP initiation worsens 
after IMP administration, a new AE should be recorded:
x
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.
x
Moderate: An AE that is usually alleviated with additional specific therapeutic intervention. 
The event interferes with usual activities of daily living, causing discomfort, but poses no 
significant or permanent risk of harm to the subject.


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x
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 pre-defined 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 IMP 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 IMP administration will be considered and 
investigated.
The investigator will also consult the IB and SmPC for LEO 90100 and the SmPC for Daivobet®
ointment in their assessment13, 14, 15.
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 that 
the investigator always make an assessment of causality for every event before the initial 
transmission of the SAE data to 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:
x
Follows a reasonable temporal sequence from administration of the IMP.
x
Could not be reasonably explained by the subject’s clinical state, environmental or toxic 
factors or other therapies administered to the subject.
x
Follows a known pattern of response to the IMP.


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x
Disappears or decreases on cessation or reduction in dose of the IMP.
x
Reappears or worsens upon re-challenge.
Possibly related:
x
Follows a reasonable temporal sequence from the administration of the IMP.
x
Could also be reasonably explained by the subject’s clinical state, environmental or toxic 
factors or other therapies administered to the subject.
x
Follows a known pattern of response to the IMP.
Not related:
x
Does not follow a reasonable temporal sequence from administration of the IMP.
x
Is better explained by other factors like the subject’s clinical state, environmental or toxic 
factors or other therapies administered to the subject.
x
Does not reappear or worsen upon re-challenge.
x
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.
Recovering/resolving: The subject is clearly recovering from an event. The event is not yet 
completely resolved.
Not recovered/ not resolved: Event is still ongoing.
Recovered/ resolved with sequelae: The event has reached a state where no further changes are 
expected and the residual symptoms are assumed to persist. An example is hemiparesis after 
stroke.
The stop date of the event must be recorded. In case of an SAE, the sequelae should be specified.


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Fatal: The subject has died as a consequence of the event. Date of death is recorded as stop date 
for the AE.
Unknown: Unknown to investigator, e.g., subject lost to follow-up.
The definitions of LEO Pharma A/S versus Clinical Data Interchange Standards 
Consortium (CDISC) definitions: Note that as per the above definition, LEO Pharma A/S 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 definitions of LEO Pharma A/S above, such an improved event will instead be 
classified as ‘not recovered/not resolved’ or ‘recovering/resolving’.
Similarly, it should be noted that as per the above definition, LEO Pharma A/S uses 
‘recovered/resolved with sequelae’ only if an event has reached a state where the residual 
symptoms are assumed to persist. According to CDISC, an event is considered ‘with sequelae’, if 
it has ‘retained pathological conditions’. Consequently, it is likely that some of the events 
classified by LEO Pharma A/S with the outcome ‘recovered/resolved with sequelae’ could have 
been classified with the outcome ‘recovered/resolved’ according to the CDISC definition.
In summary, the definitions used by LEO Pharma A/S 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 LEO Pharma A/S to
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may include 
additional laboratory tests or investigations, histopathological examinations or consultation with 
other health care professionals.
If a subject dies during participation in the trial or during a recognised follow-up period, the 
investigator will provide LEO Pharma A/S 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 LEO Pharma A/S within 24 hours of 
receipt of the information.


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10.3.4 Reporting of SAE
Investigator Reporting Responsibilities
Any SAE must be reported to LEO Pharma A/S 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 A/S using the e-mail address or fax number below:
Global Safety at LEO Pharma A/S
E-mail address: drug.safety@leo-pharma.com
Fax number: +45 7226 3287
If relevant, the investigator will enclose other information with the SAE form, such as 
anonymised reports of diagnostic procedures, hospital records, autopsy reports, etc.
Additionally, Global Safety at LEO Pharma A/S may request further information in order to fully 
assess the SAE. The investigator must forward such information to LEO Pharma A/S upon
request by fax or e-mail (see contact details above).
The investigator must notify the local IRB(s)/IEC(s) of SAEs, as required by current applicable 
legislation for the concerned country.
SAEs occurring after the completion of the clinical trial should not be routinely sought or 
recorded. However, such events should be reported immediately without undue delay and no 
later than 24 hours of obtaining knowledge to Global Safety at LEO Pharma A/S (see contact 
details above) if the investigator becomes aware of them.


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LEO Pharma A/S Reporting Responsibilities
Global Safety at LEO Pharma A/S is responsible for assessing whether an SAE is expected. The 
relevant reference safety information documents for this clinical trial are:
For LEO 90100, the latest version of the IB and SmPC must be used13, 14.
For Daivobet® ointment, the latest version of the SmPC must be used15.
Global Safety at LEO Pharma A/S 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 LEO Pharma A/S, 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
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):
x
A postmenopausal state is defined as no menses for 12 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 12 months of 
amenorrhea, confirmation with more than one FSH measurement is required.
o
Females on HRT and whose menopausal status is in doubt will be required to use one of 
the nonestrogen hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment.
x
Permanent sterilisation methods (for the purpose of this study) 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 study entry.
Note: Documentation can come from the site personnel’s review of the subject’s medical 
records, medical examination or medical history interview.
x
If fertility is unclear (e.g., amenorrhea in athletes) and a menstrual cycle cannot be confirmed 
before first dose of IMP, additional evaluation should be considered.


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Woman of Nonchildbearing Potential (WONCBP)
Women in the following categories are considered WONCBP:
1. Premenopausal female with permanent infertility due to one of the following:
a. Documented hysterectomy;
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 subject’s medical 
records, medical examination or medical history interview.
2. Postmenopausal female:
a. A postmenopausal state is defined as no menses for 12 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 12 months of amenorrhea, confirmation with more than 
one FSH measurement is required.
ii.
Females on HRT and whose menopausal status is in doubt must discontinue HRT to 
allow confirmation of postmenopausal status before randomisation.






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10.5 Appendix 5: COVID-19 Pandemic Contingency Plan
Without compromising the safety of subjects and trial integrity, it is expected that efforts are 
made to secure attendance at sites for all visits, ensuring important efficacy and safety 
assessments for the trial.
If on-site visits are not possible due to local authority-issued preventive measures, the affected 
site will postpone screening and randomisation of new subjects until on-site visits can be 
conducted. For already randomised subjects, post-baseline visits can be done remotely via phone 
or video. At phone visits, no investigator assessments of efficacy can be done, but the following 
data will be collected remotely, according to the SoA (Table 1–1):
x
AE reporting.
x
Treatment compliance (daily completion in the paper diary).
x
Concomitant medication and concurrent procedures.
x
 
x
Urine pregnancy test. WOCBP will receive 1 extra urine pregnancy test at the randomisation 
visit to keep at home in case on-site visits become impossible during the trial. The subject 
will perform the test at home and inform the investigator about the result via phone 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 subject’s home together with IMP (see below) if needed.
x
Serum cortisol and serum and urine calcium and creatinine should continue to be monitored 
by a local laboratory, at the timepoints outlined in the SoA (Table 1–1).
In the eCRF, it will be recorded whether a visit or a given assessment was done on site, remotely 
or not done. If remotely or not done, it will be recorded if this was due to pandemic restrictions 
as defined in Section 9.3.5.1.
It will be at the discretion of the investigator to decide whether clinical laboratory samples are
considered necessary to ensure subject safety in periods when on-site visits are not possible.
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 subjects to continue IMP although they are not able to go to the 
trial site. If a subject will not be able to attend on-site visits due to the COVID-19 pandemic 
before running out of IMP, the trial site will ensure shipping of IMP to the subject’s home.
CCI


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If a subject is tested positive for COVID-19, the investigator will evaluate whether this is an AE 
that contraindicates further dosing, in which case the subject will permanently discontinue IMP
as described in Section 7.1.






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10.7 Appendix 6: Protocol Elements for Redaction
10.7.1 Information About Sponsor Signatory
Approval Statement for Sponsor Signatories:
Electronic signatures made within LEO Pharma A/S 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:
Head of Medical Department
Biostatistics Lead
Medical Lead, Medical Department
Medical Monitor Name and Contact Information will be provided separately.
PPD
PPD
PPD


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11 References
1
Hrehorow E, Salomon J, Matusiak L, Reich A, Szepietowski JC. Patients with 
psoriasis feel stigmatized. Acta Derm Venereol. 2012;92(1):67-72.
2
Krueger G, Koo J, Lebwohl M, Menter A, Stern RS, Rolstad T. The impact of 
psoriasis on quality of life: results of a 1998 National Psoriasis Foundation patient-
membership survey. Arch Dermatol. 2001;137(3):280-284.
3
Tan X, Feldman S, Balkrishnan R. Quality of life issues and measurement in patients 
with psoriasis. Targets and Therapy. 2012;2:13-23.
4
Committee on Psoriasis CSoD. Guideline for the diagnosis and treatment of psoriasis 
in China. Chin J Dermatol. 2019;52(4):223-230.
5
Gisondi P, Tessari G, Conti A, Piaserico S, Schianchi S, Peserico A, Giannetti A, 
Girolomoni G. Prevalence of metabolic syndrome in patients with psoriasis: a 
hospital-based case-control study. Br J Dermatol. 2007;157(1):68-73.
6
Griffiths CE, Barker JN. Pathogenesis and clinical features of psoriasis. Lancet. 
2007;370(9583):263-271.
7
Griffiths CE, Christophers E, Barker JN, Chalmers RJ, Chimenti S, Krueger GG, 
Leonardi C, Menter A, Ortonne JP, Fry L. A classification of psoriasis vulgaris 
according to phenotype. Br J Dermatol. 2007;156(2):258-262.
8
Langley RG, Krueger GG, Griffiths CE. Psoriasis: epidemiology, clinical features, 
and quality of life. Ann Rheum Dis. 2005;64 Suppl 2:ii18-23; discussion ii24-15.
9
Dubertret L, Mrowietz U, Ranki A, van de Kerkhof PC, Chimenti S, Lotti T, Schafer 
G. European patient perspectives on the impact of psoriasis: the EUROPSO patient 
membership survey. Br J Dermatol. 2006;155(4):729-736.
10
Rapp SR, Feldman SR, Exum ML, Fleischer AB, Jr., Reboussin DM. Psoriasis causes 
as much disability as other major medical diseases. J Am Acad Dermatol. 1999;41(3 
Pt 1):401-407.
11
Menter A, Korman NJ, Elmets CA, Feldman SR, Gelfand JM, Gordon KB, Gottlieb 
A, Koo JY, Lebwohl M, Lim HW, et al. Guidelines of care for the management of 
psoriasis and psoriatic arthritis. Section 3. Guidelines of care for the management and 
treatment of psoriasis with topical therapies. J Am Acad Dermatol. 2009;60(4):643-
659.
12
Nast A, Boehncke WH, Mrowietz U, Ockenfels HM, Philipp S, Reich K, Rosenbach 
T, Sammain A, Schlaeger M, Sebastian M, et al. S3 - Guidelines on the treatment of 
psoriasis vulgaris (English version). Update. J Dtsch Dermatol Ges. 2012;10 Suppl 
2:S1-95.


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13
Investigator brochure for LEO90100, Edition no. 11, dated 18 Mar 2022.
14
Summary of Product Characteristics for Enstilar®.
https://mri.cts-mrp.eu/Human/Downloads/DK_H_2478_001_FinalSPC.pdf
15
Summary of Product Characteristics for Daivobet®.
https://www.ema.europa.eu/en/documents/referral/daivobet-article-30-referral-
annexes-i-ii-iii_en.pdf
16
Bushnell DM, Martin ML, McCarrier K, Gordon K, Chiou CF, Huang X, Ortmeier B, 
Kricorian G. Validation of the Psoriasis Symptom Inventory (PSI), a patient-reported 
outcome measure to assess psoriasis symptom severity. J Dermatolog Treat. 
2013;24(5):356-360.
17
Levin C, Maibach HI. Topical corticosteroid-induced adrenocortical insufficiency: 
clinical implications. Am J Clin Dermatol. 2002;3(3):141-147.
18
Bourke JF, Mumford R, Whittaker P, Iqbal SJ, Le Van LW, Trevellyan A, 
Hutchinson PE. The effects of topical calcipotriol on systemic calcium homeostasis in 
patients with chronic plaque psoriasis. J Am Acad Dermatol. 1997;37(6):929-934.
19
World Health Organization. (1997). WHO model prescribing information : drugs 
used in skin diseases. World Health Organization.
https://apps.who.int/iris/handle/10665/41975. Published 2021. Accessed April 7, 
2022.
20
Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI)-a simple practical 
measure for routine clinical use. Clin Exp Dermatol. 1994;19(3):210-216.
21
European Parliament Union, European CoT. Directive 2001/20/EC of the European 
Parliament and of the Council of 4 April 2001 on the approximation of the laws, 
regulations and administrative provisions of the Member States relating to the 
implementation of Good Clinical Practice in the conduct of clinical trials on 
medicinal products for human use, 2001. (Ema ed. 2001).
22
ICH. International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use: Statistical Principles for Clinical Trials. E9, Step 4; 
05 Feb 1998.
23
ICH. International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use: Addendum on estimands and sensitivity analysis in 
clinical trials to the guidelines on statistical principles for clinical trials. E9 (R1), Step 
4; 20 Nov 2019.


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24
Berglund P and Heeringa SG. Multiple Imputation of Missing Data Using SAS. SAS 
Publishing; 2014.
25
ICH. International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use: Clinical Safety Data Management. Definitions and 
Standards for Expected Reporting (E2A), Step 4; 27 Oct 1994.


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Investigator Agreement Page
Declaration of the Principal or Global Coordinating Investigator
Title: A phase 3, randomised, investigator-blind, active-controlled, parallel group, multicentre
trial comparing the efficacy and safety of 4 weeks treatment with LEO 90100 and Daivobet®
ointment in adult Chinese subjects with stable plaque psoriasis
This trial protocol was subjected to critical review and has been approved by LEO Pharma A/S.
The information it contains is consistent with the current risk/benefit evaluation of the 
investigational product as well as with the moral, ethical, and scientific principles governing 
clinical research as set out in the Declaration of Helsinki, and the guidelines on GCP.
Principal Coordinating Investigator
_____________________________________
_____________________
Signature Date
_____________________________________
Name (block letters)
_____________________________________
Title (block letters)
_____________________________________
Institution (block letters)
_____________________________________
Phone number


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Declaration of the National Coordinating Investigator
Title: A phase 3, randomised, investigator-blind, active-controlled, parallel group, multicentre
trial comparing the efficacy and safety of 4 weeks treatment with LEO 90100 and Daivobet®
ointment in adult Chinese subjects with stable plaque psoriasis
This trial protocol was subjected to critical review and has been approved by LEO Pharma A/S.
The information it contains is consistent with the current risk/benefit evaluation of the 
investigational product as well as with the moral, ethical, and scientific principles governing 
clinical research as set out in the Declaration of Helsinki, and the guidelines on GCP.
National Coordinating Investigator
_____________________________________
_____________________
Signature Date
_____________________________________
Name (block letters)
_____________________________________
Title (block letters)
_____________________________________
Institution (block letters)
_____________________________________
Phone number


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Declaration of the Investigator
Title: A phase 3, randomised, investigator-blind, active-controlled, parallel group, multicentre 
trial comparing the efficacy and safety of 4 weeks treatment with LEO 90100 and Daivobet®
ointment in adult Chinese subjects with stable plaque psoriasis
All documentation for this trial that is supplied to me and that has not been previously published 
will be kept in the strictest confidence. This documentation includes this trial protocol, eCRF, 
and other scientific data.
The study will not be commenced without the prior written approval of a properly constituted 
IRB or IEC. No changes will be made to the study protocol without the prior written approval of 
LEO Pharma A/S and the IRB or IEC, except where necessary to eliminate an immediate hazard
to the subjects.
I have read and understood and agree to abide by all the conditions and instructions contained in 
this protocol.
Responsible investigator of the Local Trial Site
_____________________________________
_____________________
Signature Date
_____________________________________
Name (block letters)
_____________________________________
Title (block letters)
_____________________________________
Institution (block letters)
_____________________________________
Phone number


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TMF-000792251 - Version
3. 0
PPD
PPD
PPD
PPD
PPD
PPD







SAP_001.pdf: 
 
 
 
 
 
 
 
 
 
 
Cover Page 
 
 
Study title: A Phase 3, Randomised, Investigator-blind, Active-controlled, Parallel Group, Multicentre 
Trial Comparing the Efficacy and Safety of 4-weeks Treatment With LEO 90100 and Daivobet® Oint-
ment in Adult Chinese Subjects With Stable Plaque Psoriasis 
LEO Pharma number: LP0053-2277 
NCT number: NCT05919082 
Date: 29-Mar-2024 
 


Parexel International
LEO Pharma A/S
LP0053-2277
Statistical Analysis Plan
Project Document Version No.:2.0; Document Effective Date:  29Mar2024
TP-GDO-WW-016-09
Effective Date:  22 Dec 21
Related to:  SOP-GDO-WW-019
Page 1 of 51
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001
LEO Pharma A/S
LP0053-2277
A phase 3, randomised, investigator-blind, active controlled, parallel group, multicentre trial comparing 
the efficacy and safety of 4 weeks treatment with LEO 90100 and Daivobet® ointment in adult Chinese 
subjects with stable plaque psoriasis
Statistical Analysis Plan
Version: 2.0
Parexel Project Number: 274109


Parexel International
Statistical Analysis Plan
Project Document Version No.: 2.0; Document Effective Date:  29Mar2024
TP-GDO-WW-016-09
Effective Date:  22 Dec 21
Related to:  SOP-GDO-WW-019
Page 2 of 51
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001
Sponsor Signature Page 
This document has been approved and signed electronically on the final page by the 
following:
Approved by:
_________________________
_______________
Date
,
Biostatistical Lead
LEO Pharma A/S
PPD
PPD




Parexel International
LEO Pharma A/S
LP0053-2277
Statistical Analysis Plan
Project Document Version No.: 2.0; Document Effective Date:  29Mar2024
TP-GDO-WW-016-09
Effective Date:  22 Dec 21
Related to:  SOP-GDO-WW-019
Page 4 of 51
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001
Table of Contents 
Sponsor Signature Page ................................................................................................................2 
Parexel Signature Page .................................................................................................................3 
Table of Contents...........................................................................................................................4 
Version History..............................................................................................................................6 
1. 
Introduction....................................................................................................................7 
1.1. 
Objectives, Endpoints, and Estimands.............................................................................7 
1.1.1. 
Primary objective, related endpoints and primary estimands...........................................7 
1.1.2. 
Secondary and 
 objectives and endpoints ......................................................9 
1.2. 
Study Design ....................................................................................................................9 
2. 
Statistical Hypotheses ..................................................................................................12 
2.1. 
Multiplicity Adjustment.................................................................................................12 
3. 
Analysis Sets..................................................................................................................14 
4. 
Statistical Analyses.......................................................................................................15 
4.1. 
General Considerations ..................................................................................................15 
4.1.1. 
Statistics Presentation.....................................................................................................15 
4.1.2. 
Baseline Definition.........................................................................................................16 
4.1.3. 
Study Day.......................................................................................................................16 
4.1.4. 
Randomisation Strata .....................................................................................................17 
4.1.5. 
Estimand Strategy...........................................................................................................17 
4.2. 
Primary Endpoint Analysis ............................................................................................25 
4.2.1. 
Definition of Endpoint(s) ...............................................................................................25 
4.2.2. 
Analytical Approach.......................................................................................................25 
4.3. 
Secondary Endpoint Analysis ........................................................................................25 
4.3.1. 
Key Secondary Endpoint................................................................................................25 
4.3.2. 
Secondary Endpoint .......................................................................................................26 
4.4. 
......................................................................................................26 
4.5. 
Safety Analyses..............................................................................................................27 
4.5.1. 
Extent of Exposure .........................................................................................................27 
4.5.2. 
Adverse Events...............................................................................................................28 
4.5.3. 
Additional Safety Assessments ......................................................................................31 
4.6. 
Other Analyses ...............................................................................................................32 
4.6.1. 
Other Variables and/or Parameters.................................................................................32 
4.6.2. 
Subgroup Analyses.........................................................................................................32 
4.6.3. 
Pharmacokinetics, Pharmacokinetic-Pharmacodynamic 
Relationships ..................................................................................................................32 
4.7. 
Interim Analysis ............................................................................................................32 
4.8. 
Changes to Protocol-planned Analyses..........................................................................32 
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LEO Pharma A/S
LP0053-2277
Statistical Analysis Plan
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Related to:  SOP-GDO-WW-019
Page 5 of 51
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001
5. 
Sample Size Determination .........................................................................................33 
6. 
Supporting Documentation .........................................................................................34 
6.1. 
Appendix 1: List of Abbreviations.................................................................................35 
6.2. 
Appendix 2: Supporting Study Information...................................................................36 
6.2.1. 
Disposition of Subjects...................................................................................................36 
6.2.2. 
Demographics.................................................................................................................36 
6.2.3. 
Baseline and Disease Characteristics .............................................................................37 
6.2.4. 
Treatment Compliance ...................................................................................................38 
6.2.5. 
Protocol Deviations ........................................................................................................38 
6.2.6. 
Medical History and Concurrent Illnesses .....................................................................38 
6.2.7. 
Prior/Concomitant Medications and Procedures............................................................39 
6.3. 
Appendix 3: Data Handling Conventions ......................................................................40 
6.3.1. 
Analysis Visit Windows.................................................................................................40 
6.3.2. 
Missing Date Imputation................................................................................................40 
6.3.3. 
Multiple Imputation and Rubin’s Rule...........................................................................41 
6.4. 
Appendix 4: Schedule of Assessments...........................................................................43 
6.5. 
Appendix 5: Efficacy Assessments................................................................................46 
6.5.1. 
PGA................................................................................................................................46 
6.5.2. 
................................................................................................................................47 
6.5.3. 
mPASI ............................................................................................................................47 
6.5.4. 
................................................................................................................................49 
6.5.5. 
..............................................................................................................................49 
6.5.6. 
..................................................................................................................................49 
7. 
References .....................................................................................................................51 
CCI
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CCI
CCI


Parexel International
LEO Pharma A/S
LP0053-2277
Statistical Analysis Plan
Project Document Version No.: 2.0; Document Effective Date:  29Mar2024
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Related to:  SOP-GDO-WW-019
Page 6 of 51
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001
Version History 
SAP 
Version
Date
Change
Rationale
1.0
01Dec2023
Not applicable
Original version
1.1
20Dec2023
Minor
Remove coding of light therapy 
(section 6.2.3).
Specify 2 additional decimal places 
to present SD (section 4.1.1).
1.2
02Feb2024
Major
Add description of estimand 
strategy when there are few subjects 
with an IMP discontinuation due to 
pandemic restriction (section 4.1.5).
Specify both baseline PGA strata 
and baseline value of the endpoint 
as covariate in logistic and 
ANCOVA model (section 4.1.5).
Update SAS sample code (section 
6.3.3).
1.3
29Feb2024
Minor
Update wording of estimand 
strategy (section 4.1.5) and add the 
updates to section 4.8.
Change summary of lab results out
of reference range from “events 
reported up to week 6” to “events 
reported up to end of study” 
(section 4.5.3.1) and add the 
updates to section 4.8.
1.4
13Mar2024
Minor
Update wording of estimand 
strategy (section 4.1.5).
Record the change of adding
baseline score value to logistic 
regression in section 4.8.
2.0
29Mar2024
Minor
Wording updates.


Parexel International
LEO Pharma A/S
LP0053-2277
Statistical Analysis Plan
Project Document Version No.: 2.0; Document Effective Date:  29Mar2024
TP-GDO-WW-016-09
Effective Date:  22 Dec 21
Related to:  SOP-GDO-WW-019
Page 7 of 51
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001
1.
Introduction 
This trial is conducted to assess efficacy and safety of LEO 90100 when used on the body for the 
treatment of stable plaque psoriasis in adult Chinese subjects, compared to Daivobet® ointment, 
which is approved in China for the treatment of stable plaque psoriasis on the body.
The Statistical Analysis Plan (SAP) details the statistical methodology to be used in analysing 
study data and outlines the statistical programming specifications for the Tables, Figures and 
Listings (TFLs). It describes the variables and populations, anticipated data transformations and 
derivations and other details of the analyses not provided in the Clinical Study Protocol (CSP). In 
case of discrepancies between CSP and SAP (Section 4.8), the SAP supersedes the CSP.
The SAP will be finalized prior to Database Lock (DBL). The analyses described in this SAP are 
based upon the following study documents:
x
Clinical Study Protocol, Version 3.0 (November 9th, 2022)
x
electronic Case Report Form (eCRF), Version 3.0 (November 2nd, 2023)
1.1.
Objectives, Endpoints, and Estimands 
1.1.1.
Primary objective, related endpoints and primary estimands 






Parexel International
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Statistical Analysis Plan
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Page 10 of 51
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001
x
A treatment period up to 4 weeks (3 visits);
x
A safety follow-up period of 2 weeks (1 visit for all subjects 2 weeks after the last IMP 
administration).
The subjects will provide written consent according to national laws and regulations before any 
trial-related activities are carried out.
Washout/Screening Period
For subjects who have been receiving prohibited medications prior to screening, the screening 
period may be extended up to 4 weeks to ensure they complete the required washout period 
before they start receiving the IMP. On completion of the washout period, confirmation of the 
subject’s ongoing eligibility for the trial will be made at Day 1 (baseline). However, if no 
washout is needed the subject will enter Day 1 (baseline) directly.
Treatment Period
The treatment period will last for up to 4 weeks and includes 3 visits: Visit 2 (Day 1), Visit 3 
(Week 2) and Visit 4 (Week 4). The start of IMP treatment will be at Day 1 and this visit will be 
considered as baseline. The first application of the IMP will be made at site under supervision and 
instruction of an unblinded member of the trial staff (not the investigator, as this is an 
investigator-blinded trial) at the Day 1 visit. The subjects also have the option to apply the first 
IMP at home after the instruction has been given at the site. 
Follow-up Period
The follow-up visit (Visit 5) will be performed at Week 6, which is 2 weeks after the last visit in 
the treatment period.
The trial design is illustrated in Figure 1-1 and visit schedule is provided in Appendix 4.


Parexel International
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Statistical Analysis Plan
Project Document Version No.: 2.0; Document Effective Date:  29Mar2024
TP-GDO-WW-016-09
Effective Date:  22 Dec 21
Related to:  SOP-GDO-WW-019
Page 11 of 51
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001
Figure 1-1
Trial Design
Abbreviations: N=number of subjects; No.=number; w=weeks.


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LP0053-2277
Statistical Analysis Plan
Project Document Version No.: 2.0; Document Effective Date:  29Mar2024
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Page 12 of 51
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001
2.
Statistical Hypotheses 
The primary endpoint will first be evaluated for non-inferiority (at threshold T=
) and 
subsequently superiority 2-sided hypotheses will be tested for LEO90100 versus Daivobet®
ointment.
The key secondary and one secondary endpoints will be evaluated for superiority 2-sided for 
LEO 90100 versus Daivobet® ointment.
Treatment effect will be defined as odds ratio (OR), and binary endpoints will be tested as 
follows for:
x
Non-inferiority: Ͳǣ൑ against ǣ൐.
x
Superiority: Ͳǣ൑ͳ against ǣ൐ͳ.
2.1.
Multiplicity Adjustment 
The primary endpoint, the key secondary endpoint and the other secondary endpoint are included 
in a closing testing procedure with hierarchical tests will be used to control the overall type I error 
at nominal 2-sided 5% level. The hypothesis relating to a specific endpoint cannot be rejected 
unless all hypotheses earlier in the hierarchy are also rejected.
The confirmatory conclusions from the confirmatory testing strategy will be based on the results 
from the primary analyses of the primary estimands. The primary endpoint will first be evaluated 
for non-inferiority and if the 95% confidence interval (CI) for the treatment effect (on the OR 
scale) not only lies entirely above the non-inferiority threshold (T=
) but also above 1 then 
there is evidence of superiority in terms of statistical significance at the 2-sided 5% level.
In this case, it is acceptable to calculate the p-value associated with a test of superiority and 
evaluate whether this is sufficiently small (two-sided p-value<0.05) to reject the hypothesis of no 
difference. In the switch from non-inferiority to superiority there is no multiplicity argument that 
affects the interpretation because, in statistical terms, it corresponds to a simple closed test 
procedure.
The complete superiority testing scheme is described below and illustrated in Figure 2-1. If 
non-inferiority is confirmed the following 3 hypotheses will be tested sequentially:
CCI
CCI


Parexel International
LEO Pharma A/S
LP0053-2277
Statistical Analysis Plan
Project Document Version No.: 2.0; Document Effective Date:  29Mar2024
TP-GDO-WW-016-09
Effective Date:  22 Dec 21
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Page 13 of 51
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001
x
No difference in the proportion of subjects with at least a 2-point PGA reduction from 
baseline having PGA score of 0 (clear) or 1 (almost clear) at Day 29 between LEO 90100 and 
Daivobet® ointment treatment.
x
No difference in the proportion of subjects having mPASI-75 at Day 29 between LEO 90100 
and Daivobet® ointment treatment.
x
No difference in the proportion of subjects having mPASI-90 at Day 29 between LEO 90100 
and Daivobet® ointment treatment.
The trial is considered a success if non-inferiority is confirmed for the primary endpoint. The 
non-inferiority margin of 10% on the OR scale, is equivalent to a non-inferiority threshold of 
T=
.
Figure 2–1
Graphical Display of Closed Testing Procedure for Primary, Key 
Secondary and Secondary Endpoints
Abbreviations: mPASI=modified Psoriasis Area and Severity Index; PGA=Physician’s Global Assessment.
CCI




Parexel International
LEO Pharma A/S
LP0053-2277
Statistical Analysis Plan
Project Document Version No.: 2.0; Document Effective Date:  29Mar2024
TP-GDO-WW-016-09
Effective Date:  22 Dec 21
Related to:  SOP-GDO-WW-019
Page 15 of 51
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001
4.
Statistical Analyses 
4.1.
General Considerations 
4.1.1.
Statistics Presentation 
Statistical analysis and generation of tables, figures, study subjects data listings, and statistical 
output will be performed using SAS software (SAS Institute, Cary NC), version 9.3 or later.
An observed-cases approach will be used for tabulations of data by visit (that is, involving only 
those subjects who attended each specific visit).
Descriptive statistics will be displayed to provide an overview of the study results. For 
continuous variables, descriptive statistics will include number of study subjects with available 
measurements (n), mean, standard deviation (SD), median, upper quartile (Q1), lower quartile 
(Q3), minimum, and maximum.
For categorical variables, the number and percentage of study subjects in each category will be 
presented. Unless otherwise noted, the denominator for percentages will be based on the number 
of study subjects included in the respective analysis set. 
Percentages will be presented to 1 decimal place. If the percentage is 100%, a decimal will not be 
presented. If the count is 0, the percentage will not be presented. Typically, the % sign will be 
presented in the column header, but not with each individual value.
For the purpose of the tabulations, the lower and upper confidence limits for the percentages will
be truncated at 0 and 100% respectively.
Decimal places for descriptive statistics will be subject to the following rules:
x
“n” will be an integer.
x
Mean, Q1, median and Q3 will use 1 additional decimal place compared to the original 
data.
x
SD will use 2 additional decimal places compared to the original data.
x
Minimum and maximum will have the same number of decimal places as the original 
value.


Parexel International
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LP0053-2277
Statistical Analysis Plan
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Page 16 of 51
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001
Derived variables in general will display the mean, SD, median, Q1 and Q3 to 1 more decimal 
place than the variables used in the derivation. If the number of decimal places reported in the 
raw data is varied then use either the maximum raw number of reported decimal places or 3, 
whichever is the lowest, as a guide for the descriptive statistics.
Significance tests will be 2-sided using the 5% significance level. All CIs will be presented with 
95% degree of confidence, unless otherwise specified.
Statistical tests of efficacy variables will be presented as 2-sided p-values rounded to 4 decimal 
places. P-values less than 0.0001 will be presented as “<0.0001” and p-values greater than 0.9999 
will be presented as “>0.9999”.
4.1.2.
Baseline Definition 
Baseline measurements will be defined as the latest available observation at or prior to the date of 
randomisation.
Scheduled assessments taken on the same day as randomisation will be assumed as prior to 
randomisation. If the unscheduled assessment is recorded on the same day as randomisation, the 
unscheduled assessment will be assumed to be post-randomisation, unless there is clear evidence 
showing that the assessment is prior to randomisation.
4.1.3.
Study Day 
Study Day will be calculated from the randomisation date or the first IMP administration date,
whichever occurs first. Study day of the randomisation or the first IMP administration date will be 
Day 1. 
x
If the date of interest is on or after the randomisation date, then:
Study Day = [date of assessment/interest – minimum (randomisation date, first IMP 
administration date)] + 1
x
If the date of interest is prior to the randomisation date, then:
Study Day = [date of assessment/interest – minimum (randomisation date, first IMP 
administration date)]
When the date of assessment/interest is partial or missing, study day will not be calculated, unless 
otherwise specified.


Parexel International
LEO Pharma A/S
LP0053-2277
Statistical Analysis Plan
Project Document Version No.: 2.0; Document Effective Date:  29Mar2024
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Effective Date:  22 Dec 21
Related to:  SOP-GDO-WW-019
Page 17 of 51
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001
4.1.4.
Randomisation Strata 
The randomisation will be stratified by PGA at baseline:
x
Mild (PGA=2)
x
Moderate (PGA=3)
x
Severe (PGA=4)
In statistical analyses where strata are included, the stratification factors will be included as
collected in the Interactive Web Response System (IWRS) at randomisation. If a subject is 
stratified incorrectly, “actual stratum” will be used rather than “randomised stratum”.
4.1.5.
Estimand Strategy 
4.1.5.1.
General Considerations 
The analysis of endpoints related to efficacy will be based on the FAS.
An intercurrent event (IE) refers to a post-randomisation event that affects either the 
interpretation or the existence of the measurements of an endpoint. For the purposes of this trial, 
the following 2 IEs are defined:
x
Permanent discontinuation of IMP not due to pandemic restrictions: This IE occurs when 
a subject permanently discontinues IMP for reasons not related to pandemic restrictions. This 
event can occur either at the subject’s own initiative or at the investigator or sponsor’s 
discretion. The timing of the event will be the date following the date of last IMP
administration. Permanent discontinuation of IMP due to sickness with COVID-19 (an AE) 
will be interpreted as permanent discontinuation of IMP not due to pandemic restrictions.


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Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001
x
Permanent discontinuation of IMP due to pandemic restrictions: This IE occurs when a 
subject permanently discontinues IMP for reasons related to pandemic restrictions. Examples 
of permanent discontinuation of IMP due to pandemic restrictions are quarantines (i.e., 
subjects who have or have a suspicion they have COVID-19 and are not allowed on to site for 
visits due to quarantine measures imposed), travel limitations, subject being unable or 
unwilling to travel to site due to personal pandemic-related reasons, site closures, reduced 
availability of site staff and interruptions to the supply chain of IMP. The timing of the event 
will be the date following the date of last IMP administration. Permanent discontinuation of 
IMP due to sickness with COVID-19 (an AE) will not be interpreted as permanent 
discontinuation of IMP due to pandemic restrictions, unless caused by quarantine measures.
Note, there is a distinction between permanent discontinuation of IMP (an IE) and withdrawal 
from trial and/or lost to follow-up. Withdrawal from trial and lost to follow-up, which are not IEs,
will be addressed when specifying methods and/or assumptions for handling missing data. If the 
withdrawal from trial is related to the pandemic restrictions, missing data will be handled as 
missing data related to the pandemic restrictions.
The death of a subject has not been described above as an IE since occurrences of this event is 
considered unlikely in the setting of this trial. Should it happen that a subject dies, then analyses 
will handle this using the same strategy as described below for addressing permanent 
discontinuation of IMP due to pandemic restrictions.
The following strategies will be implemented for handling the IEs (ICH E9 [R1] guidelines[2]):
x
The ‘hypothetical’ strategy attempts to quantify the effect of treatment in the hypothetical 
situation where IEs do not occur.
x
The ‘treatment policy’ strategy attempts to quantify the effect of the decision to treat subjects 
with the randomised treatment, thus ignoring the occurrence of IEs.
x
The ‘composite’ strategy accounts for the occurrence of IEs, through the definition of a 
suitable composite endpoint, whose components include the aforementioned IEs, as well as 
the endpoint of interest.
Depending on the strategy selected, the occurrence of an IE may lead to the exclusion of data 
observed after the occurrence of the event, be ignored, be accounted for in the definition of a 


Parexel International
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Page 19 of 51
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001
composite endpoint or restrict the relevant observation window to the time prior to the occurrence 
of the IE.
Prior to DBL, IE of permanent discontinuation of IMP due to pandemic restriction and missing 
data due to pandemic restriction were not observed among all subjects. Therefore, all estimand 
analyses will be based on the strategy of having only IE and missing data not due to pandemic 
restriction.
For each efficacy endpoint associated with a trial objective, a primary estimand will be 
pre-specified. For the binary endpoints a secondary estimand will be used to further aid in the 
interpretation of the results (see Section 4.1.5.2 and Section 4.1.5.3).
The following primary and secondary estimands will be defined:
x
The primary estimand for binary endpoints will use a ‘composite’ strategy to handle IEs for 
subjects who have permanently discontinued IMP independently of pandemic restrictions 
prior to the Week 4 visit (Visit 4). Subjects will be imputed as non-responders, reflecting an 
assumption that permanent discontinuation of IMP independent of pandemic restrictions 
indicates failure of the randomised treatment to achieve response. A ‘hypothetical’ strategy,
in the form of a multiple imputation method (see Appendix 6.3.2.1), will be used to address 
permanent discontinuation of IMP due to pandemic restrictions. For subjects who have 
permanently discontinued IMP due to pandemic restrictions prior to Week 4 (Visit 4) data 
collected after permanent discontinuation of IMP will be replaced by model-based 
predictions.
x
Differently from the primary estimand for the binary endpoints, the secondary estimand for 
binary endpoints will use “treatment policy” strategy to handle IEs for subjects who have 
permanently discontinued treatment independently of pandemic restrictions prior to the 
Week 4 visit (Visit 4). Data will be used as observed.
x
The primary estimand for continuous endpoints will use the same strategies applied for the 
secondary estimand for binary variables.
The occurrence of IEs will be listed and summarised by treatment group. Table 4-1 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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Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001
4.1.5.2.
Estimand Strategy for Binary Endpoints 
Evaluation of non-inferiority as well as superiority for LEO 90100 versus Daivobet® ointment
will be based on the Wald-type test statistic for the estimated treatment effect from a logistic 
regression model, adjusted for baseline PGA.
The main analysis is based on the following assumptions:
1. Missing data will be handled according to Table 4-1. 
2. Use of prohibited medication and procedures will be assumed to have no influence on the 
endpoint of interest among subjects not discontinuing IMP.
For each of the imputed datasets, estimates of the treatment effect along with the associated 
standard errors will be kept on the log-scale. The pooled estimate of risk difference and OR at 
Week 4, along with the associated 95% CIs and nominal p-values will be presented based on 
applying Rubin’s rules to the estimates and standard errors from the logistic regression of the 
imputed data sets and transforming to the odds-scale. 
The logistic regression will include both baseline PGA and the baseline score value of the 
endpoint (eg, continuous mPASI, 
category) for binary endpoints other than PGA.
Primary Analysis of the Primary Estimand
The purpose of ‘hypothetical’ strategy is to predict what value the estimands variable would take 
if the given subject would not permanently discontinue IMP due to pandemic restrictions, 
assuming a similar course of events as experienced by subjects from the same treatment arm who 
have not permanently discontinued IMP due to pandemic restrictions. With this purpose in mind 
2 questions naturally arise because of the composite strategy used to address permanent 
discontinuation of IMP independent of pandemic restrictions:
1. Would the subject still have been on treatment at Week 4 as opposed to having permanently 
discontinued IMP independently of pandemic restrictions beforehand?
2. If yes, would the subject have had binary response (0/1) with a 2-point reduction from 
baseline at Week 4?
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In practice, both of these hypothetical questions will be addressed, although in reverse order, by 
carrying out the following steps:
1. Under missing at random (MAR) assumption within treatment arm, binary response at 
Week 4 (or Week 2) will be imputed for subjects who have permanently discontinued IMP 
due to pandemic restrictions prior to Week 4 (or Week 2) and for subjects who have not 
permanently discontinued IMP prior to Week 4 (or Week 2) and whose score at Week 4 (or 
Week 2) is missing due to pandemic restrictions. Fully conditional specification (FCS) 
method will be implemented to impute missing binary responses by implementing logistic or 
regression methods (number of imputed datasets = 1000; seed = 2)[3]. FCS logistic regression 
will be implemented for the binary PGA and 
endpoints. FCS linear regression will be 
utilised to impute the mPASI score. Binary mPASI-75 and mPASI-90 will be derived from the 
imputed score. Response at Week 4 (or Week 2) will be imputed using the stratification PGA, 
the value baseline score value (not for PGA as it coincides with the randomisation strata) and 
response at the Week 2 visit (not applicable when imputing data for Week 2) as covariates.
2. Non-responder imputation will be applied for subjects who have not permanently 
discontinued IMP prior to Week 4 (or Week 2) and whose binary response at Week 4 (or 
Week 2) is missing for reasons other than pandemic restrictions.
3.  A logistic regression model will be implemented to estimate each subject’s probability of 
permanent discontinuation of IMP not due to pandemic restrictions up until Week 4 (Day 29) 
among subjects who permanently discontinued IMP due to pandemic restrictions. 
Stratification PGA, sex and age will be utilised as covariates. Using the subject predicted 
probability (pi) of discontinuation, the following steps will be followed to derive the treatment 
adherence variable:
a. For each imputed dataset, a value from the exponential distribution with rate piwill be 
drawn and multiplied with 29 to obtain days (starting seed = 3)
b. Person-days already spent in the trial will be added to the drawn number
c. Derive the treatment adherence variable with the following categorisation:
-
Days <15: subject discontinued before Week 2
-
15 ≤ Days < 29: subject discontinued after Week 2 and before Week 4
-
Days ≥ 29: the subject did not discontinue.
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Page 25 of 51
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001
Each of the imputed data sets will be analysed based on an analysis of covariance (ANCOVA) 
model, including treatment arm, and adjusting for the stratification PGA and baseline score as 
covariates. The pooled estimate of the difference in the least-square (LS)-mean change from 
baseline at Week 4, along with the associated 95% CIs and nominal p-values will be presented 
based on applying Rubin’s rules to the estimates and standard errors from the ANCOVA analyses 
of the imputed data sets. 
4.2.
Primary Endpoint Analysis 
4.2.1.
Definition of Endpoint(s) 
The primary endpoint is having PGA score of 0 (clear) or 1 (almost clear) at Day 29, with at least 
a 2-point reduction from baseline.
4.2.2.
Analytical Approach 
The primary endpoint will be analysed following the estimand strategy for binary endpoints 
described in Section 4.1.5.1 and Section 4.1.5.2, including a primary and a sensitivity analysis of
the primary estimand, and a primary analysis on the secondary estimand.
The non-inferiority and superiority 2-sided hypothesis, described in Section 2, will be tested for 
LEO 90100 vs Daivobet® ointment based on the primary analysis for the primary estimand.
A summary of PGA by visit will be provided by treatment group and overall.
A by-subject listing for PGA data will also be provided.
4.3.
Secondary Endpoint Analysis 
4.3.1.
Key Secondary Endpoint 
4.3.1.1.
Definition of Endpoint(s) 
The key secondary endpoint is having a decrease in mPASI of at least 75% (mPASI-75) from 
baseline to Day 29.


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Page 26 of 51
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001
4.3.1.2.
Analytical Approach 
The binary key secondary endpoint will be analysed following the estimand strategy for binary 
endpoints described in Section 4.1.5.1 and Section 4.1.5.2. The superiority 2-sided hypothesis,
described in Section 2, will be tested for LEO 90100 vs Daivobet® ointment based on the primary 
analysis for the primary estimand. 
4.3.2.
Secondary Endpoint 
The secondary endpoint is having a decrease in mPASI of at least 90% (mPASI-90) from baseline 
to Day 29.
The planned analysis on the secondary endpoint is the same as the key secondary endpoint
(mPASI-75) as described in Section 4.3.1.
4.4.
 
include:
related to primary objective:
x
x
x
x
x
The binary 
 will be analysed following the primary estimand strategy 
for binary endpoints described in Section 4.1.5.1 and Section 4.1.5.2. The continuous 
 
 will be analysed following the estimand strategy for the 
continuous endpoints, as per Section 4.1.5.3. 
A summary of the change from baseline in continuous variables (mPASI, 
) will 
be provided by visit, by treatment group and overall, for observed values.
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Page 27 of 51
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001
Observed proportions of categorical variables 
 will be summarized by visit, by treatment 
group and overall.
By-subject listing will be provided for data on mPASI, 
 score.
4.5.
Safety Analyses 
All safety analyses will be made on the safety analysis set.
4.5.1.
Extent of Exposure 
The duration of exposure to IMP in a specific week interval will be calculated as the number of 
days from date of first IMP administration in that period to the date of last IMP administration in 
that period, both days included.
Exposure to IMP will be presented as days and weeks of exposure.
Patient years of exposure is the duration of exposure to IMP in years:
Patient years of exposure (years) = (date of last IMP administration – date of first IMP 
administration + 1)/365.25
Patient years of observation is the duration of observation in years:
Patient years of observation (years) = (date of end of study – date of first IMP administration +
1)/365.25
The total amount of IMP used (g) by each visit interval is collected in the eCRF. 
The total amount of IMP used (g) during the total treatment period will be calculated as the sum 
up of IMP used per visit. If the amount of IMP used is missing for any performed visit, the total 
amount of IMP used during the total treatment period will be set to missing. 
The average weekly amount of IMP used (g) will be calculated as total amount of IMP/duration 
of exposure × 7.
The following summaries will be presented for each treatment group:
x
Exposure to IMP (days/weeks of exposure to IMP) during the total treatment period.
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Page 28 of 51
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001
x
Total exposure to IMP (weeks) for all subjects during the total treatment period.
x
Patient years of exposure and patient years of observation.
x
Total patient years of exposure and patient years of observation for all subjects.
x
The average weekly and total amount of IMP used (g) by each visit interval and the total 
treatment period.
x
Number and percent of subjects with overdose (any dose of study drug used greater than 
105 g within one week).
By-subject listings will be provided for IMP administration, IMP accountability, and exposure to 
IMP.
4.5.2.
Adverse Events 
AEs will be coded during the course of the trial according to the Medical Dictionary for 
Regulatory Activities (MedDRA, version 25.0 or later). AEs will be presented by primary system 
organ class (SOC) and preferred term (PT).
Treatment-emergent AEs will be summarised; however, all AEs recorded during the course of the 
trial will be included in subject data listings. An event will be considered treatment-emergent if it 
started after the first IMP administration or if it started before the first IMP administration and 
worsened in severity after the first IMP administration. The tabulations described in the following 
will only include the treatment-emergent AEs. In each of the tabulations, AEs are defined by 
MedDRA PTs within primary SOC.
Unless otherwise specified, AEs will be summarised in terms of the number of subjects with at 
least 1 event, the percentage of subjects with at least 1 event, the number of events and the event 
rate per 100 patient years of exposure, and the tables will only include treatment-emergent AEs 
reported in the treatment period.
Event rate = (number of events/patient years) ×100.
Related AEs are defined as AEs for which the investigator has not described the causal 
relationship to the IMP as ‘not related’.


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Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001
An overall summary will be presented for subjects with any treatment-emergent AEs in the 
following categories:
x
Any treatment-emergent AEs
x
AEs leading to Deaths
x
Serious adverse events (SAEs); Non-Serious adverse events
x
AEs leading to permanent discontinuation from IMP
x
AEs leading to withdrawals from the trial
x
Treatment-related AEs
x
Severe AEs
x
Outcome of AEs
x
Action taken with IMP
The overall summary table will also be provided for:
x
All treatment-emergent AEs reported in treatment period and the safety follow-up period.
Event rate will be per 100 patient years of observation.
Patient years of observation (years) = (date of end of study – date of first IMP 
administration + 1)/365.25.
x
Treatment-emergent AEs reported in safety follow-up period. Event rate will be per 100
patient years of safety follow-up.
Patient years of safety follow-up (years) = (date of end of study – date of last IMP 
administration)/365.25.
x
Lesional/Perilesional Treatment-emeregent AEs reported in treatment period. Event rate 
will be per 100 patient years of exposure.
x
Serious Treatment-emeregent AEs reported in treatment period. Event rate will be per 100
patient years of exposure.
x
Treatment-emeregent AEs leading to withdrawals from the trial reported in treatment 
period. Event rate will be per 100 patient years of exposure.


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Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001
Tabulations by SOC and PT will be presented for treatment-emergent AEs started in the 
treatment period for the following categories:
x
All AEs
x
Related AEs
x
AEs by severity
x
AEs by causal relationship to IMP
x
Most frequent AEs (≥5% in any treatment group)
x
Lesional/Perilesional AEs
x
SAEs
x
AEs leading to withdrawal from trial
x
AEs leading to permanent discontinuation of IMP
Tabulations by SOC and PT will also be provided for treatment-emergent AEs started in 
treatment period and the safety follow-up period (event rate based on 100 patient years of 
observation) and treatment-emergent AEs started in the safety follow-up period (event rate based 
on 100 patient years of safety follow-up). 
In the summary of AEs by severity, if an AE worsens in severity, the severity will be reported as 
the most severe recording for that AE. In the summary of causal relationship to IMP, subjects will 
be counted only once in the most related category (e.g. probably related). If the severity or 
relationship is missing, the AE will be counted as “severe” or “probably related”. The number of 
missing severity/relationship will be stated in the footnote of summary tables, and the listing will 
display the actual missing severity/relationship.
The following by-subject listings will be provided:
x
All AEs
x
SAEs 
x
AEs leading to withdrawal from trial
x
AEs leading to permanent discontinuation of IMP
x
AEs occurred after the first overdose of IMP
The detailed listing will provide an overview of the individual cases and include the age and sex 
of the subject, treatment received at the time of AE onset, the AE preferred and reported terms, 


Parexel International
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Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001
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 except for SAEs and pregnancies.
Other events involving IMP (medication error, misuse and abuse of IMP) will be tabulated by
treatment. Event rate will be calculated based on 100 patient years of exposure. Other events 
involving IMP will also be listed. No narratives will be given.
4.5.3.
Additional Safety Assessments 
4.5.3.1.
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 chemistry parameters showing the categories (“Low”, 
“Normal”, “High” according to the normal range) at baseline against those at each post-baseline 
visit.
For subjects with post-baseline values, out of reference range events reported up to end of study
will be summarised.
A by-subject listing will be provided for laboratory data.
4.5.3.2.
Physical Examination and Other Observations Related to Safety 
For physical examination, abnormalities at baseline and end-of-treatment (or early termination) as 
well as the transition from baseline to end-of-treatment (or early termination) will be summarised 
for each treatment group.
A by-subject listing will be provided for physical examination data.
Urine and Serum pregnancy test performed, reasons why not performed, and test results 
(“positive”, “negative”) will be listed.


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4.6.
Other Analyses 
4.6.1.
Other Variables and/or Parameters 
4.6.1.1.
Health Economics 
Health economics parameters are not evaluated in this trial.
4.6.1.2.
 
The analysis on 
 are described in Section 4.4.
4.6.2.
Subgroup Analyses 
Subgroup analysis is not planned in this trial.
4.6.3.
Pharmacokinetics, Pharmacokinetic-Pharmacodynamic Relationships 
Pharmacokinetic or pharmacodynamic parameters are not evaluated in this trial.
4.7.
Interim Analysis  
No interim analysis is planned during the trial.
4.8.
Changes to Protocol-planned Analyses 
Baseline PGA is added as a covariate to the ANCOVA model for continuous endpoints, which is 
not mentioned as a covariate in Protocol section 9.3.5.3.
The MedDRA search term in Protocol section 9.3.9.1 will not be applied to AE summary.
For subjects with post-baseline values, out of reference range events reported up to end of study
will be summarised, instead of up to week 6 in Protocol section 9.3.9.3.
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Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001
5.
Sample Size Determination 
Data from the EU SmPC is used for the sample size calculation[4]. Table 5–1 shows results from 
a historical comparative trial on the “Percentage of subjects with 'treatment success' according to 
the PGA of the body at Week 4 (PGA 0/1)”. These data from the SmPC give a relative risk of 
1.27 and a crude OR of 1.59 in favour of LEO 90100.
Table 5–1
EU SmPC Trial Result
Data from SmPC
LEO 90100
Daivobet® ointment
Trial Three
(N=141) 54.6%
(N=135) 43.0%
Abbreviations: SmPC=Summary of Product Characteristics.
Table 5-2 illustrates the power with 600 subjects randomised 1:1. The probability of superiority 
and non-inferiority is found by running 10,000 simulations using the data from the EU SmPC. 
The responder probabilities are used in a binomial sampling of the number of subjects with 
treatment success. For each of the simulations, the OR with 95% CI limits is calculated using 
Fisher’s exact test and the lower 95% boundary is used to evaluate superiority and non-inferiority 
at the thresholds 1 and 
 respectively.
Table 5-2
Simulated Power
Endpoint
Proportion 
responders for 
Daivobet®
ointment
Proportion 
responders for 
LEO 90100
Probability of 
superiority
Probability of 
non-inferiority 
with a NI 
margin OR=
Probability of 
point estimate 
for LEO 90100 
exceeds 
Daivobet®
ointment 
(OR > 1)
PGA 0/1 at 
Day 29
43.0%
54.6%
0.799
0.9198
0.9975
Abbreviations: NI=non-inferiority; OR=odds ratio; PGA=Physician’s Global Assessment of disease severity.
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6.
Supporting Documentation 




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6.2.
Appendix 2: Supporting Study Information 
6.2.1.
Disposition of Subjects 
A clear accounting of the disposition of all subjects who enter the study will be provided based 
upon all screened subjects, from screening to study completion.
The number of subjects in the following categories will be summarized based on the all screened 
set:
x
Subjects screened (i.e. signed informed consent)
x
Subjects passed screening
x
Subjects failed screening
o
The criteria not satisfied
x
Subjects met all eligibility but discontinued before randomisation
Disposition of subjects for treatment completion and study completion will be summarized by 
treatment group and overall. The number and percentage of subjects in the following categories 
will be summarized based on all randomised subjects.
x
Subjects randomised
x
Subjects randomised but not treated
x
Subjects treated (with at least one dose of IMP)
x
Subjects included in Full Analysis Set
x
Subjects included in Safety Analysis Set
x
Subjects completed treatment
x
Subjects permanently discontinued IMP (including reasons of IMP discontinuation)
x
Subjects completed study
x
Subjects discontinued from study (including reasons of study discontinuation)
A summary of the number and percentage of subjects in each analysis set (FAS, safety analysis 
set) will be provided. Percentage will be based on all randomised subjects.
The following by-subject listings will be provided:
x
Subjects disposition with their screening and withdrawal/study completion details 
(including reason for discontinuation) (all screened set)
x
Subjects randomisation assignment with stratification factors (all randomised subjects)
x
Subjects analysis set assignment (all randomised subjects)
6.2.2.
Demographics 


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Descriptive statistics of demographics will be presented for all randomised subjects by treatment 
group.
x
Age (years)
x
Age categories (≤35 years, 36-50 years, 51-64 years, ≥65 years)
x
Sex (Male, Female)
x
Is child-bearing potential (Yes, No)
x
Race (Chinese)
A by-subject listing of demographic for all randomised subjects will be provided.
6.2.3.
Baseline and Disease Characteristics 
Descriptive statistics of baseline and disease characteristics will be presented for all randomised 
subjects by treatment group.
x
Height (cm)
x
Weight (kg)
x
Body mass index (BMI) (kg/m2)
x
Fitzpatrick skin type
x
Psoriasis history
o
Years of having psoriasis
o
Type of psoriasis
o
Location
x
Previous anti-psoriatic treatment
o
Any previous anti-psoriatic therapy (Yes, No)
o
Treatment type
o
Medication

Systemic therapy and topical medications will be coded by World Health 
Organization (WHO) Drug Global Dictionary, version Sep 2022 or later.
ATC Level 2, ATC Level 4 and PT will be summarised.
A summary of baseline values of efficacy variables will be presented for all randomised subjects
by treatment group.
x
PGA
x
mPASI
x
x
x
x
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Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001
A by-subject listing of baseline and disease characteristics for all randomised subjects will be 
provided.
6.2.4.
Treatment Compliance 
Treatment compliance will be calculated based on the duration and frequency of IMP 
administration:
Treatment compliance (%) = (Days with once IMP administered/duration of exposure to IMP)
×100,
Duration of exposure to IMP = date of last IMP administration – date of first IMP administration 
+ 1.
Treatment compliance during the total treatment period will be presented for each treatment 
group for the safety analysis set.
A by-subject listing on treatment compliance will be provided.
6.2.5.
Protocol Deviations 
Protocol deviations will be handled in accordance with Parexel Standard Operating Procedures 
(SOPs).
Major protocol deviations are defined as those deviations from the protocol likely to have an 
impact on the perceived efficacy and/or safety of study treatments.
Decisions to exclude subjects from the will be made before DBL in a blinded manner. A by-
subject listing of major protocol deviations will be provided. A summary of the number and 
percentage of subjects with a major protocol deviation by type of deviation will be provided 
based on all screened subjects. PDs due to COVID-19 will be listed separately.
6.2.6.
Medical History and Concurrent Illnesses 
Medical history will be coded using Medical Dictionary for Regulatory Activities (MedDRA) 
version 25.0 or later.


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Medical history events will be summarized for randomised subjects by preferred term (PT) and 
system organ class (SOC) by treatment group and overall as:
x
Past medical history if confirmed not to be ongoing at screening.
x
Current medical history if confirmed to be ongoing at screening.
Past and current medical history will be listed separately.
6.2.7.
Prior/Concomitant Medications and Procedures 
Medication and/or procedure start and stop dates will be compared to the date of first IMP 
administration to be classified as below:
x
Prior only: medications/procedures that start and stop prior to the date of first IMP 
administration.
x
Both prior and concomitant: medications/procedures start before the date of first IMP 
administration and stop on or after the date of first IMP administration.
x
Concomitant only: medications/procedures start on or after the date of first IMP 
administration.
Medications/procedures start after the completion/withdrawal date will be listed but will not be 
classified or summarized.
Medications will be coded using World Health Organization (WHO) Drug Global Dictionary,
version Sep 2022 or later. The following medications will be summarized by Anatomical 
Therapeutic Chemical (ATC) code (levels 2 and 4) and PT for all randomised subjects. In case of 
missing level 4 coding the level 3 coding will be used.
x
Prior medications
x
Concomitant medications (including both prior and concomitant medications and 
concomitant medications)
x
Rescue medications (concomitant medications indicated as rescue treatment)
Procedures will be coded using MedDRA Version 25.0 or later. Concomitant procedures will be 
summarized by SOC and PT for all randomised subjects.
By-subject listings will be provided for all medications and procedures with the flag of 
classifications for all randomised subjects.


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6.3.
Appendix 3: Data Handling Conventions 
6.3.1.
Analysis Visit Windows  
6.3.1.1.
Effectiveness  
Visit windows are defined in Schedule of Assessments (SoA) (Appendix 4).
No visit window re-mapping will be performed. The analysis will be based on the nominal visit 
collected in EDC.
6.3.1.2.
Safety  
Visit windows are defined in Schedule of Assessments (SoA) (Appendix 4).
No visit window re-mapping will be performed. The analysis will be based on the nominal visit 
collected in EDC.
6.3.2.
Missing Date Imputation  
6.3.2.1.
Missing/Incomplete AE Start Date  
For analyses of AEs, a complete date must be established in order to correctly identify the AE as 
occurring during treatment or not. For purposes of imputing missing components of partially 
reported or missing start and stop dates for AEs, the algorithms listed below will be followed. 
Start and stop dates of AEs in the subject data listings will be displayed as reported (i.e., no 
imputed values will be displayed in data listings).
Partial or missing AE start dates will be imputed as follows:
Imputation of partial or missing start dates:
• If only the month and year are specified and the month and year of first dose is not the 
same as the month and year of the start date, then use the 1st of the month.
• If only the month and year are specified and the month and year of first dose is the same 
as the month and year of the start date, then use the date of first dose.
• If only the year is specified, and the year of first dose is not the same as the year of the 
start date, then use the 1st of January of the year of the start date.
• If only the year is specified, and the year of first dose is the same as the year of the start 
date, then use the date of first dose.


Parexel International
LEO Pharma A/S
LP0053-2277
Statistical Analysis Plan
Project Document Version No.: 2.0; Document Effective Date:  29Mar2024
TP-GDO-WW-016-09
Effective Date:  22 Dec 21
Related to:  SOP-GDO-WW-019
Page 41 of 51
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001
• If the start date is completely unknown and the stop date is unknown or not prior to the 
date of first dose, then use the date of first dose.
• If the start date is completely unknown and the stop date is prior to the date of first dose 
of IMP, then set the start date to the 1st of January of the year of the stop date.
6.3.2.2.
Missing/Incomplete Medication Date  
If medication/procedure start and/or stop dates are missing or partial, the dates will be compared 
as far as possible with the date of IMP administration. Medications/procedures will be assumed to 
be concomitant only, unless there is clear evidence (through comparison of partial dates) to 
suggest that the medication/procedure started prior to the IMP administration. If there is clear 
evidence to suggest that the medication/procedure started prior to the IMP administration, the 
medication/procedure will be assumed to be both prior and concomitant, unless there is clear 
evidence to suggest that the medication/procedure stopped prior to the IMP administration. If 
there is clear evidence to suggest that the medication/procedure stopped prior to the IMP 
administration, the medication will be assumed to be prior only.
6.3.3.
Multiple Imputation and Rubin’s Rule 
Multiple imputation will be utilized to primary and secondary endpoints analysis as described in 
section 4.2 and 4.3.
FCS logistic regression will be implemented for the binary PGA and SGA endpoints. FCS linear 
regression will be utilized to impute the mPASI score. 
A logistic regression or ANCOVA model will be implemented to analyse each imputed datasets 
and then combine the estimates by Rubin’s rule.
The following SAS example code will be utilized to perform MI, ANCOVA or logistic 
regression, and Rubin’s rule, in case of continuous or binary variables:
proc sort data=data; by subjid week; run; 
proc transpose data=data out=datain prefix=W; 
 
var aval; 
 
by subjid trtp strata_pga baseline_value; 
 
id week; 
run; 
 
*/MI - full conditional logistic (PGA or SGA)/; 
proc sort data=datain; by trtp; run; 
proc mi data=datain out=mi_data nimpute=1000 seed=2; 
 
by trtp; 
 
class strata_pga w2 w4 baseline_value; 


Parexel International
LEO Pharma A/S
LP0053-2277
Statistical Analysis Plan
Project Document Version No.: 2.0; Document Effective Date:  29Mar2024
TP-GDO-WW-016-09
Effective Date:  22 Dec 21
Related to:  SOP-GDO-WW-019
Page 42 of 51
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001
 
var w2 w4 strata_pga baseline_value; 
 
fcs logistic (w2 = strata_pga baseline_value /details); 
 
fcs logistic (w4 = strata_pga baseline_value w2/ details); 
run; 
proc sort data=mi_data; by _imputation_ subjid; run; 
 
*/MI - full conditional regerssion (mPASI)/; 
proc mi data=datain out=mi_data nimpute=1000 seed=2 minimum=0 maximum=64.8; 
 
by trtp; 
 
class strata_pga; 
 
var w2 w4 strata_pga baseline_value; 
 
fcs reg (w2 = strata_pga baseline_value/ details); 
 
fcs reg (w4 = strata_pga baseline_value w2/ details); 
run; 
proc sort data=mi_data; by _imputation_ subjid; run; 
 
*/Model for logistic regression/; 
proc logistic data=parameter; 
 
class trt01p(ref=first) baspga; 
 
model aval(event="1")=baspga trt01p/ covb; 
 
by _imputation_; 
 
output out=pred_probs p=p; 
 
ods output parameterestimates=lgsparms; 
run; 
 
*/Apply Rubin's Rule/; 
proc mianalyze parms(classvar=classval)=lgsparms; 
 
class trt01p; 
 
modeleffects trt01p; 
 
ods output parameterestimates=mi_lgsparms; 
run; 
 
*/Model for ANCOVA/; 
proc glm data=data; 
 
class trtp strata_pga; 
 
by _imputation_; 
 
model aval = trtp strata_pga baseline_value /solution; 
 
ods output parameterestimates=param_est; 
run; 
data param_est; 
 
set param_est; 
 
if parameter = "trtp    LEO90100"; 
 
keep _imputation_ estimate stderr; 
run; 
 
*/Apply Rubin's Rule/; 
proc mianalyze data=param_est; 
 
modeleffects estimate; 
 
stderr stderr; 
 
ods output parameterestimates=mi_ancova; 
run;






Parexel International
LEO Pharma A/S
LP0053-2277
Statistical Analysis Plan
Project Document Version No.: 2.0; Document Effective Date:  29Mar2024
TP-GDO-WW-016-09
Effective Date:  22 Dec 21
Related to:  SOP-GDO-WW-019
Page 45 of 51
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001
Abbreviations: AEs=adverse events; 
; eCRF=electronic case report form; ICF=informed consent 
form; IMP=investigational medicinal product; mPASI=modified Psoriasis Area and Severity Index; NA=not applicable; PGA=Physician’s Global Assessment; 
1
If the date of a trial visit does not fall in the visit window, subsequent visits should be planned to maintain the original visit schedule as outlined in the SoA 
above.
2
Assessments to be performed at unscheduled visits will be at the discretion of the investigator. The subject will be asked about AEs by the investigator.
3
Subjects who permanently discontinue IMP or withdraw from the trial will be asked to come for the primary endpoint visit and will be followed up (Protocol 
Section 7.1).
4
The ICF must be signed prior to performing any protocol-related procedures, including but not limited to screening evaluations and washout of prohibited 
medications. Screening evaluations can be either on the same date the ICF was signed or at a later date.
5
In case medical history is incomplete at screening visit, missing data will be retrieved at Day 1 (baseline).
6
To supplement the compliance check made at Visits 3 and 4, a subject diary should be completed daily during the treatment period.
7
Treatment compliance includes recording the number of applications missed by each subject (Protocol Section 6.5).
8
The body areas to be assessed are the trunk (including the neck) and the limbs, i.e., arms (including hands) and legs (including feet and buttocks). The face, 
scalp, genitals and skin folds (i.e., the axillae, the inguinal folds, the inter-gluteal folds and the infra-mammary folds) are not to be treated with the IMP or 
assessed as part of the efficacy analysis.
9
An end-of-treatment form (Protocol Section 7.1) and end-of-trial form (Protocol Section 4.4) must be completed in the eCRF for all subjects assigned to 
treatment.
CCI
CCI




Parexel International
LEO Pharma A/S
LP0053-2277
Statistical Analysis Plan
Project Document Version No.: 2.0; Document Effective Date:  29Mar2024
TP-GDO-WW-016-09
Effective Date:  22 Dec 21
Related to:  SOP-GDO-WW-019
Page 47 of 51
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001
6.5.2.
 
6.5.3.
mPASI 
The mPASI score will be assessed according to the SoA (Appendix 4). The investigator will 
make assessments of the extent and severity of clinical signs of the subject’s psoriasis. 
Assessment is not made for the face and hence, this PASI assessment is modified to exclude the 
face.
The extent of psoriatic involvement will be recorded for each of the areas (trunk [including the 
neck] and the limbs [such as arms and legs]; excluding any involvement on face, scalp, genitals 
and skin folds) using the following scale:
x
0=no involvement
x
1=< 10%
x
2=10%-29%
x
3=30%-49%
x
4=50%-69%
x
5=70%-89%
x
6=90%-100%
This assessment of extent is the percentage of that body area that is affected, and not the
percentage 
 affected (see Section 6.5.2). For example, if one arm was totally affected, 
and the other arm was totally unaffected, the extent assessment for the arms would be 50% (half 
of the arms affected).
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI






Parexel International
LEO Pharma A/S
LP0053-2277
Statistical Analysis Plan
Project Document Version No.: 2.0; Document Effective Date:  29Mar2024
TP-GDO-WW-016-09
Effective Date:  22 Dec 21
Related to:  SOP-GDO-WW-019
Page 50 of 51
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001
CCI
CCI
CCI
CCI


Parexel International
LEO Pharma A/S
LP0053-2277
Statistical Analysis Plan
Project Document Version No.: 2.0; Document Effective Date:  29Mar2024
TP-GDO-WW-016-09
Effective Date:  22 Dec 21
Related to:  SOP-GDO-WW-019
Page 51 of 51
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001
7.
References 
[1] ICH. International Council for Harmonisation of Technical Requirements for Pharmaceuticals 
for Human Use: Statistical Principles for Clinical Trials. E9, Step 4; 05 Feb 1998.
[2] CH. International Council for Harmonisation of Technical Requirements for Pharmaceuticals 
for Human Use: Addendum on estimands and sensitivity analysis in clinical trials to the 
guidelines on statistical principles for clinical trials. E9 (R1), Step 4; 20 Nov 2019.
[3] Berglund P and Heeringa SG. Multiple Imputation of Missing Data Using SAS. SAS 
Publishing; 2014.
[4] Summary of Product Characteristics for Enstilar®.
https://mri.cts-mrp.eu/Human/Downloads/DK_H_2478_001_FinalSPC.pdf
[5] Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI)‑a simple practical measure for 
routine clinical use. Clin Exp Dermatol. 1994;19(3):210-216.
[6] Bushnell DM, Martin ML, McCarrier K, Gordon K, Chiou CF, Huang X, Ortmeier B, 
Kricorian G. Validation of the Psoriasis Symptom Inventory (PSI), a patient-reported outcome 
measure to assess psoriasis symptom severity. J Dermatolog Treat. 2013;24(5):356-360.