Clinical trial NCT02387853
Conditions: Psoriasis Vulgaris
Sponsor: LEO Pharma
Start date: 2016-03-01; Completion date: 2018-03-28
Enrollment: 117 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
An international, multi-centre, prospective, open-label, non-controlled, single-group, 4-week trial in adolescent subjects with plaque psoriasis.

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: LEO 90100
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_001.pdf: 
 
 
 
 
 
 
 
Consolidated Clinical Trial Protocol 
 
Safety and Effect of LEO 90100 aerosol foam on the HPA Axis and Calcium 
Metabolism in Adolescent Subjects (Aged 12 to < 17 Years) with Plaque Psoriasis 
 
 
A phase 2 trial evaluating the safety and efficacy of once daily topical treatment with 
LEO 90100 aerosol foam in adolescent subjects with plaque psoriasis 
 
An international, multi-centre, prospective, open-label, non-controlled, single-group, 
4-week trial in adolescent subjects with plaque psoriasis 
 
 
 
 
 
 
 
 
ICH GCP statement: The clinical trial will be conducted in compliance with the clinical 
trial protocol, GCP and the applicable regulatory requirement(s). 
 
 
 
 
 
 
 
 
 
LEO Pharma A/S 
Trial ID: 
LP0053-1108 
Date: 
29-AUG-2016 
Version: 
5.0 
 
 
eDoc-00617435 - Version 1.0 


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1 Clinical Trial Protocol Statement 
1.1 Approval Statement LEO Pharma A/S 
The following persons have approved this clinical trial protocol by using electronic signatures 
as presented on the last page of this document: 
 
PPD 
 
Biostatistics Lead, Skin Inflammation 
 
PPD  
Medical Lead, Skin Inflammation 
 
 
1.2 Approval Statement International Coordinating Investigator 
The international coordinating investigator approves the clinical trial protocol and 
consolidated clinical trial protocol(s) comprising any subsequent amendment(s) by manually 
signing the International Coordinating Investigator Clinical Trial Protocol Approval Form, 
which is a separate document adjoined to this document. 
 
The following person has approved this clinical trial protocol: 
 
Marieke Seyger, MD, PhD 
International coordinating investigator 
 
 
1.3 Acknowledgement Statement Investigator(s) 
Each participating investigator must agree to the approved clinical trial protocol and 
consolidated clinical trial protocol(s) comprising any subsequent amendment(s) by signing a 
Clinical Trial Protocol Acknowledgement Form. 


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Table of Contents 
1 Clinical Trial Protocol Statement .......................................................................................... 2 
1.1 
Approval Statement LEO Pharma A/S ............................................................................. 2 
1.2 
Approval Statement International Coordinating Investigator ........................................... 2 
1.3 
Acknowledgement Statement Investigator(s) ................................................................... 2 
Table of Contents........................................................................................................................ 3 
List of Tables ......................................................................................................................................... 9 
List of Figures ............................................................................................................................ 9 
2 Trial Identification ............................................................................................................... 10 
3 Introduction and Rationale .................................................................................................. 10 
3.1 
Psoriasis Vulgaris (plaque psoriasis) .............................................................................. 10 
3.2 
Experience with Investigational Product ........................................................................ 11 
3.2.1 
Clinical experience with LEO 90100 .......................................................................... 11 
3.3 
Trial Rationale ................................................................................................................. 12 
3.3.1 
Overall Trial Rationale ................................................................................................ 12 
3.3.2 
Rationale for safety assessments ................................................................................. 13 
3.3.3 
Rationale for efficacy assessment................................................................................ 14 
3.4 
Ethical Consideration Statement ..................................................................................... 14 
4 Trial Objectives ................................................................................................................... 16 
4.1 
Primary Objective ........................................................................................................... 16 
4.2 
Secondary Objectives ..................................................................................................... 16 
5 Trial Endpoints .................................................................................................................... 16 
5.1 
Primary Endpoint(s) ........................................................................................................ 16 
5.2 
Secondary Endpoints ...................................................................................................... 17 
6 Trial Design ......................................................................................................................... 18 
6.1 
Overall Trial Design ........................................................................................................ 18 
6.2 
Sample Size..................................................................................................................... 20 
6.3 
Randomisation ................................................................................................................ 20 
6.4 
Blinding .......................................................................................................................... 20 
7 Trial Population and Withdrawal ......................................................................................... 20 
7.1 
Subject Eligibility ........................................................................................................... 20 
7.2 
Inclusion Criteria ............................................................................................................ 21 


7.2.1 
Inclusion Criteria for All Subjects ............................................................................... 21 
7.2.2 
Additional inclusion criteria for subjects undergoing HPA axis testing ...................... 22 
7.3 
Exclusion Criteria ........................................................................................................... 22 
7.3.1 
Exclusion Criteria for All Subjects .............................................................................. 22 
7.3.2 
Additional exclusion criteria for subjects undergoing HPA axis testing .................... 24 
7.4 
Re-screening of subjects ................................................................................................. 25 
7.5 
Subject Enrolment Log ................................................................................................... 25 
7.6 
Subject Identification List ............................................................................................... 25 
7.7 
Restrictions during Trial ..................................................................................................... 25 
7.8 
Withdrawal Criteria ........................................................................................................ 26 
8 Trial Schedule and Assessments .......................................................................................... 27 
8.1 
Schedule of Trial Procedures .......................................................................................... 27 
8.2 
Demographics ................................................................................................................. 30 
8.3 
Height and Weight .................................................................................................................... 31 
8.4 
Vital Signs ....................................................................................................................... 31 
8.5 
Physical Examination ..................................................................................................... 31 
8.6 
Medical History .............................................................................................................. 31 
8.7 
Instruction for 24-hour urine collection and dietary calcium intake diary ..................... 32 
8.8 
Concomitant Medication................................................................................................. 32 
8.9 
Pregnancy Test .......................................................................................................................... 36 
8.10 Adverse Events ............................................................................................................... 36 
8.11 Other Safety Assessments ............................................................................................... 36 
8.12 Laboratory Assessments ................................................................................................. 36 
8.12.1 
Safety Laboratory Tests ........................................................................................................ 36 
8.12.2 
Safety Urinalysis ......................................................................................................... 38 
8.12.3 
Pharmacokinetic (PK) Assessments ............................................................................ 38 
8.12.3.1 Blood sampling for analysis of LEO 90100 and metabolite(s) ............................... 38 
8.12.4 Pharmacodynamic (PD) Assessments ......................................................................... 39 
8.12.5 Total Blood Volume................................................................................................................... 40 
8.13 Patient Reported Outcomes ............................................................................................ 41 
8.14 Physicians Assessments .................................................................................................. 43 
8.15 Photography .................................................................................................................... 47 
8.16 Dispensing of IP............................................................................................................................. 47 
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8.17 Return of IP and Compliance .......................................................................................... 47 
8.18 End of Trial Form ............................................................................................................ 47 
9 Adverse Events .................................................................................................................... 47 
9.1 
Collection of Adverse Events ......................................................................................... 48 
9.2 
Reporting of Adverse Events in the CRF ........................................................................ 48 
9.3 
Actions Taken as a Consequence of an AE ..................................................................... 49 
9.4 
Other Events to be Reported ........................................................................................... 49 
9.4.1 
Pregnancy .................................................................................................................... 49 
9.4.2 
Overdose ...................................................................................................................... 49 
9.4.3 
Medication Error ......................................................................................................... 49 
9.4.4 
Misuse ......................................................................................................................... 50 
9.4.5 
Abuse ........................................................................................................................... 50 
9.4.6 
Aggravation of Condition ............................................................................................ 50 
9.4.7 
Lack of Efficacy .......................................................................................................... 50 
9.5 
Additional Reporting Requirements for Serious Adverse Events ................................... 50 
9.5.1 
Investigator Reporting Responsibilities ...................................................................... 50 
9.5.2 
LEO Reporting Responsibilities .................................................................................. 51 
9.6 
Follow-up for Final Outcome of Adverse Events ........................................................... 52 
10 Investigational Product(s) .................................................................................................... 52 
10.1 Investigational Product Description ................................................................................ 52 
10.2 Administration of Investigational Products .................................................................... 53 
10.3 Precautions/Overdosage.................................................................................................. 54 
10.4 Packaging of Investigational Products ............................................................................ 54 
10.5 Storage of Investigational Products ................................................................................ 55 
10.6 Treatment Assignment .................................................................................................... 55 
10.6.1   Randomisation Code List ............................................................................................ 55 
10.7 Non-Investigational Medicinal Products ........................................................................ 56 
10.7.1 
CORTROSYN® (cosyntropin)/Synacthen® for injection ............................................ 56 
10.7.1.1 Packaging and Labelling .......................................................................................... 57 
10.7.1.2 Storage of Non-Investigational Medicinal Products ................................................ 57 
10.7.1.3 Reconstitution and Administration .......................................................................... 57 
10.7.1.4 Precautions ............................................................................................................... 58 
10.7.2 0.9% Sodium Chloride Injection, USP ........................................................................ 58 


10.7.2.1 Packaging and Labelling .......................................................................................... 58 
10.7.2.2 Storage ..................................................................................................................... 58 
10.7.2.3 Precautions ............................................................................................................... 59 
10.8 Drug Accountability and Compliance Checks ................................................................ 59 
10.8.1 
Drug Accountability .................................................................................................... 59 
10.8.1.1 
Drug Accountability Investigational Product .......................................................... 59 
10.8.1.2 
Drug Accountability Non-Investigational Medicinal Products ............................... 60 
10.8.2 Trial Product Destruction ............................................................................................ 60 
10.8.3 Treatment Compliance ................................................................................................ 60 
10.9  Emergency Unblinding of Individual Subject Treatment ............................................... 60 
11 Statistical Methods .............................................................................................................. 60 
11.1 Determination of Sample Size ........................................................................................ 60 
11.2 Definition of Trial Analysis Sets ..................................................................................... 61 
11.3 Statistical Analysis .......................................................................................................... 62 
11.3.1 Disposition of Subjects ................................................................................................ 62 
11.3.2 Demographics and other Baseline Characteristics ...................................................... 62 
11.3.3 Exposure and Treatment Compliance ......................................................................... 62 
11.3.4 Analysis of Primary Endpoints .................................................................................... 63 
11.3.5 Analysis of Secondary Endpoints ................................................................................ 64 
11.3.6 Exploratory Analysis of Efficacy ................................................................................ 66 
11.3.7 Analysis of Patient-Reported Outcomes ..................................................................... 67 
11.3.8 Analysis of Safety ....................................................................................................... 67 
11.3.8.1 
Adverse Events ........................................................................................................ 67 
11.3.8.2 
Vital Signs ................................................................................................................ 68 
11.3.8.3 
Local Safety and Tolerability .................................................................................. 69 
11.3.8.4 
Clinical Laboratory Evaluation ................................................................................ 69 
11.3.8.5 
PK evaluation........................................................................................................... 69 
11.3.9 
Interim Analysis .......................................................................................................... 70 
11.3.10 General Principles ....................................................................................................... 70 
11.3.11 Handling of Missing Values ................................................................................................ 70 
12 Trial Committees ................................................................................................................. 70 
13 Case Report Forms and Data Handling ............................................................................... 71 
13.1 Case Report Forms (CRFs) ............................................................................................. 71 
13.2 Data Handling ................................................................................................................. 71 
 
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13.3 Source Data ..................................................................................................................... 71 
13.4 Trial Monitoring .............................................................................................................. 73 
14 Handling of an Urgent Safety Measure ............................................................................... 73 
15 Quality Assurance/Audit...................................................................................................... 74 
16 Completion of Trial .................................................................................................................. 74 
16.1 Trial Completion Procedures .......................................................................................... 74 
16.1.1 Criteria for Premature Termination of the Trial and/or Trial Site ............................... 75 
16.2 Provision for Subject Care Following Trial Completion ................................................ 75 
16.3 Archiving of Trial Documents ........................................................................................ 75 
17 Ethics and Regulatory Authorities ....................................................................................... 76 
17.1 Institutional Review Boards (IRBs)/Independent Ethics Committees (IECs) and 
Regulatory Authorities  ............................................................................................................  76 
17.2 Ethical Conduct of the Trial ............................................................................................ 76 
17.3 Subject Information and Informed Consent .................................................................... 76 
17.4 Processing of Personal Data ........................................................................................... 77 
18 Insurance .............................................................................................................................. 77 
19 Use of Information............................................................................................................... 78 
20 Publication ........................................................................................................................... 78 
21 Responsibilities .................................................................................................................... 79 
22 List of Abbreviations ........................................................................................................... 80 
23 References ........................................................................................................................... 83 
24 List of Appendices ............................................................................................................... 86 
25 Appendix 1: Protocol Summary .......................................................................................... 87 
26 Appendix 2: Definitions of Adverse Events and Serious Adverse Events .......................... 93 
26.1 Adverse Event Definition ............................................................................................... 93 
26.2 Serious Adverse Event Definition................................................................................... 93 
27 Appendix 3: Classification of Adverse Events .................................................................... 95 
27.1 Severity ........................................................................................................................... 95 
27.2 Causality ......................................................................................................................... 95 
27.3 Outcome .......................................................................................................................... 96 
28 Appendix 4: Contact list of LEO, protocol authors, vendors, trial committees and 
coordinating investigators  .......................................................................................................  97 


29 Appendix 5: Subject Assessment of Itch by use of a Visual Analogue Scale (VAS) .......... 100 
30 Appendix 6: Subject Assessment of Itch-Related Sleep Loss by use of a Visual Analogue 
Scale (VAS)  ...........................................................................................................................  102 
31 Appendix 7: Children’s Dermatology Life Quality Index (CDLQI) ................................. 103 
32 Appendix 8: The Family Dermatology Life Quality Index (FDLQI) ................................ 104 
33 Appendix 9: Mosteller Formular ....................................................................................... 106 
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List of Tables 
Table 1: Scheduled of Trial Procedures - Main Cohort ............................................................ 27 
Table 2: Scheduled of Trial Procedures – HPA Axis Cohort .................................................... 29 
Table 3: Fitzpatrick Skin Type .......................................................................................................... 31 
Table 4: Prohibited Medication including Non-Drug Therapies and Procedures (for all 
subjects) ........................................................................................................... 34 
Table 5: Prohibited Medication including Non-Drug Therapies and Procedures (for subjects 
performing HPA axis and PK assessments)  .....................................................  35 
Table 6: Permitted concomitant anti-psoriatic treatment ......................................................... 35 
Table 7: Planned Safety Analysis ............................................................................................. 37 
Table 8: Safety urinalysis ......................................................................................................... 38 
Table 9: Total blood volume ..................................................................................................... 40 
Table 10: Total blood volumes for subjects participating in the  HPA axis and PK assessments 
.......................................................................................................................... 40 
Table 11: Total blood volumes for follow-up testing ............................................................... 41 
Table 12: Subject´s Global Assessment of Disease Severity Scale .......................................... 42 
Table 13: Physician´s global assessment of disease severity (PGA) ........................................ 45 
Table 14: Physician’s Assessment of local safety and tolerability ........................................... 47 
Table 15: LEO 90100 ............................................................................................................... 52 
Table 16: Administration of IP ..................................................................................................... 53 
Table 17: CORTROSYN® (used in the US) ............................................................................ 56 
Table 18: Synacthen® (used in Europe) .................................................................................... 57 
List of Figures 
Figure 1: Course of the trial ..................................................................................................... 18 


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2 Trial Identification 
EudraCT number: 2015-000839-33 
IND number: 114063. All participating sites will conduct the trial under the IND. 
ClinicalTrials.gov Number: NCT02387853 
3 Introduction and Rationale 
3.1 Psoriasis Vulgaris (plaque psoriasis) 
Psoriasis is an immunologic disease that predominantly affects the skin and has a prevalence 
of approximately 2%, affecting any age (1,2), even though the prevalence of psoriasis in 
children is lower than in adults (3). The hallmark of psoriasis is inflammation of the skin. In 
the majority of subjects, psoriasis manifests as plaque type psoriasis, clinically seen as sharply 
demarcated, elevated, scaling, erythematous plaques located predominantly on the scalp, 
extensor sides of elbows and knees, and the sacral region (4,5,6). The presentation can 
sometimes be somewhat different in children, often with scalp involvement (7). Skin lesions 
can be painful, pruritic and may cause significant emotional and physical discomfort (8,9). 
 
The majority of affected subjects has mild to moderate disease and can be treated with topical 
therapies (9). In the group of subjects with moderate to severe psoriasis topical therapies are 
also appropriate either as adjunct to phototherapy, systemic or biologic agents (10,11). One of 
the advantages of topical therapies is a reduced risk of systemic toxicity compared to other 
treatment modalities. The most commonly used topical therapies in adults are corticosteroids 
and vitamin D analogues used either alone or in combination (12). 
 
The fixed combination of calcipotriol 50 mcg/g (as monohydrate) and betamethasone 0.5 
mg/g (as dipropionate) in an ointment and gel/topical suspension formulation for body and 
scalp have already been marketed for several years in adults. These products are marketed in 
the US under the trade name Taclonex® and in Europe under trade names such as Daivobet®, 
Dovobet® and Xamiol®. FDA has recently granted approvals for the treatment of scalp 
psoriasis with Taclonex® Topical suspension in adolescent patients aged 12-17 years and 
treatment of psoriasis vulgaris with Taclonex® Ointment in adolescent patients aged 12-17 
years. 
 
Psoriasis is a chronic, recurrent disease, and no cure exists (4). Despite availability of current 
treatment options, many subjects are not achieving optimal control of their psoriasis. Patient 
adherence may be the largest barrier to treatment success with topical therapies. The factors 
that hinder patient adherence include frustration with medication efficacy, messiness and 
time-consuming and inconvenient application, among others (13). 


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To address this need, LEO has developed a new formulation of calcipotriol/betamethasone 
dipropionate (BDP) which was demonstrated to be more effective than Daivobet ® ointment 
with a similar safety profile in adults, including systemic safety (14). The foam formulation 
may be cosmetically more acceptable and user friendly than ointment and therefore 
potentially lead to better adherence. 
 
3.2 Experience with Investigational Product 
 
LEO 90100 aerosol, foam has been developed to provide a new efficacious product intended 
for the topical treatment of plaque psoriasis. It contains calcipotriol 50 mcg/g and 
betamethasone 0.5 mg/g (as dipropionate). 
 
LEO 90100 contains the two drug substances and excipients dissolved in the propellants 
butane and dimethyl ether (DME) in an aluminium can. At administration a white to off-white 
foam is formed after evaporation of the propellants. Apart from the propellants, no new 
excipients have been used in LEO 90100 as compared to Daivobet®ointment. 
The individual active components in LEO 90100, i.e. calcipotriol and BDP, are both 
considered to be well established for topical treatment and their safety profiles are well 
known, generally well tolerated and with few side effects primarily of mild severity (15). 
 
The propellants used in LEO 90100, butane and DME, are both widely used and are generally 
regarded as non-toxic and mild or non-irritating. Based on the review of the toxicology data 
for butane and DME, as well as the non-clinical and clinical studies with LEO 90100, there is 
no evidence that the use of butane and DME poses any increased risk for adverse events 
(AEs) of a systemic or local nature. 
 
3.2.1 Clinical experience with LEO 90100 
 
The safety and efficacy of LEO 90100 in the treatment of plaque psoriasis in adults has been 
evaluated in, a maximum use systemic exposure (MUSE) trial, a vasoconstriction trial, a 
dermal safety trial, two phase 2 and a pivotal phase 3 trial. 
 
In the three controlled trials evaluating efficacy, LEO 90100, applied once daily for 4 weeks, 
was shown to be more effective than each of the individual components (calcipotriol and 
BDP), Daivobet® ointment and the foam vehicle alone in the treatment of psoriasis on the 
body. 
 
The percentage of subjects in the LEO 90100 group with ‘treatment success’ (‘clear’ or 
‘almost clear’) according to the Physician’s Global Assessment of disease severity (PGA) at 
Week 4 was 45.0% and 54.6% in the phase 2 trials, and 53.3% in the pivotal phase 3 trial. 


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The effect of LEO 90100 on adrenal function and calcium metabolism in adult subjects has 
been evaluated in the MUSE trial (16). The subjects included in the trial had extensive 
psoriasis on both scalp (at least 30% of scalp affected) and non-scalp regions of the body (15- 
30% of body surface area). Subjects applied LEO 90100 to lesions on the scalp,trunk and 
limbs once daily for 4 weeks. The adrenal function was assessed by the Adrenocorticotrophic 
Hormone (ACTH) -challenge test. There was no indication of an effect on the Hypothalmic- 
Pituitary-Adrenal (HPA) axis. None of the 35 subjects who completed 28 days of treatment 
per protocol had a serum cortisol ≤18 mcg/dL 30 minutes after the ACTH stimulation test at 
Day 28, thus all 35 subjects had an adequate response to the ACTH. 
 
Evaluation of serum and urine markers of calcium homeostastis showed no clinical relevant 
impact on calcium metabolism after 4 weeks of treatment. A mean amount of 62 g/week 
(range 14 to 113 g) of LEO 90100 was used during the study. 
 
Overall LEO 90100 was well tolerated, with a low incidence of AEs and a safety profile 
similar to that of Daivobet® ointment. The most commonly reported adverse effects were the 
application site reactions irritation and pruritus. The incidence of potentially calcipotriol- or 
corticosteroid- related AEs was low and in line with previous experience from trials with 
marketed calcipotriol plus BDP products, and gave no indication of any new concerns. 
 
Further information regarding LEO 90100 relevant to clinical trials can be found in the 
Investigator’s Brochure (IB) (14). 
 
3.3 Trial Rationale 
 
3.3.1 Overall Trial Rationale 
 
To fulfill the pediatric study requirements under the US Pediatric Research Equity Act 
(PREA), which requires an assessment of the safety and effectiveness of a new dosage form 
of a drug for the claimed adult indications in all relevant pediatric subpopulations, LEO is 
committed to conduct a trial with LEO 90100 in adolescent subjects with plaque psoriasis, 
aged 12 to < 17 years. 
The objective of the present phase 2 trial is to evaluate the safety, pharmacodynamics (effect 
on HPA axis and calcium metabolism) and pharmacokinetics of LEO 90100 in adolescent 
subjects with plaque psoriasis. Subjects will be treated once daily over a period of 4 weeks. 
 
The trial will be conducted in 100 evaluable adolescent subjects with plaque psoriasis on the 
body and scalp, to evaluate the safety and effect of LEO 90100 on the calcium metabolism. In 
a subset of a least 30 subjects treated under maximal use conditions, evaluation of the effect 
on HPA axis and pharmacokinetics will be performed. 


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3.3.2 Rationale for safety assessments 
 
To evaluate the safety of the LEO 90100 in this trial, all AEs reported by the subject or 
observed by the investigator will be recorded. In addition, any effects resulting from systemic 
absorption of the active components, calcipotriol and BDP, will be evaluated by assessing 
adrenal function and calcium metabolism, respectively. 
Laboratory evidence of adrenal insufficiency due to the use of topical corticosteroid treatment 
has been reported (17). This is due to systemic absorption of the corticosteroid, which then 
induces suppression of the HPA axis due to a negative feedback effect on the pituitary gland 
and the hypothalamus (17,18). This results in a decrease in the secretion of ACTH from the 
pituitary gland. The adrenal glands depend on ACTH as a tropic hormone in such a way that 
ACTH deficiency results in a reversible inability to produce cortisol (19). Hence, the adrenal 
glands lose the capacity to produce cortisol in response to an ACTH-challenge. Adrenal 
function can therefore be measured by injection of a synthetic subunit of ACTH into the 
subject, and then measuring the production of cortisol by the adrenal glands in response to 
this. A serum cortisol concentration of 18 mcg/dl or less at 30 and 60 minutes after the 
injection indicates possible adrenal suppression (18). 
 
In the present study LEO 90100 will be applied to lesions on both body and scalp. The risk of 
adrenal suppression with LEO 90100 is expected to be low with LEO 90100 being applied 
under maximal use conditions. 
 
A subset of subjects participating in the study will perform ACTH-challenge test before and 
after treatment. The pre-treatment test is to ensure that adrenal function is normal before 
starting the treatment with the investigational product. Serum cortisol concentrations at 30 
and 60 minutes after injection will be measured in order to show the maximum cortisol level 
achieved (18). 
 
Overdosage with topical calcipotriol can cause hypercalcemia (19), due to the systemic 
absorption of calcipotriol, which then affects calcium metabolism as it is a vitamin D 
analogue. However, extensive experience with the topical use of calcipotriol in psoriasis has 
demonstrated no significant impact on calcium metabolism when used in the recommended 
amounts (maximum weekly dose in adults of 100 g with a 50 mcg/g concentration). Doses up 
to 300 g have been used with serum calcium remaining within the normal range (20). 
 
Two studies with calcipotriol ointment have been conducted in children 2-14 years of age and 
did not show effects on calcium metabolism (21,22). One trial with Daivobet® Ointment, 
MCB 0501 INT, has been conducted in adolescent subjects and did not show any effects on 
calcium or HPA axis. 


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Calcium metabolism will be evaluated in the present study by 24-hour urinary collection (for 
subjects undergoing HPA axix testing) and spot urine sampling (for the remaining subjects), 
as well as measurement of serum calcium, -phosphate, alkaline phosphatase (ALP) and 
plasma parathyroid hormone (PTH) before, and after treatment. 
 
It is well established that there is a relationship between dietary calcium intake and the urinary 
calcium excretion in adults. However, in rapidly growing adolescents, it appears that only 
dietary calcium intake above a certain threshold of approximately 1500 mg/day will result in 
an increase in urinary calcium excretion (23). As this study includes adolescents aged 12 to 17 
years, some of the subjects may not be in a phase of rapid growth and some subjects might 
consume large amounts of dairy products. Therefore, there is a possibility of an dietary effect 
on the calcium excretion. 
 
A review of the subject’s normal diet will be done. The subject will be asked to keep a diary 
of the daily intake of diary products. 
 
The combination of high calcium intake with vitamin D supplementation, or extreme calcium 
intake alone, has been shown to significantly increase urinary calcium in adults (24). Hence, 
patients who cannot stop the use of calcium or vitamin D supplementation > 400 IU/day will 
be excluded in this study. 
 
Local safety and tolerability will be evaluated, at all visits by a clinical scoring of the signs 
and symptoms from the application site on a 4-point scale (from absent to severe). 
 
3.3.3 Rationale for efficacy assessment 
 
The present study is primarily designed as a safety study since it is an open label study 
without a comparator arm. However, the sponsor believes it is important to document any 
improvements in efficacy in the adolescent population. 
 
Efficacy will be assessed by the PGA on the body and scalp via the physician´s assessment of 
the extent and severity of clinical signs of plaque psoriasis. Further assessments are outlined 
in section 8.13 and 8.14. 
 
3.4 Ethical Consideration Statement 
The combination product of calcipotriol and BDP has been approved in two formulations 
(ointment and gel/topical suspension) for use on body and/or scalp psoriasis. LEO 90100 is a 
new aerosol foam formulation of the well-established fixed combination product of the 
vitamin D analogue calcipotriol and the potent steroid BDP. 


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The safety and efficacy of LEO 90100 has been evaluated in two phase 2 and one phase 3 
trial. For details see section 3.2 (Experience with Investigational Product) and the IB (14). 
Side effects are not common in patients using LEO 90100 and serious side effects are 
uncommon. 
 
Psoriasis vulgaris is a chronic and recurrent skin disorder. At present, no curative treatment is 
available for the disease. Psoriasis is a disabling disease, with a significant impact on the 
quality of life comparable with that observed in other chronic medical conditions such as 
diabetes and depression (25,26,27). 
 
Most topical preparations are greasy and messy to apply, have an unpleasant smell and may 
cause staining of clothes and fabrics and skin irritation. Patient’s compliance is therefore often 
poor, leading to a bad therapeutic outcome (28). Therefore, there is a need for a patient 
acceptable topical treatment also in this age group. 
 
If topical treatment is ineffective in adolescents with moderate to severe psoriasis, 
phototherapy or systemic therapy will be the next step in the treatment. As these treatment 
modalities have known (systemic) side effects, it is in the interest of the adolescents to find 
topical treatments with greater adherence and a good safety profile, in order to avoid or 
postpone systemic treatments. 
 
The safety and efficacy of calcipotriol/BDP combination in other formulations has been 
investigated in three clinical trials in adolescents aged 12 to 17 years. All three studies contain 
the elements of systemic safety testing, which would be the main concern for use of these 
combination products in patients aged 12 to 17 years. Safety information from these three 
studies and information from off label use indicate a similar safety profile in this population 
as that seen in adult, with few side effects. 
 
In the present trial, adolescent subjects with plaque psoriasis will be dosed with LEO 90100 
for 4 weeks, in alignment with the proposed labeling for adults. The risks associated with 
prolonged treatment with calcipotriol and potent steroids are well known and will be 
monitored. 
 
As LEO 90100 contains both calcipotriol and BDP, the same pattern of adverse effects as 
reported for these individual substances is expected. 
 
For calcipotriol there is an infrequent potential risk of hypercalcemia due to systemic 
absorption. Based on experience from other formulations (ointment and gel/topical 
suspension), this risk is minimal when used in the recommended doses. Reports of 
hypercalcemia with calcipotriol remain uncommon. 


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For BDP, the most commonly reported adverse events (AEs) are the well-known local class 
effects for topically applied steroids such as skin atrophy, striae and telangiectasia. 
 
The more serious potential adverse effects are systemic effects such as HPA axis suppression. 
Clinically significant adrenal insufficiency due to topical corticosteroid treatment is however 
uncommon in adults and with the data available for LEO 90100 the risk of developing adrenal 
insufficiency is low under the conditions applied in the present trial (16). 
 
Participation in this trial is voluntary and subjects are allowed to withdraw at any time. The 
parent(s)/legal guardian(s) of the subjects will give informed consent, and subjects must give 
their assent, or subjects may give informed consent as appropriate and according to national 
laws and regulations. 
 
Blood samples will be drawn at scheduled visits during the trial. The expected total blood 
volume collected is 98 ml for subjects performing HPA axis and PK assessments and 18 ml 
for subjects not performing these assessments. 
 
Subjects participating in the trial will be under careful supervision by a qualified Investigator 
during the entire trial period. If any potentially serious reactions are observed, subjects will be 
withdrawn at the Investigator’s discretion or according to withdrawal criteria (Section 7.7). 
 
4 Trial Objectives 
4.1 Primary Objective 
The primary objective is to evaluate the safety of once daily use of LEO 90100 in adolescent 
subjects (aged 12 to < 17 years) with plaque psoriasis on the body and scalp. 
 
4.2 Secondary Objectives 
The secondary objective is to evaluate the efficacy of once daily use of LEO 90100 in 
adolescent subjects (aged 12 to < 17 years) with plaque psoriasis on the body and scalp. 
 
5 Trial Endpoints 
5.1 Primary Endpoint(s) 
• Adverse events (AEs) 
• Subjects with serum cortisol concentration of ≤18 mcg/dl at 30 minutes after ACTH- 
challenge at Week 4 
• Change in albumin-corrected serum calcium from baseline (SV2) to Week 4 


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• Change in calcium excretion from baseline (SV2) to Week 4 in 24-hour urine 
• Change in calcium:creatinine ratio from baseline (SV2) to Week 4 in 24-hour urine 
 
5.2 Secondary Endpoints 
• Subjects with serum cortisol concentration of ≤18 mcg/dl at both 30 and 60 minutes 
after ACTH-challenge at Week 4 
• Change in calcium:creatinine ratio from baseline (SV2) to Week 4 in spot urine 
• Subjects with ‘treatment success’ (i.e., ‘clear’ or ‘almost clear’ for subjects with at least 
‘moderate’ disease at baseline, ‘clear’ for subjects with ‘mild’ disease at baseline) 
according to the physician´s global assessment of disease severity on the body at Week 
4 
• Subjects with ‘treatment success’ (i.e., ‘clear’ or ‘almost clear’ for subjects with at least 
‘moderate’ disease at baseline, ‘clear’ for subjects with ‘mild’ disease at baseline) 
according to the physician´s global assessment of disease severity on the scalp at Week 
4 
• Percentage change in psoriasis area and severity index (PASI) from baseline (V1) to 
Week 4 
• Subjects with ‘treatment success’ (i.e., ‘clear’ or ‘very mild’) according to the subject´s 
global assessment of disease severity on the body at Week 4 
• Subjects with ‘treatment success’ (i.e., ‘clear’ or ‘very mild’) according to the subject´s 
global assessment of disease severity on the scalp at Week 4 
• Change in itch as assessed by the Visual Analogue Scale (VAS) from baseline (V1) to 
Week 4 


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6 Trial Design 
6.1 Overall Trial Design 
 
Figure 1: Course of the trial 
 
 
Washout/ screening 
period 
 
Treatment period 
Follow-up period 
(if applicable) 
 
 
 
 
 
Day 
Visit 
-28  to -7 
before Visit 1 
SV1 
-3 to -7 
0 
SV2 
1 
14 
28 
2 
3 
+ 14 
FU1 
+ 28 
FU2 
 
 
This will be an international, multi-centre, prospective, open-label , non-controlled, single- 
group, 4-week trial in adolescent subjects (aged 12 to < 17 years) with plaque psoriasis on the 
body and scalp. 
 
The subjects will receive topical treatment with LEO 90100 once daily for up to 4 weeks. The 
trial duration for each subject (including a 4-week washout period) is planned to be 8 weeks 
and includes 5 visits to the clinic (up to 7 visits if a follow-up visit is required). 
 
Washout/Screening Period 
 
Depending on the prior use of prohibited treatments, the washout/screening period will last 
for 7 to 28 days prior to the first administration of LEO 90100 (Visit 1). 
 
Prior to attending any study procedure, a signed informed consent must be obtained from the 
parent(s)/legal guardian(s) of the subject, or by the subject (as appropriate and according to 
national laws and regulations). Written assent should also be obtained from the subject. There 
are two screening visits: Screening visit 1 (SV1) and Screening Visit 2 (SV2). Depending on 
the subjects’ use of excluded treatments, SV1 is performed up to 3 weeks before SV2; SV2 is 
performed at 3 to 7 days before Visit 1. 


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Treatment Period 
 
The treatment period will be 4 weeks and includes 3 visits: Visit 1 (Day 0), Visit 2 (Day 14) 
and Visit 3 (Day 28). Visits 2-3 should be performed within ±2 days of the scheduled time 
relative to Visit 1; if they are outside this window, the (sub)investigator should record the 
reason in the subject’s medical record. 
 
LEO 90100 will be applied once daily to body and scalp psoriasis lesions. Subjects taking part 
in the HPA axis testing and PK assessments should continue with treatment regardless if their 
lesions cleared at Visit 2. The remaining 70 subjects, whose psoriasis clears on individual 
lesions at Visit 2 according to the (sub)investigator, may discontinue treatment but will stay in 
the trial. During periods of discontinuation of treatment the subject should restart the 
treatment if psoriasis reappears. 
 
Follow-up 
 
If applicable, the treatment period will be followed by a follow-up (FU) period consisting of 
Visit FU1 and/or Visit FU2. 
 
Visit FU1 will take place 14 days after the last visit in the treatment period, but only in case a 
Serious Adverse Event (SAE) is ongoing at the last on-treatment visit or if a non-serious 
adverse event is ongoing with possible/probable/not assessable relationship to the 
investigational product. FU1 should also be performed if albumin corrected serum calcium is 
above the reference range at the last on-site visit. A new blood sample should then be 
collected. 
 
Visit FU2 will take place 28 days after the ACTH-challenge test performed at Visit 3, but 
only if this test showed a serum cortisol concentration ≤18 mcg/dl at 30 minutes after ACTH- 
challenge. 
 
Visits FU1 and FU2 should be performed within ±2 days of the scheduled time; if they are 
outside this window, the qualified site staff person should record the reason in the subject’s 
medical record/source document. 
 
Planned date of enrolment of first subject: Q3 2015 
Planned date of completion of last subject: Q1 2017 
Estimated number of trial sites and region allocation: approx. 30 sites across North America, 
Central and Eastern Europe (CEE) 


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6.2 Sample Size 
The sample size was outlined in the Pediatric Study Plan for LEO 90100 and accepted by the 
FDA as an adequate sample size. 
 
Enrolment of subjects will continue until data from 100 subjects are available for evaluation 
of the effect of LEO 90100 on calcium metabolism (i.e. the measurement of the serum 
calcium concentration is available before and at Visit 3). Therefore, the number of enrolled 
subjects can exceed 100 subjects. 
 
The 100 subjects include the enrolment of 30 evaluable subjects in the assigned sites without 
adrenal suppression at baseline who undergo an ACTH-challenge test and PK assessments at 
end of treatment (Visit 3). At the time the sponsor confirms 30 evaluable subjects has been 
obtained, there may be other subjects ongoing in the trial that have not yet had an ACTH- 
challenge test and PK assessments. Such subjects will be allowed to complete the trial without 
an ACTH-challenge test and PK assessments. 
 
Each centre should aim to enroll a minimum of three subjects. As the subjects are anticipated 
to be difficult to recruit, the suggested minimum number of subjects per centre is based on 
practical considerations rather than statistical robustness of estimates given per centre. 
 
The statistical power considerations for this sample size are described in section 11.1. 
 
6.3 Randomisation 
Not applicable. 
 
6.4 Blinding 
Not applicable. 
 
7 Trial Population and Withdrawal 
7.1 Subject Eligibility 
The (sub)investigator should only enrol 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 visits specified in “Schedule of Trial Procedures” (see section 8.1). 


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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/ethics 
committees, as applicable. 
 
7.2 Inclusion Criteria 
 
7.2.1 Inclusion Criteria for All Subjects 
 
1. Signed and dated informed consent given by parent(s), or legal guardian(s), or by the 
subject (according to national law) following their receipt of verbal and written 
information about the trial. 
2. Adolescent subjects (age 12 to 16 years, 11 months). 
3. Either sex. 
4. Any race or ethnicity. 
5. Plaque psoriasis on trunk and/or limbs affecting at least 2% BSA. 
6. Plaque psoriasis on the scalp affecting at least 10% of total scalp area. 
7. A total psoriatic involvement on trunk, limbs and scalp not exceeding 30% BSA. 
8. PGA score of at least mild on trunk and/or limbs at SV1, SV2 and V1. 
9. PGA score of at least mild on scalp at SV1, SV2 and V1. 
10. A serum albumin-corrected calcium below the upper reference limit at SV2. 
11. Female subjects must be of either 
• non-childbearing potential, i.e. premenarchal or have a confirmed clinical history of 
sterility (e.g. the subject is without a uterus or has tubal litigation) or, 
• child-bearing potential provided there is a confirmed negative pregnancy test prior to 
trial treatment to rule out pregnancy. 
12. Female subjects of child-bearing potential must be willing to use highly effective 
contraception at trial entry and until completion. Highly effective contraception is 
defined as ones which result in a low failure rate (less than 1% per year) as follows: 
• Abstinence (when this is in line with the preferred and usual life style of the subject) 
• Vasectomised partner (given that the subject is monogamous) 
• An intrauterine device 
• Double barrier method defined as two distinct methods (two actual barrier methods, 
eg. cervical cap and condom) 


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• Hormonal contraceptive in combination with a barrier method (oral hormonal birth 
control, oestrogenic vaginal ring, percutaneous contraceptive patches, implants and 
injectables) for at least one menstrual cycle prior to the pregnancy test at SV2 and 
must continue using the contraceptive method for at least 1 week after the last 
application of investigational product 
 
7.2.2 Additional inclusion criteria for subjects undergoing HPA axis testing 
 
13. Plaque psoriasis on trunk and/or limbs affecting at least 10% BSA. 
14. Plaque psoriasis on the scalp affecting at least 20% of total scalp area. 
15. PGA score of at least moderate on trunk and limbs at SV1, SV2 and V1. 
16. PGA score of at least moderate on scalp at SV1, SV2 and V1. 
17. Normal HPA axis function at SV2 (serum cortisol concentration above 5 mcg/dl before 
ACTH challenge and serum cortisol concentration above 18 mcg/dl 30 minutes after 
ACTH challenge). 
 
7.3 Exclusion Criteria 
 
7.3.1 Exclusion Criteria for All Subjects 
 
1. A history of hypersensitivity to any component of LEO 90100. 
2. Systemic treatment with biological therapies (marketed or not marketed), with a 
possible effect on scalp and/or body psoriasis within the following time period prior to 
V1 and during the trial: 
a. etanercept – within 4 weeks prior to V1 
b. adalimumab, infliximab – within 2 months prior to V1 
c. ustekinumab – within 4 months prior to V1 
d. experimental products – within 4 weeks/5 half-lives (whichever is longer) prior to 
V1 
3. Systemic treatment with therapies other than biologicals, with a possible effect on scalp 
and/or body psoriasis (e.g. methotrexate, retinoids, immunosuppressants) within 4 
weeks prior to V1 or during the trial. 
4. PUVA therapy within 4 weeks prior to V1. 
5. UVB therapy within 2 weeks prior to V1 or during the trial. 


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6. Any topical treatment on the scalp and body including corticosteroids and vitamin D 
(except for emollients and non-steroid medicated shampoos) within 2 weeks prior to V1 
or during the trial. 
7. Systemic calcium, vitamin D supplementation > 400 IU/day, antacids, diuretics, 
antiepileptics, diphosphonates or calcitonin within 4 weeks prior to SV2 or during the 
trial. (note: stable dose of vitamin D supplementation ≤ 400 IU/day is permitted 
provided there are no dose adjustments during the study period). 
8. Planned initiation of, or changes to, concomitant medication that could affect psoriasis 
(e.g., betablockers, chloroquine, lithium, ACE inhibitors) during the trial. 
9. Current diagnosis of guttate, erythrodermic, exfoliative or pustular psoriasis. 
10. Subjects with any of the following conditions present on the treatment areas: viral (e.g., 
herpes or varicella) lesions of the skin, fungal and bacterial skin infections, parasitic 
infections, skin manifestations in relation to syphilis or tuberculosis, rosacea, acne 
vulgaris, acne rosacea, atrophic skin, striae atrophicae, fragility of skin veins, 
ichthyosis, ulcers and wounds. 
11. Other inflammatory skin diseases that may confound the evaluation of scalp and/or 
body psoriasis. 
12. Planned excessive exposure to sun or artificial light sources (including tanning booths 
etc.) during the trial that may affect scalp and/or body psoriasis. 
13. Known or suspected severe renal insufficiency or severe hepatic disorders. 
14. Know or suspected disorders of calcium metabolism associated with hypercalcaemia. 
15. Any clinically significant abnormality following review of screening laboratory tests 
(blood and urine samples), physical examination or blood pressure/heart rate 
measurement performed at SV2. 
16. Current participation in any other interventional clinical trial. 
17. Previously treated with LEO 90100 in this trial. 
18. 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 a month prior to SV1 or longer, if the class of substance required a longer wash- 
out as defined above (e.g., biological treatments). 
19. In the opinion of the (sub)investigator, subjects or parent(s) or legal guardian known or 
suspected of being unlikely to comply with the Clinical Trial Protocol (e.g., alcoholism, 
drug dependency or psychotic state). 


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20. Females who are pregnant, or of child-bearing potential and wishing to become 
pregnant during the trial, or who are breast-feeding. 
21. Females of child-bearing potential with positive pregnancy test at SV2. 
22. Subject (or their partner) not using an adequate method of contraception according to 
national requirements. 
23. Subjects who are dependant on the trial sponsor or investigator. 
24. Subjects afraid of blood withdrawals. 
 
7.3.2 Additional exclusion criteria for subjects undergoing HPA axis 
testing 
25. A history of serious allergy, allergic asthma or serious allergic skin rash. 
26. Known or suspected hypersensitivity to any component of CORTROSYN®/Synacthen® 
(including ACTH/cosyntropin/tetracosactide) 
27. Systemic treatment with corticosteroids (including inhaled and nasal steroids) within 12 
weeks prior to SV2 or during the trial. 
28. Oestrogen therapy (including contraceptives) or any other medication known to affect 
cortisol levels or HPA axis integrity within 4 weeks prior to SV2 or during the trial. 
29. Enzymatic inductors (e.g., barbiturates, phenytoin, rifampicin) within 4 weeks prior to 
SV2 or during the trial. 
30. Systemic or topical cytochrome P450 inhibitors (e.g., ketoconazole, 
itraconazole,metronidazole) within 4 weeks prior to SV2 or during the trial. Topical 
ketoconazole within 2 weeks prior to SV2. 
31. Hypoglycemic sulfonamides within 4 weeks prior to SV2 or during the trial. 
32. Antidepressive medications within 4 weeks prior to SV2 or during the trial. 
33. Known or suspected endocrine disorder that may affect the results of the ACTH 
challenge test. 
34. Clinical signs or symptoms of Cushing’s disease or Addison’s disease. 
35. Subjects with diabetes mellitus. 
36. Known or suspected cardiac condition. 
37. Not following nocturnal sleep patterns. 


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7.4 Re-screening of subjects 
Re-screening of subjects will be allowed only once, e.g. in case of any abnormal safety lab 
parameters at the primary screening. Excluded from re-screening are subjects with an HPA 
axis supression at baseline. Re-screening must be discussed with and approved by the 
sponsor’s medical expert before the screening visit is taking place. The reason for re- 
screening must be stated in the medical records. 
 
7.5 Subject Enrolment Log 
All subjects screened for this study will be logged on a screening log. This log will list 
whether subjects were included or not. If a subject is not enrolled, the main reason will be 
listed. The list will be prepared according to local regulations about personal data protection. 
 
7.6 Subject Identification List 
The (sub)investigator must maintain a list of all subjects randomised/treatment assigned at the 
trial site including each subject's identity, date of enrolment and corresponding subject 
identification (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 or retained by LEO or CRO. 
 
At SV1 each subject must be assigned a unique subject ID 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. 
 
7.7 Restrictions during Trial 
The use of drugs including non-drug therapies and procedures, defined as disallowed in the 
exclusion criteria, is not permitted during the trial and as also defined in section 8.8. 
 
Use of concomitant treatment must be recorded in the subject’s medical record and the Case 
Report Form (CRF) (treatment/drug name, dose, indication and dates of start and stop). 


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7.8 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 adverse events: any adverse event 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. If applicable, the subject’s legal representative can withdraw the 
subject from the trial. 
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 or experience an 
allergic reaction to CORTROSYN®/Synacthen®. 
 
Based on the safety profile of LEO 90100, there are no expected risks that would require 
specific withdrawal criteria in addition to the reasons described above. 
 
Reason(s) for withdrawal must be recorded in the CRF and medical records. 
 
Subjects who are discovered, after enrolment/randomisation, not to have fulfilled all in- 
/exclusion criteria at the time of enrolment should discontinue treatment unless the 
(sub)investigator, based on clinical and ethical evaluation, finds discontinuation inappropriate. 
 
In case of premature withdrawal prior to Visit 3, the additional tests scheduled for this visit 
should be done at the end of treatment, with the exception of the 24-hour urine collection. 
 
For subjects withdrawn from treatment or trial, AEs should be followed up as described in 
section 9.6. 
 
Subjects withdrawn will not be substituted. 


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8 Trial Schedule and Assessments 
8.1 Schedule of Trial Procedures 
Table 1: Schedule of Trial Procedures – Non-HPA Axis Cohort 
Note: Separate schedule of trial procedures for subjects in the HPA axis cohort below. 
 
Visit 
SV1 1) 
SV2 1) 
1 
2 
3 
EW 
FU12) 
Day 
-28 to -7 
-7 to -3 
0 
14  ± 
2 
28  ± 
2 
-- 
+ 14 ± 2 
Informed consent 
X 
Demographics 
X 
Medical history and concurrent diagnoses 
X 
Physical examination 
X 
X 
X 
Height, weight and BSA 3) 
X 
X 
Inclusion/exclusion criteria 
X 
X 
X 
Vital signs (blood pressure, heart rate, oral 
or ear temperature) 
X 
X 
X 
X 
X 
25-hydroxy Vitamin D 
X 
Haematology/biochemistry/ 
urinalysis 4) 
X 
X 
X 
X 5) 
Instructions for dietary calcium intake 
diary 
X 
X 
Review of dietary calcium 
X 
X 
X 
Urine pregnancy test 6),7) 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
Local safety and tolerability 
X 
X 
X 
X 
Concomitant medication 
X 
X 
X 
X 
X 
X 
X 
Physician´s assessment of extent of 
psoriasis vulgaris 
X 
X 
X 
X 
Physician´s assessment of extent of body 
psoriasis 
X 
X 
X 
X 
Physician´s assessment of extent of scalp 
psoriasis 
X 
X 
X 
X 
Physician´s global assessment of disease 
severity on the body 
X 
X 
X 
X 
X 
Physician´s global assessment of disease 
severity on the scalp 
X 
X 
X 
X 
X 
Physician´s assessment of the extent and 
severity of clinical signs of psoriasis 
vulgaris (for PASI) 
X 
X 
X 
X 
X 
Subject´s global assessment of disease 
severity on the body 
X 
X 
X 
X 
X 
Subject´s global assessment of disease 
severity on the scalp 
X 
X 
X 
X 
X 
Subject´s assessment of itch and itch- 
related sleep loss 
X 
X 
X 
X 
CDLQI 8) 
X 
X 
X 
X 
FDLQI 8) 
X 
X 
X 
Dispensing of IP 
X 
X 
Return of IP 
X 
X 
X 
IP Compliance 
X 
X 
X 


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1) There should be at least 4 days between SV1 and SV2 so dietary information (diary) can be collected. 
2) Follow-up Visit 1 is only applicable for subjects who at the last on-treatment visit have an ongoing Serious 
Adverse Event of any causality or ongoing non-serious adverse event(s) classified as possibly/probably 
related to the investigational product and for subjects with albumin corrected serum calcium above 
reference range at the last on-treatment visit. 
3) Body surface area (BSA) to be calculated using the Mosteller formula (Appendix 9). 
4) Blood and spot urine samples should be collected at the end of treatment for subjects who are withdrawn 
from trial prior to Visit 3. 
5) If laboratory results suggest albumin corrected serum calcium above reference range at the last on-treatment 
visit, a follow-up test will be performed. 
6) For female subjects of childbearing potential. 
7) In case of early withdrawal there will be a pregnancy test if possible at their last on treatment visit. 
8) Ensure the CDLQI and the FDLQI are completed prior to starting any procedures at the visit. 


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Table 2: Schedule of Trial Procedures – HPA Axis Cohort 
 
Visit 
SV1 1) 
SV2 1),2) 
1 
2 
3 
EW 
FU13) 
FU24) 
Day 
-28 to -7 
-7 to -3 
0 
14  ± 
2 
28  ± 
2 
-- 
+ 14 ± 
2 
+ 28 ± 2 
Informed consent 
X 
Demographics 
X 
Medical history and concurrent 
diagnoses 
X 
Physical examination 
X 
X 
X 
Height, weight and BSA 5) 
X 
X 
Inclusion/exclusion criteria 
X 
X 
X 
Vital signs (blood pressure, heart rate, 
oral or ear temperature) 
X 
X 
X 
X 
X 
25-hydroxy Vitamin D 
X 
Cortisol (serum) 
X 
X 
Haematology/biochemistry/ 
urinalysis 6) 
X 
X 
X 
X 7) 
Pharmacokinetic sampling 8) 
X 
X 
ACTH challenge test 9) 
X 
X 
X 
Instruction for 24-hour urine 
collection 10) 
X 
X 
Instructions for dietary calcium intake 
diary 
X 
X 
Review of dietary calcium 
X 
X 
X 
Collection of 24-hour urine 10) 
X 
X 
Urine pregnancy test 11), 12) 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
Local safety and tolerability 
X 
X 
X 
X 
Concomitant medication 
X 
X 
X 
X 
X 
X 
X 
Physician´s assessment of extent of 
psoriasis vulgaris 
X 
X 
X 
X 
Physician´s assessment of extent of 
body psoriasis 
X 
X 
X 
X 
Physician´s assessment of extent of 
scalp psoriasis 
X 
X 
X 
X 
Physician´s global assessment of 
disease severity on the body 
X 
X 
X 
X 
X 
Physician´s global assessment of 
disease severity on the scalp 
X 
X 
X 
X 
X 
Physician´s assessment of the extent 
and severity of clinical signs of 
psoriasis vulgaris (for PASI) 
X 
X 
X 
X 
X 
Subject´s global assessment of disease 
severity on the body 
X 
X 
X 
X 
X 
Subject´s global assessment of disease 
severity on the scalp 
X 
X 
X 
X 
X 
Subject´s assessment of itch and itch- 
related sleep loss 
X 
X 
X 
X 
CDLQI 13) 
X 
X 
X 
X 
FDLQI 13) 
X 
X 
X 
Dispensing of IP 
X 
X 
Return of IP 
X 
X 
X 
IP Compliance 
X 
X 
X 


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1) There should be at least 4 days between SV1 and SV2 so dietary information (diary) can be collected. 
2) It will be acceptable that the following assessments are done on the day prior to the ACTH challenge: vital 
signs, spot urine collection, pregnancy test, AEs, concomitant medication and assessments of psoriasis. 
3) Follow-up Visit 1 is only applicable for subjects who at the last on-treatment visit have an ongoing Serious 
Adverse Event of any causality or ongoing non-serious adverse event(s) classified as possibly/probably 
related/not assessable relationship to the investigational product and for subjects with albumin corrected 
serum calcium above reference range at the last on-treatment visit. 
4) Follow-up Visit 2 is only applicable if serum cortisol is ≤18 mcg/dl at 30 min after the ACTH challenge test 
at Visit 3. 
5) Body surface area (BSA) to be calculated using the Mosteller formula (Appendix 9). 
6) Blood and spot urine samples should be collected at the end of treatment for subjects who are withdrawn 
from trial prior to Visit 3. 
7) If laboratory results suggest albumin corrected serum calcium above reference range at the last on-treatment 
visit, a follow-up test will be performed. 
8) At Visit 2, a pre-dose trough sample will be taken. At Visit 3, the first PK sample (trough) is taken prior to 
the ACTH-challenge test. Then following the 30 and 60 minute blood samples for the ACTH-challenge test, 
the study medication will be applied. Further PK analysis blood samples will be taken at 1, 3 and 5 hours 
after application of trial medication. A time window of ±10 min relative to the given time points is allowed. 
9) ACTH challenge test should be performed at 8.00 a.m. ± 30 min after checking vital signs and collecting 
blood and urine samples. 
10) It will be acceptable that the 24 hour urine sample is collected up to three days prior to the trial visit. 
11) For female subjects of childbearing potential. 
12) In case of early withdrawal there will be a pregnancy test if possible at their last on treatment visit. 
13) Ensure the CDLQI and the FDLQI are completed prior to starting any procedures at the visit. 
 
8.2 Demographics 
Demographic data will comprise of: 
 
• Date of Birth, (Only year of birth and age will be collected for EU Countries) 
• Sex 
• Ethnic origin 
• Race 
• Skin type 
The subjects will self-report their ethnicity (Hispanic or Latino, not Hispanic or Latino) and 
race (American Indian or Alaska Native, Asian, Black or African American, Native Hawaiian 
or Other Pacific Islander, White, Other). 
 
The skin type of the subject will be recorded according to the following classification and can 
be assessed by the (sub)investigator: 


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Table 3: Fitzpatrick Skin Type 
 
Skin Type 
Skin Colour 
(unexposed skin) 
History (to first 30 to 45 minutes of sun exposure after a winter 
season of no sun exposure) 
I 
White 
Always burns easily; never tans 
II 
White 
Always burns easily; tans minimally 
III 
White 
Burns moderately; tans gradually (light brown) 
IV 
White 
Burns minimally; always tans well (moderate brown) 
V 
Brown 
Rarely burns; tans profusely (dark brown) 
VI 
Black 
Never burns; deeply pigmented 
 
8.3 Height and Weight 
The subject’s height must be measured (without shoes) and weight must be determined (in 
indoor clothing and without shoes). 
 
8.4 Vital Signs 
Vital signs must be assessed. 
Recording of vital signs comprises: 
• Heart rate (beats per minute), supine after 5 min rest 
• Blood pressure, systolic and diastolic (mmHg), supine after 5 min rest 
• Oral or ear temperature (location to be recorded in the subject’s medical record) 
The same arm will be used for all measurements. The arm (right or left) used for measurement 
will be recorded in the CRF. 
 
Assessment of vital signs resulting in abnormal values will be repeated in order to exclude an 
erroneous assessment. Individual results will be classified as “normal”, “abnormal with no 
clinical significance” or “abnormal with clinical significance”. 
 
8.5 Physical Examination 
A physical examination including general appearance, regional lymph nodes and 
dermatologic examination of the skin in general must be performed. 
 
8.6 Medical History 
Relevant medical history and concurrent diagnoses must be recorded: 


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• Skin history: The duration of plaque psoriasis will be recorded to the nearest whole 
year. 
• Other medical history within the last 12 months. 
 
8.7 Instruction for 24-hour urine collection and dietary calcium intake 
diary 
Dietary calcium intake – diary instructions 
 
The (sub)investigator/site staff should perform a review of the subject’s normal dietary intake 
of calcium-rich nutrients – mainly milk and dairy products, but also a high intake of calcium- 
fortified products. The subject will be instructed to keep an eDiary of the daily intake of dairy 
products and calcium-fortified products (e.g. bread, cereals, orange juice or soy milk) in the 4- 
day period prior to SV2 (3 days prior to and during the baseline 24-hour urinary collection at 
SV2). 
 
At SV2, the number of daily servings of dairy (or calcium fortified) products defined as one 
cup (240 ml) of milk or yoghurt, 1.5 ounces (43 g) of cheese or any calcium-fortified product 
with a calcium content of 300 mg/cup will be estimated. The subject will be instructed that the 
number of daily calcium servings should not exceed five. Also the subject should keep the 
intake of calcium-rich nutrients the same three days prior to spot urine collection (SV2) and 
during the subsequent 24-hour urine collection (for subjects performing the HPA axis testing). 
At Visit 3, the (sub)investigator/site staff should review the intake of calcium-rich nutrients 
with the subject. 
 
Instruction on 24-hour urine collection (only applicable for subjects performing HPA 
Axis assessment) 
 
In addition to the instructions on dietary calcium intake, the (sub)investigator/site staff should 
instruct the subject on how to perform the 24-hour urine collection. The procedure for 
collecting a 24 hour urine sample should be for subject to pass their first urine of the day as 
normal and then to collect all urine passed in the next 24 hours which should include their 
first urine on the second morning. 
 
8.8 Concomitant Medication 
Concomitant medication is defined as any medication used by a subject during the clinical 
trial apart from the investigational product. Concomitant medication including diagnoses must 
be recorded.Use of concomitant treatment should be recorded in the subject’s medical record 
and the CRF (treatment/drug name, dose, indication and dates of start and stop). 


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Use of non-marketed/other investigational products one month prior to SV1 and during the 
trial is not permitted. 
 
Changes of doses (including starting) of drugs that, while not specifically indicated for 
treatment of the indication being studied, are known to have an effect (positive or negative) 
on the indication, are not permitted. 
 
For all subjects, treatments requiring washout before SV2/Visit 1 and prohibited during the 
trial are listed below, with the required individual washout periods: 


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Table 4: Prohibited Medication including Non-Drug Therapies and Procedures (for all 
subjects) 
 
Prohibited Medication including Non-Drug 
Therapies and Procedures 
Location 
Exclusion Period 
Restrictions 
Systemic treatment with biological therapies 
(marketed or not marketed), with a possible 
effect on body or scalp psoriasis 
Not 
applicable 
Etanercept: 4 weeks prior to Visit 1 
Adalimumab, Infliximab: 2 months prior to 
Visit 1 
Ustekinumab: 4 months prior to Visit 1 or 
experimental products: 4 weeks/5 half-lives 
(whichever is longer) prior to Visit 1 
and any time during the trial treatment phase 
Systemic treatment with therapies other than 
biologicals, with a possible effect on body or 
scalp psoriasis (e.g., retinoids, 
immunosuppressants, PUVA) 
Body and 
Scalp 
Within 4 weeks prior to visit 1 and any time 
during the trial treatment phase 
UVB therapy within 2 weeks prior to Visit 1 
Body and 
Scalp 
Within 2 weeks prior to visit 1 and any time 
during the trial treatment phase 
Any topical treatment on the body or scalp 
including corticosteroids (except for 
emollients and non-steroid medicated 
shampoos) within 2 weeks prior to Visit 1 
Body and 
Scalp 
Within 2 weeks prior to visit 1 and any time 
during the trial treatment phase 
Systemic calcium, vitamin D 
supplementation > 400 IU/day, antacids, 
diuretics, antiepileptics, diphosphonates or 
calcitonin 
Note: Stable doses of oral vitamin D 
supplementation ≤ 400 IU/day is permitted 
provided there are no dose adjustments 
during the study period) 
Not 
applicable 
Within 4 weeks prior to visit 1 and any time 
during the trial treatment phase 
Initiation of, or changes to, concomitant 
medication that could affect body or scalp 
psoriasis (e.g. beta-blockers, lithium, anti- 
malaria drugs, ACE inhibitors). 
Not 
applicable 
Any time during the trial treatment phase 
Excessive exposure of treated areas to either 
natural or artificial sunlight (including 
tanning booths, sunlamps, etc.). 
Body and 
Scalp 
Any time during the trial treatment phase 
Note: 
The time between SV1 and Visit 1 cannot be longer than 4 weeks, and between SV1 and SV2 not 
longer than 3 weeks, therefore subjects receiving, or having recently received these treatments at 
SV1 cannot be enrolled. 
 
 
For subjects performing HPA axis and PK assessments, additional treatments requiring 
washout before SV2/Visit 1 and prohibited during the trial are listed below, with the required 
individual washout periods: 


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Table 5: Prohibited Medication including Non-Drug Therapies and Procedures 
(for subjects performing HPA axis and PK assessments) 
 
Prohibited Medication including Non-Drug 
Therapies and Procedures 
Location 
Exclusion Period 
Restrictions 
Systemic treatment with corticosteroids 
(including inhaled and nasal steroids) 
Not 
applicable 
Within 12 weeks prior to SV2 and any time 
during the trial treatment phase 
Oestrogen therapy (including contraceptives) 
or any other medication known to affect 
cortisol levels or HPA axis integrity (4 
weeks prior to SV2) 
Not 
applicable 
Within 4 weeks prior to SV2 and any time 
during the trial treatment phase 
Enzymatic inductors (e.g., barbiturates, 
phenytoin, rifampicin), systemic or topical 
cytochrome P450 inhibitors (e.g., 
ketoconazole, itraconazole, metronidazole), 
hypoglycaemic sulfonamides, antidepressive 
medications (4 weeks prior to SV2). 
Body and 
Scalp 
Within 4 weeks prior to SV2 and any time 
during the trial treatment phase 
Topical ketoconazole 
Body and 
Scalp 
Within 2 weeks prior to SV2 and any time 
during the trial treatment phase 
The following concomitant anti-psoriatic treatments are allowed during the trial: 
 
Table 6: Permitted concomitant anti-psoriatic treatment 
 
Location 
Permitted concomitant anti-psoriatic treatment 
Scalp 
No other treatment allowed. 
Non-medicated shampoo and conditioners are allowed. 
Trunk/limbs 
No other treatment allowed. 
Bath oils and moisturizing soaps are allowed. 
Face and sensitive areas 
Any topical treatment allowed except corticosteroids or Vitamin 
D analogues (calcipotriol, calcitriol or tacalcitol). 
Unlimited use of emollients is allowed. 
Bath oils and moisturizing soaps are allowed 
Note: 
sensitive areas refers to armpits, groin, under the breasts and in other skin folds around the genitals 
and buttocks 
 
 
Follow-up period: 
 
During the follow-up period, subjects who require a repeat ACTH-challenge test at FU2 
should not receive corticosteroid therapy (topical or systemic), enzymatic inductors, 
cytochrome P450 inhibitors, hypoglycemic sulfonamides, anti-depressive medications, 
estrogen therapy, or any other medication known to affect cortisol levels/HPA axis integrity. 
Such subjects should also continue to use contraception if they are of child-bearing potential. 
Otherwise, there are no restrictions on the use of concomitant treatment during the follow-up 
period. 


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8.9 Pregnancy Test 
A urine pregnancy test must be performed at the trial site at SV2, Visit 3 (or on withdrawal 
from or early completion of the treatment phase of the clinical trial) and, if applicable, at FU2, 
in female subjects of child-bearing potential. The test kits will be provided by the Central 
Laboratory. 
 
8.10 Adverse Events 
Adverse events must be assessed and recorded as specified in section 9. 
 
8.11 Other Safety Assessments 
Not applicable. 
 
8.12 Laboratory Assessments 
8.12.1 Safety Laboratory Tests 
Samples for analysis of parameters must be taken according to the schedule of trial 
procedures (section 8.1) or on withdrawal from or early completion of the treatment phase of 
the clinical trial. 
 
It is recommended that indwelling catheters introduced under topical anaesthesia are used for 
the repeated blood sampling, to minimise discomfort for the subject, unless the 
(sub)investigator judges that there are reasons for not doing it. 
 
The following analyses will be performed on the blood samples: 


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Table 7: Planned Safety Analysis 
 
Analyses 
Parameter 
Haematology 
Haemoglobin 
Haematocrit 
Red blood cell (RBC) count 
Mean corpuscular volume (MCV) 
White blood cell (WBC) count, including differential count 
Platelet count 
Biochemistry (serum/plasma) 
Cortisol* 
Urea 
Creatinine 
Albumin 
Sodium 
Potassium 
Chloride 
Calcium 
Phosphate 
Alkaline phosphatase 
25-hydroxy vitamin D (SV2 only) 
Parathyroid hormone (plasma) 
* only applicable for subjects performing HPA Axis assessment 
 
The laboratory will also report: 
 
• Albumin-corrected serum calcium in mmol/l using the formula: 
 
serum calcium (total) in mmol/l + (0.02 x [40-serum albumin in g/l] 
 
If any laboratory results are abnormal, the (sub)investigator should follow-up the subject as 
clinically appropriate. 
 
Whether an abnormal laboratory finding is considered clinically significant is at the 
(sub)investigator’s discretion. However, all clinically significant abnormalities must be 
reported as an Adverse Event. For any abnormality which is above/below the predefined alert 
values, but not considered clinically significant, a written justification should be provided in 
the subject’s medical records and/or the laboratory report (as appropriate). 
 
Handling and shipment instructions are provided in a separate laboratory manual by the 
central laboratory. 


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8.12.2 Safety Urinalysis 
Samples for analysis of the parameters listed below must be taken as specified in the schedule 
of trial procedures (section 8.1) or on withdrawal from or early completion of the treatment 
phase of the clinical trial. 
 
Prior to SV2 and Visit 3, subjects taking part in the HPA axis testing and PK sampling will 
collect 24 hour urine. It is allowed to collect the 24-hour urinary sample up to three days prior 
to the study visit. 
 
Table 8: Safety urinalysis 
 
Analyses 
Parameter 
Urinalysis (will be analysed quantitatively in 
the collected 24 hour urine) 1) 
Calcium 
Phosphate 
Creatinine 
Volume 
spot urine sample: 
Glucose2) 
Ketones2) 
Calcium3) 
Phosphate3) 
Creatinine3) 
1) only for subjects performing HPA axis and PK assessments 
2) for all subjects (by dipstick test) 
3)  only for subjects not performing HPA axis and PK assessments 
 
 
 
For the 24 hour urine and spot urine samples the following will be calculated: 
 
• Total calcium excretion 
• Total phosphate excretion 
• Total creatinine excretion 
• Calcium:creatinine ratio 
• Phosphate:creatinine ratio 
 
8.12.3 Pharmacokinetic (PK) Assessments 
8.12.3.1 Blood sampling for analysis of LEO 90100 and metabolite(s) 
Subjects performing PK assessments will have a pre-dose trough sample taken at Day 14 
(Visit 2). At Day 28 (Visit 3), a trough sample will be taken prior to the ACTH-challenge test. 


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Then following the other blood samples for the ACTH-challenge test, trial medication will be 
applied and further blood samples for PK analysis will be taken at t = 1 hrs, t = 3 hrs and t = 5 
hrs after application. A window of ±10 min for taking blood samples at given time points is 
allowed. Each PK sample will require 12 ml (2 x 6ml) of blood. 
 
The exact time point of product application and blood sample collection will be noted in the 
CRF. 
 
Venous puncture should be performed through untreated areas of the skin. 
 
A validated bioanalytical assay will be used for simultaneous quantification of calcipotriol, 
betamethasone dipropionate and the metabolites MC1080 and betamethasone 17-propionate 
in the plasma samples. 
 
Collection, handling and shipment instructions for pharmacokinetic blood samples are 
provided in a separate laboratory manual. 
 
8.12.4 Pharmacodynamic (PD) Assessments 
ACTH Challenge test 
 
The ACTH-challenge test will be performed at SV2 and Visit 3. If the subject withdraws prior 
to completing treatment, the ACTH-challenge test should not be performed at early 
withdrawal. 
 
If the result of the ACTH-challenge test at Visit 3 shows a serum cortisol concentration ≤18 
mcg/dl at 30 minutes after the ACTH-challenge, a further ACTH-challenge test is required 28 
days later at Visit FU2. If the results of the ACTH-challenge test at Visit FU2 continue to 
show a serum cortisol concentration ≤18mcg/dl at 30 minutes after ACTH-challenge, further 
ACTH-challenge tests should be performed, but not more often than at 4-weekly intervals, 
until the adrenal suppression resolves (i.e., serum cortisol concentration >18mcg/dl at 30 
minutes after the ACTH-challenge). 
 
The following procedures should be performed prior to the ACTH-challenge tests at SV2 and 
Visit 3: Blood pressure/heart rate and temperature measurement, blood/urine sampling for 
central laboratory analysis (haematology/biochemistry/urinalysis) and urine pregnancy test (in 
female subjects of child-bearing potential). 
 
To perform the ACTH-challenge test, a 2.5 ml sample of venous blood will be drawn at 08.00 
a.m. ±30 minutes. After this, CORTROSYN® (used in the US)/Synacthen® (used in Europe) is 
injected, as described in Section 10.7. Two further 2.5 ml samples of venous blood will be 


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drawn exactly 30 and 60 minutes after the injection (counting from the end of the period over 
which the injection is given). Serum cortisol concentrations will be determined for each blood 
sample by the Central Laboratory. 
 
The time of injection and blood sampling will be recorded in the CRF. 
 
8.12.5 Total Blood Volume 
The following blood volumes will be drawn per subject not performing HPA axis and PK 
assessments: 
 
Table 9: Total blood volume 
 
Sample type 
Volume per 
sample (mL) 
Number of samples 
SV2 
Number of samples 
V3 
Total (mL) 
Haematology 
2 
1 
1 
4 
Biochemistry / 
25-Hydroxy-Vit D 
(only SV2)** 
5 
1 
1 
10 
Parathyroid hormone 
2 
1 
1 
4 
Total 
18 
** Note:  25-Hydroxy-Vit D is only tested for at SV2. 
 
The following blood volumes will be drawn for subjects participating in the HPA axis and PK 
assessments: 
 
Table 10: Total blood volumes for subjects participating in the HPA axis and PK 
assessments 
 
Sample type 
Volume per 
sample (mL) 
Number of 
samples SV2 
Number of 
samples V2 
Number of 
samples V3 
Total (mL) 
Haematology 
2 
1 
NA 
1 
4 
Biochemistry / 
25-Hydroxy-Vit D 
(only SV2)** 
5 
1 
NA 
1 
10 
Parathyroid hormone 
2 
1 
NA 
1 
4 
Cortisol (serum) 
2.5 
1 
NA 
1 
5 
Pharmacodynamic 
2.5 
3 
NA 
3 
15 
Pharmacokinetic 
12 
NA 
1 
4 
60 
Total 
98 
** Note:  25-Hydroxy-Vit D is only tested for at SV2. 


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Follow-up testing: 
If additional blood samples are required, the maximum blood volume to be withdrawn per 
subject will not exceed the volumes as outlined below: 
 
Table 11: Total blood volumes for follow-up testing 
 
Sample type 
Volume per 
sample (mL) 
Number of samples 
FU11) 
Number of samples 
FU22) 
Total (mL) 
Haematology 
2 
1 
NA 
2 
Biochemistry 
5 
1 
NA 
5 
Parathyroid hormone 
2 
1 
NA 
2 
Pharmacodynamic 
2.5 
NA 
3 
7.5 
Total volume 
16.5 
1) FU1: will be collected from subjects at FU1, if laboratory results suggest albumin corrected serum calcium 
above reference range at the last on-treatment visit. 
If haematology and/or PTH results are abnormal and judged by the (sub)investigator as clinically significant at 
the last on-treatment visit, a 2 ml haematology sample and/or 2 ml PTH sample will be collected at FU1. 
2) FU2: will be collected from subjects requiring additional ACTH challenge testing at FU2 if HPA-axis 
suppression is observed at Visit 3. 
 
8.13 Patient Reported Outcomes 
The subject’s assessments must be made at the very start of the visit, before they are assessed 
by site staff. The subject must make self-assessments as follows: 
 
Subject´s Global Assessment of Disease Severity – Body Psoriasis and Scalp Psoriasis 
 
At SV2 and Visits 1 to 3, and early withdrawal (if applicable), the subject will make a global 
assessment of the disease severity of body psoriasis and scalp psoriasis (separately) by use of 
the 5-point scale below. 
 
The assessment will be based on the condition of the disease at the time of evaluation and not 
in relation to the condition at a previous visit. 
 
The qualified site staff person will explain the categories of the scale to the subject and the 
subject will tell the qualified site staff person which category to tick. This assessment must be 
made prior to the investigator’s assessments. 


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Table 12: Subject´s Global Assessment of Disease Severity Scale 
 
Clear 
No psoriasis symptoms at all 
Very mild 
Very slight psoriasis symptoms, does not interfere with daily life 
Mild 
Slight psoriasis symptoms, interferes with daily life only occasionally 
Moderate 
Definite psoriasis symptoms, interferes with daily life frequently 
Severe 
Intense psoriasis symptoms, interferes or restricts daily life very frequently 
 
Subject´s Assessment of Itch 
 
At Visits 1 to 3 and early withdrawal (if applicable), subjects will complete the assessment of 
itch ). 
 
The visual analogue scale (VAS) will be used to assess itch. The horizontal line of the VAS 
represents the range of itch severity, from 0 (no itch at all) at one end to 10 (worst itch you 
can imagine) at the other. Subjects will be asked to rate the maximal intensity of itch during 
the last 24 hours, by putting a single vertical line across the horizontal line at the spot he/she 
feels best reflects this (Appendix 5). 
 
Subject´s Assessment of Itch-related Sleep Loss 
 
At Visits 1 to 3 and early withdrawal (if applicable), subjects will complete the assessment of 
itch-related sleep loss. 
 
The VAS will be used to assess itch-related sleep loss. The horizontal line of the VAS 
represents the range of sleep loss, from 0 (no sleep loss at all) at one end to 10 (worst possible 
sleep loss). Subjects will be asked to rate the itch-related sleep loss during the last night, by 
putting a single vertical line across the horizontal line at the spot he/she feels best reflects this 
(see Appendix 6). 
 
Children’s Dermatology Life Quality Index (CDLQI) 
 
At Visits 1 to 3 and early withdrawal (if applicable), subjects will be asked to complete the 
CDLQI questionnaire (Appendix 7), which is a validated dermatology specific questionnaire. 


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The Family Dermatology Life Quality Index (FDLQI) 
 
A family member of the subject will be asked to complete the FDLQI questionnaire 
(Appendix 8) at visits specified in the schedule of trial procedures (section 8.1). 
 
It is very important that it is the same family member filling in the FDLQI-questionniare 
throughout the study. 
 
Certified/Validated translations of the questionnaires into the corresponding languages will be 
used. 
 
8.14 Physicians Assessments 
The (sub)investigator must make the following assessments as listed below. Ideally, all 
assessments for a subject should be made by the same (sub)investigator. 
 
Physician´s assessment of the extent and severity of clinical signs of psoriasis vulgaris 
(Redness, Thickness, Scaliness) 
 
At SV2 and Visits 1 to 3 and early withdrawal (if applicable), the (sub) investigator will 
assess the extent and severity of clinical signs of the subject’s psoriasis on specific areas of 
the body in terms of three clinical signs: redness, thickness and scaliness. 
 
The extent of psoriatic involvement will be recorded for each of the four areas: 
Head1), arms2), trunk3) and legs4) using the following scale: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
This assessment of extent is the percentage of that body region that is affected, and not the 
percentage BSA affected. For example, if one arm was totally affected, and the other arm was 
totally unaffected, the extent assessment for the arms would be 50% (half of the arms 
affected). 
0 = no involvement 
1 = < 10% 
2 = 10 - 29% 
3 = 30 - 49% 
4 = 50 - 69% 
5 = 70 - 89% 
6 = 90 - 100% 


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Note: 
1) head includes the neck 
2) arms include hands 
3) trunk includes flexures 
4) legs include buttocks and feet 
The severity of the psoriatic lesions in each of the four areas (head, arms, trunk, legs) will be 
recorded for each of the signs of redness, thickness and scaliness. For each clinical sign, a 
single score, reflecting the average severity of all psoriatic lesions on the given body region, 
will be determined according to the scale below: 
 
Redness 
0 
= 
none (no erythema) 
1 
= 
mild (faint erythema, pink to very light red) 
2 
= 
moderate (definite light red erythema) 
3 
= 
severe (dark red erythema) 
4 
= 
very severe (very dark red erythema) 
Thickness 
0 
= 
none (no plaque elevation) 
1 
= 
mild (slight, barely perceptible elevation) 
2 
= 
moderate (definite elevation but not thick) 
3 
= 
severe (definite elevation, thick plaque with sharp edge) 
4 
= 
very severe (very thick plaque with sharp edge) 
Scaliness 
0 
= 
none (no scaling) 
1 
= 
mild (sparse, fine scale, lesions only partially covered) 
2 
= 
moderate (coarser scales, most of lesions covered) 
3 
= 
severe (entire lesion covered with coarse scales) 
4 
= 
very severe (very thick coarse scales, possibly fissured) 


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Physician´s global assessment of disease severity (PGA) – body psoriasis and scalp 
psoriasis 
 
At SV2 and Visits 1 to 3, and early withdrawal (if applicable), the (sub)investigator will make 
a global assessment of the disease severity of psoriasis of the trunk/limbs and scalp 
(separately) using the 5-point scale below. This assessment will represent the average lesion 
severity on the body and scalp, respectively. The assessment will be based on the condition of 
the disease at the time of evaluation, and not in relation to the condition at a previous visit. 
 
Table 13: Physician´s global assessment of disease severity (PGA) 
 
Clear 
Plaque thickening = no elevation or thickening over normal skin 
Scaling = no evidence of scaling 
Erythema = none (no residual red colouration but post-inflammatory hyperpigmentation may 
be present) 
Almost clear 
Plaque thickening = none or possible thickening but difficult to ascertain whether there is a 
slight elevation above normal skin level 
Scaling = none or residual surface dryness and scaling 
Erythema = light pink coloration 
Mild 
Plaque thickening = slight but definite elevation 
Scaling = fine scales partially or mostly covering lesions 
Erythema = light red colouration 
Moderate 
Plaque thickening = moderate elevation with rounded or sloped edges 
Scaling = most lesions at least partially covered 
Erythema = definite red colouration 
Severe 
Plaque thickening = marked or very marked elevation typically with hard or sharp edges 
Scaling = non-tenacious or thick tenacious scale, covering most or all of the lesions 
Erythema = very bright red colouration; extreme red colouration; or deep red colouration 
Note: 
PGA of the scalp should include all scalp psoriasis lesions, defined as those areas of the scalp 
where there are any signs of redness, thickness or scaliness caused by psoriasis. 
The scalp is defined by the hair line. Parts of scalp psoriasis lesions that extend outside the 
defined area of the scalp should not be included in the assessments. 
 
 
At SV2 and Visit 1 the disease severity of body psoriasis and scalp psoriasis must be graded at 
least as ‘mild’ in order to meet the inclusion criteria for subjects not undergoing the HPA axis 
testing whereas for subjects taking part in the HPA axis testing and pk sampling, the disease 
severity of body psoriasis and scalp psoriasis must be graded at least as ‘moderate’ at SV2 and 
Visit 1 in order to meet the inclusion criteria. 
 
Physician´s Assessment of the Extent of Psoriasis Vulgaris 
 
In order to obtain baseline data of psoriatic severity for all the subjects enrolled in the trial, 
the (sub)investigator will assess the extent of the subject’s total psoriatic involvement at SV2 


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and Visit 1. The extent of the subject’s total psoriatic involvement will also be assessed at 
Visit 3 and early withdrawal (if applicable). 
 
The total psoriatic involvement (e.g., the arms, the legs, the trunk and the scalp) will be 
recorded as a percentage of the BSA, estimating that the surface of the subject’s full, flat palm 
(including the five fingers) correlates to approximately 1% of the BSA. 
 
Physician´s Assessment of the Extent of Body Psoriasis 
 
A baseline assessment of the extent of psoriasis vulgaris on trunk and/or limbs as percentage 
of the BSA will be done at SV2 and Visit 1, estimating that the surface of the subject’s full, 
flat palm (including the five fingers) correlates to approximately 1% of the BSA. The extent 
of the subject’s body psoriasis will also be assessed at Visit 3 and early withdrawal (if 
applicable). 
 
Physician´s Assessment of the Extent of Scalp Psoriasis 
 
A baseline assessment of the extent of scalp psoriasis as percentage of the total scalp area will 
be done at SV2 and Visit 1, estimating that the surface of the subject’s full, flat palm 
(including the five fingers) correlates to approximately 25% of the scalp area. The extent of 
the subject’s scalp psoriasis will also be assessed at Visit 3 and early withdrawal (if 
applicable). 
 
Assessment of Local Safety and Tolerability 
The Assessment of Local Safety and Tolerability will be comprised of signs assessed by the 
(sub)investigator. The signs are not required to be reported as AEs. 
 
At Visits 1 to 3, the (sub)investigator will assess application site reactions for the following 
signs: perilesional erythema, perilesional oedema, perilesional dryness, and perilesional 
erosion. 
 
For perilesional erythema, oedema, dryness and erosion, the area for the (sub)investigator to 
assess is the perilesional area, defined as the band of skin within two (2) cm from the border 
of the psoriatic lesion, i.e. not the lesion itself, at any given time. The assessed signs must be 
present in this area, but may extend beyond it in a continuous manner. 
 
For each sign the highest (worst) skin reaction score across all treatment areas will be 
recorded by use of the following 4-point scale: 


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Table 14: Physician’s Assessment of local safety and tolerability 
 
0 = absent 
1 = mild 
2 = moderate 
3 = severe 
Perilesional erythema: 
No perilesional 
erythema 
Slight, barely 
perceptible 
perilesional 
erythema 
Distinct 
perilesional 
erythema 
Marked, intense 
perilesional 
erythema 
Perilesional oedema: 
No perilesional 
oedema 
Slight, barely 
perceptible 
perilesional 
oedema 
Distinct 
perilesional 
oedema 
Marked, intense 
perilesional 
oedema 
Perilesional dryness: 
No perilesional 
dryness 
Slight, barely 
perceptible 
perilesional 
dryness 
Distinct 
perilesional 
dryness 
Marked, intense 
perilesional 
dryness 
Perilesional erosion: 
No perilesional 
erosion 
Slight, barely 
perceptible 
perilesional 
erosion 
Distinct 
perilesional 
erosion 
Marked, intense 
perilesional 
erosion 
 
 
8.15 Photography 
Not applicable. 
 
8.16 Dispensing of IP 
Refer to section 10.8.1. 
 
8.17 Return of IP and Compliance 
Refer to sections 10.8.1 and 10.8.3. 
 
8.18 End of Trial Form 
The End of Trial Form must be completed for all subjects who have signed informed consent. 
This includes e.g. date of last dose, last attended scheduled visit number, primary reason for 
withdrawal, etc. 
 
9  Adverse Events 
• Adverse events and serious adverse events are defined: Appendix 2 Definitions of 
Adverse Events and Serious Adverse Events 
• Classification of adverse events in terms of serverity, causality and outcome are 
defined: Appendix 3 Classification of Adverse Events 


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9.1 Collection of Adverse Events 
Adverse events must be collected from the signing of the informed consent form until the End 
of the trial (Visit 3, Day 28). 
 
AEs must be assessed by medically qualified personnel. 
 
At all visits, the subject will be asked a non-leading question by the (sub)investigator: “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. 
 
If there are no AEs to record, no further questions should be asked and “NO” should be stated 
in the CRF. In case there are one or more AEs to record, “YES” should be stated. 
 
9.2 Reporting of Adverse Events in the CRF 
Adverse events reported by the subject or observed by the (sub)investigator must be recorded 
on the adverse event form of the CRF 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 may be described as 
either the face, scalp or trunk/limbs. Additionally, the location should be described using the 
following terminology: 
 
• Lesional/perilesional (≤ 2 cm from the border of lesion(s) treated with investigational 
product) 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. 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 3 Classification of Adverse Events 


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9.3 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. 
 
9.4 Other Events to be Reported 
 
9.4.1 Pregnancy 
 
Any pregnancy occurring during the clinical trial must be reported to LEO within 24 hours of 
first knowledge using the (paper) Pregnancy Follow Up Form (Part I). All such pregnancies 
must be followed up until delivery or termination and final outcome must be reported on the 
(paper) Pregnancy Follow Up Form (Part II) within 24 hours of first knowledge. 
 
The completed Pregnancy Follow Up Forms must be faxed or scanned and e-mailed to Global 
Pharmacovigilance, LEO (see section 9.5.1 for contact details). 
 
Please also confer with section 7.8, Withdrawal Criteria. 
 
9.4.2 Overdose 
 
Overdose refers to the administration of a quantity of a medicinal product given per 
administration or per day which is above the protocol defined dosage. 
 
The term overdose must be documented on the adverse event form of the CRF book. In 
addition, AEs originating from overdose must be documented on a separate line. 
 
9.4.3 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 adverse event form of the CRF book. In 
addition, AEs originating from a medication error must be documented on a separate line 
specifying the category of error (see definitions above). 


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9.4.4 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 adverse event form of the CRF book. In addition 
AEs originating from misuse must be documented on a separate line. 
 
9.4.5 Abuse 
 
Abuse relates to the sporadic or persistent, intentional excessive use of an investigational 
product which is accompanied by harmful physical or psychological effects. 
 
The term abuse must be documented on the adverse event form of the CRF book. In addition, 
AEs originating from abuse must be documented on a separate line. 
 
9.4.6 Aggravation of Condition 
 
Any clinically significant aggravation/exacerbation/worsening of any medical condition(s), 
compared to baseline, must be reported as an AE. 
 
9.4.7 Lack of Efficacy 
 
Not applicable. 
 
9.5 Additional Reporting Requirements for Serious Adverse Events 
 
9.5.1 Investigator Reporting Responsibilities 
 
Any Serious Adverse Event (SAE) must be reported to LEO on the (paper) Serious Adverse 
Event Form – Clinical Trials within 24 hours of first knowledge. This report should contain an 
assessment of available information on seriousness, severity, causal relationship to the 
investigational product, 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 Global 
Pharmacovigilance, LEO using the following fax number or e-mail address: 
 
Fax number: +45 7226 3287 (for Global Pharmacovigilance) 
E-mail address: drug.safety@leo-pharma.com (for Global Pharmacovigilance). 
 
It may be relevant for the (sub)investigator to enclose other information with the SAE form, 
such as reports of diagnostic procedures, hospital records, autopsy reports, etc. 


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Additionally, Global Pharmacovigilance, LEO may request further information in order to 
fully assess the SAE. The (sub)investigator must forward such information to Global 
Pharmacovigilance, LEO upon request by fax or e-mail (see contact details above). 
 
The investigator must notify the local IRB(s)/IEC(s) of SAEs as required by current 
applicable legislation for the concerned country. 
 
SAEs occurring after the completion of the clinical trial including any protocol required post- 
treatment follow-up period should not be routinely sought or collected. However, such events 
should be reported to Global Pharmacovigilance, LEO (drug.safety@leo-pharma.com) if the 
(sub)investigator becomes aware of them. 
 
The criteria qualifying the AE to be an SAE should be recorded in the CRF (see section 26.2, 
Appendix 2). 
 
9.5.2 LEO Reporting Responsibilities 
 
Global Pharmacovigilance, LEO is responsible for assessing whether or not an SAE is 
expected. The relevant reference documents for this clinical trial are: 
 
For the investigational product, the Investigator’s Brochure, edition 5 and subsequent updates 
must be used (14). 
For CORTROSYN® (used in the US), the latest version of the US Prescribing Information 
(USPI) must be used . 
 
For Synacthen® (used in Europe) the subsequent updated SmPC for Synacthen® must be 
used. 
 
Global Pharmacovigilance, LEO will notify the regulatory authorities and concerned 
investigators of SAEs according to the current applicable legislation for the concerned 
countries. 
 
The IRB(s)/IEC(s) will be notified of SAEs according to the current applicable legislation for 
the concerned countries. 
 
All SAEs that are assessed as causally related to the investigational product(s) by either the 
investigator or LEO, and which are not expected (Suspected, Unexpected Serious Adverse 
Reactions (SUSARs)) are subject to expedited reporting to regulatory authorities and 
IRB(s)/IEC(s) according to the current applicable legislation in the concerned countries. 
Investigators will be notified of these on an ongoing basis. 


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9.6  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 
investigational product for 14 ± 2 days or until the final outcome is determined, whichever 
comes first. 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. 
 
10 Investigational Product(s) 
10.1 Investigational Product Description 
 
Table 15: LEO 90100 
 
Finished product (brand) name (if 
available)/name Investigational Product 
LEO 90100 
Formulation 
Aerosol, foam 
Active ingredient name/concentration 
Calcipotriol 50 mcg/g (as hydrate) and 
betamethasone 0.5 mg/g (as dipropionate) 
Development Number 
CCI 
Excipients [not quantitative] 
White soft paraffin 
Liquid paraffin 
Polyoxypropylene-11 stearyl ether 
all-rac-alpha-tocopherol 
Dimethyl ether 
Butane 
Butylhydroxytoluene (E321) (CCI 
 
) 
Pack size(s) 
60 g (net weight excluding propellants) 
Manufacturer of bulk IP 
(ointment intermediate) 
LEO Laboratories Ltd., 285 Cashel Road, Dublin 12, Ireland 
Manufacturer of IP in primary packaging 
Colep Laupheim GmbH & Co. KG 
Fockestrasse 12 
88471 Laupheim 
Germany 
Release testing of IP in primary packaging 
LEO Pharma A/S, Industriparken 55, 2750 Ballerup, 
Denmark 
Manufacturer of secondary packaging and 
labelling 
CCI 
 
Certifier of secondary packaging and labelling 
CCI 
 


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10.2 Administration of Investigational Products 
 
Table 16: Administration of IP 
 
Route of administration 
Topical 
Dosing frequency 
Once daily 
Time of day for dosing 
No specific requirements 
Relation of time of dosing to dietary intake 
No specific requirements 
Relation of time of dosing to clinical assessments 
No dosing within 24 hours of Day 14 (Visit 2) and Day 28 
(Visit 3) 
Investigational product will be applied at Visit 2 and Visit 
3 under supervision of site staff after all clinical 
assessment have been conducted 
 
The investigational product (IP) must be dispensed by the (sub)investigator/investigational 
staff at Visit(s) 1 and 2. The subject and/or parents/legal guardian should be instructed to 
return all dispensed investigational product (used and unused cans) at the following visit. 
 
At Visit 1 the subject and/or parents/legal guardian will be carefully instructed (verbally and 
in writing by handing over a subject treatment instruction sheet) on how to apply the IP at 
home. The first application of the IP should be made by the subject and/or parents/legal 
guardian itself under supervision of the site staff. At the days of trial visits (Visit 2 and Visit 
3) however, the application of IP will be done on site under supervision of site staff. 
 
The medication should be sprayed directly on the skin at a distance of 3 to 10 cm. The foam 
should be gently spread with the fingertips until the medication is absorbed. The aerosol foam 
should be shaken before use and can be sprayed holding the can in any orientation except 
horizontally. 
 
The (sub)investigator will have the discretion to determine the number of cans required to be 
dispensed at each dispensing visit (Visits 1 and 2). 
 
As a guidance for the (sub)investigator the maximum weekly dose will be determined by the 
age and BSA at Visit 1: 
• For subjects aged 12 to < 15 years with a BSA ≤ 1.3 m2, 2 cans should be dispensed for 
the treatment period of 14 days. 
• For subjects aged 12 to < 15 years with a BSA > 1.3 m2 and subjects aged > 15 years 
with a BSA ≤ 1.7 m2, 3 cans should be dispensed for the treatment period of 14 days. 
• For subjects aged > 15 years with a BSA > 1.7 m2, 4 cans should be dispensed for the 
treatment period of 14 days. 


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The BSA will be calculated using the Mosteller formula (Appendix 9). 
Subjects taking part in the HPA axis / Pk assessments: 
For subjects performing HPA axis and PK assessments, being treated under maximal use 
conditions, a maximum weekly dose will not be established. The (sub)investigator is to ensure 
the subject has enough investigational product to apply to all affected areas of the body and 
scalp once daily. 
 
10.3 Precautions/Overdosage 
 
Overdose with calcipotriol may be associated with hypercalcaemia. Clinically important 
hypercalcaemia will be managed at the investigator’s discretion with rehydration, 
bisphosphonate administration or according to local standard of care. Hypercalcaemia should 
rapidly subside when treatment is discontinued. 
 
Overdose with corticosteroid containing products may result in suppression of adrenal 
function which is usually reversible. In such cases, symptomatic treatment is indicated. In 
case of chronic toxicity, corticosteroid treatment must be discontinued gradually. 
 
10.4 Packaging of Investigational Products 
 
Individual Visit Kits 
 
Individual cans containing LEO 90100 will be dispensed at each visit by the site. The number 
of cans dispensed at each visit is dependent on the subject’s age and BSA at Visit 1. Each 
single can will be labelled with a unique kit number and packed in a covering carton. 
 
Immediate Treatment Packaging - Individual Unit (Cans) 
 
The primary packaging for LEO 90100 aerosol foam consists of an aluminium can into which 
the formulation is pre-filled and subsequently administered through a continuous valve. 
 
Each individual unit contains 60 g of Investigational Product. 
 
The labelling of trial products must be in accordance with Europen Union (EU) Annex 13, 
local regulations and trial requirements. 


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10.5 Storage of Investigational Products 
 
All LEO supplied drugs must be stored in a secure and restricted area under the conditions 
specified on the label and remain in the original container until dispensed. 
 
Furthermore, the following storage conditions and handling precautions should be observed: 
 
LEO 90100 aerosol foam: 
 
• Shake before use 
• Wash hands before and after use 
• Keep away from heats/sparks/open flames/hot surfaces/sunlight 
• Keep out of the reach of children 
• Do not inhale 
• Do not smoke 
• Do not exceed temperatures above 50°C (122°F) 
• Do not pierce or burn, even after use 
• EU storage conditions: Store at 2°C (35.6°F) to 25°C (77°F). Do not freeze 
• US storage conditions: Store at 20°C (68°F) to 25oC (77°F). Excursions between 15°C 
to 30oC permitted. Do not freeze 
 
10.6 Treatment Assignment 
Subjects who have been found to comply with all the protocol’s inclusion and exclusion 
criteria will start treatment and be dispensed with investigational product at Visit 1. Each can 
will have a unique kit number. When a can is dispensed to the subject, the unique kit number 
for that can will be recorded in the subject’s medical record and the CRF. 
 
10.6.1  Randomisation Code List 
 
Not applicable. 


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10.7 Non-Investigational Medicinal Products 
 
10.7.1 CORTROSYN® (cosyntropin)/Synacthen® for injection 
CORTROSYN® (used in the US) is a commercial solution for injection containing 
cosyntropin that will be used for the ACTH-challenge test. One ampoule contains cosyntropin 
PhEur 250 micrograms (equivalent to 25 IU ACTH). 
 
Synacthen® (used in Europe) is a commercial solution for injection containing 
tetracosactidhexaacetate that will be used for the ACTH challenge test. One ampoule contains 
1 ml of 0.28 mg tetracosactid-hexaacetate (0.25 mg tetracosactid which equals 25 IU ACTH). 
CORTROSYN®/Synacthen®will be sourced by the investigational sites. 
 
CORTROSYN® will be used in accordance with the USPI for the marketed product . 
Synacthen® will be used in accordance with the subsequent updated SmPC. 
 
 
Table 17: CORTROSYN® (used in the US) 
 
Finished product (brand) name (if available)/name 
investigational product 
CORTROSYN® (cosyntropin) for Injection 
Formulation 
Sterile lyophilized powder to be reconstituted with 
0.9% Sodium Chloride Injection, USP 
Active ingredient name/concentration 
Cosyntropin (α 1-24 corticotropin); 0.25mg per vial 
Excipients 
Mannitol, glacial acetic acid and sodium chloride. It 
contains no antimicrobial preservative. 
Pack size(s) 
Box of 10 vials of CORTROSYN® (cosyntropin) for 
Injection 
Manufacturer’s name 
Amphastar Pharmaceuticals, Inc. 
Rancho Cucamonga, CA 91730 U.S.A. 
Supplier’s name 
Not Applicable. 
Certifier’s name 
Amphastar Pharmaceuticals, Inc. 
Rancho Cucamonga, CA 91730 U.S.A. 


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Table 18: Synacthen® (used in Europe) 
 
Finished product (brand) name (if available)/name 
investigational product 
Synacthen® 
Formulation 
Solution for injection 
Active ingredient name/concentration 
Tetracosactid 0.25 mg/mL (i.e., 25 IU ACTH) 
Excipients 
Acetic acid, sodium acetate, sodium chloride, 
aqua ad inject. 
Pack size(s) 
Ampoules: 10 times 1 ml 
Manufacturer’s name 
Products available on the local market will be used 
(according to the local marketing authorisation) 
To be sourced individually by sites (excluding Poland 
and Romania) 
Supplier’s name 
See above 
Certifier’s name 
See above 
 
10.7.1.1 Packaging and Labelling 
The marketed product, as available in the US or in Europe will be used for this study without 
any re-labelling or re-packaging of the product. US and the Netherlands will be responsible 
for purchasing the CORTROSYN®/Synacthen® , they will be reimbursed for the non- 
investigational IP. Poland and Romania will be provided the Synacthen® through the depot 
Catalent in Bathgate, UK. 
 
10.7.1.2 Storage of Non-Investigational Medicinal Products 
CORTROSYN®/Synacthen® should be stored in a safe and secure place inaccessible for 
children. The temperature for storage should be 15 to 30°C for CORTROSYN®. Synacthen® 
should be protected from light and stored in a refrigerator (2 - 8°C). The Investigator is 
responsible for ensuring that the storage of CORTROSYN®/Synacthen®is in accordance with 
these conditions. Should there be any evidence that these conditions have not been 
maintained, the product should be destroyed and spoiled stock replaced. 
 
10.7.1.3 Reconstitution and Administration 
For CORTROSYN®/Synacthen® the contents of one vial (0.25mg of CORTROSYN®) should 
be reconstituted in 2 to 5ml of 0.9% Sodium Chloride Injection, USP, and injected 
intravenously over a 2-minute period. The reconstituted drug product should be inspected 
visually for particulate matter and discoloration prior to injection. Reconstituted 
CORTROSYN®/Synacthen®should be used promptly and should not be retained. Any unused 
portion should be discarded. 


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10.7.1.4 Precautions 
Prior to injection of CORTROSYN®/Synacthen®, the investigator and staff must be prepared 
to treat any possible anaphylactic/allergic/hypersensitivity reaction. Severe anaphylactic 
reactions to CORTROSYN®/Synacthen®can be minimised by discontinuing the IV injection 
at the earliest sign of any local or general reaction such as redness, urticaria, pruritus, flushing 
of the face, malaise or dyspnoea. In the rare event of a serious allergic/anaphylactic reaction, 
local procedures should be followed and IM/IV epinephrine (adrenaline), IV high dose 
corticosteroids, IV antihistamines and intravenous fluids must be readily available and 
immediately used as appropriate. Protection of the airway must also be considered and 
managed appropriately. 
 
Because of the risk of an allergic reaction, the injections should be given under medical 
supervision and the subject kept under observation for approximately one hour. If subjects 
experience an allergic reaction to CORTROSYN®/Synacthen® they should be withdrawn from 
the trial. Repeat administration may increase the risk of hypersensitivity. Subjects should be 
instructed to inform subsequent physicians of previous use of corticotropic hormones (see the 
USPI for CORTROSYN®   and the SmPC for Synacthen® for further details). 
 
10.7.2 0.9% Sodium Chloride Injection, USP 
0.9% Sodium Chloride Injection, USP will be sourced by the investigational sites in the US 
and Europe and reimbursed by LEO Pharma A/S. There is no requirement for a specific brand 
or manufacturer to be used. 
 
0.9% Sodium Chloride Injection, USP will be used in accordance with the product monograph 
specific to the chosen product. 
 
10.7.2.1 Packaging and Labelling 
The marketed product, as available in the US and Europe will be used for this study without 
any re-labelling or re-packaging of the product. 
 
10.7.2.2 Storage 
The product should be stored in a safe and secure place inaccessible for children and in 
accordance with the manufacturer’s instructions (e.g. product monograph or labels) specific to 
the chosen product. 


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10.7.2.3 Precautions 
Product specific precautions and handling instructions will be provided in the product 
monograph specific to the chosen product. 
 
General precautions for use with 0.9% Sodium Chloride Injection, USP include: 
 
• Do not use unless the solution is clear and seal intact. 
• Do not re-use containers. 
• Discard unused portion. 
 
10.8 Drug Accountability and Compliance Checks 
10.8.1 Drug Accountability 
10.8.1.1 Drug Accountability Investigational Product 
The investigator is fully responsible for the investigational products at the trial site, for 
maintaining adequate control of the investigational products, and for documenting all 
transactions with them. 
 
Dispensing of investigational products may be delegated, e.g. to a hospital pharmacy, as 
locally applicable. 
 
At each visit, the investigational product, including (empty) cans dispensed at the previous 
visit, must be returned by the subject. An inventory (Individual Drug Accountability Form) 
must be kept, tracking the investigational product given to and returned by each subject 
enrolled 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 investigational 
product. 
 
All investigational products supplied by the Contract Manufacturing Organisation (CMO) on 
behalf of LEO 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 
investigational products. Accountability must be documented by using drug accountability 
forms. 
 
Investigational products may be returned from the trial site either to the CMO directly or via 
the LEO Pharma A/S affiliate/CRO responsible for running the clinical trial. 


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The investigational product returned to the CMO will be reconciled with the Individual Drug 
Accountability Forms. All returned cans will subsequently be weighed by the CMO to 
determine the amount of the investigational product used. 
 
10.8.1.2 Drug Accountability Non-Investigational Medicinal Products 
The investigator is fully responsible for the non-investigational medicinal products (i.e. 
CORTROSYN®/Synacthen®and 0.9% Sodium Chloride Injection) at the trial site. Dispensing 
of non-investigational medicinal products may be delegated, e.g. to a hospital pharmacy, as 
locally applicable. 
 
The person responsible for dispensing the non-investigational medicinal products will be 
responsible for maintaining adequate control and for documenting all transactions. All non- 
investigational medicinal products sourced locally by the investigator (or designee) will be 
fully documented by use of (internal) drug accountability forms. An inventory will be kept of 
all non-investigational medicinal products dispensed for each subject in the trial. The batch 
number/lot number and expiry date of the non-investigational medicinal products dispensed 
will be recorded. This inventory must be available for inspection at monitoring visits and will 
be checked to ensure correct dispensing of non-investigational medicinal products. 
 
10.8.2 Trial Product Destruction 
Used and unused trial products will be destroyed by the CMO according to LEO procedures. 
 
10.8.3 Treatment Compliance 
At all on-treatment visits, the subject should be asked if she/he has used the investigational 
product 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 taking the 
trial products as prescribed. The degree of non-compliance and the reason for it must be 
recorded in the CRF. 
 
10.9 Emergency Unblinding of Individual Subject Treatment 
Not applicable. 
 
11 Statistical Methods 
11.1 Determination of Sample Size 
The primary objective of the trial is to evaluate the safety of LEO 90100. No formal sample 
size calculation evaluating the power of the trial has been performed. However, a 
consideration regarding the sample size was made as described below. 


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For adverse events with a true (theoretical) frequency of at least 2% the probability of 
observing at least one case among the 100 subjects will be at least 86.7%. 
 
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 subjects assigned treatment 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 E9, section 5.2.1., Full Analysis Set. If it is decided to exclude a subject assigned 
treatment from the full analysis set, a justification addressing ICH E9 will be given. 
 
For the analysis of the results from the ACTH-challenge test, a per protocol analysis set will 
be defined by including subjects undergoing HPA axis assessments from the full analysis set, 
however excluding the subjects who: 
 
• receive no treatment with the investigational product 
• provide no results for the ACTH-challenge test at Week 4 
• and/or do not fulfil the inclusion criterion concerning evidence of adrenal function at 
baseline (i.e. inclusion criterion 17). 
 
A safety analysis set will be defined by excluding subjects from the full analysis set who 
either received no treatment with investigational product and/or for whom no post-baseline 
safety evaluations are available. 
 
For the analysis of PK data, a PK analysis set will be defined by including subjects 
undergoing PK assessments from the full analysis set, however excluding the subjects who: 
 
• receive no treatment with the investigational product. 
• provide no PK data at Week 4. 
The decisions regarding inclusion/exclusion of subjects and/or subject data from the trial 
analysis sets will be documented in the clinical trial report. 


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11.3 Statistical Analysis 
11.3.1 Disposition of Subjects 
The reasons for leaving the trial will be presented for all subjects assigned treatment by last 
visit attended. 
 
11.3.2 Demographics and other Baseline Characteristics 
Descriptive statistics of demographics and other baseline characteristics will be presented for 
all subjects assigned treatment and separately for per protocol analysis set. Presentations of 
age, sex, ethnicity, race and baseline disease severity according to the PGA on the body and 
scalp will also be given by centre. 
 
Demographics include age, sex, race, ethnicity and skin type. Other baseline characteristics 
include height, weight and BMI, duration of plaque psoriasis, concurrent diagnoses (from 
medical history and indications for concomitant medication), concomitant medication, PGA 
on the body and scalp, PASI (calculated from the physician’s assessment of extent and 
severity of the clinical signs), physician’s assessment of extent of psoriasis vulgaris (total 
involvement as % of BSA, on trunk and/or limbs as % of BSA and on scalp as % of scalp 
area) and subject´s global assessment of disease severity on the body and scalp. 
 
11.3.3 Exposure and Treatment Compliance 
The duration of exposure (weeks) and extent of exposure (subject-treatment-weeks) to IP will 
be summarised for safety analysis set. 
 
The amount of IP used (g) and the average weekly amount of IP used (g) will be summarised 
for safety analysis set and also for per protocol analysis set and separately for three different 
treatment periods (the first two weeks, the second two weeks and the total treatment period). 
Furthermore, a plot of the average weekly amount of IP use over the total treatment period 
against baseline extent of total BSA involvement will be presented for both analysis sets. 
 
The number and percentage of subjects who do and do not comply with the trial treatment 
instructions will be summarised for all subjects assigned treatment. The extent of non- 
compliance as categories of the percentage of applications missed (e.g. ≤ 10%, > 10 to 20%, 
etc.) will also be presented. 


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11.3.4 Analysis of Primary Endpoints 
Adverse events 
 
The number and percentage of subjects experiencing each type of adverse event will be 
tabulated for the safety analysis set. Further details are included in section 11.3.8.1. 
 
Subjects with serum cortisol concentration of ≤18 mcg/dl at 30 minutes after ACTH- 
challenge at Week 4 
 
The analysis of the results from the ACTH-challenge test will be based on the per protocol 
analysis set. 
 
The number and percentage of subjects with a serum cortisol concentration ≤18 mcg/dl at 30 
minutes after ACTH-challenge at Week 4 will be tabulated. 
 
The serum cortisol concentration at time 0 (just before the ACTH challenge) and at 30 and 60 
minutes after ACTH-challenge at baseline (SV2) and Week 4, respectively, will be 
summarised. 
 
The serum cortisol concentration at time 0 (just before the ACTH challenge) and at 30 and 60 
minutes after ACTH-challenge and also the change in serum cortisol from time 0 to 30 
minutes and 60 minutes recorded at baseline (SV2), Week 4 and FU2, respectively, will be 
listed for each subject with a value ≤18 mcg/dl at either 30 or 60 minutes after ACTH- 
challenge. Values ≤ 18 mcg/dl at 30 or 60 minutes after ACTH-challenge will be flagged. 
 
Change in albumin-corrected serum calcium from baseline (SV2) to Week 4 
 
The analysis of the albumin-corrected serum calcium data will be based on the safety analysis 
set. 
 
For the albumin-corrected serum calcium, the absolute value by visit and at end of treatment 
and the change from baseline (SV2) to Week 4 and to end of treatment will be summarised. 
Furthermore, the 95% confidence interval (CI) of mean change from baseline to Week 4 and 
to end of treatment will be presented. In addition, the albumin-corrected serum calcium will 
be classified as ‘low’, ‘normal’ or ‘high’, depending on whether the value is below, within or 
above the reference range, respectively. Shift table will be produced showing the categories at 
baseline (SV2) against those at Week 4 and at end of treatment. 
 
Summary tables and shift table will be repeated subgrouped by baseline 25-hydroxy vitamin 
D classifications (‘low’, ‘normal’ or ‘high’ with respect to its reference range). 


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Plots of the average weekly amount of IP use over the total treatment period against change 
from baseline to Week 4 and against change from baseline to end of treatment in albumin- 
corrected serum calcium will be presented. 
 
The albumin-corrected serum calcium will be listed by visit for all subjects with the values 
out of reference range at any visit. Values outside the reference range will be flagged. 
 
Change in calcium excretion from baseline (SV2) to Week 4 in 24-hour urine 
 
The analysis of the 24-hour urinary calcium excretion data will be based on a subset of the 
safety analysis set including the subjects undergoing HPA axis testing. The analysis will be 
performed as outlined above for the analysis of the albumin-corrected serum calcium data. 
 
In addition, calcium excretion at the 24-hour urine collection will also be presented separately 
for subjects with complete urinary collection. A 24-hour urinary collection is considered 
incomplete if it is either reported to be incomplete by the subject or if the creatinine excretion 
is below 0.1 mmol per kg body weight as proposed by Remer et al (29). 
 
Change in calcium:creatinine ratio from baseline (SV2) to Week 4 in 24-hour urine 
 
The analysis of the 24-hour urinary calcium:creatinine ratio data will be based on a subset of 
the safety analysis set including the subjects undergoing HPA axis testing. The analysis will 
be performed as outlined above for the analysis of the albumin-corrected serum calcium data. 
 
11.3.5 Analysis of Secondary Endpoints 
Subjects with serum cortisol concentration ≤18 mcg/dl at both 30 and 60 minutes after 
ACTH-challenge at Week 4 
 
Subjects with a serum cortisol concentration ≤18 mcg/dl at both 30 and 60 minutes after 
ACTH-challenge at Week 4 will be analysed as described for subjects with a serum cortisol 
concentration ≤18 mcg/dl at 30 minutes after ACTH-challenge at Week 4 in section 11.3.4. 


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Change in calcium:creatinine ratio from baseline (SV2) to Week 4 in spot urine 
 
The analysis of the calcium:creatinine ratio in spot urine will be based on a subset of the 
safety analysis set including the subjects not undergoing HPA axis testing. The analysis will 
be performed as described for the analysis of the albumin-corrected serum calcium data in 
section 11.3.4. 
 
Subjects with ‘treatment success’ (i.e., ‘clear’ or ‘almost clear’ for subjects with at least 
‘moderate’ disease at baseline, ‘clear’ for subjects with ‘mild’ disease at baseline) 
according to the physician’s global assessment of disease severity on the body at Week 4 
 
The statistical analysis of efficacy will be based on the full analysis set. The percentage of 
subjects who achieve ‘treatment success’ according to the PGA on the body will be presented 
by visit and at end of treatment. The 95% CI, which is based on a binomial distribution, will 
be presented for the proportion of subjects with ‘treatment success’ at Week 4 and at end of 
treatment. 
 
The percentage of subjects who achieve ‘treatment success’ according to the PGA on the body 
at Week 4 and at end of treatment will also be tabulated by age-group, sex, ethnicity, race, 
centre and baseline PGA on the body. 
 
Subjects with ‘treatment success’ (i.e., ‘clear’ or ‘almost clear’ for subjects with at least 
‘moderate’ disease at baseline, ‘clear’ for subjects with ‘mild’ disease at baseline) 
according to the physician’s global assessment of disease severity on the scalp at Week 4 
 
Subjects with ‘treatment success’ according to the PGA on the scalp will be analysed as 
outlined above for the body. 
 
Percentage change in PASI from baseline (V1) to Week 4 
 
PASI is calculated using the formula given below based on the physician’s assessment of the 
extent and severity of the disease locally (head, trunk, arms, legs) (8.14). 
 
The following formula will be used to calculate the PASI: 
 
Head 0.1 (R + T + S)E = W 
Arms 0.2 (R + T + S)E = X 
Trunk 0.3 (R + T + S)E = Y 
Legs        0.4 (R + T + S)E = Z 


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Where: R = score for redness; T = score for thickness; S = score for scaliness; E = score for 
extent 
 
The sum of W + X + Y + Z gives the total PASI, which can range from 0 to 72. 
 
The percentage change in PASI from baseline (V1) to each visit and to end of treatment will 
be summarised for the full analysis set. The 95% CI for mean percentage change in PASI 
based on a normal distribution will be calculated for Week 4 and for end of treatment. 
 
Subjects with ‘treatment success’ (i.e., ‘clear’ or ‘very mild) according to the subject’s 
global assessment of disease severity on the body at Week 4 
 
The percentage of subjects who achieve ‘treatment success’ according to the subject’s global 
assessment of disease severity on the body will be presented by visit and at end of treatment 
for the full analysis set. The 95% CI based on a binomial distribution will be calculated for 
the proportion of subjects with ‘treatment success’ at Week 4 and at end of treatment. 
 
Subjects with ‘treatment success’ (i.e., ‘clear’ or ‘very mild) according to the subject’s 
global assessment of disease severity on the scalp at Week 4 
 
Subjects with ‘treatment success’ according to the subject’s global assessment of disease 
severity on the scalp will be analysed as outlined above for the body. 
 
Change in itch as assessed by the VAS from baseline (V1) to Week 4 
 
The change in itch as assessed by the VAS from baseline (V1) to each visit and to end of 
treatment will be summarised for the full analysis set. The 95% CI for mean change in itch 
based on a normal distribution will be calculated for Week 4 and for end of treatment. 
 
11.3.6 Exploratory Analysis of Efficacy 
 
The exploratory analysis of efficacy will be based on the full analysis set. 
 
The PGA on the body and on the scalp, PASI and subject’s global assessment of disease 
severity on the body and on the scalp will be summarised by visit and at end of treatment. 
 
The physician’s assessment of extent of psoriasis (total involvement as % of BSA , on trunks 
and/or limbs as % of BSA and on scalp as % of scalp area) will be summarised by visit and at 
end of treatment. 


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11.3.7 Analysis of Patient-Reported Outcomes 
Subject’s assessment of itch 
 
Subject’s assessment of itch will be summarised by visit and at end of treatment for the full 
analysis set. 
 
Subject’s assessment of itch-related sleep loss 
 
Subject’s assessment of itch-related sleep loss will be summarised by visit and at end of 
treatment for the full analysis set. In addition, the change from baseline to each visit and to 
end of treatment will be summarised. 
 
Children’s Dermatology Life Quality Index 
 
The CDLQI total score will be analysed as outlined above for subject’s assessment of itch- 
related sleep loss. 
 
Additionally, the percentage of subjects with CDLQI scores of 0 or 1 indicating no or minimal 
impact on quality of life will be presented by visit and at end of treatment including only the 
subjects with the baseline score of > 1. 
 
Furthermore, the percentage of subjects with ≥ 5 points improvement in CDLQI score from 
baseline will be presented by visit and at end of treatment for the subjects with the baseline 
score ≥ 5. 
 
The Family Dermatology Life Quality Index 
 
The FDLQI total score will be analysed as outlined above for the CDLQI. 
 
11.3.8 Analysis of Safety 
The analysis of safety will be based on the safety analysis set, except where otherwise stated. 
 
11.3.8.1 Adverse Events 
Adverse events will be coded during the course of the trial according to MedDRA. Adverse 
events will be presented by preferred terms and primary system organ class. 
 
Treatment emergent AEs will be summarised, however all adverse events 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 investigational product 
or if started before the first application of investigational product (applicable if subject had a 


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wash-out) and worsened in severity thereafter. The tabulations described in the following will 
only include the events that are emergent with trial treatment. In each of the tabulations, 
adverse events are defined by MedDRA preferred terms within primary system organ class. 
 
An overall summary of the number (percentage) of subjects with any treatment emergent AEs, 
SAEs, premature discontinuations from the trial due to AEs, treatment related AEs and severe 
AEs will be presented. 
 
The number of subjects experiencing each type of adverse events will be tabulated regardless 
of the number of times each adverse event is reported by each subject. 
 
The severity for each type of adverse event will be tabulated. Where there are several 
recordings of severity for a given type of adverse event, severity will be taken as the most 
severe recording for that adverse event. 
 
The causal relationship to trial medication for each type of adverse events will be tabulated. 
Where there are several recordings of causal relationship to the investigational product for a 
given type of adverse event, causal relationship will be taken as the most-related recording 
from the last report of that adverse event, since that is when the (sub)investigator will be in 
possession of most information and so best able to judge causal relationship. 
 
Related adverse events are defined as adverse events for which the (sub)investigator has not 
described the causal relationship to investigational product as ‘not related’. The number of 
subjects experiencing each type of related adverse event will be tabulated regardless of the 
number of times each related adverse event is reported by each subject. 
 
The number of subjects experiencing each type of lesional/perilesional adverse event, 
lesional/perilesional adverse event on the body and lesional/perilesional adverse event on the 
scalp will be tabulated. 
 
Serious adverse events will be evaluated separately and a narrative for each will be given. 
 
AEs leading to withdrawal from trial or discontinuation of investigational product will be 
listed. 
 
11.3.8.2 Vital Signs 
For vital signs (systolic and diastolic blood pressure, heart rate and temperature), the absolute 
value by visit and change from baseline (SV2) to each visit will be summarised. 


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Clinically significant abnormalities in the vital signs at baseline (SV2) and Week 4 will be 
presented. Any abnormalities at Week 4 that were not present at baseline will be highlighted. 
 
11.3.8.3 Local Safety and Tolerability 
For each of the assessments of local safety and tolerability, the number and percentage of 
subjects in each of the four categories (‘Absent’ to ‘Severe’) will be tabulated at each visit. 
 
11.3.8.4 Clinical Laboratory Evaluation 
The albumin-corrected serum calcium, 24-hour urinary calcium excretion and 24-hour urinary 
calcium:creatinine ratio will be analysed as outlined in section 11.3.4. The calcium:creatinine 
ratio in spot urine will be analysed as described in section 11.3.5. 
 
For other biochemistry and haematology parameters, the absolute value by visit and the 
change from baseline (SV2) to Week 4 will be summarised. In addition, the laboratory 
parameters will be classified as ‘low’, ‘normal’ or ‘high’, depending on whether the value is 
below, within or above the reference range, respectively. Shift tables will be produced 
showing the categories at baseline (SV2) against those at Week 4. However, as 25-hydroxy 
vitamin D will be assessed only at baseline (SV2) then only the baseline values will be 
summarised. 
 
The 24-hour urinalysis parameters not described in section 11.3.4 will be analysed for a subset 
of the safety analysis set including the subjects undergoing HPA axis testing as outlined above 
for the biochemistry and haematology parameters. 
 
Urinalysis parameters measured in spot urine and not described in section 11.3.5 will be 
analysed for a subset of the safety analysis set including the subjects not undergoing HPA axis 
testing. The analysis will be performed as outlined above for the biochemistry and 
haematology parameters. 
 
For the urinary glucose and ketones, the values will be categorised by visit as absent or 
present. Shift tables will be produced showing the presence/absence at baseline (SV2) against 
presence/absence at Week 4. 
 
11.3.8.5 PK evaluation 
The PK analysis will be based on the PK analysis set. The following PK parameters will be 
calculated at Week 4, if possible, for each assayed compound based on the obtained plasma 
concentrations: AUC0-t, AUC0-∞, Cmax, Tmax and T1/2. 


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If it is not possible to calculate the above PK parameters at Week 4, samples with plasma 
concentration above lower limit of quantification (LLOQ) will be presented. 
 
For Week 2, the plasma concentrations above the lower limit of quantification will be 
presented as only one pre-dose trough sample will be collected at Week 2. 
 
11.3.9 Interim Analysis 
No interim analyses are planned. 
 
11.3.10 
General Principles 
 
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). 
 
The end of treatment values will be presented for laboratory parameters (primary and 
secondary endpoints), for efficacy data and for patient-reported outcomes data. Definition of 
the end of treatment value is given below in section 11.3.11. 
 
For tabulations on changes from baseline, baseline will be defined as the last assessment 
performed before application of IP. 
 
Categorical data will be summarised using the number and percentage of subjects in each 
category. Continuous data will be summarised using the mean, median, standard deviation 
(SD), minimum and maximum values. 
 
Any changes from the statistical analysis planned in this clinical trial protocol will be 
described and justified in a protocol amendment and/or in the clinical trial report dependent 
on the type of deviation. 
 
11.3.11 
Handling of Missing Values 
 
The end of treatment value for a particular parameter will be defined as the last value recorded 
for that parameter up to and including Visit 3 (Week 4). However, for laboratory parameters 
this will be the last value recorded after baseline (SV2) up to and including Visit 3. 
 
12 Trial Committees 
Not applicable. 


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13 Case Report Forms and Data Handling 
13.1 Case Report Forms (CRFs) 
Data will be collected by means of Electronic Data Capture (EDC). The investigator or staff 
authorised by the investigator must enter subject data into electronic CRFs. Data recorded in 
the electronic CRFs must be accessible to site staff through a secure internet connection 
immediately after entry. The CRFs must be maintained in an up-to-date condition at all times. 
 
The investigator must electronically sign all CRFs used. This signature information (including 
date of signature) will be kept in the audit trail and cannot be altered. Any correction(s) made 
by the investigator or authorised site staff to the CRF after original entry will be documented 
in the audit trail. Previously approved changes to the data, will require the re-signature of the 
investigator. The person making the change and the date, time and reason for the change will 
be identified in the audit trail. 
 
For archiving purposes, each investigator must be supplied with a copy of the CRFs for all 
subjects enrolled at the trial site via an electronic medium at completion of the trial and before 
access to the eCRF is revoked. Audit trail information must be included. CRFs must be 
available for inspection by authorised representatives from LEO (e.g. audit by the quality 
assurance department), from regulatory authorities and/or IEC/IRBs. 
 
13.2 Data Handling 
Subject data should be entered into the eCRF as soon as possible after the visit in accordance 
with the time requirements described in the Clinical Trial Agreement with the site. Queries for 
discrepant data may be generated automatically by the system upon entry or generated 
manually by the monitor or the trial data manager. All queries, whether generated by the 
system or by a user, will be in an electronic format. This systematic validation will ensure that 
a clean and consistent database is provided prior to the statistical analysis being performed. 
 
13.3 Source Data 
For all data recorded, the source document must be defined in a source document agreement 
at each trial site. There must only be one source defined at any time for any data elements. 
 
The trial monitor will check the CRFs for accuracy and completeness by verifying data 
recorded in the CRF against source data to ensure such records are consistent. 
 
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 


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routine part of the clinical practice at the site may be entered on a worksheet. Clinical 
assessments/safety evaluations must be signed by medically qualified (sub)investigators. 
 
If the worksheet does not become part of the subject’s medical record, the following 
parameters collected in the CRF should be verifiable from source documents available at the 
trial site : 
 
• Date of trial visits and date leaving the clinical trial 
• Relevant medical history and diagnosis, including plaque psoriasis and other skin 
diseases 
• Nature of contraception used by the subject and result of pregnancy test(s), when 
applicable 
• Data for evaluation of eligibility criteria 
• Dispensation/administration of investigational product 
• Lot number/batch number of non-investigational medicinal products used for each 
subject 
• Concomitant medication (including changes) and diagnoses 
• Subject demographics (sex, date of birth, race, ethinic origin, Fitzpatrick skin type) 
• Clinical assessments (vital signs, physical examination, investigator’s assessments: 
PGA, extent of psoriasis, monitoring of local tolerability and safety) 
• Laboratory assessments (time of start and stop for CORTOSYN®/Synacthen® injections 
and time of sampling for cortisol, PK, haematology, biochemistry and urine tests) 
• Time of application, start and stop for subjects taking part in the HPA axis testing and 
PK sampling on SV2, Visit 2 and Visit 3 
• 24-hour urine collection (start and stop times, incomplete collection, spillage and 
storage temperature excursions) for subjects taking part in the HPA axis testing and PK 
sampling 
• Adverse events, (nature, dates) 
• Dietary calcium intake diary 
 
In addition to the above, the following should be added to the subject’s medical record in 
chronological order: 


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• Date(s) of conducting the informed consent process including date of provision of 
subject information 
• CRF book number/Subject number 
• Investigational product kit number 
• The fact that the subject is participating in a clinical trial in plaque psoriasis for 4 weeks 
• Other relevant medical information 
 
13.4 Trial Monitoring 
 
During the course of the trial, the monitor will visit the trial site to ensure that the protocol 
and GCP are adhered to, that all issues have been recorded to perform source data verification 
and to monitor drug accountability 
 
The first monitoring visit should be performed as soon as possible after FSFV and no later 
than 10 days after. 
 
The monitoring visit intervals will depend on the trial site’s recruitment rate, the compliance 
of the trial site with the protocol and GCP. 
 
In order to perform their role effectively, monitors and persons involved in quality assurance 
and inspections will need direct access to source data, e.g. medical records, laboratory reports, 
appointment books, etc. If the electronic medical record does not have a visible audit trail, the 
investigator must provide the monitor 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). 
 
14 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, regulatory authority(ies) or IRB(s)/IEC(s). 


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The investigator must immediately inform LEO - by contacting the ICTM or medical expert - 
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 must act immediately upon receipt of the urgent safety measure notification in 
accordance with the internal procedures. 
 
15 Quality Assurance/Audit 
The clinical trial will be subject to audits conducted by LEO or inspections from domestic or 
foreign regulatory authorities or from IRBs/IECs. Audits and inspections may take place 
during or after the trial. The investigator and the site staff as well as LEO 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 must be notified 
immediately. 
 
16 Completion of Trial 
16.1 Trial Completion Procedures 
End of trial is defined as the date of the last subject’s last visit in each participating country 
and overall (all countries). 
 
Investigators will be informed when subject recruitment is to cease. 
 
Trial enrolment 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. 
 
Upon completion of the clinical trial, LEO must undertake arrangements for the collection 
and disposal of any unused trial material that the investigator is not required to keep in his/her 
files. 


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16.1.1 Criteria for Premature Termination of the Trial and/or Trial Site 
LEO, the investigator, the IRB/IECs or competent authorities may decide to stop the trial, part 
of the trial or a trial site at any time, but agreement on procedures to be followed must be 
obtained. 
 
If a 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, either the investigator or LEO must promptly inform IRB/IECs and provide a 
detailed written explanation. Relevant competent authorities must be informed. 
 
The trial must be terminated if the perception of the benefit/risk ratio (judged from clinical 
signs and symptoms, (S)AEs and/or remarkable safety laboratory changes) becomes 
unfavourable for the continuation of the trial. 
 
16.2 Provision for Subject Care Following Trial Completion 
After the completion of the trial, the subjects will be treated at the investigator’s discretion or 
referred to other physician(s) according to standard practice. 
 
16.3 Archiving of Trial Documents 
The investigator at each trial site must make arrangements to store essential trial docu-ments, 
including the Investigator Trial File (ICH E6, Guideline for Good Clinical Practice) until LEO 
informs the investigator that the documents are no longer to be retained or longer if required 
by local regulations. 
 
In addition, the investigator is responsible for the archiving of all relevant source documents 
so that the trial data can be compared against source data after the completion of the trial (e.g. 
in case of an inspection from regulatory authorities). 
 
The investigator is required to ensure the continued storage of the documents even if the 
investigator leaves the clinic/practice or retires before the end of the required storage period. 
 
The destruction process must ensure confidentiality of data and must be done in accordance 
with local regulatory requirements. 


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17 Ethics and Regulatory Authorities 
17.1 Institutional Review Boards (IRBs)/Independent Ethics Committees 
(IECs) and Regulatory Authorities 
Written approval or favourable opinion must be obtained from relevant IRB/IECs prior to the 
enrolment of subjects. 
 
Any amendments to the approved clinical trial must be approved by/receive favourable 
opinion from relevant IRBs/IECs and regulatory authorities as required prior to the 
implementation. 
 
The appropriate regulatory authority(ies) must be notified of/approve the clinical trial, as 
required. 
 
17.2 Ethical Conduct of the Trial 
This clinical trial must be conducted in accordance with the principles of the current revision 
at the start of the trial of the World Medical Association (WMA), Declaration of Helsinki, 
Ethical Principles for Medical Research Involving Human Subjects. 
 
17.3 Subject Information and Informed Consent 
The subject’s signed and dated informed consent to participate in the clinical trial must 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 parent(s)/legal guardian(s) of subjects will receive written and verbal information 
concerning the trial or subjects may give informed consent as appropriate and according to 
national laws or regulations. This information will emphasise that participation in the trial is 
voluntary and that the subject may withdraw from the trial at any time and for any reason. The 
parent(s)/legal guardian(s) will be given an opportunity to ask questions and will be given 
sufficient time to consider before consenting. Signed and dated informed consent for the 
subject to participate in the trial will be obtained from the parent(s)/legal guardian(s), or by 
the subject in accordance with national laws or regulations, prior to any trial related procedure 
being carried out. 
 
All subjects will also receive appropriate written and verbal information, be given an 
opportunity to ask questions and sufficient time to consider, before providing written assent. 
The subject’s decision not to participate or to withdraw will be respected, even if consent is 
given by the parent(s)/legal guardian(s). 


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The subject’s signed and dated informed consent to participate in the clinical trial must 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. 
 
17.4 Processing of Personal Data 
This protocol specifies the personal data on trial subjects (e.g. age, gender, health condition, 
height, medical history, test results, etc.) which shall be collected as part of the 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 and LEO. 
 
Processing of personal data on behalf of LEO requires a written agreement between LEO 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 must ensure that collection, processing and transfer of personal data 
are in compliance with national legislation on data protection and privacy. 
 
The investigator/institution may be considered as data controllers when they wish to use 
personal data collected in the clinical trial for their own purpose such as publication of 
clinical trial results. 
 
Subjects (or their legally acceptable representative) 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. 
 
If required, LEO will obtain the necessary authorization(s) for processing by LEO of personal 
data collected in the trial. 
 
18 Insurance 
LEO has taken out relevant insurances covering the subjects in the present clinical trial in 
accordance with applicable laws and regulations. 


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19 Use of Information 
This clinical trial protocol as well as all other information, data and results relating to this 
clinical trial and/or to the investigational product(s) is confidential information belonging to 
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 investigational product(s) and, 
therefore, may disclose and/or transfer information, data and/or results to other investigators, 
regulatory authorities and/or commercial partners. 
 
20 Publication 
Basic information of this clinical trial will be posted on the website: www.clinicaltrials.gov 
before the first subject enters into the clinical trial (30) (31). 
 
Results will be made available on LEO’s web site according to LEO’s position on access to 
clinical trial information. 
 
This clinical trial is multi-centre, and publication by an investigator of his/her trial results 
shall not be made before the first multi-centre publication is made public. Such multi-centre 
publication will be prepared in collaboration between LEO and the members of a writing 
committee, which shall be appointed by LEO. 
 
If there is no multi-centre publication within eighteen (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, 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 submitting or presenting a manuscript relating to the clinical trial to a publisher, 
reviewer or other outside person, the investigator shall provide to LEO a copy of all such 
manuscripts, and LEO shall have rights to review and comment. Upon the request of LEO, the 
investigator shall 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, delay the publication or presentation to allow LEO to protect its 
inventions and other intellectual property rights described in any such manuscripts. In case the 
first multi-centre publication is still ongoing and has not been made public at the time of 
notification, LEO and the Writing Committee may also delay the publication or presentation if 
the manuscript is deemed to harm the ongoing multi-centre publication. 


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In case of publications made by the investigator after the first multi-centre publication has 
been published, the above-mentioned requirements must be followed. 
 
LEO also subscribes to the joint position of the innovative pharmaceutical industry (32) for 
public disclosure of clinical trial results in a free, publicly accessible database, regardless of 
outcome. 
 
21 Responsibilities 
The international coordinating investigator (ICI) is responsible for the approval of the 
(Consolidated) Clinical Trial Protocol, Clinical Trial Protocol Amendment(s) and the Clinical 
Trial Report on behalf of all clinical trial investigators and as agreed to in an international 
coordinating investigator agreement. 
 
The national coordinating investigator(s) 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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22 List of Abbreviations 
 
ACTH 
Adrenocorticotrophic Hormone 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
AUC 
Area Under Curve 
BDP 
Betamethasone Dipropionate 
BSA 
Body Surface Area 
°C 
Celsius 
CDLQI 
Children´s Dermatology Life Quality Index 
CDMS 
Clinical Data Management System 
CEE 
Central and Eastern Europe 
CI 
Confidence Interval 
Cmax 
Maximum Plasma Concentration 
CMO 
Contract Manufacturing Organisation 
CRF 
Case Report Form 
CRO 
Contract Research Organisation 
DME 
Dimethyl Ether 
EDC 
Electronic Data Capture 
EU 
European Union 
F 
Fahrenheit 
FDA 
Food and Drug Administration 
FDLQI 
Family Dermatology Life Quality Index 
FSFV 
First Subject First Visit 
FU 
Follow-Up 
GCP 
Good Clinical Practice 
GPV 
Global Pharmacovigilance 
HPA 
Hypothalmic-Pituitary-Adrenal 
Hrs 
Hours 
IB 
Investigator´s Brochure 
ICH 
International Conference on Harmonisation 
ICI 
International Coordinating Investigator 


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ICTM 
International Clinical Trial Manager 
ID 
Identification 
IND 
Investigational New Drug 
IP 
Investigational Product 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IU 
International Unite 
LSLV 
Last Subject Last Visit 
LLOQ 
Lower Limit of Quantification 
mcg 
microgram 
MCV 
Mean Corpuscular Volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
miligram 
ml 
mililiter 
mmHg 
millimetre(s) of mercury 
MUSE 
Maximal Use Systemic Exposure 
PASI 
Psoriasis Area and Severity Index 
PTH 
Parathyroid Hormone 
PREA 
Pediatric Research Equity Act 
PRO 
Patient Reported Outcome 
PK 
Pharmacokinetic 
PUVA 
Psoralen plus Ultraviolet light A 
RBC 
Red Blood Cell 
SAE 
Serious Adverse Event 
SD 
Standard Deviation 
SmPC 
Summary of Product Characteristics 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
SV 
Screening Visit 
T½ 
Elimination half life 
Tmax 
Time of Maximum plasma concentration 


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TBD 
To be determined 
US 
United States 
USP 
United States Pharmacopeial Convention 
USPI 
US Prescribing Information 
UVB 
Ultraviolet light B 
V 
Visite 
VAS 
Visual Analogue Scale 
WBC 
White Blood Cell 
WMA 
World Medical Association 


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23 References 
1. Rachakonda TD, Schupp CW, Armstrong AW. Psoriasis prevalence among adults in the 
United States. J Am Acad Dermatol. 2014 Mar;70(3):512-6. 
2. Augustin M, Reich K, Glaeske G, Schaefer I, Radtke M. Co-morbidity and age-related 
prevalence of psoriasis: Analysis of health insurance data in Germany. Acta Derm 
Venereol. 2010 Mar;90(2):147-51. 
3. Tollefson MM, Crowson CS, McEvoy MT, Maradit Kremers H. Incidence of psoriasis 
in children: a population-based study. J Am Acad Dermatol. 2010 Jun;62(6):979-87. 
4. Griffiths CE, Barker JN. Pathogenesis and clinical features of psoriasis.Lancet. 2007 Jul 
21;370(9583):263-71. 
5. Langley RG, Krueger GG, Griffiths CE. Psoriasis: epidemiology, clinical features, and 
quality of life. Ann Rheum Dis. 2005 Mar;64 Suppl 2:ii18-23. 
6. Griffiths CE, Christophers E, Barker JN, Chalmers RJ, Chimenti S, Krueger GG, 
Leonardi C, Menter A, Ortonne JP, Fry L. A classification of psoriasis vulgaris 
according to phenotype. Br J Dermatol. 2007 Feb;156(2):258-62. 
7. Rogers M. Childhood psoriasis. Curr Opin Pediatr. 2002 Aug;14(4):404-9. 
8. Dubertret L, Mrowietz U, Ranki A, van de Kerkhof PC, Chimenti S, Lotti T, Schäfer G; 
EUROPSO Patient Survey Group. European patient perspectives on the impact of 
psoriasis: the EUROPSO patient membership survey. Br J Dermatol. 2006 
Oct;155(4):729-36. 
9. Rapp SR, Feldman SR, Exum ML, Fleischer AB Jr, Reboussin DM. Psoriasis causes as 
much disability as other major medical diseases. J Am Acad Dermatol. 1999 Sep;41(3 
Pt 1):401-7. 
10. Menter A, Korman NJ, Elmets CA, Feldman SR, Gelfand JM, Gordon KB, Gottlieb 
A,Koo JY, Lebwohl M, Lim HW, Van Voorhees AS, Beutner KR, Bhushan R; American 
Academy of Dermatology. Guidelines of care for the management of psoriasis and 
psoriatic arthritis. Section 3. Guidelines of care for the management and treatment of 
psoriasis with topical therapies. J Am Acad Dermatol. 2009 Apr;60(4):643-59. 
11. Nast A, Boehncke WH, Mrowietz U, Ockenfels HM, Philipp S, Reich K, Rosenbach T, 
Sammain A, Schlaeger M, Sebastian M, Sterry W, Streit V, Augustin M, Erdmann R, 
Klaus J, Koza J, Muller S, Orzechowski HD, Rosumeck S, Schmid-Ott G, Weberschock 
T, Rzany B; Deutsche Dermatologische Gesellschaft (DDG); Berufsverband Deutscher 
Dermatologen (BVDD). S3 - Guidelines on the treatment of psoriasis vulgaris (English 
version). Update. J Dtsch Dermatol Ges. 2012 Mar;10 Suppl 2:S1-95. 


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12. Shah KN. Diagnosis and treatment of pediatric psoriasis: current and future. Am J Clin 
Dermatol. 2013 Jun;14(3):195-213. 
13. Brown KK, Rehmus WE, Kimball AB. Determining the relative importance of patient 
motivations for nonadherence to topical corticosteroid therapy in psoriasis. J Am Acad 
Dermatol. 2006 Oct;55(4):607-13. 
14. Investigator’s Brochure, LEO 90100, Psoriasis vulgaris. Ballerup. Denmark: LEO 
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15. McCormack PL. Calcipotriol/betamethasone dipropionate: a review of its use in the 
treatment of psoriasis vulgaris of the trunk, limbs and scalp. Drugs 2011; 71: 709-30. 
16. Clinical Study Report. A phase 2 Maximal Use Systemic Exposure (MUSE) study 
evaluating the safety and efficacy of LEO 90100 used once daily in subjects with 
extensive psoriasis vulgaris. LEO Study Number LEO 90100-30. Report dated 17-Dec- 
2013. This trial is registered on ClinicalTrials.gov under trial Identifier Number 
NCT01600222. 
17. Levin C, Maibach HI. Topical corticosteroid-induced adrenocortical insufficiency. Am J 
Clin Dermatol. 2002;3:141-7. 
18. Forest MG. Adrenal function tests. In: Ranke MB (ed): Diagnostics of endocrine 
function in children and adolescents.  Basel, Karger, 2003, 372-426. 
19. Grinspoon SK, Biller BMK. Clinical Review 62. Laboratory assessment of adrenal 
insufficiency.  J Clin Endocrin Metabolism 1994; 79: 923-31. 
20. Bourke JF, Berth-Jones J, Iqbal SJ, Hutchinson PE. High-dose topical calcipotriol in the 
treatment of extensive psoriasis vulgaris. Br J Dermatol 1993; 129(1): 74-6. 
21. Oranje AP, Marcoux D, Svensson A, Prendiville J, Krafchik B, Toole J et al. Topical 
calcipotriol in childhood psoriasis. J Am Acad Dermatol 1997; 36(2 Pt 1):203-208. 
22. Darley CR, Cunliffe WJ, Green CM, Hutchinson PE, Klaber MR, Downes N. Safety 
and efficacy of calcipotriol ointment (Dovonex®) in treating children with psoriasis 
vulgaris. Br J Dermatol 1996; 135(3):390-393. 
23. Matkovic V, Ilich JZ, Andon MB, Hsieh LL, Tzagoumis MA, Lugger B, et al. Urinary 
calcium, sodium and bone mass of young females. Am J Clin Nutr 1995; 62: 417-25. 
24. Pacifici R, Vered I, McMurtry C, Smith S, Muckerman J, Delebar C, et al. Effect of Ca 
and vitamin D supplementation on urinary calcium excretion in an adult female popula- 
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25. Rapp SR, Feldman SR, Exum ML, Fleischer AB, Reboussin DM. Psoriasis causes as 
much disability as other major medical diseases.  J Am Acad Dermatol 1999; 41: 401-7. 
26. 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. 
27. Oostveen AM, de Jager ME, van de Kerkhof PC, Donders AR, de Jong EM, Seyger 
MM. The influence of treatments in daily clinical practice on the Children's 
Dermatology Life Quality Index in juvenile psoriasis: a longitudinal study from the 
Child-CAPTURE patient registry. Br J Dermatol. 2012 Jul;167(1):145-9. 
28. Weber MB, Lorenzini D, Reinehr CP, Lovato B. Assessment of the quality of life of 
pediatric patients at a center of excellence in dermatology in southern Brazil. An Bras 
Dermatol. 2012 Sep-Oct;87(5):697-702 
29. Remer T, Neubert A, Maser-Gluth C. Anthropometry-based reference values for 24-h 
urinary creatinine excretion during growth and their use in endocrine and nutritional 
research1-3. Am J Clin Nutr 2002,75:561-9 
30. De Angelis CD, Drazen JM, Frizelle FA, Haug C, Hoey J, Horton R et al. Clinical trial 
registration: a statement from the International Committee of Medical Journal Editors. 
JAMA 2004; 292(11):1363-4 
31. De Angelis CD. Is this clinical trial fully registered? A statement from the International 
Committee of Medical Journal Editors, available from: 
http://www.icmje.org/clin_trialup.htm. 
32. Joint Position on the Disclosure of Clinical Trial Information via Clinical Trial 
Registries and Databases, available from: 
http://clinicaltrials.ifpma.org/clinicaltrials/fileadmin/files/pdfs/EN/November_10_2009_ 
Updated_Joint_Position_on_the_Disclosure_of_Clinical_Trial_Information_via_Clinica 
l_Trial_Registries_and_Databases.pdf 


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24 List of Appendices 
Appendix 1: 
Protocol Summary 
 
Appendix 2: 
Definitions of Adverse Events and Serious Adverse Events 
Appendix 3: 
Classification of Adverse Events 
Appendix 4: 
Contact list of LEO, protocol authors, vendors, trial 
 
Appendix 5: 
Subject Assessment of Itch by use of a Visual Analogue Scale 
(VAS) 
 
Appendix 6: 
Subject Assessment of Itch-Related Sleep Loss by use of a Visual 
Analogue Scale (VAS) 
 
Appendix 7: 
Children’s Dermatology Life Quality Index (CDLQI) 
Appendix 8: 
The Family Dermatology Life Quality Index (FDLQI) 
Appendix 9: 
Mosteller Formular 


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25 Appendix 1: Protocol Summary 
 
Name of finished/ 
investigational product 
LEO 90100 aerosol foam 
Name of active 
substance 
Calcipotriol 50 mcg/g (as hydrate) and betamethasone 0.5 mg/g (as dipropionate) 
Title of trial/trial 
ID/EudraCT no. 
Safety and Effect of LEO 90100 aerosol foam on the HPA Axis and Calcium 
Metabolism in Adolescent Subjects (Aged 12 to < 17 Years) with Plaque 
Psoriasis/LP0053-1108/2015-000839-33 
Coordinating 
investigator(s) 
International coordinating investigator: 
Marieke Seyger, MD, PhD (the Netherlands) 
Sponsor’s name/ address 
LEO Pharma A/S, Industriparken 55, 2750 Ballerup, Denmark 
Estimated number of 
trial sites and 
distribution 
The trial is planned to be conducted in North America, Central and Eastern Europe. 
Approx. 30 sites across North America and CEE. 
Trial period 
Planned FSFV: Q3 2015 
Planned Last Subject Last Visit (LSLV): Jan 2017 
Main objective(s) 
The primary objective is to evaluate the safety of once daily use of LEO 90100 in 
adolescent subjects (aged 12 to < 17 years) with plaque psoriasis on the body and 
scalp. 
Methodology 
The present trial is designed as an international, multi-centre, prospective, open- 
label, non-controlled, single-group, 4-week trial in adolescent subjects (aged 12 to < 
17 years) with plaque psoriasis. 
Number of subjects to 
be enrolled 
In total, a sufficient number of subjects will be enrolled to ensure 100 subjects are 
available for evaluation of the effect of LEO 90100 on the calcium metabolism. 
The 100 subjects include the enrolment of 30 evaluable subjects without adrenal 
suppression at baseline who undergo an ACTH-challenge test (Visit 3) and PK 
assessments (Visit 2 and Visit 3). 
The ACTH-challenge test as well as PK assessments will only be performed at 
assigned sites and countries. 
Main criteria for 
inclusion (all subjects) 
• Adolescent subjects (age 12 to 16 years, 11 months). 
• Plaque psoriasis on trunk and/or limbs affecting at least 2% BSA. 
• Plaque psoriasis on the scalp affecting at least 10% of total scalp area. 
• A total psoriatic involvement on trunk, limbs and scalp not exceeding 30% BSA. 
• PGA score of at least mild on trunk and/or limbs at SV1, SV2 and V1. 


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• PGA score of at least mild on scalp at SV1, SV2 and V1. 
• A serum albumin-corrected calcium below the upper reference limit at SV2. 
• Female subjects must be of either 
• 
non-childbearing potential, i.e. premenarchal or have a confirmed clinical 
history of sterility (e.g. the subject is without a uterus or has tubal litigation) 
or, 
• 
child-bearing potential provided there is a confirmed negative pregnancy 
test prior to trial treatment to rule out pregnancy. 
• Female subjects of child-bearing potential must be willing to use highly effective 
contraception at trial entry and until completion. 
Main criteria for 
inclusion (for subjects 
undergoing HPA axis 
testing:) 
• Plaque psoriasis on trunk and/or limbs affecting at least 10% BSA. 
• Plaque psoriasis on the scalp affecting at least 20% of total scalp area. 
• PGA score of at least moderate on trunk and limbs at SV1, SV2 and V1. 
• PGA score of at least moderate on scalp at SV1, SV2 and V1. 
• Normal HPA axis function at SV2 (serum cortisol concentration above 5 mcg/dl 
before ACTH challenge and serum cortisol concentration above 18 mcg/dl 30 
minutes after ACTH challenge). 
Main criteria for 
exclusion (for all 
subjects) 
• A history of hypersensitivity to any component of LEO 90100. 
• Systemic treatment with biological therapies (marketed or not marketed), with a 
possible effect on scalp and/or body psoriasis within the following time period 
prior to V1 and during the trial: 
a. 
etanercept – within 4 weeks prior to V1 
b. 
adalimumab, infliximab – within 2 months prior to V1 
c. 
ustekinumab – within 4 months prior to V1 
d. 
experimental products – within 4 weeks/5 half-lives (whichever is longer) 
prior to V1 
• Systemic treatment with therapies other than biologicals, with a possible effect 
on scalp and/or body psoriasis (e.g. methotrexate, retinoids, 
immunosuppressants) within 4 weeks prior to V1 or during the trial. 
• PUVA therapy within 4 weeks prior to V1. 
• UVB therapy within 2 weeks prior to V1 or during the trial. 
• Any topical treatment on the scalp and body including corticosteroids and 
vitamin D (except for emollients and non-steroid medicated shampoos) within 2 
weeks prior to V1 or during the trial. 
• Systemic calcium, vitamin D supplementation > 400 IU/day, antacids, diuretics, 


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antiepileptics, diphosphonates or calcitonin within 4 weeks prior to SV2 or 
during the trial. (note: stable dose of vitamin D supplementation ≤ 400 IU/day is 
permitted provided there are no dose adjustments during the study period). 
Main criteria for 
exclusion (for subjects 
undergoing HPA axis 
testing:) 
• A history of serious allergy, allergic asthma or serious allergic skin rash. 
• Known or suspected hypersensitivity to any component of CORTROSYN®/ 
Synacthen®(including ACTH/cosyntropin/tetracosactide) 
• Systemic treatment with corticosteroids (including inhaled and nasal steroids) 
within 12 weeks prior to SV2 or during the trial. 
• Oestrogen therapy (including contraceptives) or any other medication known to 
affect cortisol levels or HPA axis integrity within 4 weeks prior to SV2 or during 
the trial. 
• Enzymatic inductors (e.g., barbiturates, phenytoin, rifampicin) within 4 weeks 
prior to SV2 or during the trial. 
• Systemic or topical cytochrome P450 inhibitors (e.g., ketoconazole, 
itraconazole,metronidazole) within 4 weeks prior to SV2 or during the trial. 
Topical ketoconazole within 2 weeks prior to SV2. 
Investigational 
product(s) 
LEO 90100 aerosol foam, containing calcipotriol (as hydrate) 50 mcg/g and 
betamethasone 0.5 mg/g (as dipropionate), 60 g per can, applied once dailyto body 
and scalp psoriasis lesions 
Investigational reference 
product(s) 
Not applicable. 
Duration of treatment 
The screening period including any washout period will last for 7-28 days, depending 
on the prior use of excluded treatments. The treatment period will be 4 weeks. 
The follow-up period will last for up to 4 weeks, depending on whether the subject 
has potential adrenal suppression and/or ongoing adverse event(s) classified as 
possibly/probably related/not assessable relationship to the investigational product. 


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Main 
assessments 
Safety Assessment 
Laboratory analysis: 
 
the following laboratory tests will be taken at SV2 and Visit 3 (Day 28). 
• haematology: hemoglobin, haematocrit, red blood cells (RBC), mean corpuscular volume 
(MCV), white blood cells (WBC) including differential count and platelets. 
• biochemistry (serum/plasma): cortisol (only for subjects in HPA Axis Cohort), urea, 
creatinine, albumin, sodium, potassium, chloride, calcium, phosphate, ALP and PTH. 
• urinalysis on 24-hour urine: calcium, phosphate, creatinine, volume. 
• urinalysis on spot urine: glucose, ketones, calcium, phosphate and creatinine 
At SV2 only, the vitamin D status will be assessed by the following laboratory analysis: 
• 25-hydroxy vitamin D 
Calcium metabolism evaluation will include serum albumin-corrected calcium, phosphate, 
alkaline phosphatase (ALP) and plasma parathyroid hormone (PTH) on a blood sample taken at 
SV2 and after 4 weeks of treatment. 
24-hour urine (only for subjects undergoing HPA axis testing) and spot urine will be collected 
at SV2 and after 4 weeks of treatment and urinary volume, calcium-, phosphate-, and creatinine 
excretion will be measured and calcium:creatinine and phosphate:creatinine ratios will be 
calculated. 
Dietary calcium intake will be monitored 3 days prior to and during collection of 24-hour 
urine/spot urine collection. Subjects will be instructed to keep a diary of daily intake of 
calcium-rich nutrients in these periods. 
ACTH challenge test: 
 
For subjects performing HPA axis assessments: the ACTH challenge test will be performed on 
2 occasions: At SV2 and Visit 3 (Day 28). In addition, an ACTH challenge test will be 
performed at Visit FU2 for subjects with possible HPA axis suppression at Visit 3. 
Vital signs: 
 
Blood pressure and temperature will be measured at SV2 and Visit 3 (Day 28). 
Adverse events: 
Adverse events will be recorded at all visits after SV1 (if applicable). 
Assessment of Local Safety and Tolerability 
At all treatment phase visits, the Assessment of Local Safety and Tolerability will comprise of 
perilesional signs of erythema, oedema, dryness and erosion assessed by the (sub)investigator. 
For each sign the highest (worst) skin reaction score across all treatment areas will be recorded 
by use of a  4-point scale: 
Pregnancy test: 
 
Urinary pregnancy test will be performed at SV2, Visit 3 (Day 28) and at FU2 (if applicable) in 


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females of childbearing potential. 
Efficacy Assessment 
At SV2 and at all on-treatment visits the following will be performed: 
• Physician´s Global Assessment (PGA) of disease severity on the body and scalp (ranging 
from “Clear” to “Severe”) 
• Physician´s assessment of the extent and severity of clinical signs of psoriasis vulgaris 
(redness, thickness and scaliness) 
• Subject´s Global Assessment of disease severity on the body and scalp (ranging from 
“Clear” to “Severe”) 
At SV2, Visit 1 and Visit 3 the physician´s assessment of extent of psoriasis (% of total BSA, % 
of body area and % of scalp area) will be performed. 
Patient Reported Outcomes 
Four Patient Reported Outcome (PRO) instruments will be used: Subject´s Assessment of Itch, 
Itch-related Sleep Loss and Children´s Dermatology Life Quality Index (CDLQI) will be 
collected at Visit 1, Visit 2 and Visit 3 or early withdrawal (if applicable). The Family 
Dermatology Life Quality Index (FDLQI) will be collected at Visit 1 and Visit 3 or early 
withdrawal (if applicable). 
Primary 
endpoint 
• Adverse events (AEs) 
• Subjects with serum cortisol concentration of ≤18 mcg/dl at 30 minutes after ACTH- 
challenge at Week 4 
• Change in albumin-corrected serum calcium from baseline (SV2) to Week 4 
• Change in calcium excretion from baseline (SV2) to Week 4 in 24-hour urine 
• Change in calcium:creatinine ratio from baseline (SV2) to Week 4 in 24-hour urine 
Secondary 
endpoint(s) 
• Subjects with serum cortisol concentration of ≤18 mcg/dl at both 30 and 60 minutes after 
ACTH-challenge at Week 4 
• Change in calcium:creatinine ratio from baseline (SV2) to Week 4 in spot urine 
• Subjects with ‘treatment success’ (i.e., ‘clear’ or ‘almost clear’ for subjects with at least 
‘moderate’ disease at baseline, ‘clear’ for subjects with ‘mild’ disease at baseline) according 
to the physician´s global assessment of disease severity on the body at Week 4 
• Subjects with ‘treatment success’ (i.e., ‘clear’ or ‘almost clear’ for subjects with at least 
‘moderate’ disease at baseline, ‘clear’ for subjects with ‘mild’ disease at baseline) according 
to the physician´s global assessment of disease severity on the scalp at Week 4 
• Percentage change in psoriasis area and severity index (PASI) from baseline (V1) to Week 
4 
• Subjects with ‘treatment success’ (i.e., ‘clear’ or ‘very mild) according to the subject´s 
global assessment of disease severity on the body at Week 4 


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• Subjects with ‘treatment success’ (i.e., ‘clear’ or ‘very mild) according to the subject´s 
global assessment of disease severity on the scalp at Week 4 
• Change in itch as assessed by the Visual Analogue Scale (VAS) from baseline (V1) to 
Week 4 
Statistical 
methods 
The number and percentage of subjects with a serum cortisol concentration ≤18 mcg/dl at 30 
minutes, and at both 30 and 60 minutes, after ACTH-challenge at Week 4 will be tabulated. The 
serum cortisol concentration at time 0 (just before the ACTH challenge) and at 30 and 60 
minutes after ACTH-challenge at baseline (SV2) and Week 4, respectively, will be summarised. 
The number and percentage of subjects experiencing each type of adverse event will be 
tabulated. 
For the albumin-corrected serum calcium, calcium excretion in 24-hour urine, 
calcium:creatinine ratio in 24-hour urine and calcium:creatinine ratio in spot urine, the absolute 
value by visit and at end of treatment and the change from baseline (SV2) to Week 4 and to end 
of treatment will be summarised. Furthermore, the 95% confidence interval of mean change 
from baseline to Week 4 and to end of treatment will be presented. In addition, the parameters 
will be classified according to the reference range, and shift tables will be produced showing the 
categories at baseline (SV2) against those at Week 4 and at end of treatment. Summary tables 
and shift tables will be repeated subgrouped by baseline 25-hydroxy vitamin D classifications. 
The following will be presented with the 95% confidence interval: 
• 
percentage of subjects with ‘treatment success’ according to the physician’s global 
assessment of disease severity on the body at Week 4 and at end of treatment 
• 
percentage of subjects with ‘treatment success’ according to the physician’s global 
assessment of disease severity on the scalp at Week 4 and at end of treatment 
• 
mean percentage change in PASI from baseline (V1) to Week 4 and to end of treatment 
• 
percentage of subjects with ‘treatment success’ according to the subject’s global 
assessment of disease severity on the body at Week 4 and at end of treatment 
• 
percentage of subjects with ‘treatment success’ according to the subject’s global 
assessment of disease severity on the scalp at Week 4 and at end of treatment 
• 
mean change in itch as assessed by the VAS from baseline (V1) to Week 4 and end of 
treatment 
For submission to IEC/IRBs and/or regulatory authorities, attach schedule of trial procedures 
(Section 8.1) 


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26 Appendix 2: Definitions of Adverse Events and Serious Adverse Events 
26.1 Adverse Event Definition 
An adverse event 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 adverse event (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, or reasons for admission to hospital or surgical procedures 
unless these were planned before enrolment. It also includes AEs commonly observed 
and AEs anticipated based on the pharmacological effect of the investigational 
product. In addition, any laboratory abnormality assessed as clinically significant by 
the (sub)investigator must be recorded as an AE. 
 
26.2 Serious Adverse Event Definition 
A serious adverse event (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 
 
• 
is a congenital anomaly/birth defect 
 
or 


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• 
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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27 Appendix 3: Classification of Adverse Events 
27.1 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 adverse event 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 adverse event 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 adverse event 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. 
 
27.2 Causality 
The causal relation of the AE to the use of the investigational product should be described in 
terms of probable, possible or not related according to the following: 
 
Probably 
related 
Follows a reasonable temporal sequence from administration of the investigational product. 
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 investigational product. 
Disappears or decreases on cessation or reduction in dose of the investigational product. 
Reappears or worsens upon re-challenge. 
Possibly 
related 
Follows a reasonable temporal sequence from the administration of the investigational 
product. 
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 investigational product. 
Not related 
Does not follow a reasonable temporal sequence from administration of the investigational 
product. 
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 investigational product. 


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27.3 Outcome 
The outcome of the event should be classified and handled as follows: 
 
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 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. 


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28 Appendix 4: Contact list of LEO, protocol authors, vendors, trial 
committees and coordinating investigators 
Contact details for the international clinical trial manager (ICTM), national lead CRA 
(NLCRA), medical expert and safety scientist/safety physician are provided to participating 
trial sites outside the protocol on a list of LEO representatives which is included in clinical 
trial applications. 
 
Sponsor 
 
LEO Pharma A/S (referred to as ‘LEO’ in this clinical trial protocol) is the sponsor of the 
clinical trial: 
 
LEO Pharma A/S 
Industriparken 55 
2750 Ballerup, DK 
 
Protocol Author(s) 
 
International Coordinating Investigator (ICI): 
 
Marieke Seyger, MD, PhD, Department of Dermatology, University Medical Centre 
Nijmegen St Radboud, PO Box 9101, 6500 HB Nijmegen, The Netherlands, 
Tel.: +31 24 361 37 24, e-mail: marieke.seyger@radboudumc.nl 
 
International Clinical Trial Manager (ICTM): 
 
PPD 
 MA, PgD, Senior International Clinical Trial Manager, Global Clinical 
Operations, LEO Pharma A/S., Industriparken 55, 2750 Ballerup, Denmark, Tel.: +45 PPD 
, email: PPD @leo-pharma.com 
 
Sponsor’s Medical Expert: 
 
PPD 
, MD, PhD, Sponsor’s Medical Expert, LEO Pharma A/S, Industriparken 
55, 2750 Ballerup, Denmark, Tel.: +45 PPD 
, Fax: +45 PPD 
, 
e-mail: PPD 
@leo-pharma.com 


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Study Statistician: 
 
PPD 
, MSc, Prinicpal Statistician, LEO Pharma A/S, Industriparken 55, 2750 
Ballerup, Denmark, Tel.: +45 PPD 
, Fax: +45 PPD 
, 
e-mail: PPD 
@leo-pharma.com 
 
Study Data Manager: 
 
PPD 
, Clinical Data Manager, LEO Pharma A/S, Industriparken 55, 2750 
Ballerup, Denmark, Tel.: +45 PPD 
, 
e-mail: PPD @leo-pharma.com 
 
Clinical Pharmacologist: 
 
PPD 
, Sponsor´s Clinical Pharmacologist, LEO Pharma A/S, Industriparken 55, 2750 
Ballerup, Denmark, Tel.: +45 PPD 
, Fax: +45 PPD 
, 
e-mail: PPD 
@leo-pharma.com 
 
Monitoring Scientist for bioanalysis: 
 
PPD 
, Sponsor´s Monitoring Scientist for Bioanalysis, LEO Pharma A/S, 
Industriparken 55, 2750 Ballerup, Denmark, Tel.: +45 PPD 
, 
e-mail: PPD 
@leo-pharma.com 
 
Safety Scientist: 
 
PPD 
, Sponsor's Safety Scientist, LEO Pharma A/S, Industriparken 55, 2750 
Ballerup, Denmark, Tel.: +45 PPD 
, Fax: +45 PPD 
, 
e-mail: PPD @leo-pharma.com 


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CRO(s)/vendors 
 
PPD 
: PPD 
, PPD 
, PPD, PPD; 
PPD 
, PPD, PPD 
, PPD 
. The CRO will be responsible 
for all services related to the central laboratory analysis as agreed to in a Service 
Agreement/Contract. Samples from Eastern and Central Europe will be shipped to and 
analysed by the UK site, whereas samples from US sites will be shipped to and analysed by 
the US site. 
 
CCI 
: CCI 
, CCI 
, CCI 
, CCI 
, 
CCI. The CMO will be responsible for the secondary packaging, labelling and distribution of 
trial medication, and also the receipt, accountability, weighing, reconciliation and destruction 
of returned trial medication, as agreed to in a Service Agreement/Contract. 
 
Colep Laupheim GmbH & Co. KG: Fockestrasse 12, 88471 Laupheim, Germany. The 
Contract Manufacturing Organisation (CMO) will be responsible for all services related to the 
filling of the Investigational Medicinal Product (incl. filling the ointment intermediate into 
cans and dissolving and dispersing the ointment intermediate in propellants) as agreed to in a 
Service Agreement/Contract. 
 
PPD 
: PPD, PPD 
, 
PPD 
, PPD 
, PPD. The CRO will be responsible for all services related to the 
laboratory PK analysis as agreed to in a Service Agreement/Contract. 
 
PPD 
: PPD 
, PPD 
, PPD 
, 
PPD 
, PPD 
 
. The CRO will be responsible for project management, clinical 
conduct, data management and monitoring as agreed to in a Service Agreement/Contract. 
 
PPD 
: 
PPD , PPD , PPD 
, PPD 
 
PPD 
, 
 
PPD 
: PPD 
PPD, PPD, PPD , PPD  
 
Coordinating Investigators 
 
International coordinating investigator: Marieke Seyger, MD, PhD, Department of 
Dermatology, University Medical Centre Nijmegen St Radboud, PO Box 9101, 6500 HB 
Nijmegen, The Netherlands, Tel.: +31 24 361 37 24, e-mail: marieke.seyger@radboudumc.nl 
 
National coordinating investigators: The contact details of National Co-ordinating 
Investigators are provided outside the protocol. 
PPD 


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29 Appendix 5: Subject Assessment of Itch by use of a Visual Analogue 
Scale (VAS) 
 
 
 
Site ID:  
 
 
Subject ID:  
 
 
Date:  
 
 
 
 
Subject Assessment of Itch by use of a Visual Analogue Scale (VAS) 
 
Protocol Code Number: 
LP0053-1108 
Protocol Title: 
Safety and Effect of LEO 90100 aerosol foam on the HPA 
Axis and Calcium Metabolism in Adolescent Subjects (Aged 
12 to < 17 Years) with Plaque Psoriasis 
 
This assessment will be made by the subject at all treatment phase visits (1-3) and early 
withdrawal (if applicable). 
 
Do not use this example for the actual assessment; a validated scale of 10 cm must be used. 
Instructions for use of Visual Analogue Scale: 
1. 
Provide the subject with a validated visual analogue scale marked with Subject ID and 
Visit Number. 
 
2. 
Ask the subject to rate the maximal intensity of itch during the last 24 hours. 
 
3. 
The subject should mark this with a vertical line on the scale between 0 and 10 (no itch 
at all and worst itch you can imagine). 
4. 
Collect back the Visual Analogue Scale and include in the study source data. 
 
5. 
Measure from the left with a ruler and record the distance (in mm) at which the subjects 
mark crosses the scale. This score (in mm) should be entered into the eCRF. 


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Page 102 of 106 
 
30 Appendix 6: Subject Assessment of Itch-Related Sleep Loss by use of a 
Visual Analogue Scale (VAS) 
 
 
Protocol Code Number: 
LP0053-1108 
Protocol Title: 
Safety and Effect of LEO 90100 aerosol foam on the HPA 
Axis and Calcium Metabolism in Adolescent Subjects (Aged 
12 to < 17 Years) with Plaque Psoriasis 
 
This assessment will be made by the subject at all treatment phase visits (1-3) and early 
withdrawal (if applicable). 
 
Do not use this example for the actual assessment; a validated scale of 10 cm must be used. 
Instructions for use of Visual Analogue Scale: 
1. Provide the subject with a validated visual analogue scale completed with Subject ID and 
Visit Number. 
 
2. Ask the subject to rate the itch-related sleep loss during the last night. 
 
3. The subject should mark this with a vertical line on the scale between 0 and 10 (no sleep 
loss at all and worst possible sleep loss). 
 
4. Collect back the Visual Analogue Scale and include in the study source data. 
 
5. Measure from the left with a ruler and record the distance (in mm) at which the subjects 
mark crosses the scale. This score (in mm) should be entered into the eCRF. 
 


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31 Appendix 7: Children’s Dermatology Life Quality Index (CDLQI) 
 


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32 Appendix 8: The Family Dermatology Life Quality Index (FDLQI) 
 


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33 Appendix 9: Mosteller Formular 
 
 
In centimeters and kilograms: 
 
BSA ( m2  ) = ( [ Height (cm) x Weight (kg) ] / 3600 ) ½ 
 
 
 
 
Reference: Mosteller RD: Simplified Calculation of Body Surface Area. N Engl J Med 1987; 
317:1098. 


LP0053-1108 2015-000839-33 Consolidated Clinical Trial 
Protocol V 5.0 29-Aug-2016 - English 
 
 
 
 
 
ELECTRONIC SIGNATURES 
 
Electronic signature made within eDoc LEO by LEO Pharma A/S employees or employees of any 
LEO Pharma A/S affiliate located anywhere in the world, are to be considered to be legally binding 
equivalent of traditional handwritten signatures. 
 
 
 
 
 
 
Biostatistics Lead, Biostatistical 
Approval 
29-Aug-2016 13:38 GMT+0 
PPD 
 
Medical Lead, Medical Approval 
29-Aug-2016 15:22 GMT+0 
Signed by 
Meaning of Signature 
Server Date 
(dd-MMM-yyyy HH:mm ‘GMT’Z) 
PPD 

SAP_000.pdf: 
Statistical Analysis Plan 
Safety and Effect of LEO 90100 aerosol foam on the HPA Axis and Calcium 
Metabolism in Adolescent Subjects (Aged 12 to < 17 Years) with Plaque Psoriasis 
A phase 2 trial evaluating the safety and efficacy of once daily topical treatment with 
LEO 90100 aerosol foam in adolescent subjects with plaque psoriasis 
An international, multi-centre, prospective, open-label, non-controlled, single-group, 
4-week trial in adolescent subjects with plaque psoriasis
LEO Pharma A/S 
Trial ID: 
LP0053-1108 
Date: 
12-Jun-2018
Version: 
1.0 
TMF-000069630 - Version 1.0


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1  St atistic al A n al ysis Pl a n  A p pr o v al  
1. 1  A p pr o v al St ate me nt  
O n be half of  L E O, t he Bi ostatistics  Lea d a n d t he Me dical Lea d , are a ut h orise d t o a p pr o ve t he 
Statistical A nal ysis Pla n . 
T he Q C statisticia n has b y a p pr o vi n g t his d oc u me nt c o nfir me d t hat t he statistical i nf or mati o n 
has bee n s u bject t o statistical q ualit y c o ntr ol. 
T he f oll o wi n g p ers o ns ha ve a p pr o ve d t his Statistical A nal ysis Pla n  usi n g electr o nic si g nat ur es 
as prese nte d o n t he last p a ge of t his d oc u me nt.  
 
 
Bi ostatistics  Lea d, Gl o bal Cli nical O perati o ns  
 
 
 
 
 
 
 
Me dical Lea d, Me dical S cie nce s a n d Safet y 
 
 
 
 
 
 
 
Q C Statisticia n, Bi ostata A ps  
 
 
 
 
 
 
 
 
 
 
P P D
P P D
P P D


Trial ID: LP0053-1108 
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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). 


Trial ID: LP0053-1108 
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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 ........................................................................................... 5 
5 Introduction ........................................................................................................................... 6 
6 Statistical Analysis ................................................................................................................. 6 
6.1 Baseline Considerations .................................................................................................... 6 
6.1.1 
Compliance .................................................................................................................... 7 
6.2 Analysis of Efficacy .......................................................................................................... 7 
6.3 Analysis of Safety ............................................................................................................. 9 
6.3.1 
Drug Accountability ...................................................................................................... 9 
6.3.2 
Exposure ...................................................................................................................... 11 
6.3.3 
Adverse Events ............................................................................................................ 11 
6.3.4 
Clinical Laboratory Evaluation ................................................................................... 12 
6.3.5 
Other observations ....................................................................................................... 13 
6.4 General Principles ........................................................................................................... 14 
6.4.1 
Pooling of Trial Sites ................................................................................................... 14 
6.4.2 
Handling of Drop-outs and Missing Values ................................................................ 14 
6.4.3 
Treatment Labels ......................................................................................................... 15 
Appendix I ................................................................................................................................ 16 


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3  List of A b bre vi ati o ns  
3. 1  List of A b bre vi ati o ns  
A C T H  
A dre n oc ortic otr o pic h or m o ne  
A E  
A d verse E v e nt  
B S A  
B o d y S urface Area  
C D L QI  
C hil dre n ’s Der mat ol o g y Lif e Q ualit y I n de x 
CI  
C o nfi de nce I nter val 
C R F  
Case Re p ort F or m  
C T R  
Cli nical Trial Re p ort  
F D L QI  
Fa mil y ’s Der mat ol o g y Life Q ualit y I n de x 
I C H 
I nter nati o nal C o nfere nce o n Har m o nisati o n 
I G A 
I n v esti gat or’s gl o bal assess me nt 
L O C F  
Last O bs er vati o n Carrie d F or war d  
L L O Q  
L o w er Li mit of Q ua ntificati o n  
I M P 
I n v esti gati o nal Me dici nal Pr o d uct 
Me d D R A  
Me dical Dicti o nar y f or R e g ul at or y Acti vities  
P A SI  
Ps oriasis Area a n d Se verit y I n de x  
P G A  
P h ysicia n ’s Gl o b al Assess me nt  
P K  
P har mac o ki netics  
P T  
Preferre d Ter m  
S A P  
Statistical A nal ysis Pla n  
S O C  
S yste m Or ga n Classificati o n  
4  St atistic al A n al ysis Pl a n  A ut h ors  
, M Sc, Se ni or Statisticia n, Bi ostatistics, L E O P har ma A/ S, D K-2 7 5 0, Baller u p, 
De n mar k, tel: + 4 5  
, e -mail: 
@le o -p har ma. c o m  
, MSc , Statistic ia n, Bi ostatistics, L E O P har ma A/ S, D K-2 7 5 0, 
Baller u p, De n mar k, t el: + 4 5  
, e -mail: 
@le o -p har ma.c o m  
, P h D, Cli nc al Pr oject Ma na ger, Trial Ma na ge me nt, L E O P har ma A/ S, D K-2 7 5 0, 
Baller u p, De n mar k, t el: + 4 5  
, e -mail:  
@le o -p har ma. c o m  
, P h D , Se ni or  Me dical Writer, Me di cal C o m m u nicati o n, L E O P har ma A/ S, D K -
2 7 5 0, Baller u p, De n mar k, tel: + 4 5  
, e -mail: 
@le o -p har m a.c o m  
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D


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, M D P h D, Se ni or Pri nci pal Me dical E x pert, Me dical De part me nt, L E O  
P har ma A/ S, D K -2 7 5 0, Baller u p, De n mar k, t el: + 4 5  
, e -mail:  
@le o -
p har ma.c o m  
5  I ntr o d ucti o n 
T he statistical a nal ysis will be perf or me d as o utli ne d i n t he C o ns oli date d C li nical Trial  
P r ot oc ol. T his Statistical A nal ysis Pla n , pre pare d after re vie w of t he data, c o ntai ns a m ore 
tec h nical a n d d etaile d ela b orati o n of s o me p oi nts i n t he statistical a nal ysis d escri be d i n the 
pr ot oc ol. Mi n or de viati o ns fr o m t he pla n ne d dat a prese ntati o n a n d a nal ysis are acc o u nte d f or.  
T he a nal ysis sets w hic h are t o be u se d f or t he statistical a nal ysis are prese nt e d i n A nal ysis S et 
Defi niti o n D oc u me nt.  
N o pr ot oc ol a me n d me nts t hat are rele va nt t o t he st atistical re p orti n g ha ve b ee n ma de. 
6  St atistic al A n al ysis  
T he statistical a nal ysis will be carrie d o ut as d escri be d i n t h e C o ns oli date d Cli nical Trial  
Pr ot oc ol wit h a fe w e x ce p ti o ns as descri be d bel o w. 
Lists of pla n ne d t a bles, fi g ures a n d i n di vi d ual s u bject data listi n gs f or t he Cli nical Trial  
Re p ort are pr o vi de d i n A p pe n di x 1.  
6. 1  B aseli ne C o nsi der ati o ns  
Acc or di n g t o t he pr ot o c ol descri pti ve statistics of de m o gra p hics a n d ot h er baseli ne 
c haracteristics will be prese nte d f or all s u bjects assi g ne d t o treat me nt a n d s e parat el y f or t he 
per pr ot oc ol a n al ysis set.  
A ge, se x, et h nicit y, race a n d baseli ne dise ase se v erit y acc or di n g t o t he PG A o n t he b o d y a n d 
scal p will be gi v e n b y c o u ntr y a n d n ot b y ce ntr e as descri be d i n t he pr ot o c ol, d ue t o t o o fe w  
n u m ber of s u bjects at m ost ce ntres.    
T he a ge will be prese nte d i n  t hree cat e g ories: 

O verall

1 2 t o 1 4  years

1 5  t o < 1 7 years.
P P D
P P D
P P D


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Tabulation of concomitant medication will be made for ACT Level 1 and ACT Level 4. The 
tabulation of the concurrent diagnoses will include SOC and PT, and will be made for Visit 1.  
The baseline is defined as last assessment performed prior the first application of IMP.  
6.1.1 Compliance 
As described in the protocol, compliance with treatment instructions will be tabulated for all 
subjects assigned to treatment. Non-compliance is defined by number of missed days due to 
other reasons than cleared psoriasis in relation to treatment period. Treatment period is 
defined as the number of days from the treatment assignment at Visit 1 to either trial 
completion or early withdrawal.  
The number and percentage of subjects who either did or did not comply with the trial 
treatment regimen will be summarized. The extent of non-compliance as categories of the 
percentage of applications missed will also be presented: 
 No 
 Yes: <=10% applications missed    
 Yes: >10% to <=20% applications missed 
 Yes: >20% to <=30% applications missed 
 Yes: >30% to <=40% applications missed 
 Yes: >40% to <=50% applications missed 
 Yes: >50% applications missed 
 Total 
6.2 Analysis of Efficacy 
The statistical analysis of efficacy will be based on the full analysis set. 
‘Treatment success’ according to PGA on the body at week 4 and at end of treatment will be 
presented in a table by age group. The categories to be used are the same as defined in section 
6.1, however the overall group will not be presented.  
‘Treatment success’ according to PGA on the body at week 4 and at end of treatment will be 
presented in a table by country and not by centre as described in the protocol.  
The following additional tables, not planned in the protocol, will be produced: 


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 Treatment success (PGA on the body and scalp) at week 4 and end of treatment by 
baseline extent of body psoriasis and scalp psoriasis: full analysis set 
The total extent of psoriasis will be presented in following three categories: 
 2-10% 
 >10-15% 
 >15-30% 
The categories of the extent of body psoriasis and scalp psoriasis will be defined later.   
Baseline for the efficacy is defined as last observation collected prior the first application of 
IMP, and is defined as Visit 1 for all assessments.  
Treatment success is defined as PGA score of ‘clear’ or ‘almost clear’ for subjects with at 
least a 2-step improvement from baseline i.e.:  
‘clear’ or ‘almost clear’ for subjects with at least ‘moderate’ disease at baseline and ‘clear’ for 
subjects with ‘mild’ disease at baseline.   
Treatment success for subject’s global assessment is defined as ‘clear’ or ‘very mild’. 
The CDLQI total score will be calculated by summing the score of each question resulting in 
a maximum of 30 and a minimum of 0. For interpretation of incorrectly completed 
questionnaires following rules will be used: 
1. If one question is left unanswered this is scored 0 and the scores are summed and 
expressed as usual out of a maximum of 30. 
2. If two or more questions are left unanswered the questionnaire is not scored. 
3. If both question 7a and 7b are completed the higher of the two scores should be 
counted 
The FDLQI total score will be calculated by summing the score of each question resulting in a 
maximum of 30 and a minimum of 0. For interpretation of incorrectly completed 
questionnaires following rules will be used: 
1. If one question is left unanswered this is scored 0 and the scores are summed and 
expressed as usual out of a maximum of 30. 
2. If two or more questions are left unanswered the questionnaire is not scored. 


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3. If two or more response options are ticked, the response option with the highest score
should be recorded.
4. If there is a response between two tick boxes, the lower of the two score options
should be recorded.
6.3 Analysis of Safety 
The analysis of safety will be based on the safety analysis set, except where otherwise stated. 
The analysis of the results from the ACTH-challenge test will be based on the per protocol 
analysis set. 
According to the ACTH-challenge procedure described in the protocol, samples of venous 
blood were to be drawn exactly 30 min and 60 min after the CORTROSYN®/Synacthen ® 
injection. However a time deviation of +/- 10 minutes is considered acceptable as the overall 
value of the test is to observe substantial increases in cortisol levels and identify adrenal 
insufficiency up to 1 hour after the initial injection, therefore the exact timing of the 
incremental time points (30 and 60 minutes) is of less importance. Samples outside the 
acceptable window will not be included in the analysis. No measurements outside the 
accepted window were observed.  
The tabulation of following two analyses will not be made due to too few number of subjects: 

serum cortisol concentration at time 0 and at 30 and 60 minutes after ACTH challenge
for subjects with serum cortisol concentration <=18 mcg/dL at either 30 minutes or 60
minutes after ACTH challenge

change in serum cortisol concentration from time 0 to 30 and 60 minutes at baseline,
week 4 and FU2 for subjects with serum cortisol concentration <=18 mcg/dL at either
30 minutes or 60 minutes after ACTH challenge
Instead the tabulation of individual data for subjects with serum cortisol concentration <=18 
mcg/dL at either 30 minutes or 60 minutes after ACTH challenge will be presented. 
Baseline for the safety analysis is defined as last observation collected prior the first 
application of IMP.  
6.3.1 Drug Accountability 
The amount of IMP used in grams and the average weekly amount used in grams will be 
tabulated for the safety analysis set and per protocol analysis set, and separately for three 


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differe nt treat me nt peri o ds ( first t w o wee ks, s ec o n d t w o wee ks , a nd t h e t otal treat me nt 
peri o d).  
F urt her m ore, a  pl ot of t h e a vera ge w ee kl y a m o u nt of I M P use o ver t h e t otal treat me nt peri o d 
a gai nst baseli ne e xte nt of t he t otal B S A i n v ol ve me nt will be prese nte d  f or t he safet y a nal ysis 
set a n d t he per pr ot oc ol  a nal ysis set . 
T he a vera ge wee kl y a m o u nt of I M P us e d, d uri n g t he t otal treat me nt peri o d, i n defi ne d usa ge 
cate g ories, will be ta b ulate d; t his ta ble was n ot pla n ne d i n t he pr ot oc ol:  

< 2 0 g/ w ee k

2 0 t o < 4 0 g/ w ee k

4 0 t o < 5 0 g/ w ee k

5 0 t o < 6 0 g/ w ee k

> = 6 0 g/ wee k

T otal
T he mea n w ei g ht of f ull ca ns, i ncl u di n g l a bel of I M P, is prese nte d i n Ta ble 1  f or eac h batc h 
a n d kit n u m ber. T h e la bel t y pe is  als o gi ve n.  
Ta ble 1 : Mea n w ei g ht of f ull ca ns of I M P b y batc h n u m ber a n d kit n u m ber  
B atc h n u m ber  
Kit n u m ber  
Wei g ht of a f ull b ottle + 
l a bel ( g) 
L a bel T y pe  
  
 
 - 
 
 
Si n gle pa nel  
  
 
 - 
 
 
B o o klet  
  
 
 - 
 
 
B o o klet  
  
 
  -
 
 
Si n gle pa nel  
  
 
 - 
 
 
B o o klet  
F or eac h tr eat me nt peri o d t he f oll o wi n g r ul es f or calc ulati n g t he a m o u nt of I MP use d will 
a p pl y: 
F or eac h s u bject t he wei g ht of I M P us e d f or a parti c ular treat me nt peri o d will be deter mi ne d  
b y calc ulati n g t he differe nce bet w ee n t he wei g ht of a set of f ull ca ns dis pe nse d a n d t he wei g ht  
of t he ret ur n e d ca ns . 
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
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C CI
C CI


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If any subject received cans for a particular treatment period but did not return them all, then 
the amount of IMP used for that treatment period will not be calculated. If any cans are not 
dispensed, they will not contribute to the weight of IMP used for that treatment period. If any 
cans are returned with their seal unbroken, the weight of IMP used from that bottle will be 
assigned a value of zero. If a returned bottle weighs more than the estimated mean weight of a 
full bottle, it will be assumed that zero grams were used. 
The average weekly amount of IMP used will be calculated for each subject as the amount of 
IMP used for a particular treatment period, divided by the duration (days) of the treatment 
period and then multiplied by 7. 
6.3.2 Exposure 
As described in the protocol, the duration of exposure (weeks) and extent of exposure 
(subject-treatment-weeks) to LEO 90100 will be summarized for the safety analysis set. 
6.3.3 Adverse Events 
The AEs will be presented for the safety analysis set as described in the protocol. 
The AEs are coded in accordance with the MedDRA dictionary version 18.0. 
The number of events will be presented in all adverse events tables where number of subjects 
is presented.  
No subjects had any serious adverse events and no subject was withdrawn early from the trial 
due to an adverse event, therefore serious adverse events and adverse events leading to 
withdrawal will not be tabulated.   
Additional tables, not planned in the protocol will be produced: 

Adverse events by age group, MedDRA, primary system organ class and preferred
term

Adverse events by sex, MedDRA primary system organ class and preferred term

Adverse events by race, MedDRA primary system organ class and preferred term

Adverse events by baseline PGA on the body, MedDRA primary system organ class
and preferred term

Adverse events by baseline PGA on the scalp, MedDRA primary system organ class
and preferred term


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 Adverse events by baseline total extent of body psoriasis,  MedDRA primary system 
organ class and preferred term 
 Adverse events by baseline total extent of scalp psoriasis,  MedDRA primary system 
organ class and preferred term 
 Adverse events by IMP usage, MedDRA primary system organ class and preferred 
term.  
Adverse events will be presented separately for two categories of IMP usage, the categories 
will be defined later. 
 
Following table will only be made for the subgroups 12 to 14 years and 15 to <17 years: 
 
 Adverse events by age group, MedDRA primary system organ class and preferred 
term 
6.3.4 Clinical Laboratory Evaluation 
The laboratory data will be presented for the safety analysis set, except where otherwise 
stated.   
The following approach will be used in case of repeated or missed laboratory measurements: 
 if an initial measurement was normal but the measurement was still repeated then the 
initial measurement will be presented in the tables and both measurements will be 
included in the listing. 
 if an initial measurement was repeated by mistake then the initial measurement will be 
presented in the tables and both measurements will be included in the listing.  
 if an initial measurement was abnormal and the measurement was repeated due to a 
technical problem then the repeated measurement will be presented in the tables and  both 
measurements will be included in the listing. 
 if an initial measurement was missing but a measurement from an unscheduled visit is 
available and the unscheduled visit was performed within 5 days after the actual visit then 
the measurement from the unscheduled visit will be used.  
 
The number of measurements outside the reference range will be presented in relevant 
laboratory tables. The number of measurements for other than primary and secondary 
endpoints that fall outside the limit for quantification will be presented in relevant laboratory 
tables.  


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The measurements below limit of quantification  for primary or secondary endpoints will 
replaced by the limit of quantification.  
 
6.3.5 Other observations 
PK evaluation 
The PK evaluation will be presented in a bioanalytical report.  
Plasma concentrations will be presented in the listing.  
Vital signs 
For systolic and diastolic blood pressure, heart rate and temperature, the absolute value by 
visit and change from baseline to each visit will be summarized 
Clinically significant abnormalities in the vital signs at baseline and Week 4 will be presented. 
Any abnormalities at Week 4 that were not present at baseline will be presented in the listing. 
The following approach will be used in case of repeated vital signs measurements: 
 if an initial measurement was normal but the measurement was still repeated then the 
initial measurement will be presented in the tables 
 if an initial measurement was abnormal and the measurement was repeated then the 
average of both measurements will be presented in the tables. 
 
All measurements will be included in the listings (initial measurement and repeated 
measurements). 
 
Baseline for vital signs is defined as last observation collected prior the first application of 
IMP (visit 1 and not screening visit 2 as written in the protocol).  
Local Safety and Tolerability 
 
Local safety and tolerability will be tabulated as described in the protocol.  


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6.4 General Principles 
6.4.1 Pooling of Trial Sites 
There will be no pooling of centres.  
6.4.2 Handling of Drop-outs and Missing Values 
An observed cases approach will be used for tabulations of data by visit (i.e. involving only 
those subjects who attended each specific visit), except for the tabulation of end of treatment. 
The end of treatment value for a particular parameter will be defined as the last value 
recorded for that parameter up to and including Visit 3 (Week 4). However, for laboratory 
parameters this will be the last value recorded after baseline (SV2) up to and including Visit 3. 
The extent of missing values are described in Table 2 for some of the primary endpoints and 
secondary endpoints involving laboratory measurements: 
Table 2: Number of observations/Total.A 
 
 (Number of 
observations/Total) 
Endpoint  
Test 
Screening Visit 2 
Week 4 
Primary 
Albumin corrected serum calciumB 
104/106 
102/103 
Primary 
24-hours urinary calcium excretionC 
33/34 
33/33 
Primary 
24-hours urinary calcium:creatinine ratioC 
32/34 
31/33 
Primary 
Serum cortisol at time 0D 
33/33 
33/33 
Primary 
Serum cortisol at time 30 minD 
33/33 
33/33 
Primary 
Serum cortisol at time 60 minD 
33/33 
33/33 
Secondary Urinary calcium:creatinine ratio in spot 
urineE 
58/72 
58/70 
A: Duplicates by subject, visit and numerical results are excluded. The table includes only subjects assigned to treatment 
B: All subjects assigned to treatment.  
C: Only for 24-hour urine HPA subjects. 
D: Only for the per protocol analysis. Serum Cortisol at time 0 and  30 min and 60 min after ACTH challenge.  
E: Only for spot urine non-HPA subjects. 
 
 
 
 


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6.4.3 Treatment Labels 
The treatment label to be used in text and tables in the CTR and in the individual subject data 
listings is ‘LEO 90100’. 
 
 
 


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Appendix I 
Tables, Figures and Listings 
 
 


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Tables and Figures, Baseline Characteristics and Investigational Product Data (Module 
2) 
Tables 
Table 1-1 Subject enrolment and treatment assignment: Enrolled subjects and subjects 
assigned treatment. 
Table 1-2 Reasons for withdrawal during the trial by last visit attended: full analysis set and 
per protocol analysis set 
Table 1-3 Sex, ethnicity, race and skin type: full analysis set and per protocol analysis set. 
Table 1-4 Age, BMI, height, weight and duration of plaque psoriasis: full analysis set and per 
protocol analysis set 
Table 1-5 Physician’s global assessment (PGA) of disease severity on the body and scalp at 
baseline: full analysis set and per protocol analysis set 
Table 1-6 Subject’s global assessment of disease severity on the body and scalp at baseline: 
full analysis set and per protocol analysis set 
Table 1-7 Physician’s assessment of extent of psoriasis vulgaris (total involvement as % of 
BSA, on trunks and/or limbs as % of BSA, and scalp as % of scalp area)  at baseline: full 
analysis set and per protocol analysis set 
Table 1-8 PASI at baseline: full analysis set and per protocol analysis set  
Table 1-9 Concomitant medication at baseline: full analysis set and per protocol analysis set 
Table 1-10 Concurrent diagnoses at baseline by MedDRA primary system organ class and 
preferred term: full analysis set and per protocol analysis set 
Note: The tabulation of the concurrent diagnoses will include SOC and PT, and will be made 
for Visit 1.  
Table 1-11 Age by country: full analysis set and per protocol analysis set 
Table 1-12 Sex by country: full analysis set and per protocol analysis set 


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Table 1-13 Ethnicity by country: full analysis set and per protocol analysis set 
Table 1-14 Race by country: full analysis set and per protocol analysis set 
Table 1-15 Physician’s global assessment of disease severity on the body and scalp at baseline 
by country: full analysis set and per protocol analysis set 
Table 1-16 Compliance with treatment instructions: full analysis set and per protocol analysis 
set 
 
Figures 
Figure 1-1 Visit attendance: enrolled subjects 
Figure 1-2 Trial analysis sets: enrolled subjects 
 
Tables and Figures, Efficacy Data (Module 3) 
Tables 
Table 2-1 Physician’s global assessment of disease severity on the body and scalp by visit and 
at end of treatment: full analysis set 
 
Table 2-2 Treatment success (PGA on the body and scalp) by visit and at end of treatment: full 
analysis set 
Note: Calculate 95% CI based on a binomial distribution for the proportion of subjects with 
‘treatment success’ at week 4 and end of treatment.  
Table 2-3 Treatment success (PGA on the body and scalp)  at week 4 and end of treatment by 
age group: full analysis set 
Table 2-4 Treatment success (PGA on the body and scalp)  at week 4 and end of treatment by 
sex: full analysis set 
Table 2-5 Treatment success (PGA on the body and scalp)  at week 4 and end of treatment by 
ethnicity: full analysis set  
 


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Table 2-6 Treatment success (PGA on the body and scalp)  at week 4 and end of treatment by 
race: full analysis set 
Table 2-7 Treatment success (PGA on the body and scalp) at week 4 and end of treatment by 
baseline PGA on the body and scalp: full analysis set 
Table 2-8 Treatment success (PGA on the body and scalp) at week 4 and end of treatment by 
country: full analysis set 
Table 2-9 Treatment success (PGA on the body and scalp) at week 4 and end of treatment by 
baseline extent of body psoriasis and scalp psoriasis: full analysis set 
Table 2-10 PASI by visit and end of treatment: full analysis set 
Table 2-11 Percentage change in PASI from baseline to each visit and end of treatment: full 
analysis set 
Note: Calculate 95% CI for mean change in PASI  based on a normal distribution for week 4 
and end of treatment.  
Table 2-12 Physician’s assessment of extent of psoriasis (total involvement as % of BSA, on 
body as % of BSA and scalp as % of scalp area) by visit and at end of treatment: full analysis 
set 
Table 2-13 Treatment success (subject’s global assessment of disease severity on the body and 
scalp) by visit and at end of treatment: full analysis set 
Note: Calculate 95% CI based on a binomial distribution for the proportion of subjects with 
‘treatment success’ at week 4 and end of treatment.  
Table 2-14 Subject’s global assessment of disease severity on the body and scalp by visit and 
at end of treatment: full analysis set  
Table 2-15 Subject’s assessment of itch by visit and end of treatment: full analysis set 
Table 2-16 Change in itch from baseline to each visit and end of treatment: full analysis set 
Note: Calculate 95% CI for mean change in itch based on a normal distribution for week 4 
and end of treatment.  


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Table 2-17 Subject’s assessment of itch-related sleep loss by visit and end of treatment: full 
analysis set 
Table 2-18 Change in itch-related sleep loss from baseline to each visit and end of treatment: 
full analysis set 
Table 2-19 CDLQI total score by visit and end of treatment: full analysis set. 
Table 2-20 Change in CDLQI total score from baseline to each visit and end of treatment: full 
analysis set 
Table 2-21 Subjects with CDLQI scores of 0 or 1 by visit and at end of treatment: full analysis 
set.  
Note: Only for subjects with baseline score >1. 
Table 2-22 Subjects with ≥ 5 points improvement in CDLQI score from baseline by visit and 
at end of treatment: full analysis set 
Note: Only for subjects with baseline score ≥5. 
Table 2-23 FDLQI total score by visit and end of treatment: full analysis set. 
Table 2-24 Change in FDLQ1 total score from baseline to each visit and end of treatment: full 
analysis set 
Table 2-25 Subjects with FDLQI scores of 0 or 1 by visit and at end of treatment: full analysis 
set 
Note : Only for subjects with baseline score >1.  
Table 2-26 Subjects with ≥ 5 points improvement in FDLQI score from baseline by visit and 
at end of treatment: full analysis set 
Note: Only for subjects with baseline score ≥5.  


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Tables and Figures, Safety Data (Module 4) 
Tables 
Table 3-1 Serum cortisol concentration at time 0 and at time 30 and 60 minutes after ACTH 
challenge at baseline and Week 4: per protocol analysis set 
Table 3-2 Subjects with serum cortisol concentration <=18 mcg/dL at both 30 and 60 minutes 
after ACTH challenge at Week 4: per protocol analysis set 
Table 3-3 Individual data for subjects with serum cortisol concentration <=18 mcg/dL at 
either 30 minutes or 60 minutes after ACTH challenge: per protocol analysis set.  
Table 3-4 Albumin-corrected serum calcium by visit and end of treatment: safety analysis set 
Table 3-5 Change in albumin-corrected serum calcium from baseline to Week 4 and end of 
treatment: safety analysis set 
Note: Calculate 95% CI of mean change from baseline to week 4 and end of treatment.  
Table 3-6 Albumin-corrected serum calcium categorised as low, normal or high at Week 4 and 
end of treatment shown against baseline category: safety analysis set 
Table 3-7 Albumin-corrected serum calcium by visit and end of treatment by 25-hydroxy 
vitamin D classifications: safety analysis set 
Table 3-8 Change in albumin-corrected serum calcium from baseline to Week 4 and end of 
treatment by 25-hydroxy vitamin D classifications: safety analysis set 
Note: Calculate 95% CI of mean change from baseline to week 4 and end of treatment.  
Table 3-9 Albumin-corrected serum calcium categorised as low, normal or high at Week 4 and 
end of treatment shown against baseline category by 25-hydroxy vitamin D classifications: 
safety analysis set 
Table 3-10 24-hour urinary calcium excretion by visit and end of treatment: 24-hour urine 
HPA set. 
Table 3-11 Change in 24-hour urinary calcium excretion from baseline to Week 4 and end of 
treatment: 24-hour urine HPA set. 


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Note: Calculate 95% CI of mean change from baseline to week 4 and end of treatment.  
Table 3-12 24-hour urinary calcium excretion categorised as low, normal or high at Week 4 
and end of treatment shown against baseline category: 24-hour urine HPA set. 
Table 3-13 24-hour urinary calcium excretion by visit and end of treatment by 25-hydroxy 
vitamin D classifications: 24-hour urine HPA set. 
Table 3-14 Change in 24-hour urinary calcium excretion from baseline to Week 4 and end of 
treatment by 25-hydroxy vitamin D classifications: 24-hour urine HPA set. 
Note: Calculate 95% CI of mean change from baseline to week 4 and end of treatment.  
Table 3-15 24-hour urinary calcium excretion categorised as low, normal or high at Week 4 
and end of treatment shown against baseline category by 25-hydroxy vitamin D 
classifications: 24-hour urine HPA set. 
Table 3-16 24-hour urinary calcium excretion by visit and end of treatment in subjects with 
complete urinary collection: 24-hour urine HPA set. 
Table 3-17 Change in 24-hour urinary calcium excretion from baseline to Week 4 end of 
treatment in subjects with complete urinary collection: 24-hour urine HPA set. 
Note: Calculate 95% CI of mean change from baseline to week 4 and end of treatment.  
Table 3-18 24-hour urinary calcium excretion categorised as low, normal or high at Week 4 
and end of treatment shown against baseline category in subjects with complete urinary 
collection: 24-hour urine HPA set. 
Table 3-19 24-hours urinary calcium:creatinine ratio by visit and end of treatment: 24-hour 
urine HPA set. 
Table 3-20 Change in 24-hours urinary calcium:creatinine ratio from baseline to Week 4 and 
end of treatment: 24-hour urine HPA set. 
Note: Calculate 95% CI of mean change from baseline to week 4 and end of treatment.  
Table 3-21 24-hours urinary calcium:creatinine ratio categorised as low, normal or high at 
Week 4 and end of treatment shown against baseline category: 24-hour urine HPA set. 


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Table 3-22 24-hours urinary calcium:creatinine ratio by visit and end of treatment by 25-
hydroxy vitamin D classifications: 24-hour urine HPA set. 
Table 3-23 Change in 24-hours urinary calcium:creatinine ratio from baseline to Week 4 and 
end of treatment by 25-hydroxy vitamin D classifications: 24-hour urine HPA set. 
Note: Calculate 95% CI of mean change from baseline to week 4 and end of treatment.  
Table 3-24 24-hours urinary calcium:creatinine ratio categorised as low, normal or high at 
Week 4 and end of treatment shown against baseline category by 25-hydroxy vitamin D 
classifications: 24-hour urine HPA set. 
Table 3-25 Calcium:creatinine ratio in spot urine by visit and end of treatment: spot urine non-
HPA set. 
Table 3-26 Change in calcium:creatinine ratio in spot urine from baseline to Week 4 and end 
of treatment: spot urine non-HPA set. 
Note: Calculate 95% CI of mean change from baseline to week 4 and end of treatment.  
Table 3-27 Calcium:creatinine ratio in spot urine categorised as low, normal or high at Week 4 
and end of treatment shown against baseline category: spot urine non-HPA set. 
Table 3-28 Calcium:creatinine ratio in spot urine by visit and end of treatment by 25-hydroxy 
vitamin D classifications: spot urine non-HPA set. 
Table 3-29 Change in calcium:creatinine ratio in spot urine from baseline to Week 4 and end 
of treatment by 25-hydroxy vitamin D classifications: spot urine non-HPA set. 
Note: Calculate 95% CI of mean change from baseline to week 4 and end of treatment.  
Table 3-30 Calcium:creatinine ratio in spot urine categorised as low, normal or high at Week 4 
and end of treatment shown against baseline category by 25-hydroxy vitamin D 
classifications: spot urine non-HPA set. 
Table 3-31 Haematology parameters by visit: safety analysis set 
Table 3-32 Change in haematology parameters from baseline to Week 4: safety analysis set 


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Table 3-33 Haematology parameters categorised as low, normal or high at Week 4 shown 
against baseline category: safety analysis set 
Table 3-34  Other biochemistry parameters by visit: safety analysis set 
Table 3-35 Change in other biochemistry parameters from baseline to Week 4: safety analysis 
set  
Table 3-36 Other biochemistry parameters categorised as low, normal or high at Week 4 
shown against baseline category: safety analysis set 
Table 3-37 Other 24-hour urinalysis parameters by visits: 24-hour urine HPA set. 
Table 3-38 Change in other 24-hour urinalysis parameters from baseline to Week 4: 24-hour 
urine HPA set. 
Table 3-39 Other 24-hour urinalysis parameters categorised as low, normal or high at Week 4 
shown against baseline category: 24-hour urine HPA set. 
Table 3-40 Other urinalysis parameters measured in spot urine by visits: spot urine non-HPA 
set. 
Table 3-41 Change in other urinalysis parameters measured in spot urine from baseline to 
Week 4: spot urine non-HPA set. 
Table 3-42 Other urinalysis parameters measured in spot urine categorised as low, normal or 
high at Week 4 shown against baseline category: spot urine non-HPA set. 
Table 3-43 Presence of urinary glucose and ketones at week 4 against presence at baseline: 
safety analysis set. 
Table 3-44 Duration and extent of exposure to IMP: safety analysis set 
Table 3-45 Amount of IMP used (g): safety analysis set and per protocol analysis set. 
Table 3-46 Average weekly amount of IMP used (g): safety analysis set and per protocol 
analysis set 
Table 3-47 Average weekly amount of IMP used in defined usage categories: safety analysis 
set and per protocol analysis set 


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Note: Make the table from baseline to week 4 and end of treatment. 
Table 3-48 Overall summary of adverse events: safety analysis set 
Table 3-49 Adverse events by MedDRA primary system organ class: safety analysis set 
Table 3-50 Adverse events by MedDRA primary system organ class and preferred term: safety 
analysis set 
Table 3-51 Severity of adverse events by MedDRA primary system organ class and preferred 
term: safety analysis set  
Table 3-52 Causal relationship of adverse events to IMP by MedDRA primary system organ 
class and preferred term: safety analysis set 
Table 3-53 Related adverse events by MedDRA primary system organ class and preferred 
term: safety analysis set 
Table 3-54 Severity of adverse drug reactions by MedDRA primary system organ class and 
preferred term: safety analysis set 
Table 3-55 Lesional/perilesional adverse events by MedDRA primary system organ class and 
preferred term: safety analysis set 
Table 3-56 Lesional/perilesional adverse events on the body by MedDRA primary system 
organ class and preferred term: safety analysis set 
Table 3-57 Lesional/perilesional adverse events on the scalp by MedDRA primary system 
organ class and preferred term: safety analysis set 
Table 3-58 Adverse events by age group, MedDRA primary system organ class and preferred 
term: safety analysis set 
Note: Only for subgroups. 
Table 3-59 Adverse events by sex,  MedDRA primary system organ class and preferred term: 
safety analysis set 
Table 3-60 Adverse events by race, MedDRA primary system organ class and preferred term: 
safety analysis set  


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Table 3-61 Adverse events by baseline PGA on the body, MedDRA primary system organ 
class and preferred term: safety analysis set 
Table 3-62 Adverse events by baseline PGA on the scalp, MedDRA primary system organ 
class and preferred term: safety analysis set 
Table 3-63 Adverse events by baseline total extent of body and scalp psoriasis, MedDRA 
primary system organ class and preferred term: safety analysis set 
Table 3-64 Adverse events by IMP usage, MedDRA primary system organ class and preferred 
term: safety analysis set 
Table 3-65 Local safety and tolerability by visit: safety analysis set 
Note: Both number and percentage of subjects in each of the four categories (‘Absent’ to 
‘Severe’). 
Table 3-66 Systolic blood pressure by visit: safety analysis set 
Table 3-67 Change in systolic blood pressure from baseline to each visit: safety analysis set 
Table 3-68 Diastolic blood pressure by visit: safety analysis set 
Table 3-69 Change in diastolic blood pressure from baseline to each visit: safety analysis set 
Table 3-70 Heart rate by visit: safety analysis set 
Table 3-71 Change in heart rate from baseline to each visit: safety analysis set 
Table 3-72 Temperature by visit: safety analysis set 
Table 3-73 Change in temperature rate from baseline to each visit: safety analysis set 
Figures 
Figure 3-1 Average weekly amount of IMP used over the total treatment period against 
change from baseline to Week 4 in albumin corrected serum calcium: safety analysis set. 
Figure 3-2 Average weekly amount of IMP used over the total treatment period against change 
from baseline to end of treatment in albumin corrected serum calcium: safety analysis set. 


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Figure 3-3 Average weekly amount of IMP used over the total treatment period against 
baseline extent of total BSA involvement: safety analysis set and per protocol analysis set. 
Patient Data Listings (Appendix 1) 
1-7: Subjects Receiving Investigational Product from Specific Batches 
Patient Data Listings (Appendix 2) 
Appendix 2.1: Discontinued Subjects 
Listing 1-1: Screening failures 
Listing 1-2: Reasons for withdrawal from trial 
 
Appendix 2.2: Protocol Deviations 
Listing 2-1: Protocol deviations 
Listing 2-2: Comments from CRF 
 
Appendix 2.3: Trial Analysis Sets 
Listing 3-1: Trial Analysis Sets 
Listing 3-2: Reasons for Exclusions from Analysis Sets 
 
Appendix 2.4: Demographic Data 
Listing 4-1: Demographics 
Listing 4-2: Duration of Psoriasis Vulgaris 
Listing 4-3: Actual Trial Period 
Listing 4-4: Medical History 


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Listing 4-5: Concomitant Diagnoses at Baseline 
Listing 4-6: Concomitant Medication 
 
Appendix 2.5: Compliance and/or Investigational Product Concentration Data  
Listing 5-1: Compliance 
Listing 5-2: Drug Accountability  
Listing 5-3: Exposure Dates 
 
Appendix 2.6: Efficacy Data 
Listing 6-1: Physician’s Global Assessment of Disease Severity  
Listing 6-2: Physician’s Assessment of Extent of Psoriasis 
Listing 6-3: Physician’s Assessment of Extent and Severity of Clinical Signs and PASI Score 
Listing 6-4: Subject’s Global Assessment of Disease Severity 
Listing 6-5: Subject’s Assessment of Itch 
Listing 6-6: Subject’s Assessment of Itch-Related Sleep Loss 
Listing 6-7: Children’s Dermatology Life Quality Index. 
Listing 6-8: The Family Dermatology Life Quality Index 
 
Appendix 2.7: Safety Data 
Listing 7-1 Deaths  
Listing 7-2 Serious Adverse Events  


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Listing 7-3 Subjects Withdrawn due to AE 
Listing 7-4 Severe Adverse Events 
Listing 7-5 Adverse Events 
Listing 7-6 Dietary Calcium Intake 
Listing 7-7 Albumin-Corrected Serum Calcium  
 
Appendix 2.8: Listing of Laboratory Values by Subject 
Listing 8-1 Physical Examination 
Listing 8-2: Laboratory Measurements 
Listing 8-3: Abnormal Laboratory Measurements 
Listing 8-4: ACTH Challenge Test 
Listing 8-5: Vital signs 
Listing 8-6 PK Measurements 
 
Additional Tables for Results Reporting in Clinical Trial Data Registries 
Table 4-1 Age group: subjects assigned to treatment 
Table 4-2 Non-serious AEs occurring in ≥[X]% subjects by MedDRA primary SOC and 
preferred term: safety analysis set 
[Note: X% is 5% or smaller percentage] 
 


Si g nat ure Pa ge f or T M F- 0 0 0 0 6 9 6 3 0 v 1. 0
Si g nat ure Pa ge f or T M F- 0 0 0 0 6 9 6 3 0 v 1. 0
Reas o n f or si g ni n g: A p pr o ve d
Ma na ge me nt / Lea d A p pr o ver Ver dict(s)
Na me:
Ca pacit y: Bi ostatistics
Date of si g nat ure: 1 2-J u n- 2 0 1 8 1 2: 1 4: 5 3
G M T + 0 0 0 0
Reas o n f or si g ni n g: A p pr o ve d
A p pr o ver Ver dict(s)
Na me:
Ca pacit y: Bi ostatistics
Date of si g nat ure: 1 2-J u n- 2 0 1 8 1 2: 1 8: 5 9
G M T + 0 0 0 0
Reas o n f or si g ni n g: A p pr o ve d
Ma na ge me nt / Lea d A p pr o ver Ver dict(s)
Na me: 
Ca pacit y: Me dical
Date of si g nat ure: 1 2-J u n- 2 0 1 8 1 3: 1 7: 1 6
G M T + 0 0 0 0
P P D
P P D
P P D