Conditions: Psoriasis Vulgaris
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 182
Healthy volunteers: no

Brief summary:
Comparison of the efficacy of LEO 90100 foam with Dovobet® ointment in the treatment of psoriasis in Japanese subjects.

Detailed description:
A phase 3, national, multi-centre, 4-week, prospective, randomised, controlled, parallel-group, open trial of LEO 90100 foam versus Dovobet® ointment (both treatments containing calcipotriol hydrate plus betamethasone dipropionate) in Japanese subjects with psoriasis vulgaris.

Arms:
arm 1: calcipotriol hydrate 52.2 µg/g \[equivalent to 50.0 µg/g calcipotriol\] plus betamethasone dipropionate 0.643 mg/g arm 2: calcipotriol hydrate 52.2 µg/g \[equivalent to 50.0 µg/g calcipotriol\] plus betamethasone dipropionate 0.643 mg/g

Interventions: intervention 1: LEO 90100 foam intervention 2: Dovobet® ointment
Intervention descriptions: intervention 1: Once daily topical application of foam from a can to psoriasis lesions. Dose depends on size of lesion. intervention 2: Once daily topical application of ointment from a tube to psoriasis lesions. Dose depends on size of lesion.

Protocol document:
Prot_000.pdf: 
 
 
 
 
 
 
 
 
 
Cover Page 
 
 
Official title: A phase 3, national, multi-centre, 4-week, prospective, randomised, controlled, parallel 
group, open trial of LEO 90100 foam versus Dovobet® ointment 
LEO Pharma number: LP0053-1422
NCT number: NCT03806790 
Date: 06-Nov-2018 
 


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Clinical Trial Protocol 
Efficacy and safety of LEO 90100 foam in Japanese subjects with 
psoriasis vulgaris 
A phase 3, national, multi-centre, 4-week, prospective, randomised, controlled, parallel-
group, open trial of LEO 90100 foam versus Dovobet® ointment  
ICH GCP statement:  The clinical trial will be conducted in compliance with the clinical 
trial protocol, ICH-GCP, J-GCP and the applicable regulatory 
requirement(s). 
LEO Pharma A/S 
Trial ID: 
LP0053-1422 
Date: 
06-Nov-2018
Version: 
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1 Clinical Trial Protocol Statements  
1.1 Approval Statement LEO Pharma A/S 
Electronic signatures made within eTMF LEO are considered to be a 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: 
, MSc Stat 
Biostatistics Lead, Global Clinical Operations 
, MD 
Vice President, Medical Sciences 
, MSc Pharm 
Clinical Operations Lead, Global Clinical Operations 
1.2 Approval Statement signatory investigator 
The signatory investigator approves the clinical trial protocol and consolidated clinical trial 
protocol(s) comprising any subsequent amendment(s) by manually signing the Signatory 
Investigator Clinical Trial Protocol Approval Form, which is a separate document adjoined to 
this document. 
The following person has approved this clinical trial protocol: 
, MD, PhD 
Signatory investigator 
1.3 Acknowledgement Statement Investigators 
Each participating investigator must agree to the approved clinical trial protocol and 
consolidated clinical trial protocol(s) comprising any subsequent amendment(s) by signing an 
Agreement for Conducting Clinical Trial - Japan form.  
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Table of Contents 
1 Clinical Trial Protocol Statements ......................................................................................... 2 
1.1 Approval Statement LEO Pharma A/S .............................................................................. 2 
1.2 Approval Statement signatory investigator ....................................................................... 2 
1.3 Acknowledgement Statement Investigators ...................................................................... 2 
Table of Contents ....................................................................................................................... 3 
List of Abbreviations and Definition of Terms .......................................................................... 7 
2 Trial Identification ................................................................................................................. 9 
3 Introduction and Rationale .................................................................................................... 9 
3.1 Psoriasis ............................................................................................................................. 9 
3.2 Experience with Investigational Medicinal Product ....................................................... 11 
3.3 Trial Rationale ................................................................................................................. 12 
3.4 Ethical Consideration Statement ..................................................................................... 13 
4 Trial Objectives ................................................................................................................... 14 
4.1 Primary Objective ............................................................................................................ 14 
4.2 Secondary Objectives ...................................................................................................... 14 
4.3 Exploratory Objectives .................................................................................................... 14 
5 Trial Endpoints .................................................................................................................... 14 
5.1 Primary Endpoint ............................................................................................................ 14 
5.2 Secondary Endpoints ....................................................................................................... 14 
5.3 Exploratory Endpoints ..................................................................................................... 15 
6 Trial Design ......................................................................................................................... 15 
6.1 Overall Trial Design ........................................................................................................ 15 
6.2 Sample Size ..................................................................................................................... 17 
6.3 Randomisation ................................................................................................................. 17 
6.4 Blinding ........................................................................................................................... 17 
6.5 End of Trial Definition .................................................................................................... 17 
6.6 Software ........................................................................................................................... 17 
7 Trial Population and Withdrawal Criteria ............................................................................ 18 
7.1 Subject Eligibility ............................................................................................................ 18 
7.2 Inclusion Criteria ............................................................................................................. 18 
7.3 Exclusion Criteria ............................................................................................................ 19 
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7.4 Subject Screening Log ..................................................................................................... 20 
7.5 Subject Identification List ............................................................................................... 21 
7.6 Restrictions during Trial .................................................................................................. 21 
7.7 Withdrawal Criteria ......................................................................................................... 22 
8 Trial Schedule and Assessments .......................................................................................... 24 
8.1 Schedule of Trial Procedures ........................................................................................... 24 
8.2 Informed Consent ............................................................................................................ 25 
8.3 Demographics and Baseline Characteristics ................................................................... 25 
8.3.1 
Medical History ........................................................................................................... 25 
8.4 Concurrent Medication and Concurrent Procedures ....................................................... 25 
8.5 Selection of Target Lesion ............................................................................................... 26 
8.6 Laboratory Assessments .................................................................................................. 26 
8.7 Adverse Events ................................................................................................................ 26 
8.8 Physical Examination ...................................................................................................... 26 
8.9 Pregnancy Test ................................................................................................................. 27 
8.10 Inclusion/Exclusion Criteria ............................................................................................ 27 
8.11 Randomisation ................................................................................................................. 27 
8.12 Investigator’s Assessment of Target Lesion .................................................................... 27 
8.13 Subject’s Assessments ..................................................................................................... 29 
8.14 Supply/Return of IMP and Compliance .......................................................................... 29 
9 Adverse Events .................................................................................................................... 29 
9.1 Collection of Adverse Events .......................................................................................... 29 
9.2 Reporting of Adverse Events in the eCRF ...................................................................... 30 
9.2.1 
Actions Taken as a Consequence of an AE ................................................................. 30 
9.3 Other Events to be Reported ........................................................................................... 30 
9.3.1 
Pregnancy .................................................................................................................... 30 
9.3.2 
Overdose ...................................................................................................................... 31 
9.3.3 
Medication Error ......................................................................................................... 31 
9.3.4 
Misuse ......................................................................................................................... 32 
9.3.5 
Abuse ........................................................................................................................... 32 
9.3.6 
Aggravation of Condition ............................................................................................ 32 
9.4 Additional Reporting Requirements for Serious Adverse Events ................................... 32 
9.4.1 
Investigator Reporting Responsibilities ...................................................................... 32 
9.4.2 
LEO Pharma Reporting Responsibilities .................................................................... 33 
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9.5 Follow-up for Final Outcome of Adverse Events ........................................................... 34 
9.6 Handling of an Urgent Safety Measure ........................................................................... 34 
10 Investigational Medicinal Products ..................................................................................... 35 
10.1 Investigational Medicinal Product Description ............................................................... 35 
10.2 Administration of Investigational Medicinal Products ................................................... 36 
10.3 Precautions/Over dosage ................................................................................................. 37 
10.4 Packaging of Investigational Medicinal Products ........................................................... 37 
10.5 Storage of Investigational Medicinal Products ............................................................... 38 
10.6 Treatment Assignment and Dispensing ........................................................................... 38 
10.6.1 Randomisation Code List ............................................................................................ 38 
10.7 Drug Accountability and Compliance Checks ................................................................ 39 
10.7.1 Drug Accountability .................................................................................................... 39 
10.7.2 Investigational Medicinal Product Destruction ........................................................... 39 
10.7.3 Treatment Compliance ................................................................................................ 39 
10.8 Provision for Subject Care following Trial Completion ................................................. 39 
10.9 Reporting Product Complaints ........................................................................................ 40 
10.10 Emergency Unblinding of Individual Subject Treatment ............................................ 40 
11 Statistical Methods .............................................................................................................. 40 
11.1 Determination of Sample Size ......................................................................................... 40 
11.2 Definition of Trial Analysis Sets ..................................................................................... 40 
11.3 Statistical Analysis .......................................................................................................... 41 
11.3.1 Disposition of Subjects ................................................................................................ 41 
11.3.2 Demographics and other Baseline Characteristics ...................................................... 41 
11.3.3 Exposure and Treatment Compliance .......................................................................... 41 
11.3.4 Analysis of Primary Efficacy Endpoint ....................................................................... 42 
11.3.5 Analysis of Secondary Efficacy Endpoints ................................................................. 42 
11.3.6 Exploratory Analysis of Efficacy ................................................................................ 42 
11.3.7 Exploratory Analysis of Subject Assessments ............................................................. 43 
11.3.8 Analysis of Safety ....................................................................................................... 43 
11.3.8.1 Adverse Events ........................................................................................................ 43 
11.3.8.2 Clinical Laboratory Evaluation ................................................................................ 44 
11.3.9 Interim Analysis .......................................................................................................... 45 
11.3.10 General Principles ....................................................................................................... 45 
11.3.11 Handling of Missing Values ........................................................................................ 45 
12 References ........................................................................................................................... 46 
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List of Appendices .................................................................................................................... 49 
13 Appendix 1: Protocol Summary .......................................................................................... 50 
14 Appendix 2: Japanese Package Insert for Dovobet® ointment ............................................ 53
15 Appendix 3: Definitions of Adverse Events and Serious Adverse Events .......................... 63 
15.1 Adverse Event Definition ................................................................................................ 63 
15.2 Serious Adverse Event Definition ................................................................................... 63 
16 Appendix 4: Classification of Adverse Events .................................................................... 65 
16.1 Severity ............................................................................................................................ 65 
16.2 Causality .......................................................................................................................... 65 
16.3 Outcome .......................................................................................................................... 66 
17 Appendix 5: Trial governance considerations ..................................................................... 68 
Appendix 5A: Regulatory and ethical considerations .............................................................. 68 
Appendix 5B: Informed consent process ................................................................................. 69 
Appendix 5C: Subject and data confidentiality ........................................................................ 69 
Appendix 5D: Record keeping, quality control, and data handling ......................................... 70 
Appendix 5E: Registration, reporting and publication policy .................................................. 73 
Appendix 5F: Insurance ........................................................................................................... 75 
Appendix 5G: Financial disclosure .......................................................................................... 75 
Appendix 5H: Committee structure ......................................................................................... 75 
Appendix 5I: Trial and site closure .......................................................................................... 75 
Appendix 5J: Responsibilities .................................................................................................. 76 
18 Appendix 6: Contact list of LEO Pharma A/S, LEO Pharma K.K., protocol authors, 
vendors,  international coordinating investigator and medical expert (Japan) .................... 77 
19 Appendix 7: WHO Classification of Topical Corticosteroids ............................................. 79 
20 Appendix 8: WHO Classification of Topical Corticosteroids compared to the Japanese 
Classification ....................................................................................................................... 81 
21 Appendix 9: Descriptors for intermediate intervals in severity score of clinical signs of 
target lesion .......................................................................................................................... 83 
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List of Abbreviations and Definition of Terms 
ADR 
adverse drug reaction 
AE 
adverse event 
ACE 
angiotensin converting enzyme 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BSA 
body surface area 
BUN 
blood urea nitrogen 
CDISC 
clinical data interchange standards consortium 
CMO 
Contract Manufacturing Organisation 
CRF 
case report form 
CRO 
contract research organisation 
CTCAE 
common terminology criteria for adverse events 
EU 
European Union 
GCP 
good clinical practice 
GGT 
gamma-glutamyl transpeptidase 
GMP 
good manufacturing practice 
HbA1c 
average blood glucose level 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IMP 
investigational medicinal product 
IRB 
institutional review board 
LDH 
lactate dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
Overall 
improvement 
rate 
A ‘substantial resolution’ of clinical signs or at least ‘moderately improved’ 
in the general change in the target lesion 
PDE4i 
phosphodiesterase 4 inhibitor 
PUVA 
psoralen plus UVA 
RBC 
red blood cell 
SAE 
serious adverse event 
SDTM 
study data tabulation model 
SGOT 
serum glutamic oxaloacetic transaminase 
SGPT 
serum glutamic pyruvic transaminase 
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Substantial 
resolution 
A clinical score for thickness and scaliness of 0 and a clinical score for 
redness of 1 or less in the severity of clinical signs of the target lesion 
SUSAR 
suspected unexpected serious adverse reaction 
UVA 
ultraviolet light A 
UVB 
ultraviolet light B 
WBC 
white blood cell 
WHO 
World Health Organisation 
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2 Trial Identification 
 LP0053-1422 
The clinical trial protocol will be registered on clinicaltrials.gov, jRCT (Japan Registry of 
Clinical Trials) and JAPIC (Japan Pharmaceutical Information Center). 
3 Introduction and Rationale 
This Phase 3 clinical trial is being conducted as part of the clinical development programme 
to obtain marketing approval of LEO 90100 foam (a combination of calcipotriol hydrate plus 
betamethasone dipropionate) in Japan.  
3.1 Psoriasis 
Psoriasis vulgaris is one of the most common chronic skin diseases, with a prevalence 
generally estimated at between 1 to 3% of the world’s population (1, 2). The prevalence of the 
disease in Japan could be low (3). It is characterised by sharply marginated areas of affected 
skin which appear thickened, red and scaly. The scalp, elbows, knees, lower back, hands, feet 
and nails are commonly affected sites. About 80% of affected patients complain of pruritus 
(4). Psoriasis is a significant problem in everyday life for the affected patients and has a 
significant impact on their health-related quality of life, an impact that increases with 
increasing skin involvement (5).  
Psoriasis is a dermatological disease which is characterised by an immune inflammatory 
reaction, proliferation of epidermal keratinocytes and a disorder of differentiation. The 
psoriatic appearance of the skin is produced by an increased rate of epidermal proliferation 
with impaired differentiation of keratinocytes resulting in a thickened, undulating epidermis 
covered by a thickened, parakeratotic stratum corneum (6,7). Activated T-cells (Th17 and 
Th1) as well as dendritic cells play an important role among immune and inflammatory 
reactions in psoriasis. Cytokines (IL-23 and IL-12) produced by dendritic cells are involved in 
T-cell proliferation and differentiation. Also, IL-22 and IL-17 produced by activated Th17
cause epidermal keratinocyte growth as well as abnormal keratinisation.  Therefore, the target 
of psoriasis treatment is epidermal keratinocytes and immune cells, as well as cytokines 
produced by these cells. The investigational drug in this trial (LEO 90100 foam) contains two 
active ingredients with different mechanisms of action: a vitamin D3 analogue and a 
corticosteroid.  The vitamin D3 analogue (calcipotriol) is mainly targeted at the epidermal 
keratinocyte, and the corticosteroid (betamethasone dipropionate) targets immune cells (8). 
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Treatment of psoriasis 
Psoriasis vulgaris is a chronic disease for which there is currently no cure. Treatment is 
targeted at reducing the signs of redness, thickness and scaliness, and associated symptoms 
such as pruritus. Psoriasis treatments can be divided into three main types: topical treatments, 
phototherapy and systemic treatments.  Each has its own advantages and disadvantages, and 
several treatment options, for example monotherapy and combination therapy, can be 
considered in medical practice (9-11).  Topical treatment is well-recognised as the first-line 
medication.  Phototherapy [Photochemotherapy (PUVA: psoralen combined with a long-
wavelength ultraviolet radiation A, UVA) and middle-wavelength ultraviolet radiation B, 
UVB (narrow-band or broad-band)] and systemic treatments [such as methotrexate (which is 
out of insurance-reimbursement in Japan), retinoids and ciclosporin] are generally used in 
extensive, therapy-resistant and socially disabling disease and in the serious forms of erythro-
dermic and pustular psoriasis (3,12).  Among the most recently approved therapies in Japan 
are the biological agents, which reduce the effect of T-cells inducing psoriasis, either by a 
direct effect on the T-cells or by inhibition of their secreted cytokines.  Currently 7 such 
biological products (adalimumab, infliximab, ustekinemab, brodalumab, secukinumab, 
ixekizumab and guselkumab) have been approved in Japan for the treatment of moderate to 
severe psoriasis.  
For the first-line therapy of psoriasis, topical corticosteroids and vitamin D3 analogues (such 
as calcipotriol, tacalcitol and maxacalcitol) are effective and the two most commonly used 
therapies for psoriasis vulgaris. Vitamin D3 analogues do not act as quickly and have to be 
applied for more than six weeks in order that similar efficacy to corticosteroids can be 
obtained (13). 
“Guidelines of care for the management and treatment of psoriasis with topical therapies” in 
the US (14) refers to the efficacy of the combination therapy of topical corticosteroids and 
vitamin D3 analogues.  It is very common in Japan to apply both topical corticosteroids and 
vitamin D3 analogues on the same area simultaneously, to make the best clinical use of each 
drug.  The efficacy of the combination therapy of topical corticosteroids and vitamin D3
analogues in patients with psoriasis vulgaris has been reported by a number of clinical trials 
performed both in and outside Japan (15-21).  In addition to the simultaneous application by 
patients of topical drugs, combined topical drugs prepared by physicians or pharmacists are 
often provided to patients in medical practice.  Ozawa presented the residual ratio of active 
vitamin D3 and corticosteroid after the mixing of various types of topical corticosteroids and 
vitamin D3 analogues and indicated that some inappropriate combinations causing degradation 
of each of the drugs were observed (22). The compatibility of topical vitamin D3 analogues 
with topical corticosteroids was also investigated in overseas trials and the results showed 
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calcipotriol had been degraded substantially when it was mixed with some corticosteroids.  
This indicates that mixing of vitamin D3 analogues and corticosteroids without regard for this 
incompatibility should be avoided (23).  In addition, as regards to combined drugs prepared 
by physicians or pharmacists, there are concerns about potential risk of contamination in 
preparation and the lack of established standard regimes.   
Moreover, the issue that increasingly attracts attention is that topical treatment becomes a 
source of stress for psoriasis patients due to the time taken to apply it. The stress caused by 
topical treatment is an important factor contributing not only to the decrease of the patients’ 
quality of life, but also to the reduction of drug compliance and therefore to the clinical 
effectiveness.   
To reduce the patient’s burden of topical treatment and realise a significant improvement over 
the currently available treatment, it is essential to decrease time and frequency required to 
apply the treatments (24-26). For these reasons, a stable and pre-fixed product of an 
appropriately combined topical corticosteroid and vitamin D3 analogue was developed 
(Dovobet® ointment), and this was approved in 2014 for use in Japan. Also, the gel 
formulation which contains the same active ingredients at the same concentration as the 
Dovobet® ointment was approved in February 2018 for use in Japan. 
3.2 Experience with Investigational Medicinal Product 
In October 2015, LEO 90100 foam was approved in the US as the first country for the topical 
treatment of plaque psoriasis in patients 18 years of age and older. Overall, the product has 
been approved in 36 countries, hereof the majority in EU. The foam was launched in US and 
EU in 2016.   
LEO 90100 foam contains the same fixed combination of calcipotriol hydrate 52.2 μg/g 
(equivalent to 50.0 μg/g calcipotriol) plus betamethasone dipropionate 0.643 mg/g as in the 
ointment and gel formulations that have been marketed for treatment of psoriasis vulgaris for 
years. Moreover, both active substances (and the combination thereof) are well established 
topical treatments for psoriasis.  
The safety profile from the marketed combination products (ointment, gel and foam) is based 
on more than 21,000 subjects involved in LEO Pharma A/S sponsored clinical trials as well as 
extensive postmarketing experience.   
For the ointment and gel formulations, various skin reactions have been reported. The 
following common and uncommon adverse drug reactions (ADRs) have been reported: 
pruritus, skin exfoliation, folliculitis, skin infection, skin atrophy, exacerbation of psoriasis, 
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dermatitis, erythema, rash, purpura or ecchymosis, skin burning sensation, skin irritation, 
application site pigmentation changes, application site pain, eye irritation, acne and dry skin. 
The most frequently reported adverse events (AEs) related to LEO 90100 foam in trials 
conducted outside Japan were application site reactions. Also, the following uncommon 
ADRs have been reported: folliculitis, hypersensitivity, hypercalcaemia, skin 
hypopigmentation, rebound effect, application site pruritus and application site irritation 
(Investigator’s Brochure section 4.8). 
The toxicological profiles of calcipotriol and betamethasone dipropionate are well 
characterised and as expected for the respective drug classes (i.e. vitamin D3 analogue and 
corticosteroid).  
For Dovobet® ointment, no differences in the safety profile have been observed in Japan 
during the clinical development programme and postmarketing surveillance compared to 
overseas. 
There has been one trial completed so far with LEO 90100 foam in Japanese subjects (27).  
Twenty healthy Japanese male adults received LEO 90100 foam and its vehicle as each single 
application on two sites on their back and the skin irritation and photo irritation were 
evaluated.  As a result, only one AE occurred in one subject in the LEO 90100 foam skin 
irritation test site, which was assessed as ‘only slight erythema’ on Day 4. No other safety 
issues related to LEO 90100 foam or vehicle of LEO 90100 foam were reported. Thus, the 
results indicate safety of LEO 90100 foam in healthy Japanese male subjects. 
3.3 Trial Rationale 
As described above, Dovobet® ointment was approved in Japan in 2014 for the treatment of 
psoriasis vulgaris.  Medicated ointments are generally considered to be the most effective type 
of formulation for the treatment of inflammatory skin disease with dry or scaly skin such as 
psoriasis. However, patients may consider ointment formulations greasy, messy and time 
consuming to apply which often results in poor adherence to therapy and a poor treatment 
outcome.   
To meet patient preferences, a foam formulation of Dovobet® (called LEO 90100 foam) was 
developed. The formulation is expected to be more convenient and less time consuming to 
apply than an ointment formulation and is therefore expected to have an improved 
compliance. 
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The LEO 90100 foam contains the same strength of active pharmaceutical ingredients and 
excipients as the Dovobet® ointment dissolved in a mixture of the propellants butane and 
dimethyl ether. The propellants evaporate immediately after application. The foam provides a 
novel solution for easy and convenient application of topical treatment for psoriasis.  
To obtain approval of LEO 90100 foam for treatment of psoriasis in Japan, a clinical 
development programme is being conducted in Japan and this trial is part of that programme. 
This trial will be performed as an open trial because the trial medications are different 
formulations, and a double-dummy design would be difficult on a practical basis. The trial 
design and endpoints are similar to those of a similar trial performed in Japan to compare 
different topical formulations of the same active ingredient (28). In addition to the target 
lesion, subjects will be instructed to treat any other psoriasis lesions they may have with the 
trial medication, apart from those on the scalp, face, genitals and skin folds, providing that all 
lesions are limited to a total area of less than or equal to 30% body surface area (BSA). This is 
for the convenience of the subjects, as they do not have to use a different medication on 
lesions other than the target lesion, and to prevent possible accidental use of this different 
medication on the target lesion which could impact both the efficacy and safety assessments. 
When the clinical trial for Dovobet® ointment, comparator of this trial, was conducted, scalp 
was excluded from the application and the evaluation, and Dovobet® ointment was approved 
based on the data. 
Subjects will be provided with 60g of medication per week. Approximately 20.2g of ointment 
covers the whole body (29). Hence, approximately 6.1g of ointment covers 30% BSA, the 
maximum area to which medication can be applied in this trial. This is equal to 42.7g per 
week as the maximum once daily dosage of ointment. Since LEO 90100 foam has the same 
composition as Dovobet® ointment, with the exception of the propellants, it should be able to 
cover at least the same area as the ointment.  Therefore, 60g per week should be an adequate 
amount of medication to provide to the subjects.  
3.4 Ethical Consideration Statement 
The purpose of this trial is to compare LEO 90100 foam and Dovobet® ointment in the 
treatment of psoriasis in Japanese subjects. The data obtained from this trial will contribute to 
the development of LEO 90100 foam, a therapy expected to be a useful treatment for psoriasis 
in the Japanese population.  
Even though LEO 90100 foam is a different formulation of the approved product Dovobet® 
ointment, it contains the same active ingredients at the same concentration and is therefore 
expected to have a similar safety and efficacy profile. The results of the clinical trials 
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conducted with Dovobet® ointment in Japan were similar to the results of the clinical trials 
conducted overseas. Postmarketing surveillance has not revealed any signals indicating a 
difference between Japanese subjects and non-Japanese subjects. 
Subjects participating in the trial will be under the careful supervision of an experienced 
dermatologist during the entire course of the trial.   
Considering the above, this trial is assumed to involve a minimal risk to the participating 
subjects. 
4 Trial Objectives 
4.1 Primary Objective 
To compare the efficacy of LEO 90100 foam with Dovobet® ointment in the treatment of 
psoriasis in Japanese subjects. 
4.2 Secondary Objectives 
To compare the safety of LEO 90100 foam with Dovobet® ointment in the treatment of 
psoriasis in Japanese subjects. 
4.3 Exploratory Objectives 
To investigate the subjects’ own assessments of the use of LEO 90100 foam compared to 
previous psoriasis treatments for non-naïve subjects. 
5 Trial Endpoints 
5.1 Primary Endpoint 
The primary endpoint is ‘overall improvement rate’ for the target lesion at Visit 4 (end of 
Week 4), defined as ‘substantial resolution’ of clinical signs or at least ‘moderately improved’ 
in the general change in the target lesion. ‘Substantial resolution’ is defined as a clinical score 
for thickness and scaliness of 0 and a clinical score for redness of 1 or less in the severity of 
clinical signs of the target lesion. 
5.2 Secondary Endpoints 
The ‘overall improvement rate’ for the target lesion at Visits 2 and 3 (end of Weeks 1 and 2). 
The change in the total sign score from Visit 1 to Visit 4; total sign score is defined as the sum 
of the scores from the 3 clinical signs assessing severity in the target lesion.  
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The change in the sum of the scores (total sign score) for the severity of the three clinical 
signs (thickness, scaliness, redness) from Visit 1 to the sum of the scores at Visit 4 (end of 
Week 4) for the target lesion.  
The number of adverse events. 
5.3 Exploratory Endpoints  
The following will be analysed as exploratory efficacy endpoints. 

The ‘substantial resolution’ of clinical signs for the target lesion for each visit

The change in the total sign score for the target lesion from Visit 1 to Visits 2 and 3 (end
of Weeks 1 and 2)

The change in score for the severity of each clinical sign for the target lesion from Visit 1
to each subsequent visit
For those subjects who have previously used topical treatment for their psoriasis, the 
following will be analysed as exploratory endpoints evaluating subject assessment on the use 
medication: 

‘time spent for application’ compared to the previous treatment (less time, slightly less
time, unchanged, slightly more time, more time) at Visit 4 (end of Week 4)

‘ease of application’ (very easy, easy, difficult, very difficult) at Visit 4 (end of Week 4)
Exposure and standard safety data will be analysed as described in sections 11.3.3 and 11.3.8. 
6 Trial Design  
6.1 Overall Trial Design 
A phase 3, national, multi-centre, 4-week, prospective, randomised, controlled, parallel-group, 
open trial of LEO 90100 foam versus Dovobet® ointment (each containing calcipotriol 
hydrate 52.2 µg/g [equivalent to 50.0 µg/g calcipotriol] plus betamethasone dipropionate 
0.643 mg/g) in Japanese subjects with psoriasis vulgaris. 
Screening period 
Prior to randomisation at Visit 1, a screening period will be required to ensure that the subject 
is eligible to participate. The screening period will last for a maximum of 4 weeks and a 
minimum of 3 days (the latter to allow time for the site to receive the laboratory results from 
the samples taken at the Screening Visit).  Subjects must give written informed consent either 
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before or at the Screening Visit. Subjects providing informed consent are considered to be 
enrolled in the trial, and eCRF should be completed for all such subjects. 
Treatment period   
The treatment period will last for up to 4 weeks. Trial visits will be performed on Day 1 (Visit 
1) and after 1, 2 and 4 weeks (Visits 2, 3 and 4).  Visit 2 and Visit 3 should be performed
within ± 1 day of the scheduled time (Day 7-9 and Day 14-16, respectively), and Visit 4 
should be performed within ± 2 days of the scheduled time (Day 27-31), in all cases relative 
to Visit 1. If they are outside this window, the (sub)investigator should record the reason in 
the patient’s medical record.  
At Visit 1, subjects will be randomised to receive treatment with either LEO 90100 foam or 
Dovobet® ointment. Trial medication will be applied once daily to psoriasis on a target lesion 
of the body.  After this application on the target lesion, subjects will also apply trial 
medication to any other areas of psoriasis, excluding psoriasis on the scalp, face, genitals, and 
skin folds (axillae, groin, infra-mammary, those around the buttocks and the perianal area).  
On the assessment day of the target lesion (Visit 1, Visit 2, Visit 3 and Visit 4), subject should 
not apply any topical treatment including emollients on the target lesion before the visit. 
Showering or bathing should also be avoided. 
Subjects with the target lesion achieving ‘substantial resolution’, as defined in section 5,  
before the end of 4 weeks’ treatment will complete the trial at this time (although they will 
still be required to attend the follow-up visit up to 14 days later, if applicable; see below).   
Follow-up period 
Follow up is only required if there is an AE present at the last visit which is of possible or 
probable relationship to trial medication or is a serious adverse event (SAE).  For non-serious 
AEs of possible or probable relationship to trial medication, the subject will return 14 days 
after the subject’s last visit or when the final outcome has been established, whichever comes 
first.  If the visit is outside this 14-day window, the reason should be recorded in the subject’s 
medical record, but LEO Pharma does not need to be notified.  All related and not related 
SAEs must be followed up until a final outcome has been established, i.e. the follow-up may 
continue beyond the end of the clinical trial.    
Planned date of enrolment of first subject: Q1 2019 
Planned date of completion of last subject: Q2 2019 
Estimated number of trial sites and country allocation: 20 trial sites in Japan 
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6.2 Sample Size 
A total of 180 subjects will be randomised in a 1:1 ratio to the two treatment groups, i.e. 90 in 
each treatment group in order to provide at least 80 subjects per group who complete the trial. 
It is anticipated that approximately 200 subjects will be screened in order to provide 180 
randomised subjects. 
The sample size is not based on power calculations, but is based on regulatory considerations, 
as 80 subjects per treatment group is the number that has been used for a similar trial in Japan 
to compare different topical formulations of the same active ingredient (28). 
6.3 Randomisation 
Subjects will be randomly assigned to either LEO 90100 foam or Dovobet® ointment in a 1:1 
ratio using a randomisation stratified by investigator site. 
6.4 Blinding 
An open trial will be performed because the trial medications are different formulations, and a 
double-dummy design would be difficult on a practical basis.   
In order to ensure that there is no selection bias in the randomisation of subjects to treatment, 
sealed envelopes will be used to randomily assign the treatment. 
6.5 End of Trial Definition 
A subject is considered to have completed the trial if they have completed all periods of the 
trial, including the last visit or the subjects was cleared, ‘substantial resolution’, of the target 
lesion as defined in section 5, before the end of 4 weeks’ treatment.  
The end of the trial is defined as the date of the last visit of the last subject in the trial. 
Final collection of data for the primary endpoint occurs at Week 4. 
6.6 Software 
CDISC controlled terminology version 22-Dec-2017 was used for definition of controlled 
terminology used throughout this protocol and will be used for statistical programming and 
output. SDTM version 3.2 will be used for data tabulations. 
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7 Trial Population and Withdrawal Criteria 
7.1 Subject Eligibility  
The (sub)investigator should only randomise subjects who meet all eligibility criteria, are not 
put at undue risk by participating in the trial and can be expected to comply with the protocol. 
The subject’s eligibility for the clinical trial must be checked according to the inclusion and 
exclusion criteria at Visit 1 before randomisation.  
Any implementation of national requirements/law for the subject’s participation in the clinical 
trial must be ensured and described in the submission documentation to authorities/IRBs, as 
applicable. 
7.2 Inclusion Criteria 
1. Signed and dated informed consent has been obtained prior to any protocol-related
procedures.
2. Japanese subjects
3. Aged 20 years or above
4. Clinical diagnosis of psoriasis vulgaris amenable to topical treatment of less than or
equal to 30% BSA (excluding psoriasis on the face/genitals/skin folds)
5. A target psoriasis lesion on the body, which is of a minimum size of 10 cm2 and
scoring at least 2 (mild) for each of the clinical signs (redness, thickness and scaliness).
The lesion must not be on the scalp, face, genitals or skin folds.
6. Females of childbearing potential must have a negative result for a urine pregnancy test
at Day 1 (Visit 1) and must agree to use an adequate method of birth control, as judged
by the (sub)investigator, during the trial. The contraceptive method should have started
an adequate amount of time before the pregnancy test, which is dependent on the
particular method used and as judged by the (sub)investigator, and must continue for at
least 1 week after the last application of trial medication. A female is defined as not of
child-bearing potential if she is postmenopausal (12 months with no menses without an
alternative medical cause) or surgically sterile (tubal ligation/section, hysterectomy or
bilateral ovariectomy).
7. Able to communicate with the (sub)investigator and understand and comply with the
requirements of the trial.
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7.3 Exclusion Criteria 
1. Systemic use of biological treatments with a potential effect on psoriasis vulgaris
within the following time periods prior to randomisation:
- etanercept, adalimumab, infliximab, guselkumab, brodalumab – 3 months
- ustekinumab – 4 months
- secukinumab – 5 months
- other products – 3 months/5 half-lives (whichever is longer).
2. Systemic treatments with all therapies other than biological treatments with a potential
effect on psoriasis vulgaris (e.g., PDE4i, corticosteroids, vitamin D3 analogues,
retinoids, immunosuppressants such as ciclosporin and methotrexate) within 4 weeks
prior to randomisation.
3. PUVA therapy, UVB therapy or UVA therapy on the full body or on the target lesion
within 4 weeks prior to randomisation.
4. Topical treatment of psoriasis on the areas to be treated with trial medication within 2
weeks prior to randomisation (use of emollients, and corticosteroids of a strength up to
Japanese classification III (strong) on psoriasis lesion other than the target lesion are
allowed during this 2-week period, but not after randomisation).
5. Topical treatment of psoriasis on the face, genitals or skin folds with vitamin D3
analogues (e.g. calcipotriol, tacalcitol, maxacalcitol) Japanese classification I and II
(very strong to strongest) corticosteroids or immunosuppressants within 2 weeks prior
to randomisation.
6.
Topical treatment of conditions other than psoriasis with vitamin D3 analogues (e.g.
calcipotriol, tacalcitol, maxacalcitol), Japanese classification I and II (very strong to
strongest) corticosteroids or immunosuppressants within 2 weeks prior to
randomisation.
7. Planned initiation of, or changes in, concomitant medication that may affect psoriasis
vulgaris (e.g., beta-blockers, antimalaria drugs, lithium and ACE inhibitors) during the
trial.
8. Patients with any of the following disorders (a) or symptoms (b) present on the areas
to be treated with trial medication: (a) viral (e.g., herpes or varicella) lesions of the
skin, fungal, spirochetal or bacterial skin infections, parasitic infections, skin
manifestations in relation to syphilis or tuberculosis, rosacea, acne vulgaris, atrophic
skin, striae atrophicae, ichthyosis, acne rosacea, ulcers, burns, frostbite, wounds,
animal skin disease (scabies, crabs, lice, etc.) or (b) fragility of skin veins.
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9. Other inflammatory skin diseases (e.g., seborrhoeic dermatitis, contact dermatitis and
cutaneous mycosis) that may confound the evaluation of psoriasis vulgaris.
10. Erythrodermic, exfoliative or pustular psoriasis on the areas to be treated with trial
medication.
11. Planned excessive exposure of areas to be treated with trial medication to either
natural or artificial sunlight (including tanning booths, sun lamps, etc) during the trial.
12. Known or suspected disorders of calcium metabolism associated with hypercalcaemia,
or albumin-corrected serum calcium above the reference range from the sample taken
during screening.
13. Known severe renal insufficiency, severe hepatic disorders or severe heart disease that
is equivalent to greater than or equal to Grade 3 (CTCAE Ver.5.0, 27-Nov-2017).
14. Known or suspected hypersensitivity to any components of the IMPs.
15. Clinical signs or symptoms of Cushing’s disease or Addison’s disease
16. Subjects who have received treatment with any non-marketed drug substance (i.e. an
agent which has not yet been made available for clinical use following registration)
within the 4 weeks prior to randomisation, or longer if the class of substance requires a
longer washout as defined in exclusion criterion number 1 for biological treatments.
17. History of cancer within the last 5 years (Except for completely cured skin cancer)
18. Current participation in any other interventional clinical trial
19. Previously randomised in this trial
20. Females who are pregnant, wishing to become pregnant or are breast-feeding
21. 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.
22. 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.
7.4 Subject Screening Log 
The investigator will maintain a log of all subjects considered for screening, whether they 
have provided written informed consent or not (Subject Screening Log). The log should 
contain such information as date of screening, subject’s age, sex, reason for not enrolled and 
CRF subject number for enrolled subject. A copy of the log will be provided to the sponsor. 
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7.5 Subject Identification List 
The (sub)investigator must maintain a list of all subjects enrolled at the trial site including 
each subject's identity, date of enrolment and corresponding subject ID so that any subject 
may be identified if required for any reason. The list is kept by the investigator and must not 
be copied to or retained by LEO Pharma. 
At enrolment, each subject must be assigned a unique subject ID (eCRF number) to protect 
the subject's identity and which will be used in lieu of the subject's name when the 
(sub)investigator reports trial-related data.  
7.6 Restrictions during Trial 
Use of concomitant treatment must be recorded in the subject’s medical record and the eCRF 
(treatment/drug name, dose, indication and dates of start and stop). 
Treatments requiring a washout before Visit 1 are listed below, with the required washout 
period given in brackets: 

Systemic use of biological treatments with a potential effect on psoriasis vulgaris:
- etanercept, adalimumab, infliximab, guselkumab, brodalumab (3 months)
- ustekinumab (4 months)
- secukinumab (5 months)
- other products (3 months/5 half-lives, whichever is longer)

Systemic treatments with all therapies other than biological treatments with a potential
effect on psoriasis vulgaris, e.g., corticosteroids, vitamin D3 analogues, retinoids,
immunosuppressants such as ciclosporin and methotrexate (use of systemic antihistamines
and nasal and inhaled corticosteroids is allowed) (4 weeks)

PUVA therapy, UVB therapy or UVA therapy on the full body or on the target lesion (4
weeks)

Topical treatment of psoriasis on areas to be treated with trial medication (2 weeks), but
use of emollients, and weak to strong corticosteroids (Japanese Classifications V and III)
on psoriasis lesion other than the target lesion are allowed.

Topical treatment of other areas with vitamin D3 analogues (e.g. calcipotriol, tacalcitol,
maxacalcitol), immunosuppressants, very strong to strongest corticosteroids (Japanese
Classifications I and II) (2 weeks).

Treatment with any non-marketed drug substance, i.e. an agent which has not yet been
made available for clinical use following registration (4 weeks, or longer if the class of
substance requires a longer washout as defined above for biological treatments).
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Treatments which cannot be used during the trial (Visits 1-4) are the same as those requiring a 
washout, as listed previously, with the addition that the following are not allowed: 

Use of an emollient on areas to be treated with trial medication

Initiation of, or changes in, concomitant medication that may affect psoriasis vulgaris
(e.g., beta-blockers, antimalaria drugs, lithium and ACE inhibitors)

Excessive exposure of areas treated with trial medication to either natural or artificial
sunlight (including tanning booths, sun lamps, etc)
Hence, during the trial (Visits 1-4), psoriasis lesions will be treated with the trial medication, 
apart from those on the scalp, face, genitals and skin folds. For treatment of psoriasis lesions 
on the scalp, corticosteroids up to a ‘very strong’ classification (Japanese classification II) are 
allowed. Bath oils, moisturizing soaps, nasal antihistamines are allowed. 
During the follow-up period, there are no restrictions on the use of concomitant treatment. 
7.7 Withdrawal Criteria  
Subjects may withdraw from the trial for any of the following reasons: 
1. Unacceptable treatment efficacy: the (sub)investigator is free to withdraw the subject at
any time based on a medical judgement.
2. Unacceptable AEs: any AE that the (sub)investigator or the subject considers
unacceptable.
3. Exclusion criteria: any exclusion criteria which emerge/become apparent during the
subject’s participation in the clinical trial.
4. Voluntary withdrawal: subjects are free to withdraw from the clinical trial at any time
and for any reason.
5. Other reasons: other reasons than stated above which require the subject to (be) with-
draw(n) should be specified.
Subjects must be withdrawn if they are found to have become pregnant. 
Subjects with the target lesion achieving ‘substantial resolution’, as defined in section 5,  
before the end of 4 weeks’ treatment will complete the trial at this time (although will still be 
required to attend the follow-up visit up to 14 days later if applicable) 
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Subjects who are discovered, after randomisation, not to have fulfilled all inclusion/exclusion 
criteria at the time of randomisation, should be withdrawn from treatment unless the 
(sub)investigator finds withdrawal inappropriate, based on clinical and ethical evaluation.    
Reason(s) for withdrawal will be recorded in the eCRF.  Withdrawn subjects will not be 
substituted. 
Completion of trial is defined as: 
A subject who attends Visit 4 on Day 29 or later 
or 
A subject who attends Visit 4 earlier than Day 29, but the reason for attending earlier than 
Day 29 is not because (a) the (sub)investigator wishes to withdraw the subject, or (b) the 
subject wishes to withdraw 
or 
Subjects with the target lesion achieving ‘substantial resolution’, as defined in section 5, 
before the end of 4 weeks treatment. 
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8 Trial Schedule and Assessments 
8.1 Schedule of Trial Procedures 
Visits 
Screening 
1 
2 
3 
4/EoT 
Unscheduled/early 
withdrawal 
Follow 
upd 
Days 
-28 to -3a
1 
8 
15 
29 
Up to +14 
Visit Windowe 
- 
- 
+/- 1 
+/- 1 
+/- 2 
- 
Informed consent 
x 
Demographics/baseline 
characteristics 
x 
Medical 
history/concurrent 
diagnoses 
x 
Concurrent procedures 
x 
x 
x 
x 
x 
Concurrent medication 
x 
x 
x 
x 
x 
x 
x 
Selection of a target 
lesion 
x 
Laboratory assessment 
x 
x 
x 
x 
Adverse events 
x 
x 
x 
x 
x 
x 
x 
Physical examination 
x 
x 
x 
x 
x 
x 
x 
Pregnancy testb 
x 
x 
x 
Inclusion/exclusion 
criteria check 
x 
x 
Randomisation 
x 
Investigator’s 
assessment – sign 
score of target lesion 
x 
x 
x 
x 
x 
Investigator’s 
assessment – general 
change in target lesion 
x 
x 
x 
x 
Subject’s assessment: 
time spent for 
applicationf 
x 
x 
Subject’s assessment: 
ease of applicationf 
x 
x 
Supply IMP 
x 
x 
x 
Collect unused IMP 
x 
x 
x 
x 
Compliance check 
x 
x 
x 
x 
Completion of End of 
trial form 
xc 
x 
xc 
a  The minimum time between Screening Visit and Visit 1 is 3 days 
b  For females of child-bearing potential 
c  For screening failures and early withdrawals only 
d  Follow-up only if ongoing related AEs present at last on-treatment visit; to be done 14 days after this visit, 
    or when final outcome established, whichever comes first 
e  Relative to Visit 1 
f Compared to previous topical treatment 
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8.2 Informed Consent 
The subject must provide signed and dated informed consent before any trial related activity 
is carried out, including activities relating to the screening period such as washout. The End of 
Trial form in the eCRF must be completed for all subjects who have signed the informed 
consent. 
8.3 Demographics and Baseline Characteristics 
Date of birth, sex, height, weight, duration of psoriasis and concurrent diagnoses will be 
recorded at the Screening Visit. 
8.3.1 Medical History 
Relevant medical history must be recorded: 

Skin disease history: all past and current skin disease history should be collected
for each diagnosis within the previous 12 months; the start date and stop date will
be recorded (it will also be recorded if the diagnosis is ongoing). For topical
treatments, record whether the disease has been present in the current treatment
area.

Other medical and surgical history including concurrent diagnoses within the
previous 12 months. For each condition, diagnosis or surgical procedure, the start
date and stop date will be recorded (it will also be recorded if the condition,
diagnosis or surgical procedure is ongoing).
Relevant medical history also includes diseases which are specifically listed as exclusion 
criteria and diseases for which specific treatments are listed as exclusion criteria. 
8.4 Concurrent Medication and Concurrent Procedures 
Concurrent medication will be recorded at the Screening Visit (treatment/drug name, dose, 
indication and dates of start/stop).  Any changes in concurrent medication will be recorded at 
subsequent visits. 
Similarly, any concurrent procedure must also be recorded in the subject’s medical record and 
the eCRF. The following details will be recorded: procedure, body location, diagnosis, and 
start and stop date (it will also be recorded if the procedure is ongoing). 
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8.5 Selection of Target Lesion 
A target lesion on the body will be selected at the Screening Visit. The location of the target 
lesion will be recorded in the eCRF as trunk, arm excluding elbow, leg excluding knee, elbow 
or knee.  Location of the lesion will be specified in more detail in the subject records to allow 
identification of the lesion at subsequent visits. The target lesion will be assessed again at 
Visit 1, when the inclusion/exclusion criteria are checked, in order to check whether it meets 
the necessary requirements for size and severity at this time (see section 8.10). 
8.6 Laboratory Assessments 
A total of 4.5 mL of venous blood and a urine sample will be taken at the Screening Visit, 
Visit 1 and at Visit 4, hence 13.5 mL of blood in total for the trial. If a subject withdraws from 
or completes the trial at Visits 2 or 3, samples should be taken at this time in lieu of the Visit 
4 samples. The samples will be analysed for the following parameters: 
Haematology, whole blood 
Haemoglobin, haematocrit, platelets, RBC count, WBC count, HbA1c 
Chemistry, serum 
Calcium, phosphorus, blood urea nitrogen (BUN), creatinine, total bilirubin, total protein, 
albumin, SGOT (AST), SGPT (ALT), GGT, LDH, alkaline phosphatase.  
Urine, semi-quantitatively 
Urine Glucose, urine protein 
The central laboratory will provide the material and instructions necessary for the collection 
and transport of the samples, analyse the samples.   
If any laboratory results are clinically abnormal, the (sub)investigator should follow-up the 
subject as clinically appropriate. Any laboratory abnormality assessed as clinically significant 
by the (sub)investigator must be recorded as an AE in eCRF. 
8.7 Adverse Events 
AEs must be assessed and recorded as specified in section 9. 
8.8 Physical Examination 
A physical examination will be performed from Screening Visit to follow-up. If a subject 
withdraws from or completes the trial at Visits 2 or 3, the examination should be made at this 
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time in lieu of the one at Visit 4. The extent of the physical examination will be at the 
discretion of the (sub)investigator and will include general appearance and dermatological 
examination of the skin. Any abnormal findings will be recorded. 
8.9 Pregnancy Test 
A urine pregnancy test will be performed at the trial site at Visit 1 (prior to randomisation) and 
Visit 4 in female subjects of child-bearing potential. If a subject withdraws from or completes 
the trial at Visits 2 or 3, the test should be done at this time in lieu of the one at Visit 4. The 
test kits will be provided by the central laboratory. 
8.10 Inclusion/Exclusion Criteria 
Subjects’ eligibility for the clinical trial will be checked during screening and re-checked at 
Visit 1 before randomisation (when results of laboratory test at screening are available). After 
results of laboratory test at Visit 1 becomes available and if any clinically significant 
abnormality which meets exclusion criteria is found, the subject will be withdrawn from the 
trial (see section 7.7). 
8.11 Randomisation 
Subjects will be randomised at Visit 1 when all inclusion/exclusion criteria are satisfied, as 
specified in section 10.6. 
8.12 Investigator’s Assessment of Target Lesion 
The (sub)investigator must make the following assessments of the target lesion. All 
assessments for a subject should be made by the same (sub)investigator. In case the same 
(sub)investigator is not able to assess the same subject, measures should be taken at the site 
ensure consistent assessments by the (sub)investigators. 
Severity of clinical signs of target lesion 
The severity will be recorded for each of the signs of redness, thickness and scaliness at Visits 
1-4, according to the 9-point scales below:
Redness 
0 
= 
none (no erythema) 
0.5* 
1 
= 
slight (faint erythema, pink to very light red) 
1.5* 
2 
= 
mild (definite light red erythema) 
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2.5* 
3 
= 
moderate (dark red erythema) 
3.5* 
4 
= 
severe (very dark red erythema) 
Thickness 
0 
= 
none (no plaque elevation) 
0.5* 
1 
= 
slight (slight, barely perceptible elevation) 
1.5* 
2 
= 
mild (definite elevation but not thick) 
2.5* 
3 
= 
moderate (definite elevation, thick plaque with sharp edge) 
3.5* 
4 
= 
severe (very thick plaque with sharp edge) 
Scaliness 
0 
= 
none (no scaling) 
0.5* 
1 
= 
slight (sparse, fine scale, lesions only partially covered) 
1.5* 
2 
= 
mild (coarser scales, most of lesions covered) 
2.5* 
3 
= 
moderate (entire lesion covered with coarse scales) 
3.5* 
4 
= 
severe (very thick coarse scales, possibly fissured) 
* intermediate intervals (0.5, 1.5, 2.5, 3.5) are to serve as mid-points between the defined
grades (0, 1, 2, 3, 4).  See ‘Appendix 9: Descriptors for intermediate intervals in severity 
score of clinical signs of target lesion’ which shows descriptors for the intermediate intervals 
for the purposes of data coding. 
General change in target lesion 
At Visits 2-4, the general change in the target lesion from Visit 1 will be recorded according to 
the 5-point scale below. 
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Markedly improved 
+++ 
A very definite improvement (approx. 75% or more) 
Moderately improved 
++ 
A definite improvement (approx. 50%) 
Slightly improved 
+ 
Some definite improvement (approx. 25%), however, 
significant signs remain 
Unchanged 
+/- 
No change 
Aggravated 
- 
Worsened 
8.13 Subject’s Assessments 
At Visit 4, the subject will make the following assessments.  If a subject withdraws from or 
completes the trial at Visits 2 or 3, the assessment should be done at this time in lieu of the 
one at Visit 4. 
Time spent for application, scored as less time, slightly less time, unchanged, slightly more 
time, more time as compared to previous topical treatments. 
Ease of application, scored as very easy, easy, difficult, very difficult as compared to previous 
topical treatments. 
8.14  Supply/Return of IMP and Compliance 
Refer to sections 10.7.1 and 10.7.3
9 Adverse Events 

AEs and SAEs are defined in Appendix 3: Definitions of Adverse Events and
Serious Adverse Events.

Classification of AEs in terms of severity, causality and outcome are defined in
Appendix 4: Classification of Adverse Events.
9.1 Collection of Adverse Events 
AEs must be collected from the signing of the informed consent form until the last trial visit. 
AEs must be assessed by (sub) investigators who are medically qualified. 
At all visits, the (sub)investigator should ask the subject a non-leading question to the effect 
of: “How have you felt since I saw you last?” No specific symptoms should be asked for. It is 
important that the (sub)investigator also observes the subject for any changes not reported by 
the subject and records these changes. 
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If there are no AEs to record, no further questions should be asked and “NO” should be ticked 
in the eCRF. In case there are one or more AEs to record, “YES” should be ticked.  
9.2 Reporting of Adverse Events in the eCRF 
AEs reported by the subject or observed by the (sub)investigator must be recorded on the AE 
form of the eCRF and should be described in the following manner: 
The AE term will be in precise English medical terminology (i.e. 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 will be described as 
either:  

lesional/perilesional (≤ 2 cm from the border of lesion(s) treated with IMP), or

distant (>2 cm from the lesion border)
The duration of the AE must be reported as the start date and stop date of the event (it will 
also be recorded if the event is ongoing). In addition, it must be recorded whether the AE 
started prior to start of trial medication. 
AEs must be classified in terms of severity, causality and outcome according to the definitions 
in  Appendix 4: Classification of Adverse Events. 
9.2.1 Actions Taken as a Consequence of an AE 
Action taken with trial treatment: Any action taken with trial medication as a consequence of 
the AE must be recorded (dose not changed, dose reduced, dose increased, drug interrupted, 
drug withdrawn, not applicable, unknown). 
Other action taken: Any other action taken as a result of the AE must be recorded (none, 
concomitant medication, concurrent procedure). 
Withdrawn due to AE: It must be recorded whether the AE leads to withdrawal from the trial. 
9.3 Other Events to be Reported 
9.3.1 Pregnancy 
Any pregnancy occurring after first exposure to IMP and until the subject has completed the 
trial must be reported to LEO Pharma K.K. within 24 hours of first knowledge using the 
(paper) Pregnancy Form (Part I).  All such pregnancies must be followed up until delivery or 
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termination and final outcome must be reported on the (paper) Pregnancy Form (Part II) 
within 24 hours of first knowledge. 
The completed Pregnancy Forms must be faxed or scanned and e-mailed to LEO Pharma 
K.K. using the following fax number or e-mail address: 
Fax number: +81 3 6735 7767 
E-mail address: drug.safetyjp@leo-pharma.com
Please also confer with section 7.7, Withdrawal Criteria. 
9.3.2 Overdose 
An overdose is defined as a subject receiving a quantity of IMP per administration or per 
week which is in excess of that specified in this protocol. An overdose is either accidental or 
intentional.   
For Dovobet® ointment and LEO 90100 foam, overdose is defined as application of 
>90g/week, based upon the package insert of the already marketed Dovobet® ointment.
The term ‘overdose’ including a specification of why it occurred (accidental or intentional) 
must be recorded on the AE form of the eCRF. In addition, AEs originating from overdose 
must be recorded as separate events. If the AE originating from the overdose qualifies as an 
SAE, expedited reporting is required (Section 9.4). 
If the overdose is accidental and due to a device deficiency, the device deficiency must be 
reported as a product complaint as described in Section 10.9. 
9.3.3 Medication Error 
Medication error refers to any unintentional error in the dispensing or administration of a 
medicinal product while in the control of the (sub)investigator or subject. Broadly, medication 
errors fall into four categories: wrong medication, wrong dose (including strength, form, 
concentration, amount), wrong route of administration or wrong subject.   
The medication error must be documented on the AE form of the eCRF. In addition, AEs 
originating from a medication error must be documented on a separate line specifying the 
category of error (see definitions above).     
If the medication error is due to a device deficiency, the device deficiency must be reported as 
a product complaint as described in Section 10.9. 
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9.3.4 Misuse 
Misuse refers to situations where the medicinal product is intentionally and inappropriately 
used not in accordance with the protocol. 
The term ‘misuse’ must be documented on the AE form of the eCRF. In addition, AEs 
originating from misuse must be documented on a separate line. If the AE originating from 
misuse qualifies as an SAE, expedited reporting is required (Section 9.4).     
9.3.5 Abuse 
Abuse relates to the sporadic or persistent, intentional excessive use of an IMP which is 
accompanied by harmful physical or psychological effects. 
The term abuse must be documented on the AE form of the eCRF. In addition, AEs 
originating from abuse must be documented on a separate line. 
9.3.6 Aggravation of Condition 
Any clinically significant aggravation/exacerbation/worsening of any medical condition(s), 
compared to baseline, must be reported as an AE. 
9.4 Additional Reporting Requirements for Serious Adverse Events 
9.4.1 Investigator Reporting Responsibilities 
Any SAE must be reported to LEO Pharma K.K on the LEO Serious Adverse Event Form 
(paper) - Clinical Trials within 24 hours of first knowledge. 
This report should contain an assessment of available information on seriousness, severity, 
causal relationship to the IMP, comparator or trial procedure, the action taken, the outcome to 
date, and a narrative description of the course of the event.  
The completed SAE form must be faxed or scanned and e-mailed to LEO Pharma K.K. using 
the following fax number or e-mail address: 
Fax number: +81 3 6735 7767 
E-mail address: drug.safetyjp@leo-pharma.com
It may be relevant for the (sub)investigator to enclose other information with the SAE form, 
such as anonymised reports of diagnostic procedures, hospital records, autopsy reports, etc.  
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Additionally, Global Safety, LEO Pharma A/S may request further information in order to 
fully assess the SAE. The (sub)investigator must forward such information to Global Safety, 
LEO Pharma A/S via LEO Pharma K.K. upon request by fax or e-mail (see contact details 
above).  
The investigator must report SAEs to the director of the trial site. The director of the trial site 
must notify the local IRB(s) of SAEs as required by current applicable legislation for the 
concerned country. 
SAEs occurring after the completion of the clinical trial, including the protocol required post-
treatment follow-up period, should not be routinely sought or collected. However, such events 
should be reported to LEO Pharma K.K. if the (sub)investigator becomes aware of them.  
9.4.2 LEO Pharma Reporting Responsibilities 
Global Safety, LEO Pharma A/S is responsible for assessing whether or not a SAE is 
expected. The relevant reference document for those randomised to LEO 90100 foam is the 
current version of the Investigator’s Brochure for LEO 90100 foam. For those randomised to 
Dovobet® ointment, the relevant reference document is the Japanese package insert for 
Dovobet® ointment.  
Global Safety, LEO Pharma A/S and LEO Pharma K.K. (collectively called as ‘LEO 
Pharma’) will notify the regulatory authorities and concerned investigators of SAEs according 
to the current applicable legislation for the concerned country.  
The IRB(s) will be notified of SAEs according to the current applicable legislation for the 
concerned country. For Japanese sites, the investigator and LEO Pharma K.K. will be notified 
of the IRB review outcome by the director of the trial site. 
All SAEs which are assessed as causally related to the IMP(s) by either the investigator or 
LEO Pharma A/S, and which are not expected (Suspected, Unexpected Serious Adverse 
Reactions (SUSARs)) are subject to expedited reporting to regulatory authorities and IRB(s) 
according to the current applicable legislation in the concerned country. Investigators will be 
notified of these on an ongoing basis. In addition, in Japan all SAEs which are assessed as 
causally related to the IMP(s) by either the investigator or LEO Pharma A/S and are subject to 
expedited reporting in Japan, will be reported to regulatory authorities, IRB(s) and 
investigators according to the current applicable legislation in Japan. 
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9.5 Follow-up for Final Outcome of Adverse Events 
During the trial, the investigator should follow up for final outcome on all AEs (including 
SAEs). Once a subject leaves the clinical trial, the investigator should follow up on the 
outcome of all non-serious AEs classified as of possible/probable relationship to the IMP for 
14 days or until the final outcome is determined, whichever comes first. All related and not 
related SAEs must be followed up until a final outcome has been established, i.e. the follow-
up may continue beyond the end of the clinical trial. 
9.6 Handling of an Urgent Safety Measure 
An Urgent Safety Measure is a measure taken to implement an action/protocol deviation 
under an emergency. This is defined within the EU Directive as “…the occurrence of any new 
event relating to the conduct of the trial or the development of the investigational medicinal 
product where that new event is likely to affect the safety of the subjects, the sponsor and the 
investigator shall take appropriate urgent safety measures to protect the subjects against any 
immediate hazard.” (Article 10(b) of Directive 2001/20/EC). 
If the investigator becomes aware of information that necessitates an immediate change in the 
clinical trial procedure or a temporary halt to the clinical trial in order to protect clinical trial 
subjects from any immediate hazard to their health and safety, the investigator can do so 
without prior approval from LEO Pharma, regulatory authority(ies) or IRB(s). 
The investigator must immediately inform LEO Pharma K.K. of this change in the clinical 
trial procedure or of the temporary halt providing full details of the information and the 
decision making process leading to the implementation of the urgent safety measure.  
LEO Pharma K.K. must act immediately upon receipt of the urgent safety measure 
notification in accordance with the internal procedures and local legislation. 
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10 Investigational Medicinal Products 
10.1 Investigational Medicinal Product Description 
Finished product (brand) name (if 
available)/name of IMP 
LEO 90100 foam 
Formulation 
Foam 
Active ingredient name/concentration 
Calcipotriol hydrate 52.2 µg/g (equivalent to 50.0 µg/g 
calcipotriol) plus betamethasone dipropionate 0.643 mg/g 
Excipients 
Paraffin, white soft 
Paraffin, liquid 
Polyoxyproylene stearyl ether 
All-rac-alpha-tocopherol 
Propellants: 
Dimethyl ether 
Butane 
Pack size 
60 g can 
Sites involved in manufacturing, 
labelling or release 
• LEO Laboratories Ltd, 285 Cashel Road, Crumlin, Dublin
12, Ireland
• LEO Pharma A/S, Industriparken 55
2750 Ballerup, Denmark
• Colep Laupheim GmbH & Co. KG, Fockestraβe 12, 88471
Laupheim, Germany
• Klifo A/S, Smedeland 36, DK 2600 Glostrup, Denmark
Finished product (brand) name (if 
available)/name of IMP 
Dovobet® ointment 
Formulation 
Ointment 
Active ingredient name/concentration 
Calcipotriol hydrate 52.2 µg/g (equivalent to 50.0 µg/g 
calcipotriol) plus betamethasone dipropionate 0.643 mg/g 
Excipients 
Paraffin, white soft 
Paraffin, liquid 
Polyoxyproylene stearyl ether 
All-rac-alpha-tocopherol 
Pack size 
30g tube 
Sites involved in manufacturing, 
labelling or release 
• LEO Laboratories Ltd, 285 Cashel Road, Crumlin, Dublin
12, Ireland
• LEO Pharma A/S, Industriparken 55
2750 Ballerup, Denmark
• Klifo A/S, Smedeland 36, DK 2600 Glostrup, Denmark
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10.2 Administration of Investigational Medicinal Products 
Route of administration 
Topical 
Dosing range 
Depending on the size of psoriasis lesion 
Dosing frequency 
Once daily 
Weekly maximum 
60g 
The instructions for use, as detailed on the subject treatment instructions, are as follows: 
For subjects receiving tubes: 

Remove the cap and break the seal of the tube using the point in the back of the cap.  Turn
the cap round while still pushing to create a round hole.

Squeeze the ointment onto a clean finger

Apply with the fingertips
For subjects receiving cans: 

Keep the cans in the supplied outer carton, to protect from light.

The can should be shaken for a few seconds before use.

Application can be performed by either applying after spraying directly on the affected
areas or by spraying in the palm and applying on to the affected areas with the fingertips.

Use enough to cover each lesion. Apply gently with fingertips

Apply the study medication by holding the spray can at least 3cm from the skin and spray.
For both groups of subjects: 

Apply the trial medication to psoriasis once daily.

Apply trial medication first to the ‘target lesion’, as instructed by the trial doctor, and
then apply to other lesions to the extent possible for lesions that may be hard to reach,
namely on the back.

Take care not to spread the medication onto unaffected skin

Avoid accidental contact to the face, eyes or mouth

Wash hands after each application

Do not use the trial medication on any psoriasis on the face, scalp, genitals or skin folds
(armpits, groin, under the breasts, those around the buttocks and the perianal area)

Do not use any other treatments on psoriasis, apart from medication which the
(sub)investigator may prescribe for use on psoriasis on the face, scalp, genitals or skin
folds

If taking a bath/shower or washing hair around the time of medication application, apply
the medication afterwards (to avoid washing it off). However, do not apply trial
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medication or emollients on the target lesion before coming to the site on the day of the 
Visits. 

Do not bandage or otherwise cover or wrap the treated areas

Avoid excessive exposure of treated areas to either natural or artificial sunlight (including
tanning booths, sun lamps, etc.)

Keep the medication out of the sight and reach of children and pets

The medication is for external use only

Return all medication at each visit

After applying, avoid contact with textiles which are easily stained by grease, e.g. silk
The subject treatment instructions will be explained to the subject at Visit 1, and the subject 
will be given a copy. A subject trial card will also be given out at Screening visit. 
Subjects with the target lesion achieving ‘substantial resolution’, as defined in section 5,  
before the end of 4 weeks’ treatment will complete the trial at this time (although will still be 
required to attend the follow-up visit up to 14 days later, if applicable).  
10.3 Precautions/Over dosage 
Calcipotriol  
Calcipotriol may cause hypercalcaemia. Serum calcium is quickly normalised, however, when 
treatment is discontinued. In addition, calcipotriol may cause decline in kidney function 
associated with hypercalcaemia. The major symptoms of hypercalcaemia include malaise, 
feelings of weakness, anorexia, nausea, vomiting, enlarged feeling of abdomen, abdominal 
pain, headache, dizziness, muscle pain and muscle weakness. 
Betamethasone dipropionate 
AEs found in connection with systemic corticosteroid treatment, such as adrenocortical 
suppression or impact on the metabolic control of diabetes mellitus, may occur also during 
topical corticosteroid treatment due to systemic absorption. 
There may be a risk of generalised pustular psoriasis or of rebound effects when discontinuing 
treatment. Medical supervision should therefore continue in the post-treatment period. 
10.4 Packaging of Investigational Medicinal Products 
The IMPs will be packaged in individually numbered kits. Primary and secondary packaging 
materials will be individually labelled. The details of the primary and secondary packaging 
are described in the trial product manual.  
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The labelling of IMPs must be in accordance with EU GMP Annex 13, local regulations and 
trial requirements. 
10.5 Storage of Investigational Medicinal Products 
All LEO Pharma supplied IMPs must be stored in a secure and restricted area under the 
conditions specified on the label. At the investigational site, they should not be stored above 
30°C, and not stored in a freezer. IMPs must remain in the original container until dispensed. 
The cans of LEO 90100 foam must be dispensed to the subject in the carton each can is 
supplied in, in order to protect it from light. 
10.6 Treatment Assignment and Dispensing 
At Visit 1, subjects who have been found to comply with all the inclusion and exclusion 
criteria will be randomised to receive treatment with either LEO 90100 foam or Dovobet® 
ointment. Treatment assignment will be pre-planned according to a computer-generated 
randomisation schedule in a 1:1 ratio, stratified by investigator site. Randomisation will be 
performed by a sealed envelope method at site. After confirming subject’s eligibility criteria, 
(sub)investigator opens only the corresponding envelope that contains treatment assignment 
in the predefined order, i.e. by specifying which of the two treatments the subject should 
receive. The person who opened the envelope writes the date, time and name on the envelope. 
The site can then choose any available outer box with the assigned medication for the subject.  
Full details of this randomisation procedure will be given in a separate document. 
From this outer box, IMP is dispensed to the subject at Visits 1, 2 and 3.  At Visit 1, the carton 
labelled ‘Week 1’ is dispensed. At Visit 2, the carton labelled ‘Week 2’ is dispensed.  At Visit 
3, the cartons labelled ‘Week 3’ and ‘Week 4’ are dispensed, and the subject should be 
instructed to use the medication labelled ‘Week 3’ for the next week, and then the medication 
labelled ‘Week 4’ for the subsequent week.  
At Visits 2, 3 and 4, the medication dispensed at Visits 1, 2 and 3, respectively, should be 
returned by the subject, including any empty cans/tubes, and retained by the site for 
collection. 
10.6.1 Randomisation Code List 
The randomisation schedule will be prepared by LEO Pharma A/S or CRO. It must not be 
provided to investigator site staff. 
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10.7 Drug Accountability and Compliance Checks 
10.7.1 Drug Accountability 
The director of the trial site is fully responsible for the IMPs at the trial site and the IMP 
administrator is responsible for maintaining adequate control of the IMPs and for 
documenting all transactions with them in Trial Medication Inventory Log.  
At Visit 2, 3 and 4, the IMP (including empty containers) dispensed at Visits 1, 2 and 3, 
respectively, must be returned by the subject. An inventory at subject level must be kept of the 
IMP given to and returned by each subject in the trial. This inventory must be available for 
inspection during monitoring visits and will be checked by the monitor to ensure correct 
dispensing of the IMP. 
All IMPs supplied by the Contract Manufacturing Organisation (CMO) on behalf of 
LEO Pharma must be returned to the CMO. Prior to their return, they must be fully accounted 
for by the monitor with the help of the person responsible for dispensing the IMPs. 
Accountability must be documented by using drug accountability forms. IMPs will be 
returned from the trial site to the CMO. The IMP returned to the CMO will be reconciled with 
the Trial Medication Inventory Log. 
10.7.2 Investigational Medicinal Product Destruction 
Used and unused IMPs will be destroyed by the CMO according to LEO Pharma procedures. 
10.7.3 Treatment Compliance 
At Visits 2, 3 and 4, the subject should be asked if she/he has used the IMP as prescribed. If a 
subject is found to be non-compliant, the (sub)investigator should remind the subject of the 
importance of following the instructions given including using the trial products as 
prescribed. The degree of non-compliance (number of applications missed, or other deviation) 
and the reason for it must be recorded in the eCRF. Subjects will be provided with a diary for 
recording of this information.   
10.8  Provision for Subject Care following Trial Completion 
In order to ensure appropriate treatment of the subjects after they have completed the trial, the 
subjects will be treated at the investigator’s discretion or referred to other physician(s) 
according to standard practice. 
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10.9 Reporting Product Complaints 
Any defects or issues with the IMP must be reported to LEO Pharma K.K. on the trial specific 
(paper) Complaint Form within 3 days of first knowledge.  
Critical complaints (defined as any defect or issue that has or potentially could have a serious 
impact for the subject [e.g., SAE]) must be reported to LEO Pharma K.K. within 24 hours of 
first knowledge.  
Complaint forms should contain a detailed description of the defect or issue, including 
whether it led to an AE. (S)AEs which occur due to a defect or issue with the IMPs will be 
reported by the investigator as described in sections 9.2 and 9.4.  
During the investigation of the product complaint, the IMP(s) must be stored at labelled 
conditions unless otherwise instructed; the trial site will be notified whether the IMP(s) needs 
to be returned for further investigation or may be destroyed. 
LEO Pharma K.K. contact information for reporting product complaints: 
Fax number: +81 3 6735 7767  
E-mail address: drug.safetyjp@leo-pharma.com
10.10 
Emergency Unblinding of Individual Subject Treatment 
Not applicable as this trial is open-label.
11 Statistical Methods   
11.1 Determination of Sample Size 
The sample size is not based on power calculations (section 6.2), but is based on regulatory 
considerations, as 80 subjects per treatment group is the number that has been used for a 
similar trial in Japan to compare different topical formulations of the same active ingredient 
(28).  
11.2 Definition of Trial Analysis Sets 
All subjects enrolled in the trial (i.e. subjects for whom informed consent has been obtained 
and who have been registered in a clinical trial) will be accounted for in the clinical trial 
report. 
All randomised subjects are included in the full analysis set and will be analysed for efficacy. 
Exclusions from the full analysis set can be considered in special cases as described in ICH 
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E9, section 5.2.1., Full Analysis Set. Any exclusion of subjects from the full analysis set will 
be justified.  
A per protocol analysis set will be defined by excluding subjects from the full analysis set 
who had less than 75% compliance or based on a review of protocol deviations with 
justification.   
A safety analysis set will be defined by excluding randomised subjects who either received no 
treatment with IMP and/or for whom no post-baseline safety evaluations are available. 
The decisions regarding inclusion/exclusion of subjects and/or subject data from the trial 
analysis sets will be documented in the analysis set definition document. 
11.3 Statistical Analysis 
11.3.1 Disposition of Subjects 
The reasons for leaving the trial will be presented for all randomised subjects by last visit 
attended and by treatment group. 
11.3.2 Demographics and other Baseline Characteristics 
Descriptive statistics of demographics and other baseline characteristics will be presented for 
all randomised subjects and by treatment group.  
Demographics include age and sex. Other baseline characteristics include height, weight, 
BMI, duration of psoriasis, baseline severity of clinical signs, location of target lesion on the 
body, concurrent diagnoses (including indications for concomitant medication) and 
concomitant medication. 
Presentations of age, sex, and baseline severity of clinical signs by treatment group will also 
be given by site. 
11.3.3 Exposure and Treatment Compliance 
Compliance with treatment instructions will be summarised for each treatment group and for 
all randomised subjects. The percentage of missed applications for each visit interval (visit 1 
to 2, visit 2 to 3 and visit 3 to 4) will be calculated as follows: the number of applications of 
trial medication missed for a particular visit interval will be divided by the total number of 
days for the visit interval, and then multiplied by 100 to give a percentage. 
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The percentage of missed applications for the total treatment period will be calculated as 
follows: the total number of applications of trial medication missed between Visit 1 and the 
last on-treatment visit will be divided by the total number of days between Visit 1 and the last 
on-treatment visit, and then multiplied by 100 to give a percentage.  
The percentage of missed applications will be allocated to one of the following categories: 
≤10%, >10% to ≤25%, >25% to ≤40%, >40% to ≤50%, >50%. 
11.3.4  Analysis of Primary Efficacy Endpoint 
The primary endpoint, as defined in section 5, will be analysed for the full analysis set and for 
the per protocol analysis set. The analysis using the full analysis set will be regarded as 
primary, while the per protocol analysis set will act as supportive. 
Rates of subjects with the event defined by the primary endpoint, ‘overall improvement rate’ 
for the target lesion at Visit 4 (end of Week 4), will be compared between treatment groups by 
means of Fisher’s exact test. Estimated rates, odds ratio and its 95% CI will be presented, 
together with the p-value from Fisher’s exact test. The number and percentage of subjects 
with the event will be tabulated for each treatment group and also presented for each site by 
treatment group.   
11.3.5 Analysis of Secondary Efficacy Endpoints 
The secondary endpoints, as defined in section 5, will be analysed for the full analysis set and 
for the per protocol analysis set.  The analysis using the full analysis set will be regarded as 
primary, while the per protocol analysis set will act as supportive. 
The number and percentage of subjects with ‘overall improvement rate’ will be tabulated for 
Visits 2 and 3 (end of Weeks 1 and 2) and by treatment group. 
Descriptive statistics for observed values and change from baseline to Visit 4 (end of Week 4) 
for the total sign score for the target lesion will be summarised as mean, SD, median, 
minimum and maximum values for each treatment group. 
In addition, for the change in the total sign score, the estimated difference between the 
treatment groups in the mean change (LEO 90100 foam group – Dovobet® ointment group) 
will be calculated with 95% confidence interval. The treatment difference of the change in the 
total sign score at Visit 4 will be estimated with an ANOVA with treatment as fixed effect. 
11.3.6 Exploratory Analysis of Efficacy  
The following will be tabulated for the full analyses set. 
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The number and percentage of subjects with ‘substantial resolution’ of clinical signs for the 
target lesion will be tabulated by visit and treatment group. 
The general change in target lesion will be tabulated by treatment group and visit. The clinical 
signs for the target lesion from baseline to all subsequent visits will be tabulated by treatment 
group, as both the number and percentage of subjects in each category (markedly improved, 
moderately improved, slightly improved, unchanged and aggravated). Further, the number and 
percentage of subjects with a change of ‘moderately improved’ or better will be tabulated by 
treatment group and visit. 
The change in total sign score for the target lesion from baseline to Visits 2 and 3 (end of 
Weeks 1 and 2) by treatment will be summarised as mean, SD, median, minimum and 
maximum values. 
The change in score for the severity of each clinical sign for the target lesion from baseline to 
each subsequent visit by treatment will be summarised as mean, SD, median, minimum and 
maximum values. In addition, the estimated difference between the treatment groups 
(LEO 90100 foam group – Dovobet® ointment group) in the mean change from baseline to 
Visit 4 (end of Week 4) will be calculated for each clinical sign with 95% confidence interval. 
11.3.7 Exploratory Analysis of Subject Assessments 
The number and percentage of subjects in each category for ‘time spent for application’ (less 
time, slightly less time, unchanged, slightly more time, more time) and ‘ease of application’ 
(very easy, easy, difficult, very difficult) will be tabulated at Visit 4 (end of Week 4) by 
treatment group. 
In addition, a difference between the two treatment groups will be calculated for each subject 
assessment with odds ratio and 95% confidence interval. 
11.3.8 Analysis of Safety 
The analysis of safety will be based on the safety analysis set. 
11.3.8.1 Adverse Events 
AEs will be coded during the course of the trial according to MedDRA. AEs will be presented 
by preferred terms and primary system organ class.  
Only treatment emergent AEs will be tabulated but all AEs recorded during the course of the 
trial will be included in the subject data listings. An event will be considered emergent with 
the trial treatment if started after the first application of IMP or if started before the first 
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application of IMP and worsened in severity thereafter. In each of the tabulations, AEs are 
defined by MedDRA preferred terms within primary system organ class. 
An overall summary of AEs and number (percentage) of subjects with any AEs, SAEs, 
premature discontinuations from the trial due to AEs, treatment related AEs and AEs stratified 
by severity will be presented. 
The number of AEs and number (percentage) of subjects for each type of AE will be tabulated 
by treatment group.  A similar tabulation will be made for AEs stratified by severity.  
The causal relationship to trial medication for each type of AEs will be tabulated by treatment 
group. Where there are several recordings of causal relationship to the IMP for a given type of 
AE for a subject, causal relationship will be taken as the most-related recording from the last 
report of that AE, since that is when the (sub)investigator will be in possession of most 
information and so best able to judge causal relationship.  
Related AEs are defined as AEs for which the (sub)investigator has not described the causal 
relationship to IMP as ‘not related’. The number of subjects experiencing each type of related 
AE will be tabulated regardless of the number of times each related AE is reported by each 
subject.  
Cutaneous AEs will be tabulated, similarly stratified as ‘lesional/perilesional’ or ‘distant’. 
SAEs will be evaluated separately and a narrative for each will be given. 
AEs leading to withdrawal from trial or discontinuation of IMP will be listed. 
11.3.8.2 Clinical Laboratory Evaluation 
The observed values and change from baseline in each of the haematology and chemistry 
laboratory parameters will be summarised as mean, geometric mean, coefficient of variation, 
SD, median, minimum and maximum values. 
The haematology and chemistry laboratory parameters will also be classified as ‘low’, 
‘normal’ or ‘high’, depending on whether the value is below, within or above the reference 
range, respectively. Urine glucose and protein will be classified as ‘absent’ or ‘present’. Shift 
tables will be produced showing the categories at Visit 1 (baseline) against those at Visit 4 
(end of Week 4). 
Laboratory parameters outside the reference range will be indicated in the subject data 
listings. 
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11.3.9 Interim Analysis 
No interim analyses are planned. 
11.3.10 
General Principles 
All significance tests will be two-sided using the 5% significance level. All confidence 
intervals will be presented with 95% degree of confidence.  
An observed cases approach will be used for tabulations of data by visit (i.e. involving only 
those subjects who attended each specific visit). 
Categorical data will be summarised using the number and percentage of subjects in each 
category and treatment group. Continuous data will be summarised using the mean, median, 
standard deviation (SD), minimum and maximum values. For laboratory data, the geometric 
mean and coefficient of variation will be included. 
‘Baseline’ value is defined as the value from the latest assessment before treatment, i.e.  at 
Visit 1 (Day 1) before randomisation. 
Any changes from the statistical analysis planned in this clinical trial protocol will be 
described and justified in a protocol amendment/the statistical analysis plan and/or in the 
clinical trial report dependent on the type of deviation.  
11.3.11 
Handling of Missing Values 
In this trial the imputation approach will be the Last Observation Carried Forward (LOCF) as 
we expect no or very few subjects to drop out. Overseas many trials have been conducted 
with LEO 90100 where the dropout rate was very low. There is no evidence to support that 
psoriasis is a different disease in Japan than is the rest of the world. This is consistent with the 
procedure for determining the primary endpoint for subjects who have substantial resolution 
of the target lesion before the end of 4 weeks of treatment. 
Sensitivity analyses where missing values of the primary endpoint are imputed by either 
achieving or not achieving ‘overall improvement rate’, will be done. Imputement will be done 
for each treatment group separately and with two treatment groups and two outcomes, there 
will be four sensitivity analyses in total. These sensitivity analyses will define the range to 
which the result of the primary analysis would belong, in case no missing values had been 
present.
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12 References 
1. National Center for Health Statistics. Current estimates from the National Health
Interview Survey: United States, 1996, Vital Health Stat 1999; 10(200): 81-6.
2. Farber EM, Nall L. Epidemiology: Natural history and genetics. In: Roenigk HHJ,
Maibach HI, editors. Psoriasis. New York: Marcel Dekker, 1998: 107-57.
3. Kawada A, Tezuka T, Nakamizo Y, Kimura H, Nakagawa H, Ohkido M et al.  A
survey of psoriasis patients in Japan from 1982 to 2001.  Journal of Dermatological
Science 2003; 31: 59-64
4. Gottlieb AB. Psoriasis. Dis Manag Clin Outcomes 1998; 1(6): 195-202.
5. Gelfand JM, Feldman SR, Stern RS, Thomas J, Rolstad T, Margolis DJ. Determinants
of quality of life in patients with psoriasis: a study from the US population. J Am
Acad Dermatol 2004; 51(5): 704-8.
6. Lowes MA, Bowcock AM, Krueger JG. Pathogenesis and therapy of psoriasis. Nature
2007; 445: 866-73.
7. Gottlieb AB, Miller B, Lowe N, Shapiro W, Hudson C, Bright R at al. Subcutaneously
administered efalizumab (anti-CD11a) improves signs and symptoms of moderate to
severe plaque psoriasis. J Cutan Med Surg 2003; 7: 198-207.
8. Griffiths CE. The immunological basis of psoriasis. J Eur Acad Dermatol Venereol
2003; 17 Suppl 2:1-5.
9. Iizuka H. Pyramid plan of the psoriasis treatment, Jpn. J. Dermatol.,
2006;116(9):1285-1293
10. Kawada A. Epidemiology and treatment of psoriasis –Recent knowledge-. Clinic all-
round. 2007;56(12):3285-3286
11. Umezawa Y: World standardized guidance for psoriasis treatment, , Jpn. J. Dermatol.,
2006; 116(12): 1721-1738.
12. Callen JP, Krueger GG, Lebwohl M, McBurney EI; Mease P, Menter A et al. AAD
consensus statement on psoriasis therapies. J Am Acad Dermatol 2003; 49(5): 897-9.
13. Koo JY. Current consensus and update on psoriasis therapy: a perspective from the
U.S. J Dermatol.1999; 26(11):723-733.
14. Menter A, Korman NJ, Elmets CA, Feldman SR, Gelfand JM, Gordon KB, et al.
Gudelines of care for the management of psoriasis and psoriasis 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.
15. Kragballe K, Barnes L, Hamberg KJ, Hutchinson P, Murphy F, Møller S, et al.
Calcipotriol cream with or without concurrent topical corticosteroid in psoriasis:
Tolerability and efficacy. Br J Dermatol 1998,139:649-654.
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16. Ruzicka R, Lorenz B. Comparison of calcipotriol monotherapy and a combination of
calcipotriol and betamethasone valerate after 2 weeks’ treatment with calcipotriol in
the topical therapy of psoriasis vulgaris: A multicentre, double-blind, z study. Br J
Dermatol 1998;138:254-258.
17. Ortonne JP, Bazek J, Binet et al. Psoriasis: new treatment modality with calcipotriol
and betamethasone dipropionate. Nouv Dermatol 1994;13:746-751.
18. Lebwohl M, Siskin SB, Epinette W, Breneman D, Funicella T, Kalb R, et al. A 
multicenter trial of calcipotriene ointment and halobetasol ointment compared with
either agent alone for the treatment of psoriasis. J Am Acad Dermatol 1996; 5:268-
269
19. Singh S, Reddy DCS, Pandey SS. Topical therapy for psoriasis with the use of
augmented betamethasone and calcipotriene on alternative weeks. J Am Acad
Dermatol 2000;43:61-65.
20. Ichihashi N, Izumi T, Takagi H, et al. Evaluation of combination therapy of topical
Vitamin D3 and steroid.–weekday and weekend therapy-. Journal of New Remedies
& Clinics. 2004;53(4):427-433.
21. Sarukawa M, Nagao M, Igarashi A. Case report of three psoriasis patients treated by
the combination of betamethasone butyrate propionate and calcipotriol. Journal of
New Remedies & Clinics. 2007;56(1):47-52.
22. Ozawa A. Psoriasis 2006. Jpn. J. Dermatol 2006;116(2):143-163.
23. Patel B, Siskin S, Krazmien R, Lebwohl M. Compatibility of calcipotriene with other
topical medications. J Am Acad Dermatol 1998; 38(6):1010-1011.
24. Nakagawa H, Igarashi A, Eto T., et al.  The results of a psoriasis patients’ satisfaction
survey (second report): analysis of factors contributing to overall satisfaction, Jpn. J.
Dermatol 2005;115(10):1449-1459.
25. Abe M, Ishikawa O. Selection of vitamin D3. Visual Dermatology 2005;4(3):222-227.
26. Nakagawa H, et al. Actual situation of drug therapy based on questionnaire survey.
Mebio 2002;19(8) 8-11.
27. Clinical Trial Report. Skin Irritation Trial of LEO 90100 foam (calcipotriol hydrate
plus betamethasone dipropionate) in healthy Japanese subjects. Ballerup, Denmark:
LEO Pharma, Medical Department; 2018 June 28. Trial No.: LP0053-1007
28. Nakagawa H, Tamaki K. The Efficacy and Safety of Maxacalcitol Lotion for Psoriasis
Vulgaris. Jpn J Clin Dermatol 2007; 61: 771-9
29. Long CC, Finlay AY.  The finger-tip unit: a new practical measure.  Clin Exp
Dermaotol 1991; 16: 444-447.
30. World Medical Association 2013. Declaration of Helsinki – ethical principles for
medical research involving human subjects. 7th (Fortaleza) amendment.
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31. International Ethical Guidelines for Health-related Research Involving Humans,
Fourth Edition. Geneva. Council for International Organizations of Medical Sciences
(CIOMS); 2016.
32. International Council for Harmonisation of Technical Requirements for
Pharmaceuticals for Human Use (ICH) 2016. Integrated addendum to ICH E6(R1):
Guideline for good clinical practice E6(R2)
33. Schulz KF, Altman DG, Moher D, CONSORT Group. CONSORT 2010 statement:
updated guidelines for reporting parallel group randomised trials. BMC Med.
2010;8:18.
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List of Appendices 
 Appendix 1: Protocol Summary 
Appendix 2: Japanese Package Insert for Dovobet® ointment 
Appendix 3: Definitions of Adverse Events and Serious Adverse Events 
 Appendix 4: Classification of Adverse Events 
Appendix 5: Trial governance considerations 
Appendix 6: Contact list of LEO Pharma A/S, LEO Pharma K.K., protocol authors, vendors,  
international coordinating investigator and medical expert (Japan) 
Appendix 7: WHO Classification of Topical Corticosteroids 
Appendix 8: WHO Classification of Topical Corticosteroids compared to the Japanese 
Classification 
Appendix 9: Descriptors for intermediate intervals in severity score of clinical signs of target 
lesion 
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13 Appendix 1: Protocol Summary 
Name of finished/ 
investigational 
medicinal 
product 
LEO 90100 foam 
Name of active 
substance 
Calcipotriol hydrate and betamethasone dipropionate 
Title of trial/trial 
ID 
Efficacy and safety of LEO 90100 foam in Japanese subjects with 
psoriasis vulgaris / LP0053-1422 
Coordinating 
investigator 
Hidemi Nakagawa, MD, PhD 
Sponsor’s name/ 
address 
LEO Pharma A/S, Denmark, Ballerup.   
LEO Pharma K.K. is the sponsor of the clinical trial in Japan on behalf 
of LEO Pharma A/S. 
LEO Pharma K.K., Tokyo, Japan. 
Estimated 
number of trial 
sites and 
distribution 
Twenty trial sites in Japan 
Trial period 
Q1 2019 to Q3 2019 
Main objectives 
and endpoints 
Objectives 
Primary objective:  
To compare the efficacy of LEO 90100 foam with Dovobet® ointment in 
the treatment of psoriasis in Japanese subjects. 
Secondary objective:  
To compare the safety of LEO 90100 foam with Dovobet® ointment in 
the treatment of psoriasis in Japanese subjects. 
Endpoints 
Primary endpoint:  
‘Overall improvement rate’ for the target lesion at Visit 4 (end of Week 
4), defined as  ‘substantial resolution’ of clinical signs or at least 
‘moderately improved’ in the general change in the lesion. ‘Substantial 
resolution’ is defined as a clinical score for thickness and scaliness of 0 
and a clinical score for redness of 1 or less in the severity of clinical 
signs of the lesion. 
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Secondary endpoint:  
Subjects with ‘overall improvement rate’ for the target lesion at Visits 2 
and 3 (end of Weeks 1 and 2) 
The change in the sum of the scores (total sign score) for the severity of 
the three clinical signs (thickness, scaliness, redness) from Visit 1 to 
Visit 4 (end of Week 4) for the target lesion. 
Final collection 
of data for the 
primary endpoint 
Visit 4 (end of Week 4) 
Methodology 
A phase 3, national, multi-centre, 4-week, prospective, randomised, 
controlled, parallel-group, open trial of LEO 90100 foam versus 
Dovobet® ointment (each containing calcipotriol hydrate 52.2 µg/g 
[equivalent to 50.0 µg/g calcipotriol] plus betamethasone dipropionate 
0.643 mg/g) in Japanese subjects with psoriasis vulgaris.  
Each subject will have one target lesion of psoriasis identified on the 
body. Subjects will be randomised to treat psoriasis with either LEO 
90100 foam or Dovobet® ointment for 4 weeks. 
Number of 
subjects to be 
enrolled 
A total of 180 subjects will be randomised in a 1:1 ratio to the two 
treatment groups, i.e. 90 in each treatment group in order to provide at 
least 80 subjects per group who complete the trial. It is anticipated that 
approximately 200 subjects will be enrolled in order to provide 180 
randomised subjects 
Main criteria for 
inclusion 
1. Japanese subjects aged 20 years or more
2. Clinical diagnosis of psoriasis vulgaris of less than or equal to  30%
BSA (excluding any psoriasis on the face/skin folds/genitals)
3. A target psoriasis lesion on the body, of a minimum size  of 10 cm2
and scoring at least 2 (mild) for each of redness, thickness and
scaliness
4. Females of childbearing potential must have a negative result for a
urine pregnancy test at Day 1 (Visit 1) and must agree to use an
adequate method of birth control
Main criteria for 
exclusion 
1. Use of systemic treatment with an effect on psoriaisis
2. Use of UV therapy on full body or on the target lesion
3. Use of topical treatment on areas to be treated with trial medication
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4. Topical treatment on areas other than treated areas with vitamin D
analogues, immunosuppressants or strong/very strong corticosteroids
5. Skin diseases besides psoriasis on the areas to be treated with trial
medication.
6. Disorders of calcium metabolism, hypercalcaemia, renal
insufficiency, hepatic disorders, heart disease.
Investigational 
medicinal 
product 
LEO 90100 foam (containing calcipotriol hydrate 52.2 µg/g [equivalent 
to 50.0 µg/g calcipotriol] plus betamethasone dipropionate 0.643 mg/g)  
applied to a target lesion and any other areas of psoriasis once daily 
Investigational 
reference product 
Dovobet® ointment (containing calcipotriol hydrate 52.2 µg/g 
[equivalent to 50.0 µg/g calcipotriol] plus betamethasone dipropionate 
0.643 mg/g) applied to a target lesion and any other areas of psoriasis 
once daily 
Duration of 
treatment 
Screening period: up to 4 weeks 
Treatment period: up to 4 weeks 
Follow-up period (if required): up to 2 weeks 
Main assessments The severity of each clinical sign (redness, thickness, scaliness) of the 
target lesion on a 9-point scale, from 0 = none to 4 = severe 
The general change in the target lesion from baseline on 5-point scale 
(markedly improved, moderately improved, slightly improved, 
unchanged, aggravated) 
Statistical 
methods 
Fisher’s exact test 
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14 Appendix 2: Japanese Package Insert for Dovobet® ointment 
Revised in Feb/2018 (2nd edition) 
Prepared in Sep/2014 
Japan standard commodity 
classification number 
872699 
Powerful drug 
Prescription drug  note 
Therapeutic drug for psoriasis vulgaris 
Dovobet® Ointment 
Calcipotriol hydrate/Betamethasone Dipropionate 
Combination 
Dovobet ® Ointment 
Approval number 
22600AMX00752 
NHI price listing 
September 2014 
Initial marketing in 
Japan 
September 2014 
International birth date March 2001 
Storage: Stored at room temperature 
Expiration date: Indicated on the carton, etc. (Two year after being manufactured) 
Note) Cautions – Use only under description as directed by a physician 
[Contraindications (This medication contraindicated in the following patients.)]
1.
Patients who have a history of hypersensitivity to any ingredients of this product
2.
Patients with bacterial, fungal, spirochetal or viral skin infection or with animal skin
disease (scabies, crab lice, etc.) [these diseases may worsen.]
3.
Ulcers (excluding Behcet’s disease), deep burns of second or severer grade, and
frostbite [skin regeneration may be suppressed, resulting in delayed healing.]
[Description] 
Ingredients 
Active 
Ingredients 
/amount (per 1 
g) 
Calcipotriol hydrate 52.2µg (equivalent to calcipotriol 
50.0µg), betamethasone dipropionate 0.643mg 
Excipients 
All-rac-α-tocopherol 
Liquid paraffin 
White soft paraffin 
Polyoxypropylene stearyl ether 
Appearance/description Yellowish white to yellow ointment 
[Indication] 
Psoriasis vulgaris 
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[Dosage and Administration] 
Apply adequate amount of Dovobet® ointment to the affected area once daily. 
<Precautions regarding dosage and administration> 
The maximum weekly dose should not exceed 90 g.  
[Precautions] 
1 Careful administration (This medication should be carefully administered to the 
following patients.) 
1.
Patients with hypercalcemia and those who are at risk for hypercalcemia [serum
calcium level may be increased more.]
2.
Patients with renal dysfunction [the administration of this product may increase
serum calcium levels.]
2. Important precautions
(1) This product is a combination drug containing calcipotriol hydrate and betamethasone
dipropionate.  Adverse drug reactions caused by the use of calcipotriol or betamethasone
may occur, therefore appropriate use of this drug should be considered.
(2) This product is an active vitamin D3 containing preparation.  This medication may
increase serum calcium level. Since hypercalcemia may induce a decrease in renal
function, patients should be monitored for serum calcium level and renal function (e.g.
creatinine and BUN) periodically (once at 2 - 4 weeks after the start of administration of
the product and when deemed necessary thereafter). If any abnormality is observed in
these values, the administration of the product should be discontinued until normal
calcium levels are restored.
(3) Efficacy and safety when this product is applied more than 4 weeks have not been
established [See section “Clinical results”].  The clinical course should be closely
observed during treatment.  Use of this product should not be continued aimlessly.
(4) Overdosage of the product may induce hypercalcemia.  Hypercalcemia may also occur
in patients using the product for eruption covering a large area of the body or in patients
with deteriorated skin barrier function which may accelerate percutaneous absorption of
the drug.  If any abnormality suggestive of hypercalcemia is observed, the administration
of the product should be discontinued immediately and the patient should be followed
up by observing biochemical parameters such as serum and urinary calcium levels1-3)
[See section 8. “Overdosage” for signs/symptoms of hypercalcemia].
(5) Local adverse reactions, such as skin atrophy, steroid flush, etc. may occur.  Therefore,
careful consideration should be given particularly when this medication is used for
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eruptions on the neck, genitals and skin folds.  
(6) This product contains a corticosteroid and concurrent treatment at the same treatment
area with other steroids must be avoided.  When use in large doses or for prolonged
periods over a large surface area [particularly under the occlusive dressing technique
(ODT)], symptoms such as those that are likely to occur in systemic administration of
adrenocortical steroids may occur.  Therefore, prolonged use in large doses or ODT
should be avoided.
(7) This medication contains calcipotriol.  The safety of the product, when applied by the
occlusive dressing technique (ODT), has not been established (incidence of skin irritation
is higher in ODT than plain application. ODT may enhance percutaneous absorption of
the drug, and may increase the incidence of systemic adverse effects as compared with
plain application).
3. Drug interactions
Precautions for coadministration (Dovobet® ointment should be administered with care
when coadministered with the following drugs.)
Drugs 
Signs, symptoms, and 
treatment 
Mechanism and risk factors 
Vitamin D and its analogues 
Alfacalcidol, calcitriol, 
tacalcitol, maxacalcitol, etc. 
Hypercalcemia may be 
induced. 
Additive effect 
Cyclosporin 
Increase of serum calcium level may 
easily be induced due to renal 
impairment by cyclosporine. 
4. Adverse drug reactions
In clinical studies conducted in Japan before approval of Ointment and before approval of 
Gel, 17 adverse drug reactions were reported in 17 of the 445 treated patients (3.8%). 
Those adverse drug reactions were folliculitis in 5 patients, anaemia and glucose urine 
present in 2 patients each, and leukocytosis, oedema peripheral, hepatic function 
abnormal, herpes simplex, rash pustular, contusion, psoriasis aggravated and skin 
depigmentation in 1 patient each.   
(1) Clinically significant adverse drug reactions
1)
Hypercalcemia (information from Package Insert of calcipotriol, frequency unknown):
Hypercalcemia and clinical symptoms that are considered to be due to hypercalcemia
(malaise, feelings of weakness, anorexia, vomiting, abdominal pain and muscle
weakness, etc.) may appear.  If any abnormalities are noted, use of this medication should
be discontinued, and biochemical tests including serum calcium and urine calcium
should be conducted.  If necessary, actions such as intravenous fluids should be taken.
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2)
Acute kidney injury (information from Package Insert of calcipotriol, frequency
unknown): Acute kidney injury accompanied by serum calcium increased may appear.
If any abnormalities such as serum creatinine increased and BUN increased are noted,
use of this medication should be discontinued, and an appropriate action should be taken.
(2) Other adverse drug reactions
If the following adverse drug reactions are observed, appropriate measures should be
taken.
≥ 1% 
< 1% 
Unknown* 
Hypersensitivity note1 
Erythema/redness, 
Skin note2 
Psoriasis 
aggravated 
Itch, pruritus, burning sensation, pricking skin feeling, skin 
irritation, dermatitis, Ichthyosis-like dermal changes, skin dryness, 
skin erosion, contact dermatitis, exfoliation, eruption, swelling 
Skin infection note3 
Folliculitis 
Bacterial infection (infectious impetigo, furuncle, etc.), 
dermatomycosis (candidiasis, tinea, etc.), viral infection 
Other skin symptoms
note4
Rash pustular, 
Skin 
depigmentatio
n 
Skin pigmentation, pustular psoriasis, acneform eruption, rosacea-
like dermatitis, steroid skin (skin atrophy, telangiectasis and 
purpura), hypertrichosis, 
Hepatic 
Hepatic 
function 
abnormal 
Increased AST(GOT),  increased ALT(GPT) increased γ-GTP, 
increased LDH, increased ALP, increased total bilirubin 
Renal 
Increased BUN, increased serum creatinine, increased urinary 
creatinine 
Hematologic 
Leukocytosis, 
anaemia 
Leukopenia, leukocytosis, decreased haemoglobin, lymphopenia, 
monocytosis, neutropenia 
Infection 
Herpes 
simplex 
Function of pituitary 
adrenocortical system 
Suppress the function of the pituitary adrenocortical system  note5 
Others 
Oedema 
peripheral, 
Contusion, 
glucose urine 
present 
Increased urinary calcium, increased serum calcium, increased serum 
phosphorus, decreased urinary phosphorus, increased serum 
1α,25(OH)2D3 , decreased serum phosphorus, decreased serum 
1α,25(OH)2D3, rebound effect 
The incidence is the sum of adverse drug reactions observed in clinical studies of Dovobet Ointment and Dovobet Gel conducted 
in Japan. 
* ADRs from overseas studies, calcipotriol preparation or betamethasone diproprionate preparation, therefore frequency is
unknown in Japanese patients.
note 1: Discontinue application of this medicine if any symptom is observed.
note 2: Discontinue application of this medicine if the adverse drug reactions occur severely.
note 3: When any of these symptoms are observed, this medication should be used in combination with a suitable antibacterial 
drug or antifungal drug, and if the symptom does not disappear promptly, the administration of this medication should be 
discontinued. [Such symptoms are liable to occur when used under the occlusive dressing technique (ODT).]
note 4: When any of these symptoms occur after long term application, the use of this medication should be avoided, and 
changed over to some other drug(s) not containing adrenocortical steroid. 
note 5: Event due to application in large doses, usage for prolonged periods over a large surface area or used under the occlusive 
dressing technique (ODT) in application of betamethasone diproprionate.  Since acute adrenocortical insufficiency may 
occur by the discontinuation of this medication, the dose should be gradually reduced under close observation of the 
patient’s conditions when the administration of this medication is discontinued. 
5. Use in the elderly
In general, elderly patients have a deterioration of physiological functions.  Therefore, 
attention should be given to overuse in elderly patients.   
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6. Use during pregnancy, delivery and lactation
(1) Pregnant women, etc.:
It is desirable not to use this medication in pregnant women or women who may be
pregnant [safety in application during pregnancy has not been established.  It has been
reported that calcipotriol is transferred to fetuses via the placenta in an animal
experiment (rats)4).  It has been reported that betamethasone has teratogenic action in
animal studies (mice, rats, rabbits)5,6)]  .
(2) Nursing women:
It is desirable to avoid the use of this medication in nursing women.  If this medication
is used in nursing women by necessity, patients should be instructed to refrain from
breastfeeding  [It has been reported that calcipotriol is excreted in milk in an animal
experiment (rats)4)]  .
7. Use in children, etc.
Safety in low birth weight infants, neonates, nursing infants, infants and children has
not been established (there is no experience). 
8. Overdosage
Signs and symptoms: The major symptoms of hypercalcemia include malaise, feelings
of weakness, anorexia, nausea, vomiting, enlarged feeling of abdomen, abdominal pain, 
headache, dizziness, muscle pain and muscle weakness, etc.   
[See Section (2), (4) of “Important precautions”.] 
Treatment: Use of this medication should be discontinued immediately.  Biochemical 
tests including serum calcium and urine calcium should be conducted.  If necessary, 
treatments such as intravenous fluids should be taken.   
[See Section (2), (4) of “Important precautions”.] 
9. Precautions concerning use
(1)
Application sites:
1)
This medication should not be applied to the face.
2)
This medication should not be used for ophthalmic application.
3)
This medication should not be applied to any sites except for the affected areas.
(2)
At the time of use: Be careful not to touch the face and wound sites with hands
exposed to this medication.
(3)
After use:
1)
Wash your hands thoroughly after using this medication to avoid the transference
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of this medication to the face, etc.  
2)
It is not recommended to take a shower or bath immediately after application of
this medication.
(4)
At the time of delivery of this medication: Special attentions should be given to
the storage of this medication to prevent inappropriate use (oral use, etc.).
Especially, this medication should be kept out of reach of children.  If a patient
takes this medication orally by mistake, the patient should be instructed to take
appropriate action such as consulting a medical institution because systemic
adverse drug reactions such as hypercalcemia may occur.
[See Section “Overdosage”.]
10. Other precautions
(1) It has been reported that in a study using male and female albino hairless mice to
which light (xenon lamp) was irradiated for 40 weeks and calcipotriol solution was
applied, the irradiation time required for inducing skin tumor was shortened
significantly in males. However, in a study in which only the drug solution was
applied to mice, no skin tumor was induced.
(2) It has been reported that erythrodermic psoriasis, pustular psoriasis, etc. occurred
during or after discontinuation of application of this medicine.
[Pharmacokinetics] 
In the study where this product once daily was applied to 13 Japanese subjects with severe 
psoriasis vulgaris, plasma concentration of calcipotriol, and betamethasone dipropionate 
were BLQ (below 50.0 pg/mL and 30.0 pg/mL, respectively) in almost all subjects.  The 
ranges of Cmax and AUClast for the two subjects with quantitative concentration of 
calcipotriol were 56.1 to 159 pg/mL and 28.1 to 311 h•pg/mL, respectively.  The Cmax and 
AUClast for the one subject with quantitative concentration of betamethasone dipropionate 
were 39.6 pg/mL and 41.24 h•pg/mL, respectively.7)   
Plasma concentration of main metabolite of calcipotriol was quantified in 1 to 3 subjects at 
each time point.  The ranges Cmax and AUClast for those subjects were 26.4 to 151 pg/mL 
and 27.9 to 736 h•pg/mL, respectively.  Plasma concentration of main metabolite of 
betamethasone dipropionate was quantified in 5 to 11 subjects at each time point.  The 
ranges Cmax and AUClast for those subjects were 30.3 to 910 pg/mL and 15.91 to 
4732 h•pg/mL, respectively.7)   
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[Clinical results] 
The clinical efficacy of this product once daily application for 4 weeks was confirmed in 
the double-blind comparative study with the calcipotriol (twice daily application) and 
betamethasone dipropionate (once daily application) in Japanese psoriasis vlugaris 
patients.  Mean percentage change in m-PASI from baseline is shown in the following 
table.  Once daily application of this medication for 4 weeks showed the excellent 
therapeutic effect compared with comparators.8)   
Calcipotriol hydrate/ 
Betamethasone dipropionate 
(n=226) 
Calcipotriol 
(n=227) 
Betamethasone 
dipropionate 
(n=223) 
Mean percentage change in 
m-PASI from baseline to
Week 4 (±SD) 
-64.3% (24.7)
-50.5% (32.1)
-53.6% (26.4)
(Calcipotriol hydrate/Betamethasone dipropionate vs Calcipotriol, Calcipotriol hydrate/Betamethasone dipropionate vs
Betamethasone dipropionate, p<0.0001 for all comparison)
[Pharmacology] 
1. Action of mechanism
Calcipotriol binds to the vitamin D receptor, and it has been reported that calcipotriol 
inhibits cell proliferation, regulates cell cycles and induces differentiation in various cell 
types, regulate abnormal expression of proinflammatory cytokines and control anti-
microbial peptide expression 9-13).   
Betamethasone dipropionate acts by binding to and activating the glucocorticoid receptor 
in the target cells.  After binding to the receptors, corticosteroids including betamethasone 
dipropionate inhibit the production of inflammatory cytokine as well as the expression of 
other types of inflammatory mediators including intercellular adhesion molecule-1, the 
enzymes phospholipase A2, cyclooxygenase type 2 and inducible nitric oxide synthase.  
Inhibition of the expression of these enzymes results in the attenuated production of 
inflammatory mediators 14-17).   
2. Effect of concomitant use
Treatment with the calcipotriol/betamethasone dipropionate combination significantly 
inhibited the differentiation and activity of human type 1 helper T (Th1) cell / IL-17 
expressing helper T (Th17) cell. The inhibitory effect of treatment with the combination on 
differentiation and activity of Th1/Th17 cells was greater than either that of calcipotriol 
alone or betamethasone dipropionate alone 18).   
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[Physicochemistry] 
Calcipotriol hydrate 
Nonproprietary name: Japanese description 
Calcipotriol hydrate 
Chemical name: (5Z,7E,22E,24S)-24-Cyclopropyl-9,10-secochola-5,7,10(19),22-tetraene-
1α,3β,24-triol monohydrate 
Structure formula: 
Molecular formula: C27H40O3 • H2O 
Molecular weight: 430.62 
Description: White crystalline powder. 
Freely soluble in methanol, in ethanol (95) and in 2-propanol.  Soluble in 
propylene glycol.  Sparingly soluble in ethyl acetate, in dichloromethane 
and in chloroform.  Practically insoluble in liquid paraffin and in water 
(0.1% disodium hydrogen phosphate solution). 
Betamethasone dipropionate 
Nonproprietary name: Japanese description (JP) 
Betamethasone dipropionate 
Chemical name: 9-Fluoro-11β,17,21-trihydroxy-16β-methylpregna-1,4-diene-3,20-dione 
17,21-dipropanoate 
Structure formula: 
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Molecular formula: C28H37FO7 
Molecular weight: 504.59 
Description: The product is a white to pale yellow crystalline powder without odor. 
It is freely soluble in acetone, 1,4-dioxane and chloroform, soluble in 
methanol, sparingly soluble in ethanol (95), slightly soluble in ether and 
practically insoluble in water and hexane. 
It gradually changes under light. 
[Package] 
15g×1, 15g×10, 30g×1 
[References] 
1) Dwyer, C. et al.: Lancet 338(8769), 764, 1991
2) Cunliffe, W. J. et al.: J. Am. Acad. Dermatol. 26 (5), 736, 1992
3) Russell, S. et al.: Br. J. Dermatol. 130(6), 795, 1994
4) Tomida M. et al.: Xenobio. Metabol. and Dispos., 11(1), 57, 1996
5) Hasegawa, Y. et al.: Pharmacometrics, 8(6), 705, 1974
6) Hasegawa, Y. et al.: Clinical Report, 11(6), 1672, 1977
7) Company data (LEO Pharma A/S)
8) Company data (LEO Pharma A/S)
9) Binderup L. et al.: Biochem Pharmacol. 37(5), 889, 1988
10) Kragballe K. et al.: Arch Dermatol Res. 282(3), 164, 1990
11) Kobayashi T. et al.: J Eur Acad Dermatol Venereol. 5(2), 132, 1995
12) Peric M et al.: PLoS One 4, e6340, 2009
13) Hegyi Z et al.: J Invest Dermatol 132, 1416, 2012
14) Ahluwalia A.: Mediators Inflamm. 7(3), 183, 1998
15) Umland SP. et al.: J Allergy Clin Immunol. 100(4), 511, 1997
16) Lange K. et al.: Skin Pharmacol Appl Skin Physiol. 13(2), 93, 2000
17) de Jong EC. et al.: J Leukoc Biol. 66(2), 201, 1999
18) Company data (LEO Pharma A/S)
[Request for literatures should be made to] 
Please request for the company data as well as literature cited in the REFERENCE to the following. 
Medical Information Office 
Kyowa Hakko Kirin Co., Ltd. 
1-6-1, Ohtemachi, Chiyoda-ku, Tokyo 100-8185, Japan
0120-850-150 (toll free) 
Tel: 03-3282-0069 
Fax: 03-3282-0102  
Open: 9:00-17:30 (except Saturday, Sunday, national holidays and company holidays) 
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DISTRIBUTED BY: 
Kyowa Hakko Kirin Co., Ltd. 
1-6-1, Ohtemachi, Chiyoda-ku, Tokyo, Japan
MANUFACTURED BY: 
LEO Pharma K.K. 
3-11-6, Iwamotocho, Chiyoda-ku, Tokyo, Japan
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15Appendix 3: Definitions of Adverse Events and Serious Adverse Events 
15.1 Adverse Event Definition 
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavourable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product. (ICH Harmonized Tripartite Guideline for Good Clinical Practice, 
E6 (R1)).  
This definition includes: 

Accidental injuries.

Events related to trial procedures.

Reasons for any unfavourable and unplanned change in medication (drug and/or
dose).

Clinically significant worsening of pre-existing conditions.

Reasons for admission to hospital or surgical procedures unless these were planned
before the subject consented to trial participation.

AEs commonly observed and AEs anticipated based on the pharmacological effect
of the IMP.

Any laboratory abnormality assessed as clinically significant by the investigator
(see Section 8.6).
15.2 Serious Adverse Event Definition 
A SAE is any untoward medical occurrence that 

results in death

is life-threatening

requires inpatient hospitalisation or prolongation of existing hospitalisation.
Planned hospitalisation or planned prolonged hospitalisation do not fulfill the
criteria for being an SAE but should be documented in the subject’s medical
record.

results in persistent or significant disability/incapacity
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
is a congenital anomaly/birth defect
or 

is a medically important condition. Events that may not be immediately life-
threatening or result in death or hospitalisation but may jeopardise the subject or
may require intervention to prevent one of the other outcomes listed in the
definition above. Examples are intensive treatment in an emergency room or at
home for allergic broncospasm, blood dyscrasias and convulsions that do not result
in hospitalization, development of drug dependency or drug abuse.
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16 Appendix 4: Classification of Adverse Events 
16.1 Severity 
The severity of the AE should be described in terms of mild, moderate or severe according to 
the (sub)investigator’s clinical judgement. 
Mild 
An AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual 
activities of daily living. 
Moderate 
An AE that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, 
causing discomfort but poses no significant or permanent risk of harm to 
the subject. 
Severe 
An AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention. 
If the severity of an AE worsens, a new AE should be recorded. 
16.2 Causality 
The causal relation of the AE to the use of the IMP should be described in terms of probable, 
possible or not related according to the investigator’s clinical judgement. The categories are 
defined below. 
Probably 
related 
Follows a reasonable temporal sequence from administration of the IMP. 
Could not be reasonably explained by the subject’s clinical state, 
environmental or toxic factors or other therapies administered to the 
subject. 
Follows a known pattern of response to the IMP. 
Disappears or decreases on cessation or reduction in dose of the IMP. 
Reappears or worsens upon re-challenge. 
Possibly 
related 
Follows a reasonable temporal sequence from the administration of the 
IMP. 
Could also be reasonably explained by the subject’s clinical state, 
environmental or toxic factors or other therapies administered to the 
subject. 
Follows a known pattern of response to the IMP. 
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Not related 
Does not follow a reasonable temporal sequence from administration of the 
IMP. 
Is better explained by other factors like the subject’s clinical state, 
environmental or toxic factors or other therapies administered to the 
subject. 
Does not reappear or worsen upon re-challenge. 
Does not follow a known pattern of response to the IMP. 
16.3 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 a SAE, the sequelae 
should be specified. 
Fatal 
The subject has died as a consequence of the event. Date of death is recorded 
as stop date for the AE. 
Unknown 
Unknown to (sub)investigator, e.g. subject lost to follow-up. 
Note that as per the above definition, LEO Pharma uses “recovered/resolved” only if an event 
has actually stopped. According to the CDISC definition, the category “recovered/resolved” 
also includes events which have improved. However, following the LEO Pharma definitions 
above, such an improved event will instead be classified as “not recovered/not resolved” or 
“recovering/resolving”. 
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Similarly, it should be noted that as per the above definition, LEO Pharma uses 
“recovered/resolved with sequelae” only if an event has reached a state where the residual 
symptoms are assumed to persist. According to CDISC, an event is considered “with 
sequelae”, if it has “retained pathological conditions”. Consequently, it is likely that some of 
the events classified by LEO Pharma with the outcome “recovered/resolved with sequelae” 
could have been classified with the outcome “recovered/resolved” according to the CDISC 
definition. 
For SAEs which have stabilised and from which the subject cannot be expected to recover 
during trial or the safety follow-up periods, for example chronic illnesses, the final outcome 
should be reported as ‘recovered’; in addition,  a statement that the SAE has stabilised or is 
chronic should be added to the narrative of the SAE on the SAE form. 
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17 Appendix 5: Trial governance considerations 
Appendix 5A: Regulatory and ethical considerations 
This trial will be conducted in accordance with the protocol and with the following: 

Consensus ethical principles derived from international guidelines including the
current version of the Declaration of Helsinki (30) and Council for International
Organizations of Medical Sciences (CIOMS) International Ethical Guidelines (31).

Current version of applicable International Council for Harmonisation (ICH) Good
Clinical Practice (GCP) Guidelines (32).

EU’s General Data Protection Regulation 2016/679 of 27 April 2016.

Applicable laws and regulations.
The appropriate regulatory authority (PMDA) must be notified of/approve the clinical trial as 
required.   
Any documents that the IRB may need to fulfil its responsibilities (such as the trial protocol, 
protocol amendments, Investigator’s Brochure, subject information sheet and informed 
consent form(s), or advertisements) will be submitted to the IRB. These documents must be 
reviewed and approved by the IRB before the trial is initiated.  
Written approval must be obtained from relevant IRBs prior to the signing of the CTA with 
the site and before enrolment of subjects. 
Any amendments to the protocol must be approved by/receive favourable opinion from 
relevant regulatory authorities and IRBs, as required, prior to implementation.  
The principal investigator will be responsible for the following, if required by local 
legislation: 

Providing written summaries of the status of the trial to the IRB annually or more
frequently in accordance with the requirements, policies, and procedures established
by the IRB.

Notifying the local IRB of SAEs or other significant safety findings as required by
IRB procedures.

Providing oversight of the conduct of the trial at the trial site and ensuring adherence
to applicable national and international legislation.
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Appendix 5B: Informed consent process 
Subjects will receive written and verbal information concerning the clinical trial. This 
information will emphasise that participation in the clinical trial is voluntary and that the 
subject may withdraw from the clinical trial at any time and for any reason. All subjects will 
be given an opportunity to ask questions and will be given sufficient time to consider before 
consenting.  
The subject’s signed and dated informed consent to participate in the clinical trial will be 
obtained prior to any clinical trial related procedure being carried out in accordance with ICH 
GCP (4.8) and all applicable laws and regulations. The authorised person obtaining the 
informed consent must also sign the ICF.    
A copy of the ICF(s) must be provided to the subject.  
Subject card 
At screening, subjects will be provided with a card stating that they are participating in a 
clinical trial and which contains contact address(es) and telephone number(s) of relevant trial 
site staff including the number for the investigator in case of emergency situations.  
Appendix 5C: Subject and data confidentiality 
This clinical trial protocol as well as all other information, data, and results relating to this 
clinical trial and/or to the IMP is confidential information of LEO and shall not be used by the 
investigator for purposes other than this clinical trial.  
The investigator agrees that LEO may use any and all information, data, and results from this 
clinical trial in connection with the development of the IMPs and, therefore, may disclose 
and/or transfer information, data and/or results to other investigators, regulatory authorities 
and/or commercial partners.  
Trial subjects will be assigned a unique identifier (subject ID) by LEO. Any subject’s records 
or datasets that are transferred to LEO will contain the identifier only; subject names or any 
information which would make the subject identifiable will not be transferred.   
Trial subjects must be informed and consent to that their personal trial-related data will be 
used by LEO in accordance with local data protection law.    
Trial subjects must be informed and consent to that their medical records may be examined by 
Clinical Quality Assurance auditors or other authorised personnel appointed by LEO, by 
appropriate IRB members, and by inspectors from regulatory authorities.  
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Processing of personal data  
This protocol specifies the personal data on trial subjects (e.g. age, gender, health condition, 
medical history, test results, etc.) which shall be collected as part of the clinical trial and 
processed during and after trial completion.  
Personal data collected as part of the clinical trial will be transferred to/from the 
institution/investigator, LEO Pharma and third parties acting on behalf of LEO Pharma. 
Processing of personal data on behalf of LEO Pharma requires a written agreement between 
LEO Pharma and the relevant party which covers collection, processing and transfer of 
personal data in the clinical trial. In certain cases an agreement on transfer of personal data 
may also be required.  
Investigators and LEO Pharma must ensure that collection, processing and transfer of 
personal data are in compliance with applicable legislation on data protection and privacy, 
including but not limited to the EU General Data Privacy Regulation.  
Subjects must be asked to consent to the collection, processing and transfer of their personal 
data to EU and non-EU countries for the purpose of conducting the clinical trial, research and 
development of new or existing products/services, improving existing products/services, 
applying for marketing authorisations for products/services, marketing of products/services 
and other related activities.  
LEO Pharma has obtained the necessary authorisations for the processing of personal data 
collected in the trial. 
Appendix 5D: Record keeping, quality control, and data handling 
Source data  
For all data recorded, the source document must be defined in a source document agreement 
or similar document at each trial site. There must only be 1 source defined at any time for any 
data elements. The eCRF cannot be a source document. 
Source data should as a general rule be recorded in the subject’s medical record or other 
defined document normally used at the trial site. Source data not normally collected as a 
routine part of the clinical practice at the site may be entered on a worksheet. Clinical 
assessments/safety evaluations must be signed and dated by medically qualified 
(sub)investigators.  
If the worksheet does not become part of the subject’s medical record, the following should as 
a minimum be added to the subject’s medical record: 
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
Date(s) of conducting the informed consent process, including date of provision of
subject information.

A statement from the investigator to verify that each of the eligibility criteria are met
and documented.

Subject ID (eCRF number)

Trial ID (LP0053-1422)

Kit number of trial medication

The fact that the subject is participating in a clinical trial in psoriasis involving 4
weeks treatment with LEO 90100 foam (containing calcipotriol and betamethasone
dipropionate) or Dovobet® ointment (it should be specified which one).

Other relevant medical information.
Trial monitoring  
During the course of the trial, CRA(s) will visit the trial site. These visits have the following 
objectives: (i) to continually verify source data to confirm that data entered into the eCRF by 
authorised site personnel are accurate, complete, and verifiable from source documents; (ii) to 
confirm that the safety and rights of subjects are being protected; and (iii) to confirm that the 
trial is being conducted in accordance with the currently approved protocol and any other trial 
agreements, ICH GCP, J-GCP, and all applicable regulatory requirements.  
The first monitoring visit should be performed as soon as after first subject first visit. 
The monitoring visit intervals will depend on the trial site’s recruitment rate and the 
compliance of the trial site with the protocol and ICH GCP/J-GCP.  
In order to perform their role effectively, CRAs and persons involved in quality assurance and 
inspections will need direct access to source data, e.g. medical records, laboratory reports, 
appointment books, etc. If source data is kept in an electronic medical record and if this 
record does not have a visible audit trail, the investigator must provide the CRA with signed 
and dated printouts. In addition, relevant site staff should be available for discussions at 
monitoring visits and between monitoring visits (e.g. by telephone).  
Protocol compliance  
Protocol deviations will be documented and notified to the investigator. Protocol deviations 
will be assessed by LEO Pharma and major deviations described in the clinical trial report.  
Sponsor audits, IRB review, and regulatory agency inspections 
The clinical trial will be subject to audits conducted by LEO Pharma or inspections from 
domestic or foreign regulatory authorities or from IRBs. Audits and inspections may take 
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place during or after the trial. The investigator and the site staff as well as LEO Pharma staff 
have an obligation to cooperate and assist in audits and inspections. This includes giving 
auditors and inspectors direct access to all source documents and other documents at the trial 
site relevant to the clinical trial. This includes permission to examine, verify and reproduce 
any records and reports that are important to the evaluation of the trial.  
If the trial site is contacted for an inspection by competent authorities, LEO Pharma must be 
notified immediately. 
Risk Assessment 
Risks in this trial will be evaluated and documented in a separate document. 
Data handling 
Data will be collected by means of electronic data capture unless transmitted electronically to 
LEO Pharma or designee (e.g., laboratory data). The investigator or staff authorised by the 
investigator will enter subject data into electronic CRFs (eCRFs). Data recorded in the eCRFs 
will be accessible to the trial site and LEO Pharma personnel immediately after entry. The 
eCRFs must be maintained in an up-to-date state by the trial site at all times.  
The investigator must verify the correctness of the data entered by the site by electronically 
dating and signing all eCRFs used. This signature information will be kept in the audit trail 
and cannot be altered. Any correction(s) made by the investigator or authorised site staff to 
the eCRF after original entry will be documented in the audit trail. Changes to data already 
approved will require the re-signature by the investigator. The person making the change to 
the data, and the date, time and reason for the change will be identified in the audit trail.  
Subject data should be entered into the eCRF no later than 5 working days after each visit, 
unless a different deadline is stated in the Clinical Trial Agreement. Queries for discrepant 
data will be generated automatically by the system upon entry or manually by the CRA, 
sponsor’s medical expert, or the data manager. All queries will be raised electronically within 
the electronic data capture system. This systematic validation will ensure that a clean and 
consistent database is provided for the statistical analysis. 
External data transfers from vendors to LEO Pharma will be transmitted and handled via a 
secure file transfer protocol site.   
Archiving of trial documentation  
The investigator/director at each trial site or the person responsible for document archiving at 
the site must make arrangements to store the essential trial documents, including the 
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investigator trial file (32). Essential trial documents must be stored until LEO Pharma informs 
the investigator that the documents are no longer to be retained, or longer if required by local 
regulations. 
In addition, this person is responsible for the archiving of all relevant source documents so 
that the trial data can be compared against source data after the completion of the trial (for 
example in case of an inspection from regulatory authorities).  
The person is required to ensure the continued storage of the documents even if the 
investigator or the person leaves the trial site or retires before the end of the required storage 
period.  
No documents may be destroyed during the retention period without the written approval of 
LEO Pharma. No documents may be transferred to another location or party without written 
acceptance from LEO Pharma.  
The destruction process must ensure confidentiality of data and must be done in accordance 
with local regulatory requirements.  
For archiving purposes, each investigator will be supplied with an electronic copy of the 
eCRFs for all screened subjects at the trial site. This is done after completion of the trial and 
before access to the eCRF is revoked. Audit trail information will be included. eCRFs must be 
available for inspection by authorised representatives from LEO Pharma, from regulatory 
authorities and/or IRBs. 
Appendix 5E: Registration, reporting and publication policy 
Trial disclosure  
LEO Pharma is committed to be transparent with respect to its clinical trials. 
Basic information of this clinical trial will be registered in the global data registry, 
www.ClinicalTrials.gov before the first subject enters into the trial. The trial may also become 
registered in other online data registries, according to applicable law and regulations.  
Results of this clinical trial will be posted on the corporate website of LEO Pharma in 
accordance with our Position on Public Access to Clinical Trial Information no later than 12 
months after trial completion. Trial results may also become reported in 
www.ClinicalTrials.gov, www.clinicaltrialsregister.eu and national data registries in 
accordance with applicable law and regulations after clinical trial completion or premature 
termination. 
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LEO Pharma may also provide researchers access to anonymised patient level data for further 
research. Publication and access will be in accordance with the Position on Public Access to 
Clinical Trials which can be found on the LEO Pharma website. 
Publications  
The investigator shall be entitled to make publications of the results generated by investigator 
in accordance with the process described here.  
A multi-centre publication will be submitted for publication within 18 months after the 
clinical trial has been completed or terminated at all trial sites and all data have been received, 
defined as database lock of the clinical trial. After such multi-centre publication is made 
public, or if no multi-centre publication has been submitted with the above-described 
deadline, the investigator shall have the right to publish the results from the clinical trial 
generated by the investigator, subject to the following notice requirements:  
Prior to submission for publication or presenting a manuscript relating to the clinical trial, the 
investigator shall provide to LEO Pharma a copy of all such manuscripts and/or presentations. 
LEO Pharma shall have rights to review and comment. The investigator shall consider  
comments provided by LEO Pharma but is not required to modify the manuscript and/or 
presentation based on such comments, provided, however, that the investigator upon the 
request of LEO Pharma remove any confidential information (other than results generated by 
the investigator) prior to submitting or presenting the manuscripts. The investigator shall, 
upon the request of LEO Pharma withhold the publication or presentation to allow 
LEO Pharma to protect its inventions and other intellectual property rights described in any 
such manuscripts.   
In case no multi-centre publication has been made public at the time of investigator’s 
notification of an independent publication to LEO Pharma, LEO Pharma and the writing 
group may also delay the publication or presentation if the manuscript is deemed to harm the 
ongoing multi-centre publication.  
In case of publications made by the investigator after the first multi-centre publication has 
been published, the above-mentioned requirements must still be followed. 
Any publication must comply with Good Publication Practice (GPP3) standards. 
LEO Pharma complies with GPP3 standards and the recommendations from the International 
Committee of Medical Journal Editors. LEO Pharma complies with the positions of the 
International Federation of Pharmaceutical Manufacturers & Associations (IFPMA), 
European Federation of Pharmaceutical Industries and Associations (EFPIA), Japan 
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Pharmaceutical Manufacturers Association (JPMA), Pharmaceutical Research and 
Manufacturers of America (PhRMA), and the joint position statement by the American 
Medical Writers Association (AMWA), the European Medical Writers Association (EMWA), 
and the International Society for Medical Publication Professionals (ISMPP) on disclosure of 
information about clinical trials, trial results and authorship. LEO Pharma also follows the 
CONSORT reporting guidelines (33). 
Appendix 5F: Insurance 
LEO Pharma has taken out relevant insurances covering the subjects in the present clinical 
trial in accordance with applicable laws and regulations. 
Appendix 5G: Financial disclosure 
Investigators will provide LEO Pharma with sufficient, accurate financial information as 
requested to allow LEO Pharma to submit complete and accurate financial certification or 
disclosure statements to the appropriate regulatory authorities. Investigators are responsible 
for providing information on financial interests during the course of the clinical trial and for 1 
year after completion of the clinical trial, or for a longer period of time if required by local 
legislation. 
Appendix 5H: Committee structure 
Not applicable. A Data Monitoring Committee will not be set up for this trial with the 
following reasons. 
Dovobet® ointment is marketed in Japan, and its use in this trial will be in keeping with the 
licensed conditions for use in Japan. Therefore, its use in this trial is not expected to reveal 
any new safety findings. LEO 90100 foam is a different formulation of  Dovobet® ointment, 
having the same active ingredients at the same concentration. In a phase 1 trial of LEO 90100 
foam, it was shown to have no safety concern in healthy Japanese subjects. LEO 90100 foam 
was approved in the US in 2015 as the first country for the topical treatment of plaque 
psoriasis in patients 18 years of age and older. The product has subsequently been approved in 
34 countries, hereof the majority in EU. Its use in Japanese subjects in this trial is not 
expected to reveal any new safety findings. 
Appendix 5I: Trial and site closure 
Premature termination of trial or trial site  
LEO Pharma, the investigator, the IRBs or competent authorities may decide to stop the 
clinical trial, part of the trial or a trial site at any time, but agreement on procedures to be 
followed must be obtained.  
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If a clinical trial is suspended or prematurely terminated, the investigator must inform the 
subjects promptly and ensure appropriate therapy and follow-up. As specified by applicable 
regulatory requirements, the investigator or LEO Pharma K.K. must promptly inform IRBs 
and provide a detailed written explanation. Relevant competent authorities must be informed. 
The trial must be terminated if the perception of the benefit/risk ratio (judged from clinical 
signs and symptoms, (S)AEs and/or remarkable safety laboratory changes) becomes 
unfavourable for the continuation of the trial.  
Reasons for the early closure of a trial site by LEO Pharma or investigator may include but 
are not limited to: 

Failure of the investigator to comply with the protocol, the requirements of the IRB
or local health authorities, LEO procedures, or GCP guidelines.

Inadequate recruitment of subjects by the investigator.
Due to the design of this trial, there are no statistical criteria for trial termination. 
Completion of trial 
Investigators will be informed when subject recruitment is to cease. Screening activities will 
be stopped at a trial site when the total requested number of subjects for the clinical trial has 
been obtained, irrespective of the specific site’s planned inclusion number.  
Trial sites will be closed upon trial completion. LEO Pharma will undertake arrangements for 
the collection and disposal of any unused trial material that the investigator is not required to 
keep in his/her files. A trial site is considered closed when all required documents and trial 
supplies have been collected and a trial site closure visit has been performed. 
Appendix 5J: Responsibilities 
The signatory investigator is responsible for the approval of the clinical trial protocol and 
the clinical trial report on behalf of all clinical trial investigators and as agreed to in a 
Signatory Investigator Agreement.  
The national coordinating investigators are responsible for national issues relating to the 
clinical trial as agreed to in a National Coordinating Investigator Agreement.  
Each participating investigator is responsible for all aspects of the clinical trial conduct at 
his/her trial site as agreed to in a Clinical Trial Agreement. 
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18 Appendix 6: Contact list of LEO Pharma A/S, LEO Pharma K.K., 
protocol authors, vendors,  international coordinating investigator and 
medical expert (Japan) 
Contact details for the clinical project manager (CPM),  medical expert (LEO) and safety 
scientist/safety physician are provided to participating trial sites outside the protocol on a list 
of LEO Pharma representatives. 
Sponsor 
The Sponsor of the clinical trial is LEO Pharma A/S: 
LEO Pharma A/S  
Industriparken 55 
DK-2750 Ballerup 
Denmark 
LEO Pharma K.K. is the Sponsor of the clinical trial in Japan on behalf of LEO Pharma A/S: 
LEO Pharma K.K. 
3-11-6 Iwamotocho
Chiyoda-ku 
Tokyo 101-0032 
Japan 
In this clinical trial protocol, LEO Pharma A/S and LEO Pharma K.K. are collectively called 
as ‘LEO Pharma’. 
Protocol Authors 
Name 
Role 
Address 
Hidemi Nakagawa, MD, PhD 
International Coordinating 
Investigator 
, MD 
Medical Expert 
 
Clinical Project Manager 
LEO Pharma K.K., Japan 
, MD 
Principal Medical Adviser 
LEO Pharma A/S, Denmark 
 
Biostatistician 
LEO Pharma A/S, Denmark 
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Pharmacovigilance 
LEO Pharma A/S, Denmark 
 
Medical Writer 
LEO Pharma A/S, Denmark 
 
Senior Clinical Project 
Manager 
(responsible for monitoring) 
LEO Pharma K.K., Japan 
CRO/vendors 
Service 
Name and address 
Data management, SDTM 
programming, Biostatistics, 
Medical writing  
CMIC Co., Ltd. East Japan, Hamamatsucho Bldg, 1-1-1 
Shibaura, Minato-ku, Tokyo 105-0023, Japan 
CMO 
Klifo A/S, Smedeland 36, DK 2600 Glostrup, Denmark 
Central lab 
Covance Central Laboratory Services LP 
8211 SciCor Drive 
Indianapolis, IN 46214 
USA 
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19 Appendix 7: WHO Classification of Topical Corticosteroids 
WHO CLASSIFICATION OF TOPICAL CORTICOSTEROIDS  
Based on the Anatomical Therapeutic Chemical (ATC) classification system 
Group I: weak  
Hydrocortisone  
Methylprednisolone 
Prednisolone  
Group II: moderately potent 
Alclometasone  
Clobetasone  
Desonide  
Flumetasone  
Fluocortin butyl  
Fluprednidene  
Hydrocortisone butyrate  
Triamcinolone  
Group III: potent  
Amcinonide  
Beclometasone  
Betamethasone  
Betamethasone dipropionate 
Budesonide  
Desoximetasone  
Diflorasone  
Diflucortolone  
Fluclorolone acetonide  
Fludroxycortide  
Fluocinolone acetonide  
Fluocinonide  
Fluocortolone  
Fluticasone  
Halometasone  
Mometasone  
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Prednicarbate 
Ulobetasol  
Group IV: very potent 
Clobetasol  
Halcinonide 
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20 Appendix 8: WHO Classification of Topical Corticosteroids compared to 
the Japanese Classification 
WHO Classification of Topical 
Corticosteroids 
Japanese Classification of Topical 
Corticosteroids 
Group I : 
Weak 
Hydrocortisone 
Methylprednisolone 
Prednisolone 
Group V : 
Weak 
Dexamethasone 
Fludroxycortide 
Hydrocortisone acetate 
Prednisolone 
Group II : 
Moderately 
Potent 
Alcometasone 
Clobetasone 
Desonide 
Flumetasone 
Fluocortin butyl 
Fluprednidene 
Hydrocortisone butyrate 
Triamcinolone 
Group IV : 
Medium 
Alclometasone 
    dipropionate 
Clobetasone butylate 
Flumetasone pivalate 
Hydrocortisone butyrate 
Triamcinolone acetate 
Group III : 
Strong 
Betamethasone valerate 
Beclometasone 
    dipropionate 
Deprodone propionate 
Dexamethasone 
    propionate 
Dexamethasone valerate 
Fluocinolone acetate 
Prednisolone valerate 
acetate 
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WHO Classification of Topical 
Corticosteroids 
Japanese Classification of Topical 
Corticosteroids 
Group III : 
Potent 
Amcinonide 
Beclometasone 
Betamethasone 
Betamethasone dipropionate 
Budesonide 
Desoximetasone 
Diflorasone 
Diflucortolone 
Fluclorolone acetonide 
Fludroxycortide 
Fluocinolone acetonide 
Fluocinonide 
Fluocortolone 
Fluticasone 
Halometasone 
Mometasone 
Prednicarbate 
Ulobetasol 
Group II : 
Very 
Strong 
Amcinonide 
Betamethasone butyrate 
   propionate 
Betamethasone 
   dipropionate 
Diflucortolone valerate 
Difluprednate 
Fluocinonide 
Hydrocortisone butyrate 
   propionate 
Halcinonide 
Mometasone fluorate 
Group IV : 
Very 
Potent 
Clobetasol 
Halcinonide 
Group I : 
Strongest 
Clobetasol propionate 
Diflorasone diacetate 
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21 Appendix 9: Descriptors for intermediate intervals in severity score of 
clinical signs of target lesion 
In the Investigator’s assessment of the severity of clinical signs of the target leson, 
intermediate intervals (0.5, 1.5, 2.5, 3.5) serve as mid-points between the defined grades (0, 1, 
2, 3, 4).  For the purposes of data coding, these intermediate levels are defined as: 
0.5 = mid-point between ‘none’ and ‘slight’  
1.5 = mid-point between ‘slight’ and ‘mild’ 
2.5 = mid-point between ‘mild’ and ‘moderate’  
3.5 = mid-point between ‘moderate’ and ‘severe’ 
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Electronic signatures made within eTMF LEO are considered to be a
legally binding equivalent of traditional handwritten signatures.
Reason for signing: Approved
Manage
Name: 
Capacit
Date of signature: 06-Nov-2018 09:12:05
GMT+0000
Reason for signing: Approved
Manage
r Verdict(s)
Name: 
Capacit
Date of signature: 06-Nov-2018 09:34:26
GMT+0000
Reason for signing: Approved
Manage
s)
Name: 
Capacit
Date of signature: 06-Nov-2018 11:23:34
GMT+0000
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SAP_001.pdf: 
 
 
 
 
 
 
 
 
 
Cover Page 
 
 
Official title: A phase 3, national, multi-centre, 4-week, prospective, randomised, controlled, parallel 
group, open trial of LEO 90100 foam versus Dovobet® ointment 
LEO Pharma number: LP0053-1422
NCT number: NCT03806790 
Date: 21-Jun-2019 
 


Statistical Analysis Plan 
Efficacy and safety of LEO 90100 foam in Japanese subjects with 
psoriasis vulgaris 
Phase 3 
A phase 3, national, multi-centre, 4-week, prospective, randomised, controlled, parallel-
group, open trial of LEO 90100 foam versus Dovobet® ointment 
LEO Pharma A/S 
Trial ID: 
LP0053-1422 
Date: 
21JUN2019 
Version: 
1.0 
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1 Statistical Analysis Plan Approval 
1.1 Approval Statement 
On behalf of LEO, the Biostatistics Lead and the Medical Lead, are authorised to approve the 
Statistical Analysis Plan. 
The QC statistician has by approving this document confirmed that the statistical information 
has been subject to statistical quality control. 
The following persons have approved this Statistical Analysis Plan using electronic signatures 
as presented on the last page of this document. 
 
Biostatistics Lead, Global Clinical Operations 
 
Medical Lead, Medical Science and Safety 
 
QC Statistician, Biostatistics 
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2 Statistical Analysis Plan Statements 
2.1 Compliance with Good Clinical Practice 
This Statistical Analysis Plan is designed to comply with the standards issued by the 
International Conference on Harmonisation (ICH) (E3: Structure and Content of Clinical 
Study Reports, E6: Good Clinical Practice, and E9: Statistical Principles for Clinical Trials). 
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Table of Contents 
1 Statistical Analysis Plan Approval ......................................................................................... 2 
1.1 Approval Statement ........................................................................................................... 2 
2 Statistical Analysis Plan Statements ...................................................................................... 3 
2.1 Compliance with Good Clinical Practice .......................................................................... 3 
Table of Contents ....................................................................................................................... 4 
3 List of Abbreviations ............................................................................................................. 5 
3.1 List of Abbreviations ......................................................................................................... 5 
4 Statistical Analysis Plan Authors ........................................................................................... 6 
5 Introduction ........................................................................................................................... 7 
6 Statistical Analysis ................................................................................................................. 8 
6.1 Baseline Considerations .................................................................................................. 10 
6.1.2 
Compliance .................................................................................................................. 10 
6.2 Analysis of Efficacy ........................................................................................................ 11 
6.2.1 
Primary Efficacy Criterion .......................................................................................... 11 
6.2.2 
Secondary Efficacy Criteria ........................................................................................ 11 
6.3 Analysis of Safety ........................................................................................................... 12 
6.3.1 
Exposure ...................................................................................................................... 12 
6.3.3 
Adverse Events ............................................................................................................ 13 
6.3.4 
Laboratory Data ........................................................................................................... 14 
6.4 General Principles ........................................................................................................... 14 
6.4.2 
Handling of Drop-outs and Missing Values ................................................................ 14 
6.4.3 
Treatment Labels ......................................................................................................... 17 
Appendix I ................................................................................................................................ 18 
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3 List of Abbreviations 
3.1 List of Abbreviations 
ATC 
Anatomical Therapeutic Chemical 
CPMP 
Committee for Proprietary Medicinal Products 
CRA 
Clinical Research Associate 
CRF 
Case Report Form 
CRO 
Contract Research Organisation 
CTP 
Clinical Trial Protocol 
GCP 
Good Clinical Practice 
ICH 
International Conference on Harmonisation 
IRB 
Institutional Review Board 
LOCF 
Last observation carried forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
PPAS 
Per protocol analysis set 
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
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4 Statistical Analysis Plan Authors 
 
, Statistical Analysis 1st Dept. Data Science Div., CMIC Co., Ltd., 
Hamamatsucho Bldg., 1-1-1 Shibaura, Minato-ku, Tokyo 105-0023 Japan, Tel: 
 
, Fax: +81 
, email: 
  
, Statistical Analysis 1st Dept. Data Science Div., CMIC Co., Ltd., 
Hamamatsucho Bldg., 1-1-1 Shibaura, Minato-ku, Tokyo 105-0023 Japan, Tel: 
 
, Fax: 
, email: 
  
, Statistical Analysis 1st Dept. Data Science Div., CMIC Co., Ltd., 
Hamamatsucho Bldg., 1-1-1 Shibaura, Minato-ku, Tokyo 105-0023 Japan, Tel: 
 
, Fax: 
, email: 
  
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5 Introduction 
The statistical analysis will be performed as outlined in the Clinical Trial Protocol (CTP). This 
Statistical Analysis Plan, prepared before the end of the blinding period, contains a more 
technical and detailed elaboration of some points in the statistical analysis described in the 
CTP. Refer to the "Blinding Plan" as referenced in eTMF, document number TMF-
000130194, for the blinding period. In addition, any changes to the analyses planned in the 
CTP are described.  
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6 Statistical Analysis 
6.1 Software and Dictionaries 
The software and its versions used in this trial are listed below. 
Software and Versions 
Operating System 
Microsoft Windows 7 
Statistical Analysis Software 
SAS Ver.9.3 or later 
Tabulation Software 
Microsoft Word 2010 
The coding items and dictionaries used in this trial are listed below. 
Category 
Dictionary 
Remarks 
Adverse Event, 
 Concurrent Diagnoses 
Indications for concurrent 
medications 
Concurrent procedures 
and their indications 
MedDRA*/J Version 21.1 Apply System Organ Class 
(SOC) and Preferred Term 
(PT) to Items listed opposite 
Product Name 
(Concurrent Medication) 
WHO Drug Version Sep 
2018 
6.2 Protocol Deviations 
Protocol deviations for all subjects will be presented in the listings. 
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6.3 Subject Disposition 
In addition to what is described in the CTP (section 6.1), date of first subject visit, date of last 
subject visit, and duration of trial period for each site and for all enrolled subjects will be 
provided. Also the number of subjects enrolled, the number of subjects randomised, and the 
number of subjects randomised to each treatment group will be presented by site. 
The reason for leaving the trial will be presented as described in the CTP (section 11.3.1). 
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6.4 Demographics and other Baseline Considerations 
The demographics and other baseline (screening visit) characteristics will be presented as 
described in the CTP (section 11.3.2). 
Concurrent diagnoses (except Psoriasis Vulgaris) including indications for concomitant 
medication at screening for concurrent medications and concurrent procedures at screening 
visit. Concurrent diagnosis coded with the MedDRA preferred term of "psoriasis" will be 
excluded from the summary tables. 
Concurrent medications started before screening visit will be presented, which are defined as 
those started before screening visit or marked as "before". 
Similarly, concurrent medications started after screening visit will be presented in a separate 
table, which are defined as those started after screening visit or, marked as "after", or those 
started on or after the screening visit. 
In addition to what is described in the CTP, the time interval (days) from visit 1 to each trial 
visit will be summarized for all randomised subjects and by treatment group. 
6.5 Compliance 
Compliance with treatment instructions will be presented as described in the CTP (section 
11.3.3). 
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6.6 Analysis of Efficacy 
6.6.1 Primary Efficacy Criteria 
The primary endpoint will be analysed as described in the CTP (section 11.3.4). 
In addition, the difference (LEO 90100 foam – Dovobet® ointment) in the proportion of 
subjects with overall improvement rate, its 95% confidence interval will also be presented. 
Refer to CTP (11.3.11) for the imputation method. 
For subjects who completed the trial before 4 weeks of treatment due to achieving substantial 
resolution, use the latest available results for LOCF imputation. This approach of imputation 
is legitimate under the assumption of short exposure time and type of population included; a 
re-lapse on the disease in the target area will not be expected. 
6.6.2 Secondary Efficacy Criteria 
The secondary endpoints will be analysed as described in the CTP (section 11.3.5). 
There are two different descriptions on total sign score in the CTP (Section 5.2): 
-
The change in the total sign score from Visit 1 to Visit 4; total sign score is defined as the
sum of the scores from the 3 clinical signs assessing severity in the target lesion.
-
The change in the sum of the scores (total sign score) for the severity of the three clinical
signs (thickness, scaliness, redness) from Visit 1 to the sum of the scores at Visit 4 (end of
Week 4) for the target lesion
Since these two endpoints are the identical endpoint, both of them will be regarded as "the 
change in the total sign score for the target lesion from baseline to Visit 4". 
Total sign score is treated as missing when the score for at least one of the clinical signs is 
missing. LOCF will be used to impute any missing values for Visit 4 for the analysis of 
change in total sign score from baseline to Visit 4 (end of Week 4). 
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6.6.3 Exploratory Efficacy Criteria 
The exploratory analysis of efficacy will be presented as described in the CTP (section 
11.3.6). 
In addition to what is stated in the CTP, the followings will also be analysed: 
The treatment difference of the change in each clinical sign (thickness, scaliness and redness) 
at Visit 4 will be estimated with an ANOVA with treatment as fixed effect. 
For the analysis of change in score for the severity of each clinical sign from baseline to Visit 
4 (end of Week 4), LOCF will be used to impute any missing values for Visit 4. 
6.6.4 Exploratory Efficacy Criteria of Subject Assessments 
The subject assessments for "time spent for application" and "ease of application" will be 
presented as described in the CTP (section 11.3.7). The tabulations will be provided for the 
full analysis set. 
The subject's assessment of "time spent for application" of trial medication will be compared 
between the treatment groups using ordinal logistic regression. The odds ratio (odds of being 
less time applying LEO 90100 foam group relative to Dovobet® ointment group), its 95% CI, 
and a p-value will be calculated from the logistic model.  
The subject's assessment of "ease of application" of trial medication will be compared 
between the treatment groups using ordinal logistic regression. The odds ratio (odds of being 
very easy applying LEO 90100 foam group relative to Dovobet® ointment group), its 95% CI, 
and a p-value will be calculated from the logistic model. 
This analysis will be performed using full analysis set. 
6.7 Analysis of Safety 
The analysis of safety will be based on the safety analysis set as described in the CTP (section 
11.3.8). 
6.7.1 Exposure 
In addition to what is stated in the CTP (section11.3.3), the number of days of exposure will 
be calculated as the date of final application minus the date of first application plus 1, 
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ignoring any interim missing applications. The duration of exposure to treatment (weeks) will 
be derived as the number of days of exposure divided by 7, and will be summarized for each 
treatment group using the mean, SD, median, minimum and maximum values. The sum of 
duration of exposures to treatment will be presented as all subjects-treatment-weeks. 
6.7.2 Adverse Events 
AEs will be analysed as described in the CTP (section11.3.8.1), with the following additions 
and clarifications. 
Three tables will be produced counting AEs by each causal relationship; not related, possibly 
related and probably related, respectively. 
If different categories of causal relationship were observed for the same SOC and preferred 
term in one subject, count as one event for each causal relationship. 
In addition, three causal relationships will be divided into two categories; "not related" and 
"related" (possibly related and probably related), and a table for "related" events will be 
presented. If several events are observed for the same SOC and preferred term in one subject, 
count as one event for the greatest causality. 
Separate tables for "lesional/perilesional" and "distant" cutaneous AEs will also be produced. 
Adverse drug reactions are defined as adverse event that is related to trial medication: 
Adverse event that is related to trial medication are those classified as the probable or possible 
relationship to trial medication.  
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6.7.3 Laboratory Data 
The analysis of laboratory parameters will be performed as outlined in the CTP (section 
11.3.8.2). 
In principle, the value measured at Visit 1 is used as baseline. If the value is missing at Visit 1 
but there is a measurement prior to first application of trial medication, then this measurement 
will be considered as the baseline value for laboratory safety examinations. 
6.8 General Principles 
6.8.1 Handling of Drop-outs and Missing Values 
A LOCF approach will be used to impute missing values at Visit 4 (end of week 4) for the 
primary endpoint as described in the CTP (section 11.3.11). 
LOCF will be used to impute missing values for the analysis of change from baseline to Visit 
4 (end of week 4) in the sum of total sign score and the analysis of change from baseline to 
Visit 4 (end of week 4) in change in score for the severity of each clinical sign. 
6.8.2 Windowing 
The “by visit tabulations” will include all subjects that attended the specific visit, irrespective 
of whether the date of the visit was within or outside the scheduled visit window. 
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6.8.3 Other 
Subjects in the trial have to be Japanese, and this requirement was an inclusion criterion. The 
EDC system requires a field to be completed for race, with the standard categories of white, 
black, Asian, or other. Therefore since the sites confirmed all subjects to be Japanese, the 
appropriate category for Japanese is Asian. Hence in the eCRF the “Race” field was auto 
populated as "Asian". However, data for this categorisation of race (Asian) does not appear 
anywhere in the CSR in text, listings or tables; it will only be described in the text of the CSR 
that all subjects were Japanese, as confirmed by the fulfilment of the inclusion criteria.  
“Single quote” is used instead of “apostrophe” mark in CO (Comments) domain in statistical 
analysis. 
6.8.4 Definition of Unit and Rounding Digit 
Definition of unit and rounding digit is shown below: 
Table [1]: Demographics: 
Category 
Unit 
Rounding Digit 
Height 
[cm] 
0.1 
Weight 
[kg] 
0.1 
Age 
[years] 
1 
BMI 
[kg/m^2] 
0.1 
Duration of psoriasis 
[days] 
1 
Duration of exposure 
to treatment 
[weeks] 
0.1 
Time interval 
[days] 
0.1 
Scores for efficacy 
- 
0.1 
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Table [2]: Laboratory safety examinations: 
Category 
Examination Component 
Abbreviation 
Unit 
Rounding 
Digit 
Haematology 
Haematocrit 
HCT 
[%] 
1 
Haemoglobin 
HGB 
[g/dL] 
0.1 
Platelets 
PLAT 
[10^9/L] 
0.1 
Erythrocytes 
RBC 
[10^12/L] 
1 
Leukocytes 
WBC 
[10^9/L] 
1 
HbA1c 
HBA1C 
[%] 
0.1 
Chemistry 
Albumin 
ALB 
[g/dL] 
0.1 
Alkaline Phosphatase 
ALP 
[U/L] 
1 
Alanine Aminotransferase 
ALT 
[U/L] 
1 
Aspartate Aminotransferase 
AST 
[U/L] 
1 
Bilirubin 
BILI 
[mg/dL] 
0.1 
Blood Urea Nitrogen 
BUN 
[mg/dL] 
1 
Calcium 
CA 
[mg/dL] 
0.1 
Calcium Corrected 
CACR 
[mg/dL] 
0.1 
Creatinine 
CREAT 
[mg/dL] 
0.01 
Gamma Glutamyl Transferase 
GGT 
[U/L] 
1 
Lactate Dehydrogenase 
LDH 
[U/L] 
1 
Phosphate 
PHOS 
[mg/dL] 
1 
Total Protein 
PROT 
[g/dL] 
0.1 
Urine Tests 
Urine Glucose 
GLUC 
- 
Urine Protein 
PROT 
- 
Statistics: 
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P-values are presented to a maximum of two significant figures and three decimal places.
Values of p-lower than 0.001 will be specified as p<0.001. 
6.8.5 Treatment Labels 
Table [3]: Treatment labels for the clinical trial report text and tables 
Label Used in Text 
Label Used in Tables 
Order in Table 
LEO 90100 aerosol foam 
LEO 90100 foam 
1 
Dovobet® ointment 
Dovobet® ointment 
2 
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Appendix I 
Tables, Figures and Listings 
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Tables, Baseline Characteristics and Investigational Product Data (Module 2) 
Tables 
101 Trial period by Site (date of first subject visit vs. date of last subject visit: Enrolled 
subjects 
102 Subject enrolment and randomisation: Enrolled and randomised subjects 
103_A Age by Site: Randomised subjects 
103_B Age, height, weight, and BMI at screening visit: Randomised subjects 
104 Sex by Site: Randomised subjects 
105 Baseline total sign score of target lesion by Site: Randomised subjects 
106 Location of target lesion and duration of psoriasis: Randomised subjects 
107 Reasons for withdrawal: Randomised subjects 
108 Reasons for withdrawal by last visit attended: Randomised subjects 
109 Concurrent diagnoses (excluding psoriasis vulgaris) including indications of concomitant 
medication at screening visit by MedDRA primary SOC: Enrolled subjects 
110 Concurrent medications started before screening visit by ATC: Enrolled subjects 
111 Concurrent medications started after screening visit by ATC: Enrolled subjects 
112 Time (days) from visit 1 to each trial visit: Randomised subjects 
113 Compliance with treatment instructions: Randomised subjects 
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Tables, Efficacy Data (Module 3) 
Tables 
E1 Subjects with "overall improvement" for the target lesion at Visit 4 (Week 4 – LOCF): 
FAS 
E1_A Subjects with "overall improvement" for the target lesion at Visit 4 (Week 4 – LOCF) 
by Site: FAS 
E2 Subjects with "overall improvement" for the target lesion at Visit 4 (Week 4 – LOCF): 
PPAS 
EI1 First sensitivity analysis of subjects with "overall improvement" for the target lesion at 
Visit 4 (Weeks 4): FAS 
EI2 Second sensitivity analysis of subjects with "overall improvement" for the target lesion at 
Visit 4 (Week 4): FAS 
EI3 Third sensitivity analysis of subjects with "overall improvement" for the target lesion at 
Visit 4 (Week 4): FAS 
EI4 Fourth sensitivity analysis of subjects with "overall improvement" for the target lesion at 
Visit 4 (Week 4): FAS 
E3 Subjects with "overall improvement" for the target lesion at Visit 2 and 3 (End of Weeks 1 
and 2): FAS  
E4 Subjects with "overall improvement" for the target lesion at Visit 2 and 3(End of Weeks 1 
and 2): PPAS 
E5 The change in the total sign score for the target lesion from baseline to Visit 4 (Week 4 – 
LOCF): FAS 
E6 The change in the total sign score for the target lesion from baseline to Visit 4 (Week 4 – 
LOCF): PPAS 
E9 The change in severity of clinical sign (redness) for the target lesion from baseline to Visit 
4 (week 4 – LOCF): FAS 
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E10 The change in severity of clinical sign (thickness) for the target lesion from baseline to 
Visit 4 (week 4 – LOCF): FAS 
E11 The change in severity of clinical sign (scaliness) for the target lesion from baseline to 
Visit 4 (week 4 – LOCF): FAS 
E12 Subjects with "substantial resolution" of clinical signs for the target lesion by visit: FAS 
E13 The general change for the target lesion from baseline to each visit: FAS 
E14 Total sign score for the target lesion from baseline to each visit: FAS 
E15 Severity of clinical sign (redness) for the target lesion from baseline to each visit: FAS 
E16 Severity of clinical sign (thickness) for the target lesion from baseline to each visit: FAS 
E17 Severity of clinical sign (scaliness) for the target lesion from baseline to each visit: FAS 
E14_A Total sign score for the target lesion from baseline to each visit: PPAS 
E15_A Severity of clinical sign (redness) for the target lesion from baseline to each visit: 
PPAS 
E16_A Severity of clinical sign (thickness) for the target lesion from baseline to each visit: 
PPAS 
E17_A Severity of clinical sign (scaliness) for the target lesion from baseline to each visit: 
PPAS 
E18 Subject assessment of use of medication for "time spent for application" relative to 
previous topical treatment on target lesion at Visit 4 (Week 4): FAS 
E19 Subject assessment of use of medication for "ease of application" relative to previous 
topical treatment on target lesion at Visit 4 (Week 4): FAS 
E20 Summary of statistical analyses for the change in clinical signs (total sign, redness, 
thickness, scaliness): FAS 
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Tables, Safety Data (Module 4) 
Tables 
201 Duration and extent of exposure to treatment: Safety Analysis Set 
202 Overall summary of AEs: Safety Analysis Set 
203 AEs by primary SOC: Safety Analysis Set 
204 AEs by primary SOC and preferred term: Safety Analysis Set 
205 AEs assessed as mild by primary SOC and preferred term: Safety Analysis Set 
206 AEs assessed as moderate by primary SOC and preferred term: Safety Analysis Set 
207 AEs assessed as severe by primary SOC and preferred term: Safety Analysis Set 
208 AEs assessed as not related by primary SOC and preferred term: Safety Analysis Set 
209 AEs assessed as possibly related by primary SOC and preferred term: Safety Analysis Set 
210 AEs assessed as probably related by primary SOC and preferred term: Safety Analysis Set 
211 Related AEs by primary SOC and preferred term: Safety Analysis Set 
212 Lesional/perilesional AEs by primary SOC and preferred term: Safety Analysis Set 
213 Distant AEs by primary SOC and preferred term: Safety Analysis Set 
214AEs leading to withdrawal by primary SOC and preferred term: Safety Analysis Set 
215 Haematology laboratory parameters from baseline (Visit 1) to Visit 4 (Week 4): Safety 
Analysis Set 
216 Chemistry laboratory parameters from baseline to Visit 4 (Week 4): Safety Analysis Set 
217Haematology laboratory parameters categorised as low, normal or high at Visit 4 (Week 4) 
shown against baseline category: Safety Analysis Set 
218 Chemistry laboratory parameters categorised as low, normal or high at Visit 4 (Week 4) 
shown against baseline category: Safety Analysis Set 
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219 Urinary parameters categorised as absent or present at Visit 4 (Week 4) shown against 
baseline category: Safety Analysis Set 
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Patient Data Listings (Appendix 1) 
Listing 1.7.1 Randomisation code and treatment: Randomised subjects 
Patient Data Listings (Appendix 2) 
Appendix 2.1: Discontinued Subjects 
Listing 2.1.1 Screening failures: Non-randomised subjects 
Listing 2.1.2 Reason for withdrawal from trial: Randomised subjects 
Appendix 2.2: Protocol Deviations 
Listing 2.2.1 Major Protocol deviations: Enrolled subjects 
Listing 2.2.2 Comments from CRF: Enrolled subjects 
Appendix 2.3: Trial Analysis Sets 
Listing 2.2.3 Inclusion/exclusion criteria met: Enrolled subjects 
Listing 2.3.1 Trial analysis sets: Randomised subjects 
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Appendix 2.4: Demographic Data 
Listing 2.4.1 Demographics: Enrolled subjects 
Listing 2.4.2 Baseline characteristics: Enrolled subjects 
Listing 2.4.3 Actual trial period: Enrolled subjects 
Listing 2.4.4 Concurrent diagnoses (excluding psoriasis vulgaris) including indications for 
concomitant medication at screening visit: Enrolled subjects 
Listing 2.4.5 Concurrent medications started before screening visit: Enrolled subjects 
Listing 2.4.6 Concurrent medications started after screening visit: Enrolled subjects 
Listing 2.4.7 Concurrent procedure: Enrolled subjects 
Appendix 2.5: Compliance and/or Investigational Product Concentration Data 
Listing 2.5.1 Compliance: Randomised subjects 
Listing 2.5.2 Drug accountability: Randomised subjects 
Listing 2.5.3 End of trial form: Enrolled subjects 
Appendix 2.6: Efficacy Data 
Listing 2.6.1 Severity of clinical signs for the target lesion: Enrolled subjects 
Listing 2.6.2 Overall improvement for the target lesion: Enrolled subjects 
Listing 2.6.3 General change in target lesion from visit 1: Enrolled subjects 
Listing 2.6.4 Subject's assessment of use of medication on target lesion: Enrolled subjects 
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Appendix 2.7: Safety Data 
Listing 2.7.1 Adverse events: Enrolled subjects 
Listing 2.7.2 Severe adverse events: Enrolled subjects 
Listing 2.7.3 Adverse events leading to death: Enrolled subjects 
Listing 2.7.4 Serious adverse events: Enrolled subjects 
Listing 2.7.5 Physical examination: Enrolled subjects 
Appendix 2.8: Listing of Laboratory Values by Subject 
Listing 2.8.1 Laboratory measurements: Enrolled subjects 
Listing 2.8.2 Pregnancy test: Enrolled subjects 
Listing 2.8.3 Abnormal laboratory measurements: Enrolled subjects 
Listing 2.8.4 "Not done" reason for Laboratory test: Enrolled subjects 
Additional Tables for Results Reporting in Clinical Trial Data Registries 
Listing 2.9.1 All randomised patients: Randomised subjects 
Listing 2.9.2 Subjects with adverse drug reactions: Enrolled subjects 
Listing 2.9.3 Subject with serious adverse events: Enrolled subjects 
Listing 2.9.4 Subjects with adverse events leading to withdrawal: Enrolled subjects 
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Signature Page for TMF-000126355 v1.0
Electronic signatures made within eTMF LEO are considered to be a
legally binding equivalent of traditional handwritten signatures.
Reason for signing: Approved
Approv
Name: 
Capacit
Date of signature: 25-Jun-2019 09:43:42
GMT+0000
Reason for signing: Approved
Approv
Name: 
Capacit
Date of signature: 04-Jul-2019 08:21:43 GMT+0000
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PPD
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