clinical study report leo 90100 compared to vehicle in...

This document has been downloaded from \V'.v-w.leo-pharma.com subject to the terms of use state on the website. It contains data and results regarding approved and non-approved uses, formulations or treatment regimens, and it is provided for transparency and informational purposes only. The content does not :reflect the complete results from all studies related to a product. As a document of scientific nature it is not to be seen as a recommendation or advic.e regarding the use of any products and you must always consult the specific prescribing information approved for the product prior to any prescription or use.

Clinical Study Report

LEO 90100 Compared to Vehicle in Subjects with Psoriasis Vulgaris

A phase 3 trial comparing once daily treatment with LEO 90100 calcipotriol 50 mcg/g plus betamethasone 0.5 mg/g (as dipropionate) with vehicle in subjects with psoriasis

vulgaris

A multi-centre, prospective, randomised, double-blinded, 2-arm, parallel group, 4-week trial in subjects with psoriasis vulgaris

LEO 90100 in PSOriasis vulgaris, a Fom weeks, vehicle controlled, efficacy And Safety Trial- the PSO-FAST trial

The clinical study report has been redacted using the following principles: \Vhere necessary, information is anonymise d to protect the privacy of study subjects and named persons a sse cia ted t-vith the trial a;, well as to retain commercial confidential information. Summary data are included but data on individual study subjects, including data listings, are removed. This rna y result in page numbers not being consecutively numbered. Access to anonymise d data on individualstudy subject rna y be o bt aine d up on approval of a research proposal by the Patient and Scientific Review Board. Appendices to the clinical study report are omitted. Further details and principles for anonymisationis availableinthe document LEOPH.tUUvl.A PRINCIPLES FOR JI.J.'jONThllSATION OF CLINICAL TRIAL DATA

LEO Pharma A/S

Clinical Development and Safety

00425289

LP0053-1001

04-Mar-2014

EudraCT Number: N/A

LP0053-1001 04-Mar-2014 of 315

Clinical Study Report Statement

Approval Statement, Sponsor

The following persons have approved this Clinical Study Report on behalf of

LEO Pharma A/S using electronic signatures:

Biostatistics and Data Management

Medical Department

Approval Statement, Investigator

The International co-ordinating investigator approves the Clinical Study Report by manually

signing the International Co-ordinating Investigator Clinical Study Report Approval Form,

which is a separate document adjoined to this report.

The following person has approved this Clinical Study Report:

, MD

International co-ordinating investigator

LP0053-1001 04-Mar-2014 of 315

Compliance with Good Clinical Practice

This Clinical Study Report is designed to comply with the standards issued by the

International Conference on Harmonisation (ICH) (E3 Structure and Content of Clinical

Study Reports and clarified in the ICH E3 Q&A document 07-Jun-2012; E6 Good Clinical

Practice; E9 Statistical Principles for Clinical Trials and M4 Common Technical Document)

(1,2,3,4,5).

Public Registration of the Clinical Trial

The trial was registered on www.Clinicaltrials.gov on 28-May-2013 under the identifier

NCT01866163.

Synopsis

The synopsis of this clinical study report exists as a separately approved document.

LP0053-1001 04-Mar-2014 of 315

Table of Contents

Clinical Study Report Statement ................................................................................................ 2

Compliance with Good Clinical Practice ................................................................................... 3

Synopsis ..................................................................................................................................... 3

Table of Contents ....................................................................................................................... 4

List of Tables (In-Text)............................................................................................................... 9

List of Figures (In-Text) ........................................................................................................... 11

List of Appendices.................................................................................................................... 12

List of Abbreviations and Definition of Terms ........................................................................ 14

1 Ethics ................................................................................................................................... 17

1.1 Independent Ethics Committee (IEC) or Institutional Review Board (IRB) .................. 17

1.2 Ethical Conduct of the Trial ............................................................................................ 17

1.3 Subject Information and Informed Consent .................................................................... 17

2 Investigators and Trial Administrative Structure................................................................. 19

3 Introduction ......................................................................................................................... 23

3.1 Psoriasis Vulgaris ............................................................................................................ 23

3.2 Investigational Product.................................................................................................... 23

3.3 Trial Rationale ................................................................................................................. 24

4 Trial Objectives ................................................................................................................... 25

4.1 Primary Objective............................................................................................................ 25

4.2 Secondary Objectives ...................................................................................................... 25

5 Investigational Plan ............................................................................................................. 26

5.1 Overall Trial Design ........................................................................................................ 26

5.1.1 Overview of the Trial .................................................................................................. 26

5.1.2 Trial Periods ................................................................................................................ 27

5.1.2.1 Washout/Screening Phase ........................................................................................ 27

5.1.2.2 Treatment Phase....................................................................................................... 27

5.1.2.3 Follow-up Phase ...................................................................................................... 28

5.2 Discussion of Trial Design, Including the Choice of Control Groups ............................ 29

5.3 Selection of Trial Population........................................................................................... 31

5.3.1 Inclusion Criteria ......................................................................................................... 31

5.3.2 Exclusion Criteria........................................................................................................ 32

LP0053-1001 04-Mar-2014 of 315

5.3.3 Removal of Subjects from Therapy or Assessment..................................................... 34

5.4 Treatments ....................................................................................................................... 35

5.4.1 Treatments Administered............................................................................................. 35

5.4.2 Investigational Products .............................................................................................. 36

5.4.3 Method of Assigning Subjects to Treatment Groups................................................... 37

5.4.4 Selection and Timing of Dose for each Subject .......................................................... 38

5.4.5 Blinding ....................................................................................................................... 38

5.4.6 Prior and Concomitant Therapy .................................................................................. 39

5.4.7 Treatment Compliance and Extent of Exposure.......................................................... 41

5.5 Assessments..................................................................................................................... 41

5.5.1 Frequency and Timing of Measurements .................................................................... 41

5.5.2 Baseline Characteristics and Demographics Assessed ................................................ 44

5.5.3 Efficacy Measurements Assessed................................................................................ 45

5.5.3.1 Investigator Assessments ......................................................................................... 45

5.5.3.2 Subject Assessments ................................................................................................ 49

5.5.3.3 Imaging Assessments............................................................................................... 50

5.5.4 Safety Measurements Assessed ................................................................................... 51

5.5.4.1 Local Safety and Tolerability................................................................................... 51

5.5.4.2 Laboratory Analysis................................................................................................. 52

5.5.4.3 Adverse Events ........................................................................................................ 53

5.5.4.4 Reporting of Adverse Events ................................................................................... 54

5.5.4.5 Other Events to be Reported.................................................................................... 57

5.5.4.6 Serious Adverse Events ........................................................................................... 57

5.5.4.7 Vital Signs................................................................................................................ 58

5.5.5 Appropriateness of Measurements .............................................................................. 58

5.6 Endpoints/Response Criteria ........................................................................................... 59

5.6.1 Efficacy Evaluation ..................................................................................................... 59

5.6.1.1 Primary Endpoint..................................................................................................... 59

5.6.1.2 Secondary Endpoints ............................................................................................... 59

5.6.1.3 Additional (Tertiary) Endpoints............................................................................... 59

5.6.2 Safety Evaluation ........................................................................................................ 60

5.6.3 Evaluation of Other Observations ............................................................................... 60

5.7 Data Quality and Assurance ............................................................................................ 61

5.8 Changes to the Conduct of the Trial ................................................................................ 62

6 Statistical Methods .............................................................................................................. 63

6.1 Determination of Sample Size......................................................................................... 63

6.2 Statistical and Analytical Plan......................................................................................... 63

LP0053-1001 04-Mar-2014 of 315

6.2.1 Summary ..................................................................................................................... 63

6.2.2 General Principles ....................................................................................................... 63

6.2.3 Subject Qualification for Analysis .............................................................................. 64

6.2.4 Reasons for Leaving the Trial ..................................................................................... 64

6.2.5 Demographics and Baseline Characteristics ............................................................... 64

6.2.6 Treatment Compliance and Extent of Exposure.......................................................... 65

6.2.7 Analysis of Efficacy .................................................................................................... 66

6.2.7.1 Primary Endpoint..................................................................................................... 66

6.2.7.2 Secondary Endpoints ............................................................................................... 67

6.2.7.3 Further (Tertiary) Endpoints .................................................................................... 68

6.2.7.3.1 Investigator’s Assessments................................................................................... 68

6.2.7.3.2 Subject’s Assessments .......................................................................................... 69

6.2.7.4 Handling of Drop-outs and Missing Values............................................................. 70

6.2.8 Analysis of Safety ....................................................................................................... 72

6.2.8.1 Adverse Events ........................................................................................................ 72

6.2.8.2 Laboratory Safety Examinations ............................................................................. 73

6.2.8.3 Vital Signs................................................................................................................ 74

6.2.8.4 Evaluation of Local Safety and Tolerability ............................................................ 74

6.3 Changes to the Statistical Analysis Plan.......................................................................... 74

6.4 Software and Dictionaries ............................................................................................... 74

7 Trial Population ................................................................................................................... 75

7.1 Disposition of Subjects.................................................................................................... 75

7.2 Protocol Deviations ......................................................................................................... 78

7.3 Trial Analysis Sets ........................................................................................................... 79

7.3.1 Full Analysis Set.......................................................................................................... 79

7.3.2 Safety Analysis Set ...................................................................................................... 79

7.3.3 Per Protocol Analysis Set ............................................................................................ 80

7.4 Demographic and other Baseline Characteristics............................................................ 81

7.4.1 Demographic Data....................................................................................................... 81

7.4.2 Disease-Related Baseline Characteristics.................................................................... 84

7.4.3 Medical History and Use of Concomitant Medication................................................ 87

8 Exposure and Treatment Compliance.................................................................................. 88

8.1 Exposure.......................................................................................................................... 88

8.2 Treatment Compliance .................................................................................................... 90

9 Efficacy Evaluation ............................................................................................................. 92

9.1 Primary Efficacy Endpoint .............................................................................................. 92

LP0053-1001 04-Mar-2014 of 315

9.2 Secondary Efficacy Endpoints ........................................................................................ 93

9.2.1 m-PASI at Week 4 and Week 1.................................................................................... 93

9.3 Further (Tertiary) Endpoints............................................................................................ 94

9.3.1 Investigator’s Assessments.......................................................................................... 94

9.3.1.1 Treatment Success over Time .................................................................................. 94

9.3.1.2 Investigator’s Global Assessment of Disease Severity............................................ 96

9.3.1.3 m-PASI over Time ................................................................................................... 98

9.3.1.4 PASI-50 and PASI-75 ............................................................................................ 101

9.3.1.5 Investigator’s Assessment of Severity of the Target Lesion .................................. 104

9.3.1.6 Change in BSA Involvement over Time................................................................ 104

9.3.2 Subject’s Assessments ............................................................................................... 105

9.3.2.1 Patient’s Global Assessment of Disease Severity.................................................. 105

9.3.2.2 Subject’s Assessment of Itch as Assessed by Use of a Visual Analogue Scale ..... 108

9.3.2.3 Subject’s Assessment of Itch-Related Sleep Loss by Use of a Visual Analogue Scale............................................................................................................................... 112

9.3.2.4 Change in DLQI over Time ................................................................................... 116

9.3.2.5 Change in EQ-5D-5L over Time ........................................................................... 118

9.4 Efficacy Conclusions..................................................................................................... 119

10 Safety Evaluation............................................................................................................... 122

10.1 Adverse Events.............................................................................................................. 122

10.1.1 Brief Summary of Adverse Events ............................................................................ 122

10.1.2 Incidence of Adverse Events ..................................................................................... 123

10.1.3 Adverse Events by Intensity...................................................................................... 128

10.1.4 Adverse Drug Reactions............................................................................................ 128

10.1.5 Adverse Events Leading to Withdrawal .................................................................... 129

10.2 Deaths, other Serious Adverse Events, and other Significant Adverse Events ............. 130

10.2.1 Narratives of Serious Adverse Events ....................................................................... 130

10.2.2 Lesional/Perilesional Adverse Events ....................................................................... 131

10.3 Other Safety Assessments ............................................................................................. 132

10.3.1 Local Safety and Tolerability .................................................................................... 132

10.4 Vital Signs ..................................................................................................................... 139

10.5 Clinical Laboratory Evaluation ..................................................................................... 139

10.5.1 Laboratory Values Over Time ................................................................................... 139

10.5.2 Individual Changes in Laboratory Values ................................................................. 140

10.5.3 Pregnancies................................................................................................................ 144

10.6 Safety Conclusions ........................................................................................................ 144

11 Discussion and Overall Conclusions ................................................................................. 145

LP0053-1001 04-Mar-2014 of 315

11.1 Discussion ..................................................................................................................... 145

11.2 Overall Conclusions ...................................................................................................... 147

12 References ......................................................................................................................... 148

End-of-Text Tables and Figures, Baseline Characteristics and Investigational Product

Data

End-of-Text Tables and Figures, Efficacy [and/or Other as Appropriate] Data

End-of-Text Tables and Figures, Safety Data

End-of-Text Listings

LP0053-1001 04-Mar-2014 of 315

List of Tables (In-Text)

Table 2–1 Investigators and Trial Administrative Structure ............................................. 20

Table 5–1 Identity of LEO 90100 ..................................................................................... 36

Table 5–2 Identity of Vehicle ............................................................................................ 37

Table 5–3 Schedule of Trial Procedures............................................................................ 42

Table 5–4 Fitzpatrick Skin Type ....................................................................................... 45

Table 5–5 Investigator’s Global Assessment of Disease Severity – 5-point Scale ........... 47

Table 5–6 Severity Score for Redness, Thickness, and Scaliness..................................... 48

Table 5–7 Patient’s Global Assessment of Disease Severity – 5-point Scale ................... 49

Table 5–8 Investigator Assessment of Skin Reaction Score ............................................. 52

Table 5–9 Subject Assessment of Skin Reaction Score .................................................... 52

Table 5–10 Serum Biochemistry and Urinalysis................................................................. 53

Table 7–1 Sex, Race, Ethnicity and Skin Type: Randomised Subjects............................. 83

Table 7–2 Duration of Psoriasis Vulgaris, BSA and Baseline m-PASI: Randomised Subjects ............................................................................................................ 85

Table 7–3 Baseline IGA: Randomised Subjects ............................................................... 85

Table 7–4 Other Locations of Psoriasis: Randomised Subjects........................................ 86

Table 7–5 Previous Psoriasis Treatments: Randomised Subjects ..................................... 87

Table 7–6 Target Lesion Location: Randomised Subjects ................................................ 87

Table 8–1 Duration and Extent of Exposure to Treatment: Safety Analysis Set .............. 88

Table 8–2 Average Weekly Amount of Trial Medication Used: Safety Analysis set........ 89

Table 8–3 Total Amount of Trial Medication Used: Safety Analysis Set ......................... 90

Table 8–4 Compliance with Treatment Instructions Over the Total Trial Period: Randomised Subjects ....................................................................................... 91

Table 9–1 Statistical Analysis of Treatment Success According to the IGA at Week 4 (Multiple Imputation): Full Analysis Set ......................................................... 92

Table 9–2 Statistical Analysis of Treatment Success According to the IGA at Week 4: Per Protocol Analysis Set ....................................................................................... 93

LP0053-1001 04-Mar-2014 of 315

Table 9–3 Statistical Analyses of m-PASI at Week 4 and Week 1 (Multiple Imputation): Full Analysis Set............................................................................................... 94

Table 9–4 Treatment Success According to the IGA by Visit (Observed Cases): Full Analysis Set...................................................................................................... 95

Table 9–5 IGA by Visit (Observed Cases): Full Analysis Set........................................... 97

Table 9–6 Treatment Success According to the IGA at Week 4 by Baseline Disease Severity (Observed Cases): Full Analysis Set.................................................. 98

Table 9–7 m-PASI by Visit (Observed Cases): Full Analysis Set..................................... 99

Table 9–8 Percentage Change in m-PASI by Visit (Observed Cases): Full Analysis Set101

Table 9–9 PASI-50 by Visit (Observed Cases): Full Analysis Set .................................. 102

Table 9–10 Statistical Analysis of PASI-50 at Week 4 (Multiple Imputation): Full Analysis Set................................................................................................................... 102

Table 9–11 PASI-75 by Visit (Observed Cases): Full Analysis Set .................................. 103

Table 9–12 Statistical Analysis of PASI-75 at Week 4 (Multiple Imputation): Full Analysis Set................................................................................................................... 104

Table 9–13 Patient's Global Assessment by Visit (Observed Cases): Full Analysis Set... 106

Table 9–14 Treatment Success According to Patient's Global Assessment by Visit (Observed cases): Full Analysis Set ............................................................... 107

Table 9–15 Statistical Analysis of Treatment Success According to Patient's Global Assessment at Week 4 (Observed Cases): Full Analysis Set ......................... 107

Table 9–16 Analysis of Change in Subject's Assessment of Itch (VAS) by Time Point (Observed Cases): Full Analysis Set .............................................................. 109

Table 9–17 Analysis of Change in Subject's Assessment of Itch (VAS) by Time Point (Observed Cases): Full Analysis Set (Continued).......................................... 110

Table 9–18 Analysis of Subjects Achieving a 70 Percent Reduction in Itch by Time Point (Observed Cases): Full Analysis Set .............................................................. 111

Table 9–19 Analysis of Change in Subject's Assessment of Itch-Related Sleep Loss (VAS) by Time Point (Observed Cases): Full Analysis Set ...................................... 113

Table 9–20 Analysis of Subjects Achieving a 70 Percent Reduction in Itch-Related Sleep Loss by Time Point (Observed Cases): Full Analysis Set.............................. 115

Table 9–21 Analysis of Change in DLQI by Visit (Observed Cases): Full Analysis Set . 117

LP0053-1001 04-Mar-2014 of 315

Table 10–1 Overall Summary of Adverse Events: Safety Analysis Set............................ 122

Table 10–2 Adverse Events by MedDRA primary SOC: Safety Analysis Set ................. 124

Table 10–3 Adverse Events by SOC and Preferred Term: Safety Analysis Set................ 125

Table 10–4 Adverse Drug Reactions by SOC and Preferred Term: Safety Analysis Set.. 129

Table 10–5 Lesional/Perilesional Adverse Events by SOC and Preferred Term: Safety Analysis Set.................................................................................................... 132

Table 10–6 Local Safety and Tolerability by Visit: Safety Analysis Set........................... 134

Table 10–7 Summary of Albumin-Corrected Serum Calcium and Change from Baseline: Safety Analysis Set......................................................................................... 139

Table 10–8 Summary of Urinary Calcium:Creatinine Ratio and Change from Baseline: Safety Analysis Set......................................................................................... 140

Table 10–9 Shift Table for Albumin-Corrected Serum Calcium: Safety Analysis Set ..... 142

Table 10–10 Shift Table for Albumin-Corrected Serum Calcium Based on LEO Defined Clinically Significant Values: Safety Analysis Set......................................... 142

Table 10–11 Shift Table for Urinary Calcium:Creatinine Ratio: Safety Analysis Set ........ 143

List of Figures (In-Text)

Figure 5–1 Trial design for LP0053-1001 .......................................................................... 26

Figure 7–1 Visit Attendance: All Enrolled Subjects ........................................................... 76

Figure 7–2 Visit Attendance by Treatment – LEO 90100 .................................................. 77

Figure 7–3 Visit Attendance by Treatment – Vehicle ......................................................... 78

Figure 7–4 Trial Analysis Sets by Treatment – LEO 90100............................................... 81

Figure 7–5 Trial Analysis Sets by Treatment – Vehicle...................................................... 81

Figure 9–1 Treatment Success (IGA) by Visit (Observed Cases): Full Analysis Set ......... 96

Figure 9–2 Mean m-PASI by Visit (Observed Cases): Full Analysis Set......................... 100

Figure 10–1 Local Safety and Tolerability – Safety Analysis Set ...................................... 138

LP0053-1001 04-Mar-2014 of 315

List of Appendices

Trial Information

Appendix No.

Appendix Title Status

1.1 Clinical Study Protocol and Amendments Enclosed

1.2 Sample CRF Enclosed

1.3 List of IEC or IRBs and Representative Written Information for the Subjects and Sample Consent Form

Enclosed

1.4 List of Investigators and CV for International Coordinating Investigator

Enclosed

1.5 Signatures of International Coordinating Investigator Enclosed

1.6 Listing of Subjects receiving Investigational Product from Specific Batches

Available upon request

1.7 Randomisation Scheme and Codes Enclosed

1.8 Audit Certificates Enclosed

1.9 Documentation of Statistical Methods Enclosed

1.10 Documentation of Laboratory Standardisation Methods and Quality Assurance Procedures

NA

1.11 Publications based on the Trial NA

1.12 Important Publications Referenced in the Clinical Study Report


LP0053-1001 04-Mar-2014 of 315

Listings

Appendix No Appendix Title Status

2.1 Discontinued Subjects Enclosed

2.2 Protocol Deviations Enclosed

2.3 Trial Analysis Sets Enclosed

2.4 Demographic Data Enclosed

2.5 Compliance and/or Investigational Product Concentration Data

Enclosed

2.6 Efficacy Data Enclosed

2.7 Safety Data Enclosed

2.8 Listing of Laboratory Values by Subject Enclosed

Case Report Forms

Appendix No Appendix Title Status

3.1 CRFs for Deaths, other SAEs, and Withdrawals due to AEs


3.2 Other CRFs Submitted NA

4.1 Individual Subject Data Listings

4.1.1 Photo Report Site US04 Enclosed












LP0053-1001 04-Mar-2014 of 315

List of Abbreviations and Definition of Terms

ADL Activities of daily life

ADR Adverse drug reaction

AE Adverse event

ANOVA Analysis of variance

BMI Body mass index

BSA Body surface area

CMO Contract Manufacturing Organisation

CRF Case report form

CRO Contract Research Organisation

eCRF Electronic case report form

DLQI Dermatology Life Quality Index

EQ-5D-5L A standardised measure of health status developed by EuroQol Group

FDA Food and Drug Administration

GCP Good Clinical Practice

ICH International Conference on Harmonisation

ICTM International clinical trial manager

IEC Independent ethics committee

IGA Investigator’s Global Assessment of disease severity

IP Investigational product

IRB Institutional review board

IWRS Interactive Web Response System

LOCF Last observation carried forward

MAR Missing at random

MCMC Markov Chain Monte Carlo

MedDRA Medical Dictionary for Regulatory Activities

m-PASI Modified Psoriasis Area and Severity Index

NLCRA National lead clinical research associate

PaGA Patient’s Global Assessment of Disease Severity

PASI-50 A 50% reduction in the Psoriasis Area and Severity Index

PASI-75 A 75% reduction in the Psoriasis Area and Severity Index

PASI Psoriasis Area and Severity Index

PUVA Psoralen combined with Ultraviolet A

SAE Serious adverse event

SD Standard deviation

LP0053-1001 04-Mar-2014 of 315

SAPU Statistical analysis plan update

SOC System organ class

SOP Standard Operating Procedure

UVB Ultraviolet B

VAS Visual Analogue Scale

WHO World Health Organisation

DEFINITION OF TERMS

Terms defined by ICH Guidelines are not mentioned here.

Assessment

A (cluster of) characteristic(s) measured and/or recorded for a subject.

Concomitant Medication

Any medication used by a subject during the clinical trial apart from the trial medication.

DAIVOBET®/DOVOBET®/TACLONEX® Ointment

Referred to as Daivobet® ointment.

Enrolled Subject

A subject for whom informed consent has been obtained and who has been registered in a

clinical trial.

International Clinical Trial Manager (ICTM)

The qualified person appointed by LEO to be the main international sponsor representative

responsible for all aspects of a clinical trial as outlined in Global Clinical Operations Standard

Operational Procedures (SOPs).

LEO

LEO (no suffix): refers to the corporate organisation of LEO Pharma A/S.

Monitor

A person appointed by LEO to carry out monitoring of a clinical trial.

National Lead Clinical Research Associate (NLCRA)

LP0053-1001 04-Mar-2014 of 315

The person appointed to be the national sponsor representative responsible for all aspects of a

clinical trial within a country as outlined in Global Clinical Operations SOPs.

Randomisation Code List

A list of (sequential) numbers to each of which a treatment is allocated (assigned). Treatment

may be revealed as a code letter (e.g. A, B, …) or by directly revealing the specific treatment

(investigational product).

Endpoint

An assessment or a transformation of the assessment(s) described on a subject level, for

which a statistical analysis is performed, i.e. a p-value or a confidence interval is stated, or for

which tabulation serves as important supportive evidence of efficacy/safety.

LP0053-1001 04-Mar-2014 of 315

1 Ethics

1.1 Independent Ethics Committee (IEC) or Institutional Review Board

(IRB)

The clinical study protocol and any relevant amendments to the clinical study protocol were

approved by the relevant Institutional Review Boards (IRBs).

The appropriate regulatory authority was notified of/approved the clinical trial, as required.

A list of all IRBs consulted is given in Appendix 1.3.

1.2 Ethical Conduct of the Trial

This clinical trial conformed to the principles of the Declaration of Helsinki as adopted by the

18th World Medical Association, General Assembly, June 1964 and subsequent amendments.

The clinical trial was conducted in compliance with the principles of Good Clinical Practice

(GCP). The trial was conducted in accordance with applicable national regulatory

requirements and under a US Investigational New Drug (IND) Application.

All subjects received written and verbal information concerning the clinical trial as specified

in Section 1.3.

Subjects were asked to consent that their personal data were recorded, collected, processed

and could be transferred to EU and non-EU countries in accordance with any national

legislation regulating privacy and data protection.

All information containing personal data was to be handled in accordance with the general

terms of the authorisation granted by the Danish Data Protection Agency to LEO Pharma A/S

(hereafter referred to as LEO), as appended to the clinical study protocol, in accordance with

the EU Data protection Directive (95/46/EC) as well as any national data protection

legislation.

1.3 Subject Information and Informed Consent

All subjects received written and verbal information concerning the clinical trial. This

information emphasised that participation in the clinical trial was voluntary and that the

subject could withdraw from the clinical trial at any time and for any reason. All subjects

were given an opportunity to ask questions and were given sufficient time to consider all

relevant issues before consenting.

LP0053-1001 04-Mar-2014 of 315

The subject’s signed and dated informed consent to participate in the clinical trial was

obtained prior to any trial-related activities being carried out. An additional signed and dated

informed consent was obtained for those subjects who had clinical photographs taken (Section

5.5.3.3) prior to any trial-related activities being carried out.

A representative subject information sheet and informed consent form is provided in

Appendix 1.3.

LP0053-1001 04-Mar-2014 of 315

2 Investigators and Trial Administrative Structure

LEO was the sponsor of the clinical trial and participating LEO affiliates were authorised by

the sponsor to act on behalf of the sponsor in the countries where the clinical trial was

conducted.

LP0053-1001 04-Mar-2014 of315

Table 2-1

Role

Investigators and Trial Administrative Structure

Name, Title, Affiliation

futemational co-ordinating investigator:

Head of Medical Department

Head of Biostatistics:

Trial statistician:

futemational clinical trial manager (ICTM):

National Lead CRA (NLCRA):

Sponsor 's medical expe1i:

Contract Research Organisation (CRO):

, MD, Central De1matology, 1034 S.

- ,MSc LEOPhanna Denmruk Tel. : email:

-MD, ~en 5 . , e-mail:

Suite 600, St. . MO 63117, USA, Fax:

Medical Depruiment, LEO DK-2750 Ballemp, Denmark,

Biostatistics and Data Management, 1pru·ken 55 DK-2750 Ballemp,

Fax:

LEO Phruma A/S, Tel. :-

, LEO Phanna :-LEO Phruma

'-'llll.IL<UA' Tel.: II

LEO PhannaA/S, k,Tel. :-

The CRO was responsible for project management, clinical conduct, monitoring, data management, and randomisation code list production.

LP0053-1001

Emergency un-blinding CRO

Clinical Trial Supply:

04-Mar-2014 of315

The CRO designated the following subcontracted vendors for the conduct of this u·ial:

eCRF&IWRS DSG Inc., Great Valley Cmporate Cenu·e, 325 Technology Drive, Malvem, PA, 19355, USA The CRO was responsible for the creation, implementation and maintenance of the elecu·onic case repmi fmm ( eCRF) and the Interactive Web Response System (IWRS) used for cenu·alised randomisation and kit assignment to subjects.

Central Laboratories ACM Global Cenu·al Laboratmy, 160 Elmgt·ove Park, Rochester, NY 14624, USA The CRO was responsible for cenu·allaboratmy analysis

Clinical Photography Canfield Scientific Inc. , 253 Passaic Avenue, Fairfield, NJ, 07004, USA The CRO was responsible for services relating to clinical imaging as perfonned at designated sites

C3i Europe Inc., Business Park Sofia, Mladost 4, Bldg. 7 Fl. 1, 1766 Sofia, Bulgaria. The CRO was responsible for providing emergency lm-blinding suppmi and services as agt·eed to in a Service Agreement/Conu·act

LEO Phruma el.: -

LEO Phanna A/S u·ansfened ce1iain responsibilities and services related to clinical u·ial supply (primruy and secondruy packaging) to Conu·act Manufacturing Organisations (CMOs) as relevant for the conduct of the clinical u·ial.

The CMO was responsible for all services related to the prima1y packaging (including dissolution of investigational product into propellants and filling of cans) .

LP0053-1001

Phrumacovigilance Scientist, Global Phrumacovigilance:

Medical writer:

04-Mar-2014 of315

The CMO was responsible for the seconda!y packaging, labelling and disu·ibution of u·ial medication, and also the receipt, accountability, weighing, reconciliation and destruction of retumed u·ial medication.

-PhD,- , Medical Deprutment, LEO ~usu·ip~750 TeL:

The cmTiculum vita.e of the intemational coordinating investigator and a list of other persons

whose pruiicipation materially affected the conduct of the u·ial are included in Appendix 1.4.

LP0053-1001 04-Mar-2014 of 315

3 Introduction

The trial was performed as a phase 3 clinical trial of LEO 90100 aerosol foam (hereafter

referred to as LEO 90100), a fixed combination product containing calcipotriol plus

betamethasone dipropionate in an aerosol foam formulation, in adult subjects with psoriasis

vulgaris. The trial was conducted in accordance with applicable US regulatory requirements

and under an US IND Application.

3.1 Psoriasis Vulgaris

Psoriasis is one of the most common chronic skin diseases with predominantly skin and joint

manifestations affecting approximately 1–3% of the population (6,7,8). The major

manifestation of psoriasis vulgaris (also known as plaque psoriasis) is chronic inflammation

of the skin, characterised by sharply demarcated, scaling, and erythematous plaques that may

be painful and often severely pruritic. In order to reduce the risk of systemic toxicity, topical

therapy is the regimen of choice for subjects with less extensive disease which comprises two

thirds of all subjects with psoriasis (9). The most commonly used topical treatments are

corticosteroids and vitamin D analogues which can be used alone or in combination.

However, application of topical therapies can be cumbersome, messy and time-consuming,

which can have a negative impact on adherence to the prescribed treatment regimen and

ultimately result in poor control of the disease. Thus there is an ongoing need for development

of topical psoriasis treatments that, in addition to being highly efficacious, are also convenient

and easy to use, which could reduce the burden of daily treatment and improve adherence to

therapy.

3.2 Investigational Product

LEO 90100 is an aerosol formulation of calcipotriol 50 mcg/g (as hydrate) and betamethasone

0.5 mg/g (as diproprionate) currently under development for the topical treatment of psoriasis

vulgaris. LEO 90100 is packed in an aluminum can with dimethyl ether and butane

propellants. At administration, the majority of propellants (butane and dimethyl ether)

evaporate quickly leaving a foam with propellant residues on the skin. Apart from the

propellants, no new excipients have been added to LEO 90100 as compared to the marketed

formulation of the investigational product, DAIVOBET®/DOVOBET®/TACLONEX®

ointment (hereafter referred to as Daivobet® ointment).

LEO 90100 has been developed with the purpose of improving the convenience and ease of

use of the product for patients with psoriasis vulgaris. It may be a more cosmetically accept-

able alternative to Daivobet® ointment, which contains the same active ingredients in the

same concentration.

LP0053-1001 04-Mar-2014 of 315

The efficacy and safety of LEO 90100 were evaluated in two phase 2 trials including a total of

678 subjects with psoriasis vulgaris; a proof-of-concept trial comparing LEO 90100 to each of

its active components in the same aerosol foam vehicle (hereafter referred to as vehicle) (18)

and a comparator trial with Daivobet® ointment (19). The proof-of-concept trial showed that

the efficacy of LEO 90100 applied once daily for 4 weeks was superior to that of each active

component used alone in the same vehicle in the treatment of psoriasis vulgaris on the trunk

and limbs. In the comparator trial, LEO 90100 was shown to be more effective than

Daivobet® ointment in the treatment of psoriasis vulgaris on the body over 4 weeks. Overall,

LEO90100 appeared to be well tolerated with a safety profile comparable to that of Daivobet®

ointment.

3.3 Trial Rationale

Daivobet® ointment has proven highly effective in the treatment of psoriasis vulgaris on trunk

and limbs with an improved benefit/safety profile compared with each active component used

as monotherapy. The hypothesis that the same constituents (calcipotriol plus betamethasone

dipropionate) combined in an aerosol delivery system would also be effective in the treatment

of psoriasis vulgaris was supported by the results of an exploratory clinical trial (modified

psoriasis plaque test), in which LEO 90100 showed better anti-psoriatic effect than Daivobet®

ointment and betamethasone dipropionate in the LEO 90100 vehicle. The hypothesis was also

supported by the results of 2 completed phase 2 trials (see Section 3.2) that demonstrated that

LEO 90100 is a highly effective and well tolerated treatment for psoriasis vulgaris on trunk

and limbs and that both active components make a contribution to the overall anti-psoriatic

effect of LEO 90100, in accordance with the US Food and Drug Administration (FDA)

regulation regarding the development of fixed-combination prescription drugs for use in

humans (21 CFR 300.50).

The purpose of this phase 3 trial was to confirm the safety and efficacy of LEO 90100 in the

treatment of subjects with psoriasis vulgaris on the trunk and limbs in a larger, vehicle-

controlled trial.

LP0053-1001 04-Mar-2014 of 315

4 Trial Objectives

4.1 Primary Objective

To compare the efficacy of treatment with LEO 90100 to that of treatment with vehicle for

up to 4 weeks in subjects with psoriasis vulgaris.

4.2 Secondary Objectives

To compare the safety of treatment with LEO 90100 to that of treatment with vehicle for

up to 4 weeks in subjects with psoriasis vulgaris.

LP0053-1001

5 Investigational Plan

5.1 Overall Trial Design

5.1.1 Overview of the Trial

04-Mar-2014 of315

Trial LP0053-1001 was a multi-centre, prospective, randomised, double-blinded, 2-ann ,

parallel group trial comparing the efficacy and safety of treatment with LEO 90100 to that of

treatment with vehicle in subjects with psoriasis vulgaris.

It was planned to randomise approximately 400 subjects in a 3: 1 ratio to receive up to 4

weeks ' treatment once daily with either LEO 90100 (300 subjects) or vehicle (100 subjects)

on psoriasis lesions on the tmnk and/or limbs. The randomisation of subjects was su·atified by

site.

The u·ial design is presented in Figme 5-1 .

Figure 5-1

lnf01med

consent

Trial design for LP0053-1001

Randomisation

Washout 1 Treatment Follow-uo ..._ _____ ____.,+-----------.....- -------·

Day -28

Visit SV

Treatment:

0

1

7

2

LEO 90100

vehicle

14

3

28

4

+14

FU

LP0053-1001 04-Mar-2014 of 315

5.1.2 Trial Periods

The trial consisted of a wash-out/screening period for up to 4 weeks (28 days) for withdrawal

of pre-trial medication, a 4-week treatment period (Visits 1 to 4) and, if required, a 2-week

safety follow-up period.

5.1.2.1 Washout/Screening Phase

Prior to participating in any trial procedure, a signed informed consent was obtained from the

subject.

Prior to randomisation, the subject entered a washout phase (if required) where anti-psoriatic

treatment and other relevant medication/treatments were discontinued as defined by the

exclusion criteria (see Section 5.3.2). The wash-out/screening phase could last for up to 4

weeks, depending on which disallowed treatments the subject received (see Section 5.4.6).

However, if no washout was needed the subject could enter Visit 1 directly.

5.1.2.2 Treatment Phase

The treatment phase was scheduled to be 4 weeks. There were 4 visits: Visit 1 (Week 0,

randomisation, baseline), Visit 2 (Week 1), Visit 3 (Week 2) and Visit 4 (Week 4).

Visits 2 to 4 were to be performed within ±2 days of the scheduled time relative to Visit 1; if

the visit was performed outside of the visit window, the (sub)investigator recorded the reason

in the subject’s medical record.

Subjects were assessed at all treatment visits, i.e., at baseline and after 1, 2, and 4 weeks of

treatment. Efficacy assessments included the Investigator’s Global Assessment of disease

severity (IGA) and the modified Psoriasis Area and Severity Index (m-PASI) (see Section

5.5.3.1 for details). For the IGA, the (sub)investigator made a global assessment of the disease

severity of the psoriasis vulgaris on the trunk and limbs, which represented the average lesion

severity on the trunk and limbs. The assessment was based on the condition of the disease at

the time of evaluation, and not in relation to the condition at a previous visit. For the m-PASI,

the (sub)investigator assessed the extent and severity of the three clinical signs (redness,

thickness, and scaliness) on the arms, trunk and legs.

At Visit 1, the (sub)investigator selected a target lesion. The target lesion was to be a

minimum of 5 cm at its longest axis and preferably not located on the extensor surface of an

elbow or knee. At Visits 1 to 4, the (sub)investigator assessed the severity of the target lesion

for each clinical sign (redness, thickness, scaliness) according to the same scale as the m-

PASI.

LP0053-1001 04-Mar-2014 of 315

The subject’s assessments included global assessment of disease severity and assessments of

itching, itch-related sleep loss and quality of life. Clinical photographs of the full body

(excluding the head) and the selected target lesion on the trunk or limbs were taken in a subset

of subjects as supportive data to clinical assessments and eligibility criteria.

Subjects classified as ‘clear’ according to the IGA on the trunk and limbs at either Visit 2 or

Visit 3 were allowed to stop treatment at the (sub)investigator’s discretion. Should such occur,

the subject was to remain in the trial and attend all scheduled visits. If the psoriasis

reappeared on the treatment areas, the subject was to reinitiate treatment without consulting

the (sub)investigator. More than one discontinuation/restart cycle was allowed.

Safety assessments included recordings of vital signs, adverse events (AEs), and local safety

and tolerability assessments. In addition, blood and spot urine samples were taken for

evaluation of albumin-corrected serum calcium level and calcium:creatinine ratio,

respectively.

Subjects were provided with a diary at Visits 1 to 3 to record adherence to the once daily

treatment regimen during the visit interval. The diary was to be returned to the site staff at the

subsequent trial visit.

Additionally, the diary provided at Visit 1 included subject’s assessment of itch and itch-

related sleep loss by use of a Visual Analogue Scale (VAS). The 2 VAS were to be completed

by the subject on Days 3 and 5.

5.1.2.3 Follow-up Phase

A follow-up visit/contact was to be conducted 14 (±2) days after the last on-treatment visit,

unless the final outcome of the event had been determined before then.

A follow-up visit/contact would take place only if:

There was an on-going (serious or non-serious) AE at the last on-treatment visit which

was classified as possibly or probably related or not assessable in relation to the

investigational products.

The albumin-corrected serum calcium was above the reference range at the last on-

treatment visit

Any laboratory parameter was abnormal and judged as clinically significant by the

(sub)investigator at the last on treatment visit

LP0053-1001 04-Mar-2014 of 315

Where the (sub)investigator considered it appropriate, the follow-up visit was performed as a

telephone contact.

5.2 Discussion of Trial Design, Including the Choice of Control Groups

The consolidated clinical study protocol and erratum sheet are included in Appendix 1.1 and

the unique pages of the case report form (CRF) are enclosed in Appendix 1.2.

Trial Design

The trial was a multi-centre, prospective, randomised, double-blinded, 2-arm, parallel group

trial. This design is the established standard for comparison of safety and efficacy and is

intended to minimise any potential bias that could compromise the conduct and outcome of

the trial.

Subjects

The inclusion/exclusion criteria were designed to select a population that was representative

of the target population; i.e., subjects of all disease severities (‘mild’ to ‘severe’ according to

the IGA) amenable to topical therapy. The eligibility criteria prevented confounding issues

with diagnosis and eliminated any possible effect of concurrent diseases or concomitant

medications on clinical assessment.

Randomisation was stratified by investigational site to ensure a 3:1 ratio between treatment

groups. To ensure the independence of each of the clinical trials in this clinical development

programme, subjects enrolled in this clinical trial had not participated in the phase 2 trials.

Treatment Duration

The treatment duration of 4 weeks was considered appropriate to obtain sufficient data on the

efficacy and safety of the evaluated investigational product. A treatment duration of 4 weeks

was shown to be safe and effective in previous studies of Daivobet® ointment (8,11,12,13) as

well as in the completed phase 2 trials with LEO 90100 (18,19).

Dosing Regimen

A once daily treatment regimen was chosen as this was considered more convenient for the

subject than a twice daily treatment and was shown to be effective in previous trials of

ointment and topical suspension/gel, as well as in the phase 2 trials with LEO 90100. It

decreases drug exposure and time spent on application and is thus expected to enhance subject

compliance. The maximum weekly allowance of investigational product was 90 g and was

within the 100 g limit used for the ointment.

LP0053-1001 04-Mar-2014 of 315

Approximately 100 subjects were planned to receive a treatment for their psoriasis with no

active ingredients for 4 weeks. Given the short duration of treatment, this was considered

ethically justified.

Endpoints

The IGA was chosen as the primary efficacy assessment. The IGA is a static skin disease

severity scoring- system, consisting of a five point scale from ‘clear’ to’ severe’.

The primary endpoint was subjects with ‘treatment success’ according to the IGA of trunk and

limbs at Week 4. ‘Treatment success’ was defined as ‘clear’ or ‘almost clear’ for subjects with

at least moderate disease at baseline, and ‘clear’ for subjects with mild disease at baseline.

The percentage of subjects who achieved ‘treatment success’ was regarded as the best

evidence of efficacy (20). Comparison of the percentage of subjects with ‘controlled disease’

between the treatment arms reflects the difference in the effect of the treatments. To facilitate

standardisation of assessments and to minimise inter-rater variability, the IGA scale includes a

detailed description of the morphological characteristics for each severity category, thus

assisting the investigator in evaluation.

The Psoriasis Area and Severity Index (PASI), used as a secondary endpoint, is a well

established assessment that has been used in all previous studies of psoriasis conducted by

LEO. The PASI was included to enable comparison of results across several studies and also

to assess the development of response to treatment over time. This trial used a modified PASI

(m-PASI), calculated as described in Section 5.6.1.2.

Because of the potential effect of the vitamin D analogue containing investigational product

on calcium metabolism and homeostasis, safety analysis of parameters of calcium metabolism

was made following sampling of venous blood and urine collected on Day 0 and Week 4 (or

the last on-treatment visit as applicable).

Local safety and tolerability was evaluated by scoring of application site skin reactions.

Clinical signs and symptoms were assessed on a 4-point scale (from absent to severe) on the

perilesional area and the lesional/perilesional area.

To support clinical decision-making when treating subjects with psoriasis, an evaluation of

quality of life was included in this trial by means of the generic EQ-5D-5L questionnaire,

which is a standardised instrument for use as a measure of health outcome and also the

Dermatology Life Quality Index (DLQI) which is a validated dermatology specific

questionnaire measuring specific factors influencing the quality of life for subjects with skin

disease.

LP0053-1001 04-Mar-2014 of 315

A common symptom in subjects with psoriasis is itch, which adversely affects quality of life.

For instance, itch may interfere with sleep quality by increasing nocturnal awakenings and

sleep fragmentation. In this trial the subjects were asked to assess both the intensity of itch

and how it affected sleep by use of a VAS. A special focus was on potential early relief of itch

and sleep impairment. Therefore, in addition to completing the assessments at each visit, the

subjects recorded the VAS scores in a subject diary on Day 3 and Day 5.

Concomitant Treatments

During the course of the trial, subjects were not allowed to use any concomitant treatments

that might have had a possible effect on psoriasis vulgaris on the treatment area (trunk and/or

limbs). This included various systemic treatments (e.g. systemic corticosteroids, retinoids,

methotrexate, ciclosporin and other immunosuppressants and biological therapies).

Use of any drug except the investigational product for the treatment of psoriasis vulgaris was

not allowed except for some topical treatments on the face, skin folds, and scalp (see Section

5.4.6).

Prior to randomisation, a washout period was to be completed if the subject was treated, or

had recently been treated with anti-psoriatic treatments or other relevant medication that could

influence the outcome of the trial.

5.3 Selection of Trial Population

The trial population was chosen to include subjects ≥18 years of age with psoriasis vulgaris

on the trunk and/or limbs of at least mild severity according to the IGA and amenable to

topical therapy with up to 90 g of trial medication per week.

5.3.1 Inclusion Criteria

To be included in the trial subjects had to fulfil all of the following criteria:

1. Signed and dated informed consent obtained prior to any trial related activities

(including washout period)

2. Age 18 years or above

3. Either sex

4. Any race or ethnicity

5. All skin types

6. Attending a hospital outpatient clinic or the private practice of a board certified

dermatologist

LP0053-1001 04-Mar-2014 of 315

7. A clinical diagnosis of psoriasis vulgaris of at least 6 months duration involving the

trunk and/or limbs amenable to treatment with a maximum of 90 g of trial medication

per week

8. Psoriasis vulgaris on the trunk and/or limbs (excluding psoriasis on the genitals and

skin folds) involving 2-30% of the body surface area (BSA)

9. An Investigator’s Global Assessment of disease severity (IGA) of at least mild on trunk

and/or limbs on Day 0 (Visit 1)

10. A modified PASI (m-PASI) score of at least 2 on the trunk and/or limbs on Day 0 (Visit

1)

11. A target lesion of a minimum of 5 cm at its longest axis and preferably not located on

the extensor surface on an elbow or knee, scoring at least 1 for each of redness,

thickness and scaliness, and at least 4 in total by the Investigator’s assessment of

severity of the target lesion

12. Females of childbearing potential must have had a negative pregnancy test ont Day 0

(Visit 1)

13. Females of childbearing potential must have agreed to use a highly effective method of

birth control during the trial*

14. Able to communicate with the investigator and understand and comply with the

requirements of the trial

*A highly effective method of birth control was defined as one which results in a low failure

rate (less than 1% per year) such as implants, injectables, combined oral contraceptives, some

intra-uterine devices, sexual abstinence or vasectomised partner. The subjects were to have

used the contraceptive method continuously for at least 1 month prior to the pregnancy test,

and must have continued using the contraceptive method for at least 1 week after the last

application of trial medication. A female was defined as not of child-bearing potential if she

was postmenopausal (12 months with no menses without an alternative medical cause), or

surgically sterile (tubal ligation/section, hysterectomy, or bilateral ovariectomy).

5.3.2 Exclusion Criteria

Any of the following was regarded as a criterion for exclusion from the trial:

1. Systemic treatment with biological therapies, whether marketed or not, with a possible

effect on psoriasis vulgaris within the following time periods prior to randomisation:

Etanercept – within 4 weeks prior to randomisation

LP0053-1001 04-Mar-2014 of 315

Adalimumab, infliximab – within 8 weeks prior to randomisation

Ustekinumab – within 16 weeks prior to randomisation

Other products – within 4 weeks/5 half-lives prior to randomisation

(whichever was longer)

2. Systemic treatment with all other therapies with a possible effect on psoriasis vulgaris

(e.g., corticosteroids, retinoids, methotrexate, ciclosporin and other

immunosuppressants) within 4 weeks prior to randomisation

3. Subjects who received treatment with any non-marketed drug substance (i.e. a drug

which had not yet been made available for clinical use following registration) within 4

weeks/5 half-lives (whichever was longer) prior to randomisation

4. Psoralen combined with Ultraviolet A (PUVA) therapy within 4 weeks prior to

randomisation

5. Ultraviolet B (UVB) therapy within 2 weeks prior to randomisation

6. Topical anti-psoriatic treatment on the trunk and limbs (except for emollients) within 2

weeks prior to randomisation

7. Topical treatment on the face, scalp and skin folds with corticosteroids, vitamin D

analogues or prescription shampoos within 2 weeks prior to randomisation

8. Planned excessive exposure of area(s) to be treated with trial medication to either

natural or artificial sunlight (including tanning booths, sun lamps etc.) during the trial

9. Planned initiation of, or changes to, concomitant medication that could affect psoriasis

vulgaris (e.g. beta blockers, antimalarial drugs, lithium, angiotensin converting enzyme

inhibitors) during the trial

10. Current diagnosis of guttate, erythrodermic, exfoliative or pustular psoriasis

11. Subjects with any of the following conditions present on the treatment area: viral (e.g.

herpes or varicella) lesions of the skin, fungal and bacterial skin infections, parasitic in-

fections, skin manifestations in relation to syphilis or tuberculosis, acne vulgaris,

atrophic skin, striae atrophicae, fragility of skin veins, ichtyosis, ulcers and wounds

12. Other inflammatory skin disorders (e.g. seborrhoeic dermatitis or contact dermatitis) on

the treatment area that may have confounded the evaluation of psoriasis

13. Known or suspected disorders of calcium metabolism associated with hypercalcaemia

14. Known or suspected severe renal insufficiency or severe hepatic disorders

15. Known or suspected hypersensitivity to component(s) of the investigational products

LP0053-1001 04-Mar-2014 of 315

16. Current participation in any other interventional clinical trial

17. Previously randomised in this trial or any previously conducted trial of LEO 90100

18. Females who were pregnant, wished to become pregnant during the trial or were

breast-feeding

5.3.3 Removal of Subjects from Therapy or Assessment

Subjects could have been withdrawn for any of the following reasons:

1. Unacceptable treatment efficacy: the investigator was free to withdraw the subject at

any time for medical reasons

2. Unacceptable AEs: any AE that the investigator or the subject considered unacceptable

3. Exclusion criteria: any exclusion criteria which emerged/became apparent during the

subject’s participation in the clinical trial

4. Voluntary withdrawal: subjects were free to withdraw from the clinical trial at any time

and for any reason

5. Other reasons: other reasons than stated above which required the subject to (be)

withdraw(n) were to be specified

Subjects who were discovered, after enrolment/randomisation, not to have fulfilled all in-

/exclusion criteria at time of enrolment, were to continue treatment unless the investigator,

based on clinical and ethical evaluation, found continuation inappropriate. The final efficacy

assessment (at the correct scheduled time) should have been attempted to be completed for all

subjects. Such deviation(s) from the consolidated clinical study protocol had to be reported to

LEO (and IRBs) and recorded in the clinical study report.

Subjects that experienced an AE which required the discontinuation of treatment were to

remain in the trial and assessed at all subsequent trial visits according to the trial schedule.

The subject was to continue to be evaluated until the AE resolved or the aetiology was

identified and the AE stabilised.

Subjects who withdrew from treatment for any other reasons had to remain in the trial and at

minimum, be asked to complete the final efficacy assessment (at the correct scheduled time).

In addition, subjects had to be withdrawn from treatment in case of an AE that was judged to

be possibly or probably related to treatment by the investigator and was of Grade 3 or 4

according to the general guideline in the US National Cancer Institute Common Terminology

Criteria for Adverse Events, i.e. one of the following:

LP0053-1001 04-Mar-2014 of 315

Was severe or medically significant but not immediately life-threatening

Had life-threatening consequences

Required hospitalisation or prolongation of hospitalisation

Required urgent intervention

Was disabling

Limited self-care activities of daily life (ADL)

Note: Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet,

taking medications, and not bed ridden.

Reason(s) for withdrawal from trial had to be recorded in the CRF.

Withdrawn subjects were not replaced.

5.4 Treatments

5.4.1 Treatments Administered

Subjects who fulfilled all inclusion and exclusion criteria were randomised in a 3:1 ratio to

receive one of the following treatments:

LEO 90100 aerosol foam, containing calcipotriol 50 mcg/g plus betamethasone 0.5 mg/g

(as dipropionate) (LEO 90100)

Aerosol foam vehicle (vehicle)

On Day 0 (Visit 1) subjects were given a treatment instruction sheet and received verbal

instruction on how to apply the investigational product. The first application of the

investigational product was made under the supervision and instruction of the trial staff. The

investigational product was applied to psoriasis vulgaris affected areas on the trunk, arms, and

legs once daily for 4 weeks. Subjects were instructed not to apply the investigational product

on psoriasis vulgaris on the face, scalp, genitals, or skin folds. Skin folds included the axillae,

the inguinal folds, the intergluteal folds, and the inframammary folds. There was no specific

requirement with regard to the time of day for application.

Subjects classified as ‘clear’ according to the IGA on the trunk and limbs at either Visit 2 or

Visit 3 were allowed to stop treatment at the (sub)investigator’s discretion. If this occurred,

investigational product was still dispensed and the subject was to remain in the trial and

attend all scheduled visits. If the psoriasis vulgaris reappeared on the treatment areas, the

LP0053-1001 04-Mar-2014 of315

subject was to reinitiate treatment without consulting the (sub )investigator. More than one

discontinuationlrestmi cycle was allowed.

5.4.2 Investigational Products

LEO 90100 and vehicle were provided as cans containing 30 g of aerosol f01mulation. Details

of the investigational products m·e presented in Table 5- 1 and Table 5- 2.

Table 5-1 Identity of LEO 90100

Name investigational product

F01mulation

Active ingredient name/concenu·ation

Excipients

Manufacturer's name of ointment bulk

Manufacturer's name of filled bulk (aerosol foam)

Ce1iifier 's name of filled bulk (aerosol foam)

Supplier's name

Manufacturer's name of secondmy packaging and labelling

Ce1iifier 's name of seconda1y packaging and labelling

Lot number/expi1y date

LEO 90100 aerosol foam

Aerosol foam

Calcipou·iol50 mcg/g (as hydrate) and betamethasone 0.5 mg/g (as dipropionate)

Pm·affm, white soft; pm·affin, liquid; PPG-11 stemyl ether, all-rae-a-tocopherol, dimethyl ether, butane

LEO Phmma, 285 Cashel Road, Dublin 12, Ireland

LP0053-1001 04-Mar-2014 of315

Table 5-2 Identity of Vehicle

's name of ointment bulk

's name of filled bulk aen>sol foam)

's name of filled bulk (aerosol

's name of secondruy and labelling

's name of secondruy packaging labelling

number/expi1y date

foam vehicle

•'"""''"" .'" white soft; paraffin, liquid; PPG-11 ether, all-rae-a-tocopherol, dimethyl ether,

For details on labelling, storage and accountability of the investigational product, see Sections

1 0.6.1, 1 0.6.2 and 1 0.6.8 of the clinical study protocol (Appendix 1.1 ).

A listing of subjects receiving investigational product from specific batches is provided in

Appendix 1. 6.

5.4.3 Method of Assigning Subjects to Treatment Groups

Subjects who were fmmd to comply with all inclusion and exclusion criteria were randomised

in a 3:1 ratio to receive treatment with either LEO 90100 (300 subjects) or vehicle (100

subjects). Randmnisation was stratified by investigational site. Treatment assignment was

perfmmed using a central IWRS in accordance with a pre-plrumed computer generated

randomisation schedule.

At Visit 1 (Day 0), once a subject's eligibility was confi1med, the (sub )investigator/(site

personnel) supplied the IWRS with the subject number and the IWRS randmnised the subject

to either LEO 90100 or vehicle. At each visit, the IWRS analysed the investigational product

inventmy at the site and allocated a kit number to the subject according to the investigational

product assigned. Thus, each subject attending Visit 1 to Visit 4 was assigned 4 kit numbers

LP0053-1001 04-Mar-2014 of 315

during the course of the trial. The subject number, randomisation number and visit kit

numbers for each subject were distinct from each other.

5.4.4 Selection and Timing of Dose for each Subject

A once daily treatment regimen was chosen as this had been shown to be effective in previous

studies of ointment and topical suspension/gel, as well as in the phase 2 trials with LEO

90100. It decreases drug exposure and time spent on application and was thus expected to

enhance subject adherence. The maximum weekly dose of LEO 90100 was selected based on

the approved maximum dose for Daivobet® ointment, which is 100 g. However, for practical

purposes (30 g was the only available pack-size) the maximum weekly dose was set to 90 g (3

cans) per week.

A description of application of the investigational product is provided in Section 5.4.1.

5.4.5 Blinding

The trial was a double-blind trial. The packaging and labelling of the investigational products

contained no evidence of their identity. It was not considered possible to differentiate between

the investigational products solely by sensory evaluation. No effects of the investigational

products which would reveal the identity of the individual treatment allocations were

expected. Consequently, the subjects and the (sub)investigators remained unaware of the

individual treatment assignment during the conduct of the clinical trial.

Emergency un-blinding of individual subject treatment could be performed by contacting the

IWRS. An emergency un-blinding request could be made by the (sub)investigators, other

health care professionals, or authorised LEO personnel.

For other healthcare professionals not directly involved in the trial but with the need to un-

blind an individual subject in an emergency scenario, the CRO responsible for emergency un-

blinding was to be contacted via the emergency number on the subject trial card. This CRO

then accessed the IWRS on behalf of the third-party requester and provided the subject’s

treatment assignment.

If code break was considered necessary for other safety concerns, for example due to adverse

drug reactions (ADRs), un-blinding could be performed by Global Pharmacovigilance at

LEO, and the reason for un-blinding had to be documented.

Treatment codes were not broken for the planned analyses of data until all decisions on the

evaluability of the data from each individual subject had been made and documented.

LP0053-1001 04-Mar-2014 of 315

5.4.6 Prior and Concomitant Therapy

Use of concomitant treatment was recorded in the subject’s medical record and the CRF

(treatment/drug name, dose, route of administration, indication and dates of start and stop).

Prior to the Trial Treatment Phase

The washout phase was up to 4 weeks (28 days). Subjects who had been treated with medica-

tions requiring more than 4 weeks washout were not eligible for the trial. However, a subject

would be eligible if she/he had a treatment free period prior to entering the trial (i.e. having

signed the Informed Consent), e.g. if a subject had been off infliximab 6 weeks prior to

entering the trial, the subject could still be eligible for the trial after 2 weeks of washout.

Note: if the subjects had themselves initiated a treatment free period prior to entering the trial,

this was not considered a trial-related procedure and accordingly not part of the trial defined

wash-out phase. The earliest possible wash-out start date to record in the CRF was the day the

subject entered the trial (i.e. having signed the Informed Consent).

To account for an adequate treatment-free period, the date of last use of the excluded

medication was recorded in the CRF.

All previous anti-psoriatic treatment (systemic and topical medications and light therapy)

used by the subject to treat their psoriasis vulgaris was recorded by pre-defined categories.

Inhaled steroids were allowed during the washout phase.

Treatments requiring washout

Treatments requiring washout before Visit 1 are listed below, with the required individual

washout periods indicated in brackets:

Systemic treatment with biological therapies, whether marketed or not, with a potential

effect on psoriasis vulgaris (e.g. etanercept, infliximab, adalimumab and ustekinumab)

(see exclusion criterion No.1)*

Systemic treatments with all other therapies with a potential effect on psoriasis vulgaris

(e.g. corticosteroids, retinoids, methotrexate, ciclosporin and other immunosuppressants)

(4 weeks)

PUVA therapy (4 weeks)

UVB therapy (including excimer laser therapy) (2 weeks)

Topical anti-psoriatic treatment on the trunk and/or limbs (2 weeks)**

LP0053-1001 04-Mar-2014 of 315

Topical treatment with corticosteroids, vitamin D analogues, and/or prescription shampoos

on face, scalp and skin folds (2 weeks)**

Use of non-marketed drug substances (see exclusion criterion No.3)

*) Note: duration of the washout phase should not exceed 4 weeks

**) Note: use of emollients was allowed on treatment areas during this 2 week period

During the Trial Treatment Phase

Concomitant medications for conditions other than psoriasis vulgaris (with no potential effect

on psoriasis vulgaris) could be continued throughout the trial without any change in dosage.

Inhaled steroids were allowed during the trial.

Bath oils and moisturising soaps were allowed during the trial.

Sunscreens were allowed, but were not to be applied at the same time as the investigational

product.

Treatments which could not be used during the treatment phase (visits 1 to 4) were the same

as those requiring a washout period, listed previously, with the addition of the following

which were not allowed:

Emollients on the areas of psoriasis that were to be treated with trial medication

(trunk/limbs)

Planned initiation of, or changes to, concomitant medication during the trial that, while

not specifically indicated for treatment of the indication being studied, could positively or

negatively affect psoriasis vulgaris (e.g. beta blockers, antimalarial drugs, lithium, ACE

inhibitors)

Planned excessive exposure of area(s) to be treated with trial medication to either natural

or artificial sunlight (including tanning booths, sun lamps etc.) during the trial

Use of any drug except the investigational product for the treatment of psoriasis vulgaris was

not allowed except for some topical treatments on the face, scalp and skin folds. Accordingly,

only the following concomitant topical anti-psoriatic treatments on face, scalp and skin folds

were permitted during the trial:

All topical medications except corticosteroids, vitamin D analogues and/or prescription

shampoos

LP0053-1001 04-Mar-2014 of 315

Unlimited use of emollients

This restriction on concomitant topical therapies on other body regions was to assert a level of

control over the concomitant medication related effects observed during the trial and to allow

use of the trial medication up to the maximum recommended level.

A stable concomitant treatment regimen (no start or change of dosage during the trial) with

drugs that have a potential effect on psoriasis (e.g., beta blockers, anti-malarials, ACE

inhibitors and lithium) was allowed during the trial. Although these drugs have a potential

effect on psoriasis, they are not known to cause fluctuations in disease severity and therefore

should not have affected the subject’s response to trial medication.

5.4.7 Treatment Compliance and Extent of Exposure

Subjects were provided with a diary at Visit 1 to Visit 3 to record adherence to the once daily

treatment regimen during the visit interval. The diary was returned to the site staff at the

subsequent trial visit. At all on-treatment visits, the subject was asked if she/he had used the

medication as prescribed. If this was not the case, the degree and nature of non-compliance

was recorded.

The investigational product was applied once daily to psoriasis vulgaris lesions. Subjects

classified as ‘clear’ according to the IGA on the trunk and limbs at either Visit 2 or Visit 3

were allowed to stop treatment at the (sub)investigator’s discretion. If this occurred,

investigational product was still dispensed and the subject remained in the trial and attended

all scheduled visits. If psoriasis vulgaris reappeared on the treatment areas, the subject was to

reinitiate treatment without consulting the (sub)investigator. More than one discontinuation/

restart cycle was allowed.

Prior to secondary packaging, but following individual unit labelling, 10 cans were weighed

by the CMO and the average used as an estimate of the known filled weight for each can. At

the end of the trial, the investigational products returned to the CMO were reconciled with the

Individual Drug Accountability Forms. All returned cans which were dispensed to a subject

were weighed by the CMO to determine the amount of the investigational product used per

treatment phase visit interval for each subject.

5.5 Assessments

5.5.1 Frequency and Timing of Measurements

The schedule of all trial procedures for all trial visits is presented in Table 5–3.

LP0053-1001 04-Mar-2014 of 315

Table 5–3 Schedule of Trial Procedures

Phase Screening Treatment Follow-up

if required

Visit SV(a) V1 Day 3

subject

diary(l)

Day 5

subject

diary(l)

V2 V3 V4(g) FU(f)(p)

Week Up to -4 0 1 2 4 6

Visit window (days) Up to -28 0 7±2 14±2 28±2 +14±2

Informed consent(b) (x) x

Subject demographics (x) x

In-/exclusion criteria (x) x

Concurrent diagnoses (x) x

Concomitant medication (x) x x x x x

Relevant medical history (x) x

Physical examination (x) x

Vital signs x x

Pregnancy test(c) x x

Investigator’s Global

Assessment of Disease

Severity

x x x x

Investigator’s Assessment

of BSA Involvementx x x x


of Extent and Severity of

Clinical Signs (m-PASI)

x x x x


of the Severity of the

Target Lesion (Redness,

Thickness, Scaliness)

x x x x

Clinical Photography(o) x(n) x(j) x(j)

Local Safety and

Tolerability Assessmentx x x x

Adverse Event(s)(e) x x x x x

Laboratory sampling;

biochemistry(h) x x x(d)(i)

Laboratory sampling;

25-OH Vitamin Dx

Laboratory sampling; x x x(i)

LP0053-1001 04-Mar-2014 of 315


if required


subject

diary(l)

Day 5

subject

diary(l)


Week Up to -4 0 1 2 4 6


Spot Urinalysis(h)

Patient’s Global

Assessment of Disease

Severity

x x x x

Subject’s Assessment of

Itch by use of a Visual

Analogue Scale (VAS)

x x x x x x

Subject’s Assessment of

Itch-Related Sleep Loss by

use of a Visual Analogue

Scale (VAS)

x x x x x x

Subject Diary; Provided x x x

Subject Diary; Collected x(m) x(m) x(m)

Quality of Life

Questionnaire; DLQI x x x x

Quality of Life

Questionnaire; EQ-5D-5Lx x

Randomisation x

Subject Treatment

Instructionsx

Dispensing of trial

medicationx x x

Compliance check(m) x x x

Return of trial medication x x x

End of treatment Form(k) x

a) A washout period of up to 4 weeks was completed if the subject was treated or had recently been treated

with anti-psoriatic treatments or other relevant medication, as defined by the exclusion criteria. Items

denoted by brackets were reviewed at a Screening Visit prior to commencing a washout, to assess if the

subject was otherwise eligible. Such items were checked for any change in eligibility status at Visit 1

after the washout was completed.

b) Informed consent was signed both by subject and (sub)investigator (medically qualified) before any trial

related procedures were carried out. For subjects requiring a washout period, informed consent was

LP0053-1001 04-Mar-2014 of 315


if required


subject

diary(l)

Day 5

subject

diary(l)


Week Up to -4 0 1 2 4 6


completed prior to washout.

c) For women of child-bearing potential, a pregnancy test was performed at Visit 1 and Visit 4 (or at the last

on-treatment visit)

d) If albumin-corrected serum calcium was above the reference range at the last on-treatment visit, a follow

up test was performed.

e) AEs were collected from the date of signing the informed consent form, i.e. during the washout period

f) If an adverse event (serious or non-serious) classified as possibly or probably related to the trial treatment

or not assessable in relation to the trial treatment was on-going at the last on-treatment visit.

g) For subjects prematurely withdrawn from treatment, the final efficacy assessments scheduled for Visit 4

were completed at the last on-treatment visit.

h) If a laboratory result was abnormal and judged as clinically significant, the (sub)investigator was to

follow-up as clinically appropriate (this could involve requesting repeat samples).

i) If any laboratory parameter was abnormal and judged as clinically significant by the (sub)investigator at

the last on treatment visit, a follow-up visit was performed.

j) Clinical photography to include target lesion only

k) If the subject was not randomised or did not complete the treatment period, the End of Trial form

wascompleted as appropriate.

l) Conducted as self-assessment by the subject and recorded in the diary provided at Visit 1.

m) To supplement the compliance check made at Visit 2 to Visit 4, a subject diary was completed daily

during each visit interval.

n) Clinical photography included target lesion and full body anterior and posterior images.

o) Clinical photography was a voluntary additional procedure for a subset of the studied population.

p) Where the (sub)investigator considered it appropriate, the follow-up visit was performed as a telephone

contact.

5.5.2 Baseline Characteristics and Demographics Assessed

Subject’s eligibility for the clinical trial was checked according to the inclusion and exclusion

criteria at visits specified in the trial procedure schedule in Table 5–3.

Demographic Data

Demographic data consisted of date of birth, sex, ethnic origin (ethnicity), race, and skin type.

The subjects were asked to 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)

In addition, the skin type of subjects was recorded using the classification in Table 5–4 (21).

LP0053-1001 04-Mar-2014 of 315

Table 5–4 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

Height and Weight

The subject’s weight (with indoor clothing and without shoes) and height (without shoes)

were recorded. Body mass index (BMI) was calculated.

Duration of Psoriasis Vulgaris

The duration of psoriasis vulgaris was recorded, to the nearest whole year.

Relevant Medical History, Concurrent Diagnoses and Concomitant Medication

Relevant medical history, concurrent diagnoses and concomitant medication(s) were recorded,

including all previous anti-psoriatic treatment (systemic and topical medications and light

therapy) used by the subject to treat their psoriasis vulgaris.

The presence of psoriasis vulgaris affecting regions of the body not considered to be part of

the treatment area (i.e. face, scalp, skin folds, genitals and nails) was recorded.

Vital Signs

Vital signs included blood pressure (systolic and diastolic recorded in mmHg) and heart rate

(beats per minute). Heart rate and blood pressure were measured after the subject had been

resting in a supine position for five minutes.

Physical Examination

A routine physical examination was performed.

5.5.3 Efficacy Measurements Assessed

5.5.3.1 Investigator Assessments

Definition of the Body Areas to be Assessed (Treatment Areas)

The treatment areas to be assessed were the trunk and limbs.

LP0053-1001 04-Mar-2014 of 315

The trunk and limbs included the arms (including hands), trunk (including the neck), and the

legs (including the buttocks and feet).

The face, scalp, genitals and skin folds (i.e. the axillae, the inguinal folds, the inter-gluteal

folds and the infra-mammary folds) were not to be treated with the investigational product or

assessed as part of the efficacy analysis.

The (sub)investigator made the following clinical assessments (ideally, all assessments for a

subject were to be made by the same (sub)investigator).

Investigator’s Global Assessment of Disease Severity (IGA)

At all treatment visits (Visit 1 to Visit 4) the (sub)investigator made a global assessment of the

disease severity of the psoriasis vulgaris on the trunk and limbs by use of the 5-point scale

presented in Table 5–5. This assessment represented the average lesion severity on the trunk

and limbs. The assessments were based on the condition of the disease at the time of

evaluation, and not in relation to the condition at any previous visit.

LP0053-1001 04-Mar-2014 of 315

Table 5–5 Investigator’s Global Assessment of Disease Severity – 5-point Scale

Clear Plaque thickening = no elevation or thickening of normal skin

Scaling = no evidence of scaling

Erythema = none (no residual red coloration 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 coloration

Moderate Plaque thickening = moderate elevation with rounded or sloped edges

Scaling = most lesions at least partially covered

Erythema = definite red coloration

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 coloration; extreme red coloration; deep red coloration

Note: On Day 0 (Visit 1) disease severity had to be graded as at least ‘mild’ in order to meet

the inclusion criterion.

Investigator’s Assessment of the Extent and Severity of Clinical Signs (Redness, Thick-

ness, Scaliness)

At all treatment visits (Visit 1 to Visit 4) the (sub)investigator made assessments of the extent

and severity of clinical signs of the subject’s psoriasis vulgaris.

The extent of psoriatic involvement was recorded for each of the three areas (arms, trunk and

legs) using the following scale:

0 = no involvement

1 = <10%

2 = 10-29%

3 = 30-49%

LP0053-1001 04-Mar-2014 of 315

4 = 50-69%

5 = 70-89%

6 = 90-100%

The severity of the psoriatic lesions in each of the three areas was recorded for each of the

clinical signs of redness, thickness, and scaliness. For each clinical sign, a single score,

reflecting the average severity of all psoriatic vulgaris lesions on a given body region, was

determined according to the scale in Table 5–6.

Table 5–6 Severity Score for Redness, Thickness, and Scaliness

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)

Investigator’s Assessment of the Severity of the Target Lesion (Redness, Thickness,

Scaliness)

At Visit 1, the (sub)investigator selected a target lesion per protocol. The target lesion had to

be a minimum of 5 cm at its longest axis and preferably not located on the extensor surface of

an elbow or knee. Location was recorded in the CRF as trunk, limb excluding elbow/knee,

elbow or knee, and in more detail in the subject medical records to allow identification of the

target lesion at subsequent visits.

At Visits 1 to 4, the (sub)investigator assessed the severity of the target lesion for each clinical

sign (redness, thickness, scaliness) according to the same scale as for the Investigator’s

Assessment of the Severity of Clinical Signs (Redness, Thickness, Scaliness); see Table 5–6.

At Visit 1, the scoring of the target lesion must have been at least 1 for each of the three

categories, and at least 4 in total.

LP0053-1001 04-Mar-2014 of 315

Investigator’s Assessment of the Body Surface Area (BSA) Involvement of Psoriasis

Vulgaris on Trunk and Limbs

At all treatment phase visits (Visit 1 to Visit 4) the (sub)investigator assessed the extent of the

subject’s psoriatic involvement on the trunk and limbs. The total psoriatic involvement on the

trunk and limbs (excluding skin folds and genitals) was recorded as a percentage of the total

BSA, estimating that the surface of the subject’s full, flat palm (including the five digits)

correlated to approximately 1% of the total BSA. The purpose was to obtain an estimate of the

area on the trunk and limbs to be treated with investigational product for each subject.

5.5.3.2 Subject Assessments

The subject’s assessments were to be made prior to the investigator’s assessments.

Patient’s Global Assessment of Disease Severity (PaGA)

This assessment was made at all treatment visits (Visit 1 to Visit 4) based on the condition of

the disease at the time of the evaluation and not in relation to the condition at a previous visit,

by use of the 5-point scale presented in Table 5–7. The (sub)investigator explained the

categories of the scale to the subject and the subject told the (sub)investigator which category

to mark.

Table 5–7 Patient’s Global Assessment of Disease Severity – 5-point Scale

Assessment Severity of symptomsClear No psoriasis symptoms/signs at all

Very mild Very slight psoriasis symptoms/signs, does not interfere with daily lifeMild Slight psoriasis symptoms/signs, interferes with daily life only occasionallyModerate Definite psoriasis symptoms/signs, interferes with daily life frequentlySevere Intense psoriasis symptoms/signs, interferes or restricts daily life very

frequently

Subject’s Assessment of Itch by Use of a Visual Analogue Scale (VAS)

This assessment was made by the subject at baseline (Day 0; Visit 1), Day 3, Day 5, Week 1,

Week 2, and Week 4 by means of a subject diary. A VAS was used to assess itch using a

horizontal line. The line represented the range of itch severity, from 0 mm (no itch at all) at

one end to 100 mm (worst itch you can imagine) at the other. Subjects were 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 felt best reflected this.

Subject’s Assessment of Itch-Related Sleep Loss by Use of a Visual Analogue Scale (VAS)

This assessment was made by the subject at baseline (Day 0; Visit 1), Day 3, Day 5, Week 1,

Week 2, and Week 4 by means of a subject diary. A VAS was used to assess itch-related sleep

LP0053-1001 04-Mar-2014 of 315

loss using a horizontal line. The line represented the range of sleep loss, from 0 mm (no sleep

loss at all) at one end to 100 mm (worst possible sleep loss). Subjects were asked to rate the

itch-related sleep loss during the preceding night, by putting a single vertical line across the

horizontal line at the spot he/she felt best reflected this.

Quality of Life Assessments

The subject’s assessments of quality of life were assessed by means of the generic EQ-5D-5L

questionnaire which is a standardised instrument for use as a measure of health outcome and

the DLQI which is a validated dermatology specific questionnaire. EQ-5D-5L was assessed at

Visit 1 and at Visit 4 or the last on-treatment visit, as applicable. DLQI was assessed at all

treatment phase visits (Visit 1 to Visit 4). The questionnaires were completed by the subject

while at the investigator site, and before the subject was assessed by the (sub)investigator.

5.5.3.3 Imaging Assessments

Clinical Photography

At designated centres, clinical photographs were planned to be taken in approximately 100

subjects for whom specific consent had been obtained. If a subject at one of the designated

centres wished to take part in the trial, but consent had not been provided to allow the extra

photographic procedure, the subject was still invited to take part in the trial without having

photographs taken (i.e. having these photographs taken was entirely voluntary).

Photographs were taken of the psoriasis lesions affecting the trunk and/or limbs only and the

images were only to be used as supportive data to the clinical assessments (i.e. no

adjudication of images or statistical analysis).

Image requirements:

Full body, anterior (excluding the head)

Full body, posterior (excluding the head)

Target lesion on the trunk or limbs

The target lesion used for clinical photography had to be the same as that selected for the

investigator’s assessment of the severity of the target lesion (redness, thickness, scaliness).

The location of the target lesion was recorded by means of a visual representation in the

source records.

The exact specifications of the images to be taken were stated in a clinical photography

manual. All imaging assessments were made with standardised equipment and methodolo-

LP0053-1001 04-Mar-2014 of 315

gies with use of appropriate software and methods of data transfer which in no way revealed

the identity of the subject.

Full body images (anterior and posterior) were taken at Visit 1. Target lesions images were

taken at Visits 1, 2, and 4.

Subjects consented that LEO would be allowed to use the photographs obtained from this trial

in publications intended for scientific, marketing and training purposes. Subject

confidentiality will be maintained at all times. The informed consent form is provided in

Appendix 1.1.

5.5.4 Safety Measurements Assessed

5.5.4.1 Local Safety and Tolerability

The assessment of local safety and tolerability consisted of signs assessed by the

(sub)investigator and symptoms reported by the subject.

At Visits 1 to 4, the (sub)investigator assessed application site reactions for the following

signs: perilesional erythema, perilesional oedema, perilesional dryness, and perilesional

erosion. The subject assessed the symptoms of application site burning or pain.

For perilesional erythema, oedema, dryness and erosion, the area for the (sub)investigator to

assess was 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 had to be

present in this area, but could extend beyond it in a continuous manner.

The area for the subject to assess application site burning or pain was the lesional and

perilesional area. The reported symptoms had to be present in this area, but could extend

beyond it in a continuous manner.

For each sign and symptom the highest (worst) skin reaction score across all treatment areas

was coded by use of the 4-point scale presented in Table 5–8 and Table 5–9.

LP0053-1001 04-Mar-2014 of 315

Table 5–8 Investigator Assessment of Skin Reaction Score

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

Table 5–9 Subject Assessment of Skin Reaction Score

0 = absent 1 = mild 2 = moderate 3 = severe

Application site burning or pain:

No burning or pain after application

Slight, barely perceptible burning or pain after application

Distinct burning or pain after application

Marked, intense burning or pain after application

The (sub)investigator explained the categories of the scale to the subject and the subject told

the (sub)investigator which category to mark.

5.5.4.2 Laboratory Analysis

Samples of blood and urine were taken for analysis as scheduled in the flowchart (Table 5–3)

or on withdrawal from or early completion of the treatment phase.

A urine pregnancy test was performed at Visit 1 prior to randomisation and at the last on-

treatment visit (Visit 4 unless early withdrawal) in female subjects of child-bearing potential.

The test kits were provided by the central laboratory. All other laboratory analyses were

performed centrally.

LP0053-1001 04-Mar-2014 of 315

A sample of venous blood and a spot urine sample were taken on Day 0 (Visit 1/baseline) and

on Day 28 (Visit 4). The central laboratory provided the materials and instructions necessary

for the collection and transportation of the samples.

Parameters analysed in blood and urine samples are presented in Table 5–10.

Table 5–10 Serum Biochemistry and Urinalysis

Serum Biochemistry Urinalysis(spot urine sample)

Calciuma Visit 1 and 4 Calciumb Visit 1 and 4Albumina Visit 1 and 4 Creatinineb Visit 1 and 425-hydroxy vitamin D Visit 1 - -

a Albumin-corrected serum calcium was calculated in mmol/L using the formula:

serum calcium (total) in mmol/L + (0.02 × [40-serum albumin in g/L])b

Calcium:creatinine ratio was calculated.

Review of Laboratory Results

If any of the laboratory results were abnormal and judged as clinically significant, the

(sub)investigator followed-up with the subject as clinically appropriate (this could have

involved requesting repeat samples). Likewise, if the albumin-corrected serum calcium result

was above the reference range at the last on-treatment visit, a follow-up visit was performed

for repeat sampling Laboratory values evaluated by the (sub)investigator as clinically

significant were to be regarded as AEs ). Clinically significant threshold levels for albumin-

corrected serum calcium as defined by LEO are described in Sections 6.2.8.2 and 10.5.2.

5.5.4.3 Adverse Events

An AE is defined as:

Any untoward medical occurrence in a subject or clinical investigation subject administered a

pharmaceutical product and which does not necessarily have a causal relationship with this

treatment. An AE can therefore be any unfavourable and unintended sign (including an

abnormal laboratory finding), symptom, or disease temporally associated with the use of a

medicinal (investigational) product, whether or not related to the medicinal (investigational)

product. (ICH Harmonized Tripartite Guideline for Good Clinical Practice, E6 (R1)).

A serious adverse event (SAE) is any untoward medical occurrence that

Results in death

Is life-threatening

Requires in subject hospitalisation or prolongation of existing hospitalisation

LP0053-1001 04-Mar-2014 of 315

Results in persistent or significant disability/incapacity

Is a congenital anomaly/birth defect

or

Other medically important conditions*)

*) 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 out-comes

listed in the definition above. Examples of such events are allergic bronchospasm, blood

dyscrasias and convulsions.

Global Pharmacovigilance, LEO was responsible for the assessment of expectedness

according to LEO procedures. The relevant reference document for this clinical trial was the

Investigator’s Brochure for LEO 90100, edition 3 and subsequent updates as agreed between

the head of the Medical Department and the medical director, Global Pharmacovigilance,

LEO.

At all visits, the subject was asked a non-leading question by the investigator: “How have you

felt since I saw you last?” No specific symptoms were asked for.

If there were no AEs to record, no further questions were asked and “NO” was stated. In case

there were one or more AEs to record, “YES” was stated and the investigator recorded the

event term, intensity, duration, suspected causal relationship to the investigational product and

outcome.

The investigator also observed the subject for any changes not reported by the subject and

recorded these changes.

All treated lesions were examined by the investigator for any signs of AEs.

Only medically qualified personnel assessed AEs.

5.5.4.4 Reporting of Adverse Events

Events reported by the subject or observed by the (sub)investigator and that fell into any of

the above definitions were to be recorded on the AE page of the CRF and were described in

the following manner:

The nature of the event was described in precise English medical terminology (i.e. not

necessarily the exact words used by the subject). Whenever possible, a specific diagnosis was

to be stated (e.g. allergic contact dermatitis).

LP0053-1001 04-Mar-2014 of 315

For cutaneous AEs the location had to be part of the AE description and was 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 intensity of the event was described in terms of mild, moderate or severe according to the

investigator’s clinical judgement.

Mild: The AE does not interfere in a significant manner with the subject’s normal

functioning level and requires no medical intervention.

Moderate: The AE interferes with the subject’s normal functioning level and may or may

not require medical intervention.

Severe: The AE produces significant impairment of the subject’s functioning or requires

medical intervention.

The duration of the event was reported as the start date and stop date of the event.

The causal relation of the event to the use of the investigational product was described in

terms of probable, possible, not related or not assessable 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 administration of the investigational

product

LP0053-1001 04-Mar-2014 of 315

Could also be reasonably explained by the subject’s clinical state, environmental or toxic


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


Does not follow a known pattern of response to the investigational product

Not assessable

The AE cannot yet be judged otherwise because present information is in-sufficient or

contradictory. A final assessment (i.e. probably, possibly or not related) shall be made as

more information becomes available, at the latest when the subject has completed the trial.

The outcome of the event was 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, however, not yet completely resolved.

Follow-up on the event is required until final

outcome is established

Not recovered/not resolved Event is still on-going. Follow-up on the event is

required until final outcome is established

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

Fatal The subject has died as a consequence of the event.

Date of death is recorded as stop date for the AE

LP0053-1001 04-Mar-2014 of 315

Unknown Unknown to investigator, e.g. subject lost to follow-

up

Once a subject completed the clinical trial, the investigator followed up for outcome on all

non-serious AEs classified as possibly/probably related to the investigational product or not

assessable until last follow-up visit or until final outcome was determined, whichever came

first.

5.5.4.5 Other Events to be Reported

Pregnancy

Pregnancy that occurred during the clinical trial was to be reported to LEO within 24 hours of

first knowledge using the (paper) LEO Pregnancy Follow-Up form Part I supplied by LEO.

Follow-up on pregnancy outcome was to be reported on the LEO Pregnancy Follow-Up form

Part II. All pregnancies were to be followed to delivery or termination. The completed LEO

Pregnancy Follow-Up form was to be reported to LEO and TKL in the same manner as an

SAE (see Section 5.5.4.3).

Overdose

Any overdose defined as any higher dose than prescribed for the individual subject was to be

reported on the AE form of the CRF book. AEs originating after the overdose were to be

documented on a separate line.

Aggravation of Condition

Any clinically significant aggravation/exacerbation/worsening of the initially treated

condition compared with baseline, judged by an overall medical assessment, was to be

reported as an AE.

5.5.4.6 Serious Adverse Events

Reporting of Serious Adverse Events

Any SAE, related or unrelated to the investigational product or any trial procedure after

signature of the Informed Consent Form, was reported to LEO on the (paper) Serious Adverse

Event Form – Clinical Trial within 24 hours.

Note: Planned hospitalisation or planned prolonged hospitalisation does not fulfil the criteria

for being an SAE. The elective nature of the event had to be clearly documented in the

subject’s medical record.

SAEs were reported on the AE form of the CRF book. Additionally reports were made using

the paper Serious Adverse Event Form – Clinical Trial, supplied by LEO. Apart from the

LP0053-1001 04-Mar-2014 of 315

assessment of the intensity, causal relationship to the investigational product(s) and/or trial

procedures, the action taken and the outcome to date, this report contained a comprehensive

narrative description of the course of the event.

The completed Serious Adverse Event Form – Clinical Trial was faxed or scanned and

emailed to both LEO and TKL Research as specified in the clinical study protocol (Appendix

1.1).

All other relevant reports of diagnostic procedures, hospital records, autopsy reports etc. were

also forwarded, as applicable or upon request from Global Pharmacovigilance.

The IRBs, regulatory authorities, and concerned investigators were notified of SAEs

according to current regulation and local requirements.

All suspected, unexpected serious adverse reactions (SUSARs) were subject to expedited

reporting to regulatory authorities. Global Pharmacovigilance was to unblind such cases prior

to reporting. Investigators would remain blinded.

SAEs were followed indefinitely until a final outcome was established, i.e. the follow-up

could continue beyond the end of the clinical trial.

SAEs occurring after completion of the trial were not routinely sought or collected beyond the

last follow-up visit. However, if reported, such cases were to be regarded as expedited for

reporting purposes for other trial case reports. Therefore, a causality assessment and

determination of expectedness were made to determine whether or not expedited reporting

was required.

5.5.4.7 Vital Signs

Vital signs were evaluated at Visit 1 (Week 0) and at Visit 4 (Week 4).

5.5.5 Appropriateness of Measurements

The efficacy measures used in this trial (IGA, PASI) are standard in clinical trials of psoriasis.

The 5-point scale used for the IGA was developed in consultation (pre-IND meeting) with the

FDA. The DLQI is a validated dermatology specific questionnaire which measures specific

factors influencing the quality of life for subjects with skin disease. The generic EQ-5D-5L

questionnaire is a standardised instrument for use as a measure of health outcome. A VAS is a

commonly used method to quantify pruritus. All safety measures used in this trial were also

standard.

LP0053-1001 04-Mar-2014 of 315

5.6 Endpoints/Response Criteria

5.6.1 Efficacy Evaluation

5.6.1.1 Primary Endpoint

The primary endpoint was subjects with ‘treatment success’ (‘clear’ or ‘almost clear’ for

subjects with at least moderate disease at baseline, ‘clear’ for subjects with mild disease at

baseline) according to the IGA at Week 4.

5.6.1.2 Secondary Endpoints

The secondary endpoints were

m-PASI at Week 4

m-PASI at Week 1

m-PASI was calculated using the formula given below based on the investigator’s assessment

of the extent and severity of the disease locally (trunk, arms, legs) (22).

Arms 0.2 (R + T + S)E = X

Trunk 0.3 (R + T + S)E = Y

Legs 0.4 (R + T + S)E = Z

where: R = score for redness; T = score for thickness; S = score for scaliness; E = score for

extent

Trunk and limbs: The sum of X + Y + Z gives the m-PASI, which can range from 0 to 64.8.

5.6.1.3 Additional (Tertiary) Endpoints

Investigator’s Assessments

Subjects achieving ‘treatment success’ (‘clear’ or ‘almost clear’ for subjects with at least

moderate disease at baseline, ‘clear’ for subjects with mild disease at baseline) according

to the IGA at Week 1 and Week 2

IGA at Week 1, Week 2, and Week 4

m-PASI at Week 2

Subjects achieving PASI-75 (at least 75% reduction in m- PASI from baseline) at Week 1,

Week 2, and Week 4

LP0053-1001 04-Mar-2014 of 315

Subjects achieving PASI-50 (at least 50% reduction in m-PASI from baseline) at Week 1,

Week 2, and Week 4

Change in BSA involvement from baseline (Day 0; Visit 1) to Week 1, Week 2, and Week

4

Subject’s Assessments

Subjects achieving ‘treatment success’ (‘clear’ or ‘very mild’) according to the PaGA at

Week 1, Week 2, and Week 4

PaGA at Week 1, Week 2, and Week 4

Change in itch as assessed by VAS from baseline (Day 0; Visit 1) to Day 3, Day 5, Week

1, Week 2, and Week 4

Severity of itch as assessed by VAS at baseline (Day 0; Visit 1), Day 3, Day 5, Week 1,

Week 2, and Week 4

Change in itch-related sleep loss as assessed by VAS at baseline (Day 0; Visit 1) to Day 3,

Day 5, Week 1, Week 2, and Week 4

Change in DLQI from baseline (Day 0; Visit 1) to Week 1, Week 2 and Week 4

EQ-5D-5L; The five dimensions in the descriptive system at baseline (Day 0; Visit 1) and

Week 4 and the score according to EQ VAS at baseline (Day 0; Visit 1) and Week 4

5.6.2 Safety Evaluation

The evaluation of safety was based on the following parameters:

Any reported AE

Any reported ADR

Change in albumin-corrected serum calcium from baseline to Week 4

Change in urine calcium:creatinine ratio from baseline to Week 4

5.6.3 Evaluation of Other Observations

Reason for withdrawal from the trial

Change in vital signs (blood pressure, heart rate) from baseline to Week 4

Local safety and tolerability parameters.

Weight of investigational product used

LP0053-1001 04-Mar-2014 of 315

Compliance with treatment instructions (treatment application missed)

5.7 Data Quality and Assurance

LEO has implemented a system of quality assurance, including all the elements described in

this report. Within this system company SOPs are implemented to ensure that clinical trials

are conducted in compliance with regulatory requirements and GCP. Quality control is

applied to each stage of data handling to ensure that data are accurate, reliable and processed

correctly.

Trial sites, facilities, laboratories and all data (including sources) and documentation were

available for GCP audit by LEO or inspection by competent authorities.

For this trial, two site audits were conducted. The audit certificates are provided in Appendix

1.8.

Training of Site Staff

LEO held a 2 day investigator meeting just prior to the start of the trial to familiarise the

investigators and other trial site personnel with the trial protocol and to provide training on

the clincial assessments, procedures, and GCP, if required. Additionally, an initiation visit was

performed in person for all sites. For those few sites that were unable to attend the

investigator meeting, the same training materials as used at the investigator meeting were

delivered with a LEO representative present to ensure adequate and consistent training across

sites.

Trial Monitoring

As sponsor of this clinical trial, LEO was responsible for assuring the proper conduct of the

clinical trial with regard to protocol adherence and validity of the data recorded in the CRFs.

Monitors were assigned to serve as the principal link between (sub)investigators and LEO and

advise the investigator on the collection and maintenance of accurate, complete, legible, well

organised and easily retrievable data for the clinical trial. In addition, they explained any

aspect of the (conduct of the) clinical trial to the investigators, including interpretation of the

protocol, the purpose of collecting the specified data and reporting responsibilities.

Case Report Forms

An electronic data capture system was used in this trial. Data were captured onto source

documents and were entered into the electronic data capture system by staff at the clinical

sites. Following data entry, the data were 100% monitored. Queries for discrepant data were

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, were in an

LP0053-1001 04-Mar-2014 of 315

electronic format. This systematic process ensured that a clean and consistent database was

provided prior to the statistical analysis being performed.

Following all data validation steps, the investigator, or designee, electronically signed each

eCRF prior to database lock. For archiving purposes each investigator was supplied with a

copy of the eCRFs, for all subjects enrolled at the trial site, via an electronic medium at

completion of the trial. Audit trail information was included. CRFs were available for

inspection by authorised representatives from LEO (e.g. audit by the quality assurance

department), from regulatory authorities and/or IRBs.

Data Handling

Subject data were entered into the eCRF by authorised site staff in a timely manner. Data were

entered by site staff and systematic data validation was performed through the discrepancy

management system within the data collection software.

For subject reported data captured via a subject diary (i.e. compliance data and VAS scores for

itch and itch-related sleep loss assessments) the diary was considered the source document.

The data were transcribed into the eCRF and handled as described above.

5.8 Changes to the Conduct of the Trial

Protocol Amendments

An amendment to the clinical study protocol was issued on the 12-Sep-2013 to specify

additional details regarding the handling of missing values and the methodology for multiple

imputation analysis. In addition, the protocol amendment updated the administrative

information on the sponsor’s responsible medical expert. The consolidated clinical study

protocol dated 12-Sep-2013 implemented the above changes (see Appendix 1.1). The protocol

amendment is also enclosed in Appendix 1.1.

Note on the Size of the Photography Cohort

The clinical study protocol required that 100 subjects were included in the photographic

cohort. Images were therefore not mandatory and could be performed as an assessment at

designated centres. It was identified during the trial that the proportion of subjects consenting

to the additional photographic images was lower than the expected rate. Actions were taken to

increase the number of subjects in the photo cohort, however, the overall subject recruitment

increased as an unintended consequence. The trial completed with 426 subjects randomised

representing an increase in the population by 6.5%. The number of subjects in the

photographic cohort ended on 73.

Protocol deviations are addressed in Sections 7.2 and 7.3.3.

LP0053-1001 04-Mar-2014 of 315

6 Statistical Methods

6.1 Determination of Sample Size

In total, 400 subjects were planned to be randomised in a 3:1 ratio, i.e. 300 subjects in the

LEO 90100 treatment group and 100 in the vehicle group.

In clinical terms the hypothesis was as follows: LEO 90100 is superior to vehicle with respect

to the proportion of subjects achieving ‘treatment success’ according to the IGA.

The sample size calculation in the trial was based on the response rates obtained from 2

completed phase 2 trials with LEO 90100 in subjects with at least mild disease severity at

baseline. The percentage of subjects having ‘controlled disease/ treatment success’ at Week 4

according to the IGA was approximately 45% and 55% in the LEO 90100 group (18,19) and

8% in the vehicle group (19). The sample size calculation assumed that the true percentages

of subjects with ‘controlled disease/treatment success’ were the same as the observed

percentages in the phase 2 trials mentioned above and a two-tailed Fisher’s exact test was

used at a 5% significance level.

With 300 subjects in the LEO 90100 group and 100 subjects in the vehicle group, the Fisher's

exact test would have at least 95% power to reject the null hypothesis of no difference

between the two treatment groups regarding the primary endpoint.

The sample size calculations were carried out using Proc Power in SAS®, version 9.2.

6.2 Statistical and Analytical Plan

6.2.1 Summary

Overall, the statistical analyses were performed as outlined in the consolidated clinical study

protocol (Appendix 1.1). The applied statistical analyses are further detailed in the statistical

analysis plan update (SAPU) (Appendix 1.9), and relevant information therefrom is included

in the following sections. The SAPU was finalised before unblinding of the trial, but after a

blind review of the data.

6.2.2 General Principles

All significance tests were two-sided and all confidence intervals were presented with 95%

degree of confidence.

Each centre was planned to recruit a minimum of 10 subjects. Centres recruiting fewer than

16 subjects were pooled with one or more other centres to form a pooled centre of 16 or more

LP0053-1001 04-Mar-2014 of 315

randomised subjects. Where possible, centres were pooled in order of geographical proximity.

No centre was allowed to recruit more than 50 subjects (approximately 12.5% of the total

sample size). The pooling of centres is detailed in the SAPU (Appendix 1.9).

An observed cases approach was used for tabulations of data by visit (i.e. involving only

those subjects who attended each specific visit).

6.2.3 Subject Qualification for Analysis

The statistical analysis was planned in the clinical study protocol (Appendix 1.1) and further

detailed in the SAPU (Appendix 1.9).

All enrolled subjects, defined as having signed the informed consent form and with a subject

number assigned, were accounted for. All randomised subjects were included in the full

analysis set and analysed for efficacy.

A per protocol analysis set was defined by excluding subjects from the full analysis set who

received no treatment with trial medication, who provided no efficacy data following start of

treatment, who were known to have taken the wrong investigational product throughout the

treatment phase of the trial and/or who did not fulfill the disease defining inclusion criteria

(i.e. inclusion criteria No. 7, 8, 9, 10, and 11; see Section 5.3.1). Further exclusion of subjects

or subject data were decided upon after a blind review of the data, reviewing all the remaining

in- and exclusion criteria, but focusing on concomitant medication that could affect psoriasis

and also considering compliance/adherence and violations of visit windows.

A safety analysis set was defined by excluding subjects from the full analysis set who

received no treatment with investigational product and for whom data on the presence or

confirmed absence of AEs were not available.

The decisions regarding inclusion/exclusion of subjects and/or subject data from the trial

analysis sets were documented in the SAPU before breaking the randomisation code.

6.2.4 Reasons for Leaving the Trial

The reasons for leaving the trial were presented for all randomised subjects, by last visit

attended, and by treatment group.

6.2.5 Demographics and Baseline Characteristics

Descriptive statistics of demographics (age, sex, race, ethnicity, and skin type) and other

baseline characteristics were presented for all randomised subjects and by treatment group.

Age, sex, ethnicity, race, and baseline IGA by treatment were also presented by centre.

LP0053-1001 04-Mar-2014 of 315

Other baseline characteristics were weight, height, BMI, vital signs, duration of psoriasis,

other location(s) of psoriasis, concurrent diagnoses, concomitant medication(s), previous

psoriasis treatment(s), IGA, m-PASI (calculated from the investigator’s assessment of extent

and severity of clinical signs), and the investigator’s assessment of BSA involvement of

psoriasis vulgaris.

Categorical data were summarised using the number and percentage of subjects in each

category and treatment group. Continuous data were summarised using the mean, median,

standard deviation (SD), minimum, and maximum values.

6.2.6 Treatment Compliance and Extent of Exposure

Weight of Trial Medication Used

As described in Section 5.4.7, the average weight of 10 cans was used as an estimate of the

known filled weight for each can. For each subject, the weight of investigational product used

for a particular visit interval was determined by calculating the difference between the weight

of a set of full cans dispensed and the weight of the returned cans multiplied by the correction

factor 0.41 to subtract the propellant gasses.

If any subjects received investigational product cans for a particular visit interval, but did not

return them all, then the amount of investigational product used for that visit interval was not

calculated. If cans were not dispensed, they would not contribute to the weight of

investigational product used for that visit interval. If any cans were returned with their seal

unbroken, the weight of investigational product used from that can was assigned a value of

zero. If a returned can weighed more than the estimated mean weight of a full can, it was

assumed that zero grams were used.

The average weekly amount of investigational product used was calculated for each subject as

the amount of investigational product used for a particular visit interval, divided by the

duration (days) of the visit interval and then multiplied by 7. The amount and the average

weekly amount of investigational product used was summarised using mean, SD, median,

minimum, and maximum values for each treatment group.

If a subject used investigational product from the same kit over several visit intervals (for

example due to a missed visit) the amount of investigational product used over the total trial

period was still calculated, provided all cans were returned non-empty. The amount used

during the visit interval before and after the missed visit was not calculated as it could not be

determined.

LP0053-1001 04-Mar-2014 of 315

Compliance with Treatment Instructions

Compliance with treatment instructions was summarised for each treatment group for all

randomised subjects. The percentage of missed applications for each visit interval (Visit 1 to

Visit 2, Visit 2 to Visit 3, and Visit 3 to Visit 4) was calculated as follows: the number of

applications of investigational product missed for a particular visit interval was divided by the

total number of days for the visit interval and multiplied by 100 to give a percentage.

The percentage of missed applications for the total treatment period was calculated as

follows: the total number of applications of investigational product missed between Visit 1

and the last on-treatment visit was divided by the total number of days between Visit 1 and the

last on-treatment visit and multiplied by 100 to give a percentage.

The percentage of missed applications was allocated to one of the following categories:

≤10%, >10% to ≤20%, >20% to ≤30%, >30% to ≤40%, >40% to ≤50%, and >50%.

Extent of Exposure

The duration of exposure to treatment was calculated as the number of days from Visit 1 to

the date of last application of investigational product. If this date was missing, the date of the

last visit (excluding follow-up visit) was used. If the subject only attended Visit 1, the

duration of exposure was set at one day.

The duration of exposure (weeks) was summarised using the mean, SD, median, minimum,

and maximum values. The extent of exposure was summarised as subject-treatment-weeks.

6.2.7 Analysis of Efficacy

The statistical analysis of efficacy was based on the defined endpoints (see Section 5.6.1).

6.2.7.1 Primary Endpoint

The primary endpoint was analysed for the full analysis set and the per protocol analysis set.

The analysis for the full analysis set was regarded as primary while the analysis for the per

protocol analysis set was supportive.

The number and proportion of subjects who achieved ‘treatment success’ according to the

IGA at Week 4 was tabulated for each treatment group and also presented for each centre by

treatment group.

Multiple imputation of IGA values was carried out as detailed in the protocol and described in

Section 6.2.7.4. For each imputated dataset, the odds ratio of ‘treatment success’ at Week 4 for

LEO 90100 relative to vehicle was estimated by calculating the Mantel-Haenszel odds ratio

LP0053-1001 04-Mar-2014 of 315

adjusted for pooled centres and its 95% confidence interval. For combined inference using

Rubin’s pooling methodology (24) a log transformation was applied to the estimated odds

ratio, and the standard error of the transformed estimate was obtained from the log-

transformed lower and upper confidence limits for the odds ratio estimate as (log(upper)-

log(lower))/(2*1.96). Combined inference for the log transformed odds ratio was obtained

using SAS® PROC MIANALYZE and the combined estimate was back-transformed to the

original scale.

For each of the imputed datasets, the Breslow-Day chi-square statistic for testing

homogeneity of odds ratios across pooled centres was calculated and the multiple chi-square

statistics were combined into an overall p-value using the approach of Li et al. (25). If

significant at a 10% significance level; a sensitivity analysis was performed to identify

possible extreme centres, omitting centres with the smallest and highest odds ratios,

respectively. To investigate centre-to-centre variability, the primary efficacy criterion was

tabulated by (unpooled) centre.

6.2.7.2 Secondary Endpoints

The secondary endpoints were analysed for the full analysis set.

The investigator’s assessment of extent and severity of clinical signs was converted to an

m-PASI score.

Multiple imputation of m-PASI values was carried out as detailed in the protocol and

described in Section 6.2.7.4. Combined inference was obtained using Rubin’s methodology

(24). The secondary endpoints m-PASI at Week 4 and m-PASI at Week 1 were tested

sequentially, as the treatments initially first were compared at Week 4. Only if a statistically

significant result (p< 0.05) was obtained were the treatments compared at Week 1. For both

endpoints, LEO 90100 and vehicle were compared using an analysis of variance (ANOVA)

including (pooled) centre, treatment and baseline m-PASI in the model. The adjusted

difference between LEO 90100 and vehicle and the corresponding p-value as well as a 95%

confidence interval were calculated.

To investigate centre-to-centre variability, the secondary efficacy criteria were tabulated by

(unpooled) centre.

The m-PASI at each visit was summarised for each treatment group.

The principal investigator from one site confirmed by signature of a protocol deviation that

that the extent scores for the m-PASI assessment might not have been conducted as per

LP0053-1001 04-Mar-2014 of 315

protocol at this site (Section 7.2). Consequently, sensitivity analyses excluding this site were

conducted for all PASI endpoints. For these sensitivity analyses, separate multiple imputation

datasets were generated excluding data from the site.

6.2.7.3 Further (Tertiary) Endpoints

6.2.7.3.1 Investigator’s Assessments

Investigator’s Global Assessment of Disease Severity (IGA)


IGA at all visits were tabulated for each treatment group.

The number and proportion of subjects in each of the 5 categories (‘clear’ to ‘severe’) were

tabulated for each of the treatments, pooling all centres. These tabulations were intended for

descriptive purposes only and no statistical analyses of these data were undertaken.

PASI-50 and PASI-75

The number and proportion of subjects who achieved at least a 50% reduction in m-PASI

from baseline (PASI-50) were tabulated at each visit for each treatment group. The number

and proportion of subjects who achieved at least a 75% reduction in m-PASI from baseline

(PASI-75) were presented similarly.

The odds ratio of proportion of PASI-50 at Week 4 for LEO 90100 relative to vehicle was

estimated using the Cochran-Mantel-Haenszel method adjusting for (pooled) centre. The odds

ratio of proportion of PASI-75 at Week 4 for LEO 90100 relative to vehicle was estimated

similarly.

Investigator’s Assessment of Severity of the Target Lesion

The severity of clinical signs of the target lesion (redness, thickness, scaliness) was tabulated

by visit. These tabulations were intended for descriptive purposes only and no statistical

analyses of these data were undertaken.

Change in BSA Involvement from Baseline (Day 0; Visit 1) to Week 1, Week 2, and Week

4

The change in BSA involvement from baseline to each visit was summarised for each

treatment group. These tabulations were intended for descriptive purposes only and no statisti-

cal analyses of these data were undertaken.

LP0053-1001 04-Mar-2014 of 315

6.2.7.3.2 Subject’s Assessments

For the analysis of the subject reported assessments described below no adjustments of p-

values for multiplicity were done.

Patient’s Global Assessment of Disease Severity (PaGA)

The number and proportion of subjects in each of the five categories (‘clear’ to ‘severe’) were

tabulated at each visit for each treatment group.


PaGA at Week 1, Week 2, and Week 4 were tabulated for each treatment. The proportion of

subjects achieving ‘treatment success’ at week 4 was analysed similarly to analyses conducted

for PASI-50.

Subject’s Assessment of Itch by Use of a Visual Analogue Scale

The change in the VAS from baseline to each visit was summarised for each treatment group.

For the change in the VAS from baseline to Day 3, Day 5, Week 1, Week 2, and Week 4, the

LEO 90100 and the vehicle arms were compared using ANOVA including (pooled) centre,

treatment and baseline VAS score in the model. For the adjusted difference of LEO 90100 to

vehicle, the corresponding p-value as well as a 95% confidence interval was calculated for

each week.

The proportion of subjects who achieved at least a 50% itch reduction from baseline in the

VAS was tabulated by time-point and compared between treatment groups at each time-point

using the Cochran-Mantel-Haenszel method adjusting for (pooled) centre. The number of

subjects who achieved at least a 70% reduction was analysed similarly.

Subject’s Assessment of Itch-Related Sleep Loss by Use of a Visual Analogue Scale

The change in the VAS from baseline to each visit was summarised for each treatment group.

For the change in the VAS from baseline to Day 3, Day 5, Week 1, Week 2, and Week 4, the

LEO 90100 and the vehicle arms were compared using ANOVA including (pooled) centre,

treatment and baseline VAS score in the model. For the adjusted difference of LEO 90100 to

vehicle, the corresponding p-value as well as a 95% confidence interval was calculated for

each week.

The proportion of subjects who achieved at least a 50% reduction in itch-related sleep loss

from baseline in the VAS was tabulated by time-point and compared between treatment

groups at each time-point using the Cochran-Mantel-Haenszel method adjusting for (pooled)

centre. The number of subjects who achieved at least a 70% reduction was analysed similarly.

LP0053-1001 04-Mar-2014 of 315

Subjects with no itch at baseline were excluded from these responder analyses of itch and

itch-related sleep loss.

Change in DLQI from Baseline (Day 0; Visit 1) to Week 1, Week 2 and Week 4

The change in DLQI score from baseline was analysed as the analysis of subject’s assessment

of itch.

Change in EQ-5D-5L from Baseline (Day 0; Visit 1) to Week 4

For each dimension, the number and proportion of subjects in each of the five categories

(scored as 1 to 5) were tabulated at baseline and Week 4 for each treatment group.

For each EQ-5D-5L dimension, the distribution of subjects in the 5 categories at Week 4 was

compared between treatment groups using a proportional odds model.

The change in EQ-5D-5L index score from baseline to Week 4 was calculated and analysed as

the analysis of subject’s assessment of itch.

The EQ VAS scores were summarised by visit and treatment group. The change in EQ VAS

from baseline to Week 4 was analysed as subject’s assessment of itch.

6.2.7.4 Handling of Drop-outs and Missing Values

Missing values for the primary and secondary endpoints were handled using a multiple

imputation method. The imputation method relied on an assumption that the missing data

were missing at random, i.e. that the probability that an observation was missing could

depend on observed data but was unrelated to the data not observed. Missing values for IGA

were imputed sequentially for Visits 2, 3, and 4 from an ordinal logistic regression model

using the IGA values at the previous visits, treatment group and (pooled) centre as covariates.

The outcome "treatment success" was derived from the imputed IGA values. Missing values

for m-PASI were imputed sequentially for Visits 2, 3 and 4 from a linear regression model

using the values of m-PASI at the previous visits, treatment group and (pooled) centre as

covariates.

Sensitivity analyses of the method of handling missing data were performed. As a sensitivity

analysis not relying on the missing at random (MAR) assumption, control-based pattern

imputation was used, i.e. a multiple imputation procedure where the imputation model was

estimated using data from vehicle treated subjects only (23). Also last observation carried

forward (LOCF), non-responder imputation and a complete case analysis were performed as

sensitivity analyses. For the non-responder imputation sensitivity analysis, missing values

LP0053-1001 04-Mar-2014 of 315

were imputed as no treatment success for the IGA endpoint and imputed as the baseline m-

PASI value for the m-PASI endpoints.

If a monotone missing pattern did not exist (i.e. one or more subjects with missing data at

intermediate visits), data at intermediate visits were imputed using the Markov Chain Monte

Carlo (MCMC) method as implemented in SAS® PROC MI including treatment arm effect

and outcome at Visits 1 to 4 as continuous variables. For the IGA outcome, the MCMC

imputed missing values were rounded to nearest integer between 0 and 4. For the m-PASI

outcome, any negative MCMC imputed values were set to 0, and values above 64.8 were set

at 64.8. For each MCMC imputed dataset with monotone missingness structure, the remaining

data were imputed following the methods described above. For the control-based pattern

imputation, the imputation was performed in separate steps for each visit following the

method described in (23). In the final imputed datasets, any negative m-PASI values were set

to 0 and m-PASI values above 64.8 were set to 64.8.

For the primary endpoint, imputation was based on an ordinal logistic regression model.

Convergence of the models used for imputation was examined at each visit by fitting the

logistic model based on observed data with IGA at the current visit as outcome variable and

IGA at previous visits, treatment group and pooled site as covariates. Based on blinded data,

no convergence problems were seen when fitting these models using any random treatment

assignment as replacement for the unknown treatment group variable. The convergence

including actual treatment assignment as a covariate was confirmed after unblinding. For the

control-based pattern imputation sensitivity analysis, the imputation model was fit based on

vehicle treated subjects only, which may cause convergence problems due to increased

sparseness of the data. If convergence problems were seen, IGA values at one or more visits

were collapsed to the extent necessary to obtain model convergence.

After unblinding note: To obtain model convergence for the control-based pattern imputation

sensitivity analysis, IGA categories ‘moderate’ and ‘severe’ were collapsed at Visit 1 and Visit

2, and the ‘clear’, ‘almost clear’ and ‘mild’ categories were collapsed at Visit 2 for the

purpose of this analysis. Also pooled site was not used as an explanatory variable in the

imputation model for the control-based pattern imputation.

For PASI-50 and PASI-75, missing values were handled using multiple imputation. The

imputed PASI datasets were the same as those used for the analysis of the secondary

endpoints.

For the remaining endpoints (PaGA and quality of life), an observed cases approach was used.

LP0053-1001 04-Mar-2014 of 315

For subjects withdrawing at Visit 2 or Visit 3 EQ-5D-5L data, laboratory data, and vital signs

from the last visit (if available) were presented together with Visit 4 data since these

assessments were not planned to be recorded at Visit 2 and Visit 3.

There were no attended visits with missing values of the primary and/or secondary endpoints.

Hence, the extent of missing values for the primary endpoint was 14/426=3.3% corresponding

to 14 withdrawn subjects, and the extent of missing values for the secondary endpoints were

8/426=1.9% (Week 1) and 14/426=3.3% (Week 4).

6.2.8 Analysis of Safety

The analysis of safety was based on the safety analysis set.

6.2.8.1 Adverse Events

Adverse events (AEs) were coded during the course of the trial in accordance with the current

version of the Medical Dictionary for Regulatory Activities (MedDRA) dictionary. The AEs

were presented by preferred terms and primary system organ class (SOC).

All AEs recorded during the course of the trial were included in the subject data listings. An

event was considered emergent with the trial treatment if started after the first application or if

started before the first application (applicable if subject had a wash-out) and worsened in

intensity after. One AE (abdominal discomfort, subject No. ) started before

randomisation and was excluded from tabulations. Two AEs (subject No. , contact

dermatitis, subject No. , psoriasis flare) started after Visit 4, but were included in

tabulations.

An overall summary table was prepared to show the number of subjects with any AEs, ADRs,

SAEs, AEs leading to withdrawal from the trial, AEs leading to discontinuation of treatment,

and/or lesional/perilesional AEs.

The number of subjects experiencing any type of AE (according to MedDRA Preferred Term

within primary SOC) was tabulated by treatment group regardless of the number of times

each AE was reported by each subject. The percentage of subjects with AEs was compared

between treatment groups by a chi-square test or Fisher’s exact test.

The intensity for each type of AE (according to the preferred term) was tabulated by treatment

group. If there were several recordings of intensity for a given type of AE (according to the

Preferred Term), intensity was taken as the most severe recording for that AE.

LP0053-1001 04-Mar-2014 of 315

The causal relationship to investigational product for each type of AEs (according to the

coding system) was tabulated by treatment group. If there were several recordings of causal

relationship to investigational product for a given type of AE (according to the coding

system), causal relationship was taken as the worst recording from the last report of that AE,

since that is when the investigator was in possession of the most information and so was best

able to judge causal relationship.

ADRs were defined as AEs for which the investigator had not described the causal

relationship to trial medication as ‘not related’. The number of subjects who experienced each

type of ADR (according to the preferred term) was tabulated regardless of the number of

times each ADR was reported by each subject. The percentage of subjects with ADRs was

compared between treatment groups by a chi-square test or Fisher’s exact test.

Finally, tabulations by preferred term and SOC were given for SAEs, AEs leading to

withdrawal from the trial, AEs leading to discontinuation of treatment and

lesional/perilesional AEs.

6.2.8.2 Laboratory Safety Examinations

Biochemistry

The change in albumin-corrected serum calcium from baseline to Week 4 was summarised for

each treatment group.

The albumin-corrected serum calcium was classified as ‘low’, ‘normal’ or ‘high’, depending

on whether the value was below, within or above the reference range, respectively. A shift

table was produced showing the categories at baseline against those at Week 4. Subjects with

albumin-corrected serum calcium outside the reference range were listed. Laboratory

reference ranges are provided in Appendix 2.8 Listing 8-1.

Additionally a shift table as described above was produced based on LEO defined clinically

significant values. The low and high threshold level for concern for a clinically significant

change for albumin-corrected serum calcium was <2.0 mmol/L and >2.9 mmol/L,

respectively.

The Vitamin D level was classified as ‘low’, ‘normal’ or ‘high’, depending on whether the

value was below, within or above the reference range, respectively, at Visit 1.

Urinalysis

The change in the urinary calcium:creatinine ratio from baseline to Week 4 was summarised

for each treatment group.

LP0053-1001 04-Mar-2014 of 315

The calcium:creatinine ratio was classified as ‘low’, ‘normal’ or ‘high’, depending on whether

the value was below, within or above the reference range, respectively. A shift table was

produced showing the categories at baseline against those at Week 4. Subjects with

calcium:creatinine ratio outside the reference range were listed. Laboratory reference ranges

are provided in Appendix 2.8 Listing 8-1.

6.2.8.3 Vital Signs

The change in vital signs (blood pressure, heart rate) from baseline to Week 4 was

summarised as mean, SD, median, minimum, and maximum values for each treatment group.

6.2.8.4 Evaluation of Local Safety and Tolerability

The five assessments of local safety and tolerability were summarised and presented

graphically for each treatment group as categorical data at all visits for the safety analysis set.

6.3 Changes to the Statistical Analysis Plan

There were no changes to the planned statistical analyses described in the clinical study

protocol (Appendix 1.1) and in the SAPU (Appendix 1.9).

6.4 Software and Dictionaries

SAS ® version 9.3 was used to create listings, tables, and figures, and for power calculations

and statistical analyses.

MedDRA version 16.0 was used for coding of AEs and medical history.

WHO-DD version 1.Q13 was used for coding concomitant medication.

LP0053-1001 04-Mar-2014 of 315

7 Trial Population

7.1 Disposition of Subjects

In total, 491 subjects from 27 centres in the USA were enrolled into the trial (i.e., informed

consent form signed and subject number assigned) ((End-of-Text [EoT] Table 1-3). The first

subject was enrolled on 17-Jun-2013 and the last subject completed the trial (last visit) on 02-

Oct-2013.

All 491 subjects were screened, among whom 65 were screening failures. The most common

reasons for failing screening were not fulfilling inclusion criteria No. 7, 8, 9, and 11 (i.e,

criteria related to the required disease severity in terms of % BSA, IGA and m-PASI; see

Appendix 2.2 Listing 1-1). The remaining 426 subjects were randomised; 323 to LEO 90100

and 103 to vehicle (EoT Table 1-1).

In total, 14 of the randomised subjects withdrew from the trial and 412 (97%) subjects

completed the trial. The most common reason for withdrawal was ‘lost to follow-up’

(8 subjects).

The number of subjects who attended each visit is shown in Figure 7–1 and are presented by

treatment group in Figure 7–2 and Figure 7–3.

LP0053-1001 04-Mar-2014 of 315

Figure 7–1 Visit Attendance: All Enrolled Subjects

Note: the 2 subjects who withdrew for other reasons were unable to continue in the trial for logistical reasons.

Cross-reference: EoT Figure 1-5.

418

416

412

5

1

Number of subjects

65

3 not attending

Primary reason for

withdrawal

Visit 1 (Randomisation)

Visit 1 (Enrolled)

Visit 2 (Week 1)

Visit 3 (Week 2)

Visit 4 (Week 4)

2 lost to follow-up ( )1 other reason(s) ( )2 voluntary ( )

426

491

8

1 lost to follow-up ( )


1 other ( )2 voluntary ( )

1 not attending

2 not attending

65 screen failure

LP0053-1001 04-Mar-2014 of 315

Figure 7–2 Visit Attendance by Treatment – LEO 90100


316

315

313

4

1

Number of subjects

2 not attending

Primary reason for

withdrawal


Visit 2 (Week 1)

Visit 3 (Week 2)

Visit 4 (Week 4)


2 voluntary ( )

323

5



1 other ( )

1 not attending

2 not attending

LP0053-1001 04-Mar-2014 of 315

Figure 7–3 Visit Attendance by Treatment – Vehicle


7.2 Protocol Deviations

Deviations from Inclusion and Exclusion Criteria

All randomised subjects fulfilled all inclusion and exclusion criteria.

Procedure Compliance Deviations

One site (Site confirmed by signature of a protocol deviation that they could not

confirm that the scores given for the m-PASI assessments conformed to the directions

specified in the consolidated clinical study protocol. It was identified that the errors in clinical

judgment were isolated to the extent calculation in the m-PASI transformation and were not

implicated in any other investigator assessments. The site recruited several subjects and hence

completed multiple randomisation blocks. Any effect was therefore expected to be balanced

between LEO 90100 and the vehicle group with a limited impact on the results of the trial.

Nevertheless, before unblinding, LEO decided to perform and report the outcome of

102

101

99

1

Number of subjects

1 not attending

Primary reason for

withdrawal


Visit 2 (Week 1)

Visit 3 (Week 2)

Visit 4 (Week 4)

1 other reason(s) ( )

103

31 lost to follow-up ( )2 voluntary ( )

LP0053-1001 04-Mar-2014 of 315

sensitivity analyses excluding Site for all PASI endpoints as described in Section

6.2.7.2 and in the SAPU.

In total, 7 subjects were dispensed incorrect kits in error. For each of these subjects it was

determined after unblinding whether the dispensed kit contained the correct treatment (i.e. the

treatment the subject was randomised to). If not, the subject was to be excluded from the per

protocol analysis set (see Section 7.3.3).

In total, 8 subjects missed more than 7 treatment applications (corresponding to 25% of all

planned applications). For 7 subjects, these applications were all missed due to approved stop

(i.e. clearance). The last subject missed 8 applications, but exceeded also the allowed visit

window of 5 days for Visit 4 and was therefore excluded from the per protocol analysis set

(Section 7.3.3).

Additional protocol deviations in this trial were 14 subjects who did not attend Visit 4, 1

subject who received treatment with methylprednisolone from Day 8 to Day 12, and 12

subjects who attended Visit 4 more than 5 days after the scheduled visit date.

Important protocol deviations related to procedure compliance that led to exclusion from the

per protocol analysis set were identified for 28 subjects (see EoT Table 1-4 and Section 7.3.3)

For information regarding the criteria for exclusion of subjects from the per protocol analysis

set, see Section 7.3.3.

Protocol deviations are listed in Appendix 2.2 and are also detailed in the SAPU (Appendix

1.9).

7.3 Trial Analysis Sets

The analysis sets were determined based on the criteria defined in Section 6.2.3, according to

the consolidated clinical study protocol (Appendix 1.1) and the SAPU (Appendix 1.9). All

decisions on the inclusion and exclusion of subjects from analyses were made while the data

were still blinded.

7.3.1 Full Analysis Set

All 426 randomised subjects were included in the full analysis set.

7.3.2 Safety Analysis Set

All 426 randomised subjects received treatment with investigational product, had presence or

confirmed absence of AEs, and were therefore included in the safety analysis set.

LP0053-1001 04-Mar-2014 of 315

7.3.3 Per Protocol Analysis Set

The per protocol analysis set was defined by excluding subjects from the full analysis set who

Provided no efficacy data following start of treatment

Received no treatment with investigational product

Took the wrong investigational product during the treatment phase of the trial

Did not fulfil the disease defining inclusion criteria (i.e. inclusion criteria 7, 8, 9, 10 and

11; see Section 5.3.1)

Violated Visit 4 (Day 28) extended visit window of +/- 5 days

Did not attend Visit 4

Missed more than 25% of applications of investigational product on the trunk/limbs

Received concomitant medication that could affect psoriasis

In total, 28 subjects were excluded from the per protocol analysis set for the reasons stated

above and were distributed as follows:

14 subjects who did not attend Visit 4

1 subject who received treatment with methylprednisolone from Day 8 to Day 12

12 subjects who attended Visit 4 more than 5 days after the scheduled visit date

1 subject who was dispensed an incorrect kit in error. The subject was randomised to

LEO 90100, but received vehicle at Visit 1. The subject received treatment according to

the randomisation at Visit 2 and Visit 3 and except for the per protocol analysis where the

subject was excluded, all data from this subject was analysed according to the

randomisation.

The per protocol analysis set thus comprised 398 subjects.

Individual data on subjects excluded from the analysis sets are listed in Appendix 2.3 Listing

3-1 and the reasons for exclusions from analysis sets are presented in Appendix 2.3 Listing 3-

2.

The number of subjects in the trials analysis sets is presented by treatment in Figure 7–4 and

Figure 7–5.

LP0053-1001 04-Mar-2014 of 315

Figure 7–4 Trial Analysis Sets by Treatment – LEO 90100


Figure 7–5 Trial Analysis Sets by Treatment – Vehicle


7.4 Demographic and other Baseline Characteristics

7.4.1 Demographic Data

Demographic data (sex, race, ethnicity, and skin type) are summarised in Table 7–1.

Of the 426 randomised subjects, 253(59.4%) were men and 173 (40.6%) were women (Table

7–1) and their mean age was 50.0 years (range: 18 to 87 years) (EoT Table 1-5). In total, 366

(85.9%) subjects were white and 319 (74.9%) self-reported Not Hispanic or Latino ethnicity.

All skin types were represented, with the most common being type II (25.4%), type III

(30.8%), and type IV (25.8%).

Demographic data are summarised by centre EoT for the following parameters: age (EoT

Table 1-16), sex (EoT Table 1-17), ethnicity (EoT Table 1-18), race (EoT Table 1-19), and

IGA (EoT Table 1-20).

Summary displays of height, weight, and BMI for all randomised subjects are presented in

EoT Table 1-5.

Randomised subjects

=Full analysis set

=Safety analysis set

Per protocol analysis set

10 withdrew prior to Visit 4

9 violated Visit 4 visit window1 disallowed treatment

1 wrong kit dispensed302

323

Randomised subjects

=Full analysis set



4 withdrew prior to Visit 4

3 violated Visit 4 visit window

96

103

LP0053-1001 04-Mar-2014 of 315

Individual subject demographic, both disease-related and other baseline data, are enclosed in

Appendix 2.4.

LP0053-1001 04-Mar-2014 of 315

Table 7–1 Sex, Race, Ethnicity and Skin Type: Randomised Subjects

All randomised subjects(n=426)

LEO 90100(n=323)

Vehicle(n=103)

Baseline Characteristic

Number of subjects %



SexMale 253 59.4 204 63.2 49 47.6 Female 173 40.6 119 36.8 54 52.4 Total 426 100.0 323 100.0 103 100.0

RaceWhite 366 85.9 276 85.4 90 87.4 Black or african american

30 7.0 24 7.4 6 5.8

Asian 13 3.1 10 3.1 3 2.9 American indian or alaska native

4 0.9 3 0.9 1 1.0

Native hawaiian or other pacificislander

3 0.7 2 0.6 1 1.0

Other 10 2.3 8 2.5 2 1.9 Total 426 100.0 323 100.0 103 100.0

EthnicicyNot hispanic or

latino 319 74.9 238 73.7 81 78.6

Hispanic or latino 107 25.1 85 26.3 22 21.4 Total 426 100.0 323 100.0 103 100.0

Skin typeType I = White:

always burns easily; nevertans

20 4.7 16 5.0 4 3.9

Type II = White: always burnseasily; tansminimally

108 25.4 83 25.7 25 24.3

Type III = White: burns moderately;tans gradually(light brown)

131 30.8 92 28.5 39 37.9

Type IV = White: burns minimally; alwaystans well (moderatebrown)

110 25.8 89 27.6 21 20.4

Type V = Brown: rarely burns; tansprofusely (darkbrown)

42 9.9 33 10.2 9 8.7

Type VI = Black: never burns; deeplypigmented

15 3.5 10 3.1 5 4.9

Total 426 100.0 323 100.0 103 100.0

29NOV13:11:17:21 LP0053 1001 t06_sex_race.doc

Cross-reference: EoT Table 1-6.

LP0053-1001 04-Mar-2014 of 315

7.4.2 Disease-Related Baseline Characteristics

The key disease-related baseline characteristics are summarised in Table 7–2 to Table 7–6.

Overall, disease-related characteristics at baseline were in line with the targeted trial

population. All subjects fulfilled eligibility requirements to a minimum duration of psoriasis

vulgaris of 6 months (range: 1-67 years), a BSA of 2 to 30% (range: 2-30%), an IGA of at

least ‘mild’ in severity, and an m-PASI score of at least 2 (range 2-47).

At baseline, the IGA of the psoriasis vulgaris on the trunk and limbs was ‘moderate’ in the

majority of subjects (74.9%), while 15.3% and 9.9%, respectively, had ‘mild’ and ‘severe’

disease (Table 7–3). Baseline IGA scores were comparable between treatment groups.

The assessment of the extent of psoriasis on other locations included the scalp (51.4% of

subjects), the nails (26.8%), the skin folds (25.6%), the face (23.2%), and the genitals (16.0%)

(Table 7–4). In total, 87.6% of subjects had previously received treatment for their psoriasis,

most frequently with topical corticosteroids (75.1% of subjects) (Table 7–5), none of which

had been used within 2 weeks prior to randomisation.

The majority of target lesions were located on the limbs (67.4%) and the trunk (20.7%), while

only a minority was located on the elbow (8.2%) or knee (3.8%) (Table 7–6).

Levels of 25-hydroxy vitamin D at baseline were ‘low’ in 311 (73.5%) and ‘normal’ in 112

(26.5%) of subjects, with no noteworthy differences between treatment groups (EoT Table 1-

14).

There were no clinically relevant observations with regard to vital signs at baseline (EoT

Table 1-15).

LP0053-1001 04-Mar-2014 of 315

Table 7–2 Duration of Psoriasis Vulgaris, BSA and Baseline m-PASI: Randomised Subjects



LEO 90100(n=323)

Vehicle(n=103)

Duration of Psoriasis Vulgaris (years) Mean 15.9 16.3 14.9 SD 13.8 14.4 11.4 Median 11.0 10.0 11.0 Minimum 1 1 1 Maximum 67 67 53 Number 426 323 103 BSA (%) Mean 7.5 7.4 8.0 SD 6.5 6.4 7.0 Median 5.0 5.0 5.0 Minimum 2 2 2 Maximum 30 30 30 Number 426 323 103 m-PASI Mean 7.5 7.4 7.9 SD 5.3 4.8 6.6 Median 6.0 6.0 6.1 Minimum 2 2 2 Maximum 47 37 47 Number 426 323 103

28NOV13:12:13:34 LP0053 1001 t07dur.doc


Table 7–3 Baseline IGA: Randomised Subjects


LEO 90100(n=323)

Vehicle(n=103)

Baseline IGANumber of subjects %



Mild 65 15.3 50 15.5 15 14.6 Moderate 319 74.9 244 75.5 75 72.8 Severe 42 9.9 29 9.0 13 12.6 Total 426 100.0 323 100.0 103 100.0

28NOV13:12:13:50 LP0053 1001 t08baseiga.doc


LP0053-1001 04-Mar-2014 of 315

Table 7–4 Other Locations of Psoriasis: Randomised Subjects


LEO 90100(n=323)

Vehicle(n=103)

Location of Psoriasis Vulgaris




Psoriasis vulgaris on the faceYes 99 23.2 73 22.6 26 25.2 No 327 76.8 250 77.4 77 74.8 Total 426 100.0 323 100.0 103 100.0

Psoriasis vulgaris on the skin foldsYes 109 25.6 86 26.6 23 22.3 No 317 74.4 237 73.4 80 77.7 Total 426 100.0 323 100.0 103 100.0

Psoriasis vulgaris on the genitalsYes 68 16.0 53 16.4 15 14.6 No 358 84.0 270 83.6 88 85.4 Total 426 100.0 323 100.0 103 100.0

Psoriasis vulgaris on the nailsYes 114 26.8 88 27.2 26 25.2 No 312 73.2 235 72.8 77 74.8 Total 426 100.0 323 100.0 103 100.0

Psoriasis vulgaris on the scalpYes 219 51.4 167 51.7 52 50.5 No 207 48.6 156 48.3 51 49.5 Total 426 100.0 323 100.0 103 100.0

28NOV13:12:13:57 LP0053 1001 t09locations.doc


LP0053-1001 04-Mar-2014 of 315

Table 7–5 Previous Psoriasis Treatments: Randomised Subjects


LEO 90100(n=323)

Vehicle(n=103)

Previous treatmentsNumber of subjects %



Phototherapy 92 21.6 71 22.0 21 20.4 Systemic: any treatment (excludingbiologics)

53 12.4 39 12.1 14 13.6

Systemic: biologics 50 11.7 37 11.5 13 12.6 Topical: calcineurin inhibitors

10 2.3 7 2.2 3 2.9

Topical: coal tar 114 26.8 96 29.7 18 17.5 Topical: corticosteroids

320 75.1 244 75.5 76 73.8

Topical: fixed combinationcorticosteriod plusVitamin D analogues

70 16.4 56 17.3 14 13.6

Topical: Vitamin D analogues

69 16.2 56 17.3 13 12.6

Total number of subjects

373 87.6 287 88.9 86 83.5

06FEB14:09:30:15 LP0053 1001 t10prevtrt.doc


Table 7–6 Target Lesion Location: Randomised Subjects


LEO 90100(n=323)

Vehicle(n=103)

Target lesion location




Elbow 35 8.2 25 7.7 10 9.7 Knee 16 3.8 14 4.3 2 1.9 Limbs 287 67.4 215 66.6 72 69.9 Trunk 88 20.7 69 21.4 19 18.4 Total 426 100.0 323 100.0 103 100.0

28NOV13:12:14:23 LP0053 1001 t13target.doc


7.4.3 Medical History and Use of Concomitant Medication

A full list of medical history and concomitant medications used during the trial is given in

Appendix 2.4. No medical history or use of concomitant medications contradicted the

eligibility requirements. One subject received concomitant medication (methylprednisolone)

during the trial that could affect psoriasis and this subject was therefore excluded from the per

protocol analysis set (Section 7.3.3).

LP0053-1001 04-Mar-2014 of 315

8 Exposure and Treatment Compliance

8.1 Exposure

The duration of exposure to treatment was calculated as the number of days from Visit 1 to

the date of last application of investigational product (Section 6.2.6).

The duration and extent of exposure to treatment are summarised in Table 8–1 for the safety

analysis set. The average weekly amount of investigational product and the total amount of

investigational product used during each visit interval and over the entire trial period is shown

in Table 8–2 and Table 8–3, respectively.

The mean duration of treatment was approximately 4 weeks in both treatment groups (Table

8–1). The mean amount of investigational product used per week over the total treatment

period was comparable between LEO 90100 (29.8 g) and vehicle (32.1 g) and the mean

weekly amounts recorded during each visit interval were also similar (Table 8–2). The total

amount of exposure during the treatment period was well balanced between treatment groups

(LEO 90100:120.8 g; vehicle: 128.9 g) (Table 8–3).

Table 8–1 Duration and Extent of Exposure to Treatment: Safety Analysis Set

Exposure (weeks)LEO 90100(n=323)

Vehicle(n=103)

Mean 4.0 4.1 SD 0.6 0.6 Minimum 0.1 0.1 Maximum 6.0 6.3 Number 323 103 Extent of exposure to treatment(subject-treatment-weeks)

1290 418

28NOV13:12:11:54 LP0053 1001 t01expo.doc


LP0053-1001 04-Mar-2014 of 315

Table 8–2 Average Weekly Amount of Trial Medication Used: Safety Analysis set

IntervalAmount (grams per week)

LEO 90100(n=323)

Vehicle(n=103)

Baseline to week 1Mean 29.9 32.9 SD 21.9 23.5 Median 22.5 25.5 Minimum 0.9 2.7 Maximum 97.3 87.7 Number 314 101

Week 1 to week 2Mean 28.5 32.6 SD 23.1 24.1 Median 20.4 23.4 Minimum 0.0 2.0 Maximum 121.5 89.0 Number 309 100


Total treatment periodMean 29.8 32.1 SD 21.2 23.6 Median 24.3 23.1 Minimum 2.1 2.5 Maximum 89.7 87.7 Number 293 98

28NOV13:14:52:09 LP0053 1001 t02amount.doc


LP0053-1001 04-Mar-2014 of 315

Table 8–3 Total Amount of Trial Medication Used: Safety Analysis Set

IntervalAmount (grams)

LEO 90100(n=323)

Vehicle(n=103)





28NOV13:14:59:57 LP0053 1001 t03totamount.doc


8.2 Treatment Compliance

At all on-treatment visits, the subject was asked if she/he has used the investigational product

as prescribed. Compliance with treatment instructions for the assigned investigational product

was comparable between treatment groups, as shown in Table 8–4 and is presented by visit in

EoT Table 1-23. In general, subjects were compliant with treatment instructions throughout

the trial, but with a lower compliance frequency between Week 2 and Week 4 than previous

periods.

Individual subject data on drug accountability and compliance is presented in Appendix 2.5.

LP0053-1001 04-Mar-2014 of 315

Table 8–4 Compliance with Treatment Instructions Over the Total Trial Period: Randomised Subjects


LEO 90100(n=323)

Vehicle(n=103)

Compliance1Number of subjects %



No applications missed

331 78.6 243 76.2 88 86.3

<= 10% applications missed

67 15.9 54 16.9 13 12.7

>10% and <=20% applications missed

15 3.6 14 4.4 1 1.0


1 0.2 1 0.3 0 0.0


4 1.0 4 1.3 0 0.0

>50% applications missed

3 0.7 3 0.9 0 0.0

Total 421 100.0 319 100.0 102 100.0

28NOV13:14:21:52 LP0053 1001 t22cmptotal.doc

1) Percentage of applications missed between Visit 1 and last attended visit. Subjects withdrawn before Visit 2 not included in table.


LP0053-1001 04-Mar-2014 of 315

9 Efficacy Evaluation

9.1 Primary Efficacy Endpoint

The outcome of the primary endpoint analysis, subjects with ‘treatment success’ according to

the IGA at Week 4, is presented in Table 9–1 for the full analysis set (applying multiple

imputation for missing data). The proportion of subjects achieving ‘treatment success’ at

Week 4 was 53.3% in the LEO 90100 group and 4.8% in the vehicle group. LEO 90100 was

statistically significantly more effective than vehicle (odds ratio [OR] 30.3; 95% CI 9.7 to

94.3; p<0.001).

Similar results were obtained for the sensitivity analyses applying LOCF for missing data, the

vehicle-based multiple imputation analysis, the non-responder imputation analysis, and the

analysis for observed cases (EoT Table 2-3). In summary, results were robust to the method of

handling missing data due to the high completion rate in the trial. The results for the per

protocol analysis set were similar and thus supported the primary analysis (Table 9–2).

Table 9–1 Statistical Analysis of Treatment Success According to the IGA at Week 4 (Multiple Imputation): Full Analysis Set

LEO 90100(n=323)

Vehicle(n=103)

Treatment success Week 4Number of subjects %


Yes1 172.1 53.3 4.9 4.8 No1 150.9 46.7 98.1 95.2 Total 323 100.0 103 100.0 Odds ratio2 30.27 95% CI 9.72 to

94.30

p-value < 0.001 Breslow-Day test p-value3 0.14

06FEB14:09:31:20 LP0053 1001 t01_succ_fas.doc

1) Mean number of subjects across imputations.

2) Mantel-Haenszel odds of treatment success in LEO 90100 group relative to vehicle group, adjusted for pooled

centres.

3) Breslow-Day test for homogeneity of odds ratios across pooled centres.


LP0053-1001 04-Mar-2014 of 315

Table 9–2 Statistical Analysis of Treatment Success According to the IGA at Week 4: Per Protocol Analysis Set

LEO 90100(n=302)

Vehicle(n=96)



Yes 162 53.6 4 4.2 No 140 46.4 92 95.8 Total 302 100.0 96 100.0 Odds ratio2 28.28 95% CI 9.19 to

87.02


06FEB14:09:39:19 LP0053 1001 t02 succ pp.doc

1) No imputation since all subjects in per protocol analysis set completed the trial.

2) Mantel-Haenszel odds of treatment success in LEO 90100 group relative to vehicle group, adjusted for

pooled centres.



The percentage of subjects with treatment success according to IGA at Week 4 is presented by

(unpooled) centre for the full analysis set in EoT Table 2-7. There were no indications of

variability between centres.

Individual IGA subject data are presented in Appendix 2.6.

9.2 Secondary Efficacy Endpoints

9.2.1 m-PASI at Week 4 and Week 1

Mean m-PASI scores (averaged across multiple imputations) at Week 4 and Week 1 are

presented in Table 9–3 together with the results from the statistical analyses of m-PASI at

Week 4 followed by m-PASI at Week 1.

When adjusting for the effect of pooled centres and baseline m-PASI, the mean m-PASI at

Week 4 was 2.0 in the LEO 90100 group and 5.3 in the vehicle group with a statistically

significant difference between treatments (mean difference -3.3; 95% CI: -3.9 to -2.7;

p<0.001), thereby supporting the outcome of the analysis of the primary endpoint.

A reduction in mean m-PASI score was seen as early as Week 1 (Table 9–3). When adjusting

for the effect of pooled centres and baseline m-PASI, the mean m-PASI at Week 1 was 4.7 in

LP0053-1001 04-Mar-2014 of 315

the LEO 90100 group and 5.9 in the vehicle group and LEO 90100 was statistically

significantly more effective than vehicle (mean difference -1.3; 95% CI -1.8 to -0.8; p<0.001).

Similar results were obtained for the sensitivity analyses applying alternative imputation

methods for missing data (LOCF, the vehicle-based multiple imputation, the non-responder

imputation), and for observed cases (EoT Table 2-9 and EoT Table 2-10). For the sensitivity

analyses excluding Site the overall conclusions were unaltered, however lower mean

m-PASI scores were observed (EoT Table 2-34).

Table 9–3 Statistical Analyses of m-PASI at Week 4 and Week 1 (Multiple Imputation): Full Analysis Set

Mean m-PASI score1LEO 90100(n=323)

Vehicle(n=103)

Week 4 1.99 5.50 Week 4 adjusted2 2.04 5.33 Difference2 -3.28 95% CI -3.90 to -2.67 p-value2 < 0.001 Week 1 4.53 6.21 Week 1 adjusted2 4.66 5.93 Difference2 -1.27 95% CI -1.76 to -0.78 p-value2 < 0.001

02DEC13:13:21:17 LP0053 1001 t08 PASI mi.doc

1) Averaged across imputations.

2) Adjusted for the effect of pooled centres and baseline m-PASI by analysis of covariance.


9.3 Further (Tertiary) Endpoints

For the analysis of PASI 75 and PASI 50, missing data was handled using multiple

imputation. The analyses and/or tabulations of the remaining tertiary endpoints were based on

observed cases, i.e. no imputations were used.

9.3.1 Investigator’s Assessments

9.3.1.1 Treatment Success over Time

The percentage of subjects with ‘treatment success’ according to IGA as defined in Section

5.6.1.1 is presented by visit for the full analysis set in Table 9–4 and is depicted by visit in

Figure 9–1.

LP0053-1001 04-Mar-2014 of 315

In the LEO 90100 group, the proportion of subjects achieving ‘treatment success’ increased as

the trial progressed (Week 1: 8.5%; Week 2: 26.3%; Week 4: 53.4%), while only 1.0%, 2.0%,

and 4.0% of subjects allocated to the vehicle group obtained ‘treatment success’ at Week 1,

Week 2, and Week 4, respectively.

Table 9–4 Treatment Success According to the IGA by Visit (Observed Cases): Full Analysis Set

LEO 90100(n=323)

Vehicle(n=103)

VisitTreatment success (IGA)



Week 1Treatment success: Yes 27 8.5 1 1.0 Treatment success: No 289 91.5 101 99.0 Total 316 100.0 102 100.0



02DEC13:10:30:26 LP0053 1001 t04 succ vis.doc


LP0053-1001 04-Mar-2014 of 315

Figure 9–1 Treatment Success (IGA) by Visit (Observed Cases): Full Analysis Set


9.3.1.2 Investigator’s Global Assessment of Disease Severity

The individual IGA categories are presented by visit in Table 9–5. At baseline, the distribution

of IGA categories was comparable between treatment groups. The proportion of subjects with

‘severe’ disease was reduced in both treatment groups as early as Week 1. The proportion of

subjects with ‘severe’ disease decreased from 29 subjects (9%) at baseline to 0 subjects at

Week 4 in the LEO 9010 group, and from 13 subjects (12.6%) at baseline to 5 subjects (5.1%)

at Week 4 in the vehicle group. In the LEO 90100 group, the proportion of subjects with

‘clear’ or ‘almost clear’ disease increased over time and the proportion of subjects with

‘moderate’ disease decreased considerably more in the LEO 90100 group than in the vehicle

group, indicating continual improvement over time with active treatment.

LP0053-1001 04-Mar-2014 of 315

Table 9–5 IGA by Visit (Observed Cases): Full Analysis Set

LEO 90100(n=323)

Vehicle(n=103)

VisitIGA



BaselineMild 50 15.5 15 14.6 Moderate 244 75.5 75 72.8 Severe 29 9.0 13 12.6 Total 323 100.0 103 100.0

Week 1Clear 2 0.6 1 1.0 Almost clear 40 12.7 0 0.0 Mild 164 51.9 32 31.4 Moderate 103 32.6 63 61.8 Severe 7 2.2 6 5.9 Total 316 100.0 102 100.0



02DEC13:10:30:32 LP0053 1001 t05 iga vis.doc


‘Treatment success’ at Week 4 is presented by baseline disease severity in Table 9–6. In the

LEO 90100 group, ‘treatment success’ was achieved by 15 (30.6%) subjects with ‘mild’

severity at baseline, 141 (60.0%) subjects with ‘moderate’ disease severity at baseline, and 11

(37.9%) subjects with ‘severe’ disease severity at baseline. Corresponding rates were 0%, 3

(4.2%) subjects, and 1 (7.7%) subjects in the vehicle group. Note that the definition of

‘treatment success’ differs between subject groups (‘clear’ or ‘almost clear’ for subjects with

at least moderate disease at baseline, and ‘clear’ for subjects with mild disease at baseline).

LP0053-1001 04-Mar-2014 of 315

Table 9–6 Treatment Success According to the IGA at Week 4 by Baseline Disease Severity (Observed Cases): Full Analysis Set

LEO 90100(n=323)

Vehicle(n=103)

Baseline IGATreatment success (IGA)



MildTreatment success: Yes 15 30.6 0 0.0 Treatment success: No 34 69.4 14 100.0 Total 49 100.0 14 100.0

ModerateTreatment success: Yes 141 60.0 3 4.2 Treatment success: No 94 40.0 69 95.8 Total 235 100.0 72 100.0

SevereTreatment success: Yes 11 37.9 1 7.7 Treatment success: No 18 62.1 12 92.3 Total 29 100.0 13 100.0

02DEC13:10:30:37 LP0053 1001 t06 succ bas.doc


9.3.1.3 m-PASI over Time

The m-PASI was calculated from investigator’s assessment of extent and severity of the

disease locally (trunk, arms, legs) (Section 5.6.1.2).

m-PASI scores are summarised by visit in Table 9–7 and depicted in Figure 9–2. The

percentage changes in m-PASI scores compared to baseline (Week 0) are presented in Table

9–8. Decreasing m-PASI scores (indicating improvements) were observed successively during

the course of the trial. In the LEO 90100 group, the mean percentage decreases from baseline

were 38.3%, 58.3% and 72.3% at Week 1, Week 2, and Week 4, respectively (Table 9–8). In

the vehicle group, the mean percentage decreases at corresponding visits were 20.0%, 27.0%,

and 26.2%, respectively.

Slightly lower mean m-PASI scores were observed when excluding Site from the

dataset (Section 6.2.7.2, EoT Table 2-35, EoT Table 2-40, and EoT Figure 2-3).

LP0053-1001 04-Mar-2014 of 315

Table 9–7 m-PASI by Visit (Observed Cases): Full Analysis Set

Visitm-PASI

LEO 90100(n=323)

Vehicle(n=103)

BaselineMean 7.36 7.95 SD 4.83 6.63 Median 6.00 6.10 Minimum 2.0 2.0 Maximum 36.6 47.4 Number 323 103

Week 1Mean 4.54 6.23 SD 3.61 4.89 Median 3.60 5.00 Minimum 0.0 0.0 Maximum 26.0 33.6 Number 316 102



02DEC13:10:30:48 LP0053 1001 t11_PASI_vis.doc


LP0053-1001 04-Mar-2014 of 315

Figure 9–2 Mean m-PASI by Visit (Observed Cases): Full Analysis Set


LP0053-1001 04-Mar-2014 of 315

Table 9–8 Percentage Change in m-PASI by Visit (Observed Cases): Full Analysis Set

VisitPercentage change in m-

PASILEO 90100(n=323)

Vehicle(n=103)

Week 1Mean -38.3 -20.0 SD 24.8 25.7 Median -36.3 -18.9 Minimum -100.0 -100.0 Maximum 27.8 80.0 Number 316 102



02DEC13:10:33:13 LP0053 1001 t29 pchg PASI.doc


9.3.1.4 PASI-50 and PASI-75

The percentage of subjects with a 50% reduction in m-PASI is summarised by visit in Table

9–9. In the LEO 90100 group, the proportions of subjects achieving PASI-50 increased during

the course of the trial and were 32.6%, 65.7%, and 82.7% at Week 1, Week 2, and Week 4,

respectively. In the vehicle group, the proportion of subjects achieving PASI-50 at

corresponding visits were 13.7%, 20.8%, and 28.3%, respectively.

The percentage of subjects with a 50% reduction in m-PASI at Week 4 (applying multiple

imputation for missing data) was 82.3% in the LEO 90100 group and 28.0% in the vehicle

group (Table 9–10). LEO 90100 was statistically significantly more effective than vehicle

(OR 13.9; 95% CI 7.6 to 25.7; p<0.001).

Similar findings were obtained for the sensitivity analyses excluding Site (EoT Table 2-

36 and EoT Table 2-38).

LP0053-1001 04-Mar-2014 of 315

Table 9–9 PASI-50 by Visit (Observed Cases): Full Analysis Set

LEO 90100(n=323)

Vehicle(n=103)

VisitPASI-50



Week 1Yes 103 32.6 14 13.7 No 213 67.4 88 86.3 Total 316 100.0 102 100.0

Week 2Yes 207 65.7 21 20.8 No 108 34.3 80 79.2 Total 315 100.0 101 100.0

Week 4Yes 259 82.7 28 28.3 No 54 17.3 71 71.7 Total 313 100.0 99 100.0

02DEC13:10:31:09 LP0053 1001 t16 PASI50 vis.doc


Table 9–10 Statistical Analysis of PASI-50 at Week 4 (Multiple Imputation): Full Analysis Set

LEO 90100(n=323)

Vehicle(n=103)

PASI-50 Week 4Number of subjects %



25.73


02JAN14:15:19:28 LP0053 1001 t14 PASI50.doc


2) Mantel-Haenszel odds of PASI-50 in LEO 90100 group relative to vehicle group, adjusted for pooled centres.



The percentage of subjects with a 75% reduction in m-PASI is summarised by visit in Table

9–11. In the LEO 90100 group, the proportions of subjects achieving PASI-75 increased

during the course of the trial and were 9.2%, 31.4%, and 53.0% at Week 1, Week 2, and Week

LP0053-1001 04-Mar-2014 of 315

4, respectively. In the vehicle group, the proportion of subjects achieving PASI-75 at

corresponding visits were 1.0%, 2.0%, and 8.1%, respectively.

The percentage of subjects with a 75% reduction in m-PASI at Week 4 (applying multiple

imputation for missing data) was 52.9% in the LEO 90100 group and 8.2% in the vehicle

group (Table 9–12). LEO 90100 was statistically significantly more effective than vehicle

(OR 14.9; 95% CI 6.5 to 34.0; p<0.001).

Similar findings were obtained for the sensitivity analyses excluding Site (EoT Table 2-

37 and EoT Table 2-39).

Table 9–11 PASI-75 by Visit (Observed Cases): Full Analysis Set

LEO 90100(n=323)

Vehicle(n=103)

VisitPASI-75



Week 1Yes 29 9.2 1 1.0 No 287 90.8 101 99.0 Total 316 100.0 102 100.0

Week 2Yes 99 31.4 2 2.0 No 216 68.6 99 98.0 Total 315 100.0 101 100.0

Week 4Yes 166 53.0 8 8.1 No 147 47.0 91 91.9 Total 313 100.0 99 100.0



LP0053-1001 04-Mar-2014 of 315

Table 9–12 Statistical Analysis of PASI-75 at Week 4 (Multiple Imputation): Full Analysis Set

LEO 90100(n=323)

Vehicle(n=103)




33.98


02JAN14:15:20:48 LP0053 1001 t15 PASI75.doc


2) Mantel-Haenszel odds of PASI-75 in LEO 90100 group relative to vehicle group, adjusted for pooled centres.



9.3.1.5 Investigator’s Assessment of Severity of the Target Lesion

The severity of clinical signs of the target lesion (redness, thickness, scaliness) is tabulated by

visit in EoT Table 2-24.

At baseline, the severity of clinical signs of the target lesion was evaluated as ‘moderate’ or

‘severe’ in approximately 80-90% of subjects with no notable differences between treatment

groups. In the LEO 90100 group, the severity of the clinical signs of target lesions decreased

during the course of the trial and at Week 4, the redness, thickness, and scaliness of the target

lesion had disappeared completely in 32.6%, 57.5%, and 70.0% of subjects, respectively. The

corresponding rates in the vehicle group were 3.0%, 4.0%, and 18.2%, respectively.

9.3.1.6 Change in BSA Involvement over Time

At Week 4, the mean decrease from baseline in percentage BSA involvement of psoriasis on

the trunk and limbs (excluding skin folds and genitals) was 3.7%-points (baseline mean 7.4%)

in the LEO 90100 group and 1.0%-point (baseline mean 8.0%) in the vehicle group (EoT

Table 2-23).

LP0053-1001 04-Mar-2014 of 315

9.3.2 Subject’s Assessments

9.3.2.1 Patient’s Global Assessment of Disease Severity

Overall, the results for subject’s assessments of disease severity were in line with those of the

investigator. The individual PaGA categories are presented by visit in Table 9–13. At baseline,

the distribution of PaGA categories was comparable between treatment groups. The

proportion of subjects with ‘severe’ disease was reduced in both treatment groups as early as

Week 1. The proportion of subjects with ‘severe’ disease decreased from 61 subjects (18.9%)

at baseline to 4 subjects (1.3%) Week 4 in the LEO 9010 group, and from 22 subjects (21.4%)

at baseline to 10 subjects (10.1%) at Week 4 in the vehicle group. In the LEO 90100 group,

the proportion of subjects with ‘clear’ or ‘very mild’ disease increased over time and the

proportion of subjects with ‘moderate’ disease decreased considerably more in the LEO

90100 group than in the vehicle group, indicating continual improvement over time with

active treatment.

LP0053-1001 04-Mar-2014 of 315

Table 9–13 Patient's Global Assessment by Visit (Observed Cases): Full Analysis Set

LEO 90100(n=323)

Vehicle(n=103)

VisitPatients GlobalAssessment



BaselineVery mild 9 2.8 6 5.8 Mild 86 26.6 22 21.4 Moderate 167 51.7 53 51.5 Severe 61 18.9 22 21.4 Total 323 100.0 103 100.0

Week 1Clear 9 2.9 1 1.0 Very mild 60 19.0 17 16.7 Mild 138 43.8 38 37.3 Moderate 100 31.7 31 30.4 Severe 8 2.5 15 14.7 Total 315 100.0 102 100.0



02DEC13:10:31:21 LP0053 1001 t20 pga vis.doc


The proportion of subjects with ‘treatment success’ (‘clear’ or ‘very mild’) according to the

PaGA is presented by visit for the full analysis set in Table 9–14. In the LEO 90100 group, the

proportion of subjects achieving ‘treatment success’ increased as the trial progressed. The

outcome of the analysis of ‘treatment success’ according to PaGA at Week 4 is presented in

Table 9–15 for the full analysis set. At Week 4, ‘treatment success’ was achieved by 65.2% in

the LEO 90100 group and 22.2% in the vehicle group. LEO 90100 was statistically

significantly more effective than vehicle (OR 7.9; 95% CI 4.4 to 14.1; p<0.001).

LP0053-1001 04-Mar-2014 of 315

Table 9–14 Treatment Success According to Patient's Global Assessment by Visit (Observed cases): Full Analysis Set

LEO 90100(n=323)

Vehicle(n=103)

VisitTreatment success (Patients GlobalAssessment)



Week 1Yes 69 21.9 18 17.6 No 246 78.1 84 82.4 Total 315 100.0 102 100.0

Week 2Yes 133 42.2 22 21.8 No 182 57.8 79 78.2 Total 315 100.0 101 100.0

Week 4Yes 204 65.2 22 22.2 No 109 34.8 77 77.8 Total 313 100.0 99 100.0

02DEC13:10:32:17 LP0053 1001 t19 succp vis.doc


Table 9–15 Statistical Analysis of Treatment Success According to Patient's Global Assessment at Week 4 (Observed Cases): Full Analysis Set

LEO 90100(n=323)

Vehicle(n=103)

Treatment success Week 4(Patients Global Assessment)




14.11


06FEB14:09:34:48 LP0053 1001 t18 succp.doc

1) Mantel-Haenszel odds of ‘treatment success’ in LEO 90100 group relative to vehicle group, adjusted for

pooled centres.



LP0053-1001 04-Mar-2014 of 315

9.3.2.2 Subject’s Assessment of Itch as Assessed by Use of a Visual

Analogue Scale

Itch severity was assessed by subjects by means of a VAS (scale range 0 to 100 mm) as

described in Section 5.5.3.2. Subjects assessed itching as increasingly less severe during the

course of the trial, particularly in the LEO 90100 group. The results from the ANOVA for the

change from baseline (adjusted for baseline score and pooled centres) in the VAS are

presented in Table 9–16. At Week 4, the mean change from baseline (adjusted for pooled

centres and baseline score) was -43.1 in the LEO 90100 group and -22.7 in the vehicle group.

LEO 90100 was statistically significantly more effective than vehicle at all time-points

analysed.

LP0053-1001 04-Mar-2014 of 315

Table 9–16 Analysis of Change in Subject's Assessment of Itch (VAS) by Time Point (Observed Cases): Full Analysis Set

VisitItch VAS/Change in itch VAS

LEO 90100(n=323)

Vehicle(n=103)

BaselineMean 50.3 55.3 SD 29.7 29.4 Median 51.0 62.0 Minimum 0 0 Maximum 100 100 Number 323 102

Day 3 (change)Mean -22.9 -18.7 SD 24.5 24.3 Median -19.0 -15.0 Minimum -94 -71 Maximum 59 38 Number 312 98 Adjusted mean1 -23.5 -17.1 Difference1 -6.44 95% CI -11.33 to -1.55 p-value1 0.010

Day 5 (change)Mean -30.8 -23.3 SD 26.2 24.7 Median -27.0 -20.0 Minimum -100 -76 Maximum 45 31 Number 310 98 Adjusted mean1 -31.5 -21.3 Difference1 -10.26 95% CI -14.94 to -5.58 p-value1 < 0.001

Week 1 (change)Mean -33.9 -24.2 SD 27.7 25.3 Median -32.0 -22.0 Minimum -100 -77 Maximum 34 30 Number 314 101 Adjusted mean1 -34.8 -21.9 Difference1 -12.88 95% CI -17.59 to -8.17 p-value1 < 0.001

29JAN14:09:45:06 LP0053 1001 t21_itch_vas.doc Continued...

LP0053-1001 04-Mar-2014 of 315

Table 9–17 Analysis of Change in Subject's Assessment of Itch (VAS) by Time Point (Observed Cases): Full Analysis Set (Continued)


LEO 90100(n=323)

Vehicle(n=103)



29JAN14:09:45:06 LP0053 1001 t21 itch vas.doc

1) Calculated from ANOVA adjusted for pooled centres and baseline score.Cross-reference: EoT Table 2-21.

The outcome of the comparison (adjusted for pooled centres) between treatment groups of the

proportion of subjects who achieved at least a 70% itch reduction from baseline is presented

in Table 9–18. In the LEO 90100 group, 110 subjects (36.8%) achieved a 70% itch reduction

on Day 3. Responder rates in the LEO 90100 group increased successively during the course

of the trial, and at Week 4, 248 subjects (83.5%) had achieved a 70% itch reduction versus 39

subjects (40.6%) in the vehicle group. The odds ratio for achieving a 70% reduction in itch in

the LEO 90100 group relative to the vehicle group (adjusted for pooled centres) was

statistically significant at all time-points analysed (Table 9–18).

LP0053-1001 04-Mar-2014 of 315

Table 9–18 Analysis of Subjects Achieving a 70 Percent Reduction in Itch by Time Point (Observed Cases): Full Analysis Set

LEO 90100(n=323)

Vehicle(n=103)

Visit70 percent reduction in itch1



Day 3Yes 110 36.8 23 24.0 No 189 63.2 73 76.0 Total 299 100.0 96 100.0 Odds ratio2 1.89 95% CI 1.11 to 3.20 p-value 0.018

Day 5Yes 157 52.9 28 29.2 No 140 47.1 68 70.8 Total 297 100.0 96 100.0 Odds ratio2 2.74 95% CI 1.67 to 4.52 p-value < 0.001

Week 1Yes 181 60.1 31 31.3 No 120 39.9 68 68.7 Total 301 100.0 99 100.0 Odds ratio2 3.18 95% CI 1.97 to 5.15 p-value < 0.001


Week 4Yes 248 83.5 39 40.6 No 49 16.5 57 59.4 Total 297 100.0 96 100.0 Odds ratio2 7.01 95% CI 4.19 to

11.74

p-value < 0.001

02DEC13:10:33:40 LP0053 1001 t31 itch70.doc

1) Subjects with no itch at baseline are excluded from table.

2) Mantel-Haenszel odds of treatment response in LEO 90100 group relative to vehicle group, adjusted for

pooled centres.


Similar analyses were conducted for the proportion of subjects achieving a 50% itch reduction

and the results are presented in EoT Table 2-30. Responder rates in the LEO 90100 group

LP0053-1001 04-Mar-2014 of 315

increased successively during the course of the trial and, at Week 4, 264 subjects (88.9%) had

obtained a 50% itch reduction. The odds ratio for achieving a 50% itch reduction in the LEO

90100 group relative to vehicle group (adjusted for pooled centres) was statistically

significant at all time-points analysed (p=0.004 on Day 3 and p<0.001 at all subsequent visits)

(EoT Table 2-30).

9.3.2.3 Subject’s Assessment of Itch-Related Sleep Loss by Use of a Visual

Analogue Scale

Itch- related sleep loss was assessed by subjects by means of a VAS (scale range 0 to 100 mm)

as described in Section 5.5.3.2. Subjects assessed itch-related sleep loss as increasingly less

severe during the course of the trial, particularly in the LEO 90100 group. The results from

the ANOVA for the change from baseline (adjusted for baseline score and pooled centres) in

the VAS are presented in Table 9–19. At Week 4, the mean change from baseline (adjusted for

pooled centres and baseline score) was -21.9 in the LEO 90100 group and -10.0 in the vehicle

group. LEO 90100 was statistically significantly more effective than vehicle at all time-points

analysed (Table 9–19).

LP0053-1001 04-Mar-2014 of 315

Table 9–19 Analysis of Change in Subject's Assessment of Itch-Related Sleep Loss (VAS) by Time Point (Observed Cases): Full Analysis Set

VisitSleep loss VAS/Change in Sleep lossVAS

LEO 90100(n=323)

Vehicle(n=103)





29JAN14:09:42:12 LP0053 1001 t22_sleep_vas.doc Continued...

LP0053-1001 04-Mar-2014 of 315

Table 9–19 Analysis of Change in Subject's Assessment of Itch-Related Sleep Loss (VAS) by Time Point (Observed Cases): Full Analysis Set (Continued)


LEO 90100(n=323)

Vehicle(n=103)



29JAN14:09:42:12 LP0053 1001 t22 sleep vas.doc

1) Calculated from ANOVA adjusted for pooled centres and baseline score.


The outcome of the comparison (adjusted for pooled centres) between treatment groups of the

proportion of subjects who achieved at least a 70% reduction from baseline in itch-related

sleep loss is presented in Table 9–20. In the LEO 90100 group, 87 subjects (35.5%) achieved

a 70% reduction on Day 3. Responder rates in the LEO 90100 group increased successively

during the course of the trial, and at Week 4, 172 subjects (70.8%) had obtained a 70%

reduction in itch-related sleep loss versus 33 (39.8%) in the vehicle group. The odds ratio for

achieving a 70% reduction in itch-related sleep loss in the LEO 90100 group relative to the

vehicle group (adjusted for pooled centres) was statistically significant at all time-points

analysed (Table 9–20).

LP0053-1001 04-Mar-2014 of 315

Table 9–20 Analysis of Subjects Achieving a 70 Percent Reduction in Itch-Related Sleep Loss by Time Point (Observed Cases): Full Analysis Set

LEO 90100(n=323)

Vehicle(n=103)

Visit70 percent reduction in itch-related

sleep loss1Number of subjects %




Week 1Yes 126 51.2 30 34.9 No 120 48.8 56 65.1 Total 246 100.0 86 100.0 Odds ratio2 2.03 95% CI 1.21 to 3.40 p-value 0.007



02DEC13:10:33:49 LP0053 1001 t33_sleep70.doc

1) Subjects with no itch-related sleep loss at baseline are excluded from table.

2) Mantel-Haenszel odds of treatment response in LEO 90100 group relative to vehicle group, adjusted for

pooled centres.


Similar analyses were conducted for the proportion of subjects achieving a 50% reduction in

itch-related sleep loss and the results are presented in EoT Table 2-32. Responder rates in the

LP0053-1001 04-Mar-2014 of 315

LEO 90100 group increased successively during the course of the trial, and at Week 4, 193

subjects (79.4%) had achieved a 50% reduction in itch-related sleep loss. The odds ratio for

achieving a 50% reduction in itch in the LEO 90100 group relative to vehicle group (adjusted

for pooled centres) was statistically significant at all time-points analysed (p=0.012 on Day 3,

p=0.005 on Day 5, and p<0.001 at subsequent visits) (EoT Table 2-32).

9.3.2.4 Change in DLQI over Time

A DLQI total score is the sum of the 10 equal-weighted items and ranges from 0 to 30, with

higher scores indicating poorer quality of life.

The change in DLQI score from baseline (Day 0) to Week 1, Week 2, and Week 4 is

summarised in Table 9–21 together with the statistical comparison between treatment groups.

Statistically significantly greater improvement in quality of life was demonstrated for LEO

90100 versus vehicle at all visits (p<0.001) (Table 9–21).

LP0053-1001 04-Mar-2014 of 315

Table 9–21 Analysis of Change in DLQI by Visit (Observed Cases): Full Analysis Set

VisitDLQI/Change in DLQI

LEO 90100(n=323)

Vehicle(n=103)





29JAN14:09:51:12 LP0053 1001 t25_DLQI.doc

1) Calculated from ANOVA adjusted for pooled centres and baseline score.


LP0053-1001 04-Mar-2014 of 315

9.3.2.5 Change in EQ-5D-5L over Time

The subject’s assessments of quality of life were assessed by means of the generic EQ-5D-5L

questionnaire at Visit 1 (Day 0), and at Week 4, or the last on-treatment visit, as applicable.

Change in EQ-5D-5L from Baseline (Day 0; Visit 1) to Week 4

For each of the dimensions ‘mobility’, ‘self-care’, ‘usual activities’, ‘pain/discomfort’,

‘anxiety/depression’, the number and proportion of subjects in each of the five categories

(scored as 1 to 5) are tabulated by treatment group at baseline and Week 4 in EoT Table 2-26.

In the LEO 90100 group, the proportion of subjects evaluating their pain/discomfort as non-

existing (‘I have no pain or discomfort’) increased from 30.1% at baseline to 68.4% at Week

4, and the difference between treatment groups at Week 4 was statistically significant

(p<0.001) (EoT Table 2-26).

For the dimension ‘usual activities’, the proportion of subjects in the LEO 90100 group

reporting ‘I have no problems doing my usual activities’ increased from 71.1% at baseline to

86.1% at Week 4. For the dimension ‘anxiety/depression the proportion of subjects in the

LEO 90100 reporting ‘I am not anxious or depressed’ increased from 54.7% at baseline to

71.9% at Week 4. These incidences were higher than those observed in the vehicle group, but

there was no statistically significant difference between treatment groups for either

dimension. For the remaining 2 dimensions (‘mobility’ and ’self-care’), only minor

improvements were observed from baseline to Week 4 and there was no statistically

significant difference between treatment groups (EoT Table 2-26).

The observed EQ-5D-5L index scores at baseline and Week 4/end of treatment visit and the

change in EQ-5D-5L index score from baseline to Week 4 are presented together with the

statistical comparison between treatment groups in EoT Table 2-28. When adjusting for the

effect of pooled centres and baseline score, the mean change in EQ-5D-5L index score from

baseline to Week 4 was 0.08 in the LEO 90100 group and 0.04 in the vehicle group. The

comparison of LEO 90100 to vehicle was statistically significant (mean difference 0.04; 95%

CI 0.01 to 0.07; p=0.005) (EoT Table 2-28).

The observed EQ VAS scores at baseline and Week 4/end of treatment visit and the change in

EQ VAS scores from baseline to Week 4 are presented together with the statistical comparison

between treatment groups in EoT Table 2-27. When adjusting for the effect of pooled centres

and baseline score, the mean change in EQ VAS score from baseline to Week 4 was 5.1 in the

LEO 90100 group and 0.9 in the vehicle group. The comparison of LEO 90100 to vehicle was

statistically significant (mean difference 4.3; 95% CI 1.4 to 7.1; p=0.004) (EoT Table 2-27).

LP0053-1001 04-Mar-2014 of 315

9.4 Efficacy Conclusions

Primary Endpoint

The proportion of subjects achieving ‘treatment success’ at Week 4 was 53.3% in the LEO

90100 group and 4.8% in the vehicle group (applying multiple imputation for missing

data). LEO 90100 was statistically significantly more effective than vehicle (OR 30.3;

95% CI 9.7 to 94.3; p<0.001). The sensitivity analyses applying LOCF for missing data,

the vehicle-based multiple imputation analysis, the non-responder imputation analysis, the

analysis for observed cases, and the per protocol analysis supported the results of the

primary analysis.

Secondary Endpoints

When adjusting for the effect of pooled centres and baseline m-PASI, the mean m -PASI at

Week 4 was 2.0 in the LEO 90100 group and 5.3 in the vehicle group (applying multiple

imputation for missing data) with a statistically significant difference between treatments

(mean difference -3.3; 95% CI: -3.9 to -2.7; p<0.001), thereby supporting the outcome of

the analysis of the primary endpoint.

A reduction in mean m-PASI score was seen as early as Week 1 and LEO 90100 was

statistically significantly more effective than vehicle (mean difference -1.3; 95% CI -1.8 to

-0.8; p<0.001) at this time-point (applying multiple imputation for missing data).

The sensitivity analyses applying LOCF for missing data, the vehicle-based multiple

imputation analysis, the non-responder imputation analysis and the analysis for observed

cases supported the results of the primary analysis. For the sensitivity analyses excluding

Site the overall conclusions were unaltered.

Tertiary Endpoints – Investigator’s Assessments

In the LEO 90100 group, the proportion of subjects achieving ‘treatment success’

increased as the trial progressed (Week 1: 8.5%; Week 2: 26.3%; Week 4: 53.4%), while

1.0%, 2.0%, and 4.0% of subjects allocated to the vehicle group obtained ‘treatment

success’ at Week 1, Week 2, and Week 4, respectively.

The percentage of subjects with a 50% reduction in PASI at Week 4 was estimated at

82.3% in the LEO 90100 group and 28.0% in the vehicle group. LEO 90100 was

statistically significantly more effective than vehicle (OR 13.9; 95% CI 7.6 to 25.7;

p<0.001). Similar findings were obtained for the sensitivity analyses excluding Site

LP0053-1001 04-Mar-2014 of 315

The percentage of subjects with a 75% reduction in PASI at Week 4 was estimated as

52.9% in the LEO 90100 group and 8.2% in the vehicle group. LEO 90100 was

statistically significantly more effective than vehicle (OR 14.9; 95% CI 6.5 to 34.0;

p<0.001). Similar findings were obtained for the sensitivity analyses excluding Site

At baseline, the severity of clinical signs of the target lesion was evaluated as 'moderate'

or 'severe' in approximately 80-90% of subjects with no notable differences between

treatment groups. In the LEO 90100 group, the severity of target lesions decreased during

the course of the trial and at Week 4, the redness, thickness, and scaliness of the target

lesion had disappeared completely in 32.6%, 57.5%, and 70.0% of subjects, respectively.

The corresponding rates in the vehicle group were 3.0%, 4.0%, and 18.2%, respectively.

At Week 4, the mean decrease from baseline in percentage BSA involvement of psoriasis

on the trunk and limbs (excluding skin folds and genitals) was 3.7%-points (baseline mean

7.4%) in the LEO 90100 group and 1.0%-points (baseline mean 8.0%) in the vehicle

group.

Tertiary Endpoints – Subject’s Assessments

Overall, the results for subject’s assessments of disease severity were in line with those of

the investigator. In the LEO 90100 group, the proportion of subjects achieving ‘treatment

success’ increased as the trial progressed (Week 1: 21.9%; Week 2: 42.2%; Week 4:

65.2%), while 17.6%, 21.8%, and 22.2% of subjects allocated to the vehicle group

obtained ‘treatment success’ at Week 1, Week 2, and Week 4, respectively. At Week 4,

LEO 90100 was statistically significantly more effective than vehicle (OR 7.9; 95% CI 4.4

to 14.1; p<0.001).

Subjects assessed itching as increasingly less severe during the course of the trial,

particularly in the LEO 90100 group. At Week 4, the mean change from baseline (adjusted

for pooled centres and baseline score) in itch (VAS) was -43.1 in the LEO 90100 group

and -22.7 in the vehicle group. LEO 90100 was statistically significantly more effective

than vehicle at all visits. In the LEO 90100 group, 110 subjects (36.8%) achieved 70%

itch reduction on Day 3. Responder rates in the LEO 90100 group increased successively

during the course of the trial, and at Week 4, 248 subjects (83.5%) had obtained 70% itch

reduction versus 39 subjects (40.6%) in the vehicle group. The odds ratio for achieving

70% reduction in itch in the LEO 90100 group relative to the vehicle group (adjusted for

pooled centres) was statistically significant at all visits.

LP0053-1001 04-Mar-2014 of 315

Subjects assessed itch-related sleep loss as increasingly less severe during the course of

the trial, particularly in the LEO 90100 group. At Week 4, the mean change from baseline

(adjusted for pooled centres and baseline score) in itch-related sleep loss (VAS) was -21.9

in the LEO 90100 group and -10.0 in the vehicle group. LEO 90100 was statistically

significantly more effective than vehicle at all visits. In the LEO 90100 group, 87 subjects

(35.5%) achieved 70% reduction on Day 3. Responder rates in the LEO 90100 group

increased successively during the course of the trial, and at Week 4, 172 subjects (70.8%)

had obtained 70% reduction in itch-related sleep loss versus 33 (39.8%) in the vehicle

group. The odds ratio for achieving 70% reduction in itch-related sleep loss in the LEO

90100 group relative to the vehicle group (adjusted for pooled centres) was statistically

significant at all visits.

Statistically significantly greater improvement in quality of life (as measured by DLQI)

was demonstrated for LEO 90100 versus vehicle at all visits (p<0.001).

For EQ-5D-5L, subjects evaluated significantly improvements for the dimension

pain/discomfort. In the LEO 90100 group, the proportion of subjects evaluating their

pain/discomfort as non-existing increased from 30.1% at baseline to 68.4% at Week 4, and

the difference between treatment groups was statistically significant (p<0.001) at Week 4.

LP0053-1001 04-Mar-2014 of 315

10 Safety Evaluation

10.1 Adverse Events

This section gives an overview of all treatment emergent AEs (i.e., those that started after the

first application of the trial medication, or started before this and worsened in intensity after).

Throughout this section treatment-emergent AEs will be denoted as AEs. The summary of the

overall frequency of AEs is done on the preferred term level, which means that multiple

occurrences of AEs on a particular preferred term level in the same subject count as one

occurrence. For a given preferred term, severity is recorded as the worst severity experienced

and relationship is recorded from the last available assessment.

As stated in Section 6.2.8.1, 2 AEs (subject No. , contact dermatitis, and subject No.

, psoriasis flare) started after Visit 4, but were included in the tabulations.

10.1.1 Brief Summary of Adverse Events

In total, 78 AEs were reported during the trial and occurred with similar incidence in the two

treatment groups (Table 10–1). There were no deaths in the trial and other serious AEs were

few (2 events in 2 subjects). One of the SAEs led to discontinuation of treatment (see Section

10.2.1). The vast majority of the AEs were mild or moderate and only 5 AEs were rated as

severe, see Section 10.1.3. Likewise, very few ADRs were reported and no AEs led to

withdrawal of the subject from the trial.

Table 10–1 Overall Summary of Adverse Events: Safety Analysis Set

LEO 90100(n=323)

Vehicle(n=103)

Adverse event categoryNumberof AEs1

Number of subjects (%)

Numberof AEs1


All adverse events 63 51 (15.8) 15 12 (11.7) Severe adverse events 5 5 ( 1.5) 0 0 ( 0.0) Adverse drug reactions 10 10 ( 3.1) 5 2 ( 1.9) AEs leading to withdrawal from trial

0 0 ( 0.0) 0 0 ( 0.0)

AEs leading to discontinuation of treatment

1 1 ( 0.3) 0 0 ( 0.0)

Lesional/perilesional AEs 9 9 ( 2.8) 6 3 ( 2.9) SAEs 2 2 ( 0.6) 0 0 ( 0.0)

14FEB14:09:01:54 LP0053 1001 t04overall.doc

1) Different adverse events within the same preferred term and system organ class and involving the same

subject have been counted as one.


LP0053-1001 04-Mar-2014 of 315

10.1.2 Incidence of Adverse Events

The incidence of AEs is presented by MedDRA SOC in Table 10–2 and by MedDRA SOC

and preferred term in Table 10–3.

The overall incidence of AEs was low and comparable between treatment groups, with 51

(15.8%) of subjects in the LEO 90100 group and 12 (11.7%) subjects in the vehicle group.

AEs were most frequently reported in the SOCs ‘Infections and infestations’, and ‘General

disorders and administration site conditions’. In these 2 SOCs, ‘nasopharyngitis’ was reported

by 6 subjects (1.9%) in the LEO 90100 group and ‘application site pain’ was reported by 3

subjects (0.9%) in the LEO 90100 group and 2 subjects (1.9%) in the vehicle group (Table

10–3). The remaining individual AEs in the 2 SOCs were reported by single subjects.

Few AEs were reported in the remaining SOCs.

Individual AE data are listed in Appendix 2.7.

LP0053-1001 04-Mar-2014 of 315

Table 10–2 Adverse Events by MedDRA primary SOC: Safety Analysis Set

LEO 90100(n=323)

Vehicle(n=103)

System Organ Class1Number of subjects %


Infections and infestations 15 4.6 3 2.9General disorders andadministration site conditions

11 3.4 3 2.9

Injury, poisoning and proceduralcomplications

4 1.2 2 1.9

Gastrointestinal disorders 4 1.2 1 1.0Musculoskeletal and connectivetissue disorders

4 1.2 1 1.0

Skin and subcutaneous tissuedisorders

4 1.2 1 1.0

Investigations 4 1.2 0 0.0Respiratory, thoracic andmediastinal disorders

4 1.2 0 0.0

Nervous system disorders 2 0.6 1 1.0Psychiatric disorders 2 0.6 0 0.0Vascular disorders 2 0.6 0 0.0Cardiac disorders 1 0.3 0 0.0Ear and labyrinth disorders 1 0.3 0 0.0Eye disorders 1 0.3 0 0.0Renal and urinary disorders 1 0.3 0 0.0Surgical and medical procedures 1 0.3 0 0.0 Total number of adverseevents2

63 15

Total number of subjects 51 15.8 12 11.7

20FEB14:08:37:09 LP0053 1001 t05soc.doc

1) Classification according to MedDRA version 16.0.


subject have been counted as one. A single subject could appear in multiple classes.


LP0053-1001 04-Mar-2014 of 315

Table 10–3 Adverse Events by SOC and Preferred Term: Safety Analysis Set

LEO 90100(n=323)

Vehicle(n=103)

System Organ Class (SOC)Preferred Term1



Infections and infestationsNasopharyngitis 6 1.9 0 0.0Cellulitis 1 0.3 0 0.0Eye infection 0 0.0 1 1.0Folliculitis 1 0.3 0 0.0Fungal skin infection 1 0.3 0 0.0Gastroenteritis viral 0 0.0 1 1.0Groin abscess 1 0.3 0 0.0Hordeolum 1 0.3 0 0.0Rhinitis 1 0.3 0 0.0Streptococcal infection 0 0.0 1 1.0Tinea cruris 1 0.3 0 0.0Tooth abscess 1 0.3 0 0.0Upper respiratory tractinfection

1 0.3 0 0.0

SOC total 15 4.6 3 2.9General disorders and administration siteconditionsApplication site pain 3 0.9 2 1.9Application sitediscolouration

1 0.3 0 0.0

Application site dryness 0 0.0 1 1.0Application site erosion 0 0.0 1 1.0Application siteerythema

0 0.0 1 1.0

Application siteirritation

1 0.3 0 0.0

Application site oedema 0 0.0 1 1.0Application sitepruritus

1 0.3 0 0.0

Application sitereaction

1 0.3 0 0.0

Influenza like illness 1 0.3 0 0.0Oedema peripheral 1 0.3 0 0.0Pain 1 0.3 0 0.0Thirst 1 0.3 0 0.0SOC total 11 3.4 3 2.9

14FEB14:08:56:03 LP0053 1001 t06socterm.doc Continued...

LP0053-1001 04-Mar-2014 of 315

Table 10–3 Adverse Events by SOC and Preferred Term: Safety Analysis Set (Continued)

LEO 90100(n=323)

Vehicle(n=103)




Injury, poisoning and proceduralcomplicationsLigament sprain 1 0.3 1 1.0Sunburn 1 0.3 1 1.0Contusion 1 0.3 0 0.0Excoriation 1 0.3 0 0.0Laceration 1 0.3 0 0.0SOC total 4 1.2 2 1.9

Gastrointestinal disordersDiarrhoea 2 0.6 1 1.0Nausea 2 0.6 0 0.0SOC total 4 1.2 1 1.0

Musculoskeletal and connective tissuedisordersFlank pain 2 0.6 0 0.0Back pain 1 0.3 0 0.0Muscle spasms 1 0.3 0 0.0Pain in extremity 0 0.0 1 1.0SOC total 4 1.2 1 1.0

Skin and subcutaneous tissue disordersAngioedema 0 0.0 1 1.0Dermatitis contact 1 0.3 0 0.0Hyperhidrosis 1 0.3 0 0.0Psoriasis 1 0.3 0 0.0Skin irritation 1 0.3 0 0.0SOC total 4 1.2 1 1.0

InvestigationsBlood pressure increased 3 0.9 0 0.0Blood calcium increased 1 0.3 0 0.0SOC total 4 1.2 0 0.0

Respiratory, thoracic and mediastinaldisordersChronic obstructivepulmonary disease

1 0.3 0 0.0

Cough 1 0.3 0 0.0Epistaxis 1 0.3 0 0.0Sinus congestion 1 0.3 0 0.0SOC total 4 1.2 0 0.0

Nervous system disordersDizziness 0 0.0 1 1.0


LP0053-1001 04-Mar-2014 of 315

Table 10–3 Adverse Events by SOC and Preferred Term: Safety Analysis Set (Continued)

LEO 90100(n=323)

Vehicle(n=103)




Nervous system disordersHeadache 1 0.3 0 0.0Paraesthesia 1 0.3 0 0.0SOC total 2 0.6 1 1.0

Eye disordersBlepharitis 1 0.3 0 0.0Keratitis 1 0.3 0 0.0SOC total 1 0.3 0 0.0

Psychiatric disordersBipolar disorder 1 0.3 0 0.0Substance-inducedpsychotic disorder

1 0.3 0 0.0

SOC total 2 0.6 0 0.0Vascular disordersFlushing 1 0.3 0 0.0Hot flush 1 0.3 0 0.0SOC total 2 0.6 0 0.0

Cardiac disordersTachycardia 1 0.3 0 0.0SOC total 1 0.3 0 0.0

Ear and labyrinth disordersVertigo 1 0.3 0 0.0SOC total 1 0.3 0 0.0

Renal and urinary disordersDysuria 1 0.3 0 0.0SOC total 1 0.3 0 0.0

Surgical and medical proceduresTooth extraction 1 0.3 0 0.0SOC total 1 0.3 0 0.0

Total number of adverseevents2

63 15


Fisher's exact test

P-value 0.34

14FEB14:08:56:03 LP0053 1001 t06socterm.doc





LP0053-1001 04-Mar-2014 of 315

10.1.3 Adverse Events by Intensity

All AEs were assessed for intensity (mild, moderate, or severe). A summary of AEs by

MedDRA primary SOC and preferred term with information on maximum intensity is given

in EoT Table 3-12.

The vast majority of the AEs were mild or moderate and only 5 AEs were rated as severe. All

5 severe AEs were reported in the LEO 90100 group and were single occurrences of

‘cellulitis’, ‘oedema peripheral’, ‘bipolar disorder’, ‘substance-induced psychotic disorder’,

and ‘psoriasis’.

The events ‘bipolar disorder’ and ‘substance induced psychotic disorder’ were also SAEs, see

Section 10.2.1.

10.1.4 Adverse Drug Reactions

All AEs were to be assessed for causal relationship to the investigational product, as judged

by the investigator. Adverse drug reactions (defined as AEs for which the investigator had not

described the causal relationship to trial medication as ‘not related’) are presented by

MedDRA primary system organ class and preferred term in Table 10–4.

In total, 15 ADRs occurred in the trial and were reported for 10 subjects (3.1%) in the

LEO 90100 group and 2 subjects (1.9%) in the vehicle group. The most common SOC was

‘General disorders and administration site conditions’, reported for 6 subjects (1.9%) in the

LEO 90100 group and 2 subjects (1.9%) in the vehicle group. The remaining ADRs occurred

in the LEO 90100 group and were reported for 1 to 2 subjects in each represented SOC (Table

10–4).

LP0053-1001 04-Mar-2014 of 315

Table 10–4 Adverse Drug Reactions by SOC and Preferred Term: Safety Analysis Set

LEO 90100(n=323)

Vehicle(n=103)




General disorders and administration siteconditionsApplication site pain 2 0.6 1 1.0Application sitediscolouration

1 0.3 0 0.0


0 0.0 1 1.0


1 0.3 0 0.0


1 0.3 0 0.0


1 0.3 0 0.0

SOC total 6 1.9 2 1.9InvestigationsBlood calcium increased 1 0.3 0 0.0SOC total 1 0.3 0 0.0

Skin and subcutaneous tissue disordersPsoriasis 1 0.3 0 0.0Skin irritation 1 0.3 0 0.0SOC total 2 0.6 0 0.0

Infections and infestationsFolliculitis 1 0.3 0 0.0SOC total 1 0.3 0 0.0

Total number of drugreactions2

10 5


Fisher's exact test

P-value 0.74

14FEB14:09:02:25 LP0053 1001 t07adrs.doc


2) Different adverse drug reactions within the same preferred term and system organ class and involving the

same subject have been counted as one. A single subject could appear in multiple classes.


10.1.5 Adverse Events Leading to Withdrawal

There were no AEs leading to withdrawal of any subject from the trial (EoT Table 3-9). There

was one SAE leading to discontinuation of treatment with investigational product. The event

LP0053-1001 04-Mar-2014 of 315

was assessed as unrelated to trial medication by the investigator and is further described in

Section 10.2.1.

10.2 Deaths, other Serious Adverse Events, and other Significant Adverse

Events

10.2.1 Narratives of Serious Adverse Events

There were no deaths in the trial. Two SAEs were reported. Narratives are given below.

Subject number: Treatment group: LEO 90100

SAE: Substance induced psychotic disorder/ severe

This case concerns a diagnosed with psoriasis vulgaris and topically

treated with LEO 90100 once daily from to . Relevant medical

history included post-traumatic stress disorder from . Relevant current

medical conditions included bipolar disorder from insomnia from obsessive

compulsive disorder from depression, anxiety, and sciatica. Concomitant medication

included duloxetine hydrochloride 90mg once daily from for depression; esomeprazole

magnesium 40mg as required from for GERD; propranolol 40mg twice daily from

for anxiety and ibuprofen 220mg, as required from for left shoulder tendonitis and

sciatica. On , the subject had a nervous breakdown and was overdosed with an

unknown drug. The subject was hospitalised on the same day and remained in the psychiatric

ward for evaluation. Treatment with investigational product was discontinued. It was reported

that the subject did not attend the scheduled follow up appointment. Several attempts were

made to contact the subject, but the subject was lost to follow up. The outcome of the AE is

unknown as the subject was lost to follow-up. Causality per investigator: not related.

Causality per sponsor: not related.

Subject number: Treatment group: LEO 90100

SAE: Bipolar disorder/ severe

This case concerns a diagnosed with psoriasis vulgaris and topically treated

with LEO 90100 once daily from to . Relevant current medical

conditions included bipolar disorder from . Concomitant medication included

alprazolam 1 mg daily from for sleep disorder; trazodone 50 mg daily from for

sleep disorder; methadone 20 mg daily from to aid weaning off pain medication;

methadone 10 mg daily, from an unknown date in for pain management; doxepin 25 mg

from for insomnia; and risperidone 2 mg from for bipolar disorder.

LP0053-1001 04-Mar-2014 of 315

On , the subject was hospitalised with an episode of psychiatric instability.

Initially the subject was suspected of having an opioid induced mood disorder, but the final

diagnosis was 'bipolar disorder not otherwise specified'. , the subject was

discharged from the hospital as recovered and the subject continued in the trial. Causality per

investigator: not related. Causality per sponsor: not related.

10.2.2 Lesional/Perilesional Adverse Events

In total, 15 lesional/perilesional AEs occurred in the trial and were reported in 9 subjects

(2.8%) in the LEO 90100 group and 3 subjects (2.9%) in the vehicle group. The most

commonly reported lesional/perilesional AE was‘application site pain’, reported by 3 subjects

(0.9%) in the LEO 90100 group and 2 subjects (1.9%) in the vehicle group. The remaining

individual lesional/perilesional AEs were reported by single subjects. (Table 10–5).

LP0053-1001 04-Mar-2014 of 315

Table 10–5 Lesional/Perilesional Adverse Events by SOC and Preferred Term: Safety Analysis Set

LEO 90100(n=323)

Vehicle(n=103)





1 0.3 0 0.0


0 0.0 1 1.0


1 0.3 0 0.0


1 0.3 0 0.0

SOC total 6 1.9 3 2.9Skin and subcutaneous tissue disordersPsoriasis 1 0.3 0 0.0Skin irritation 1 0.3 0 0.0SOC total 2 0.6 0 0.0

Injury, poisoning and proceduralcomplicationsSunburn 1 0.3 0 0.0SOC total 1 0.3 0 0.0


9 6


28NOV13:12:11:39 LP0053 1001 t11lesional.doc





10.3 Other Safety Assessments

10.3.1 Local Safety and Tolerability

At Visits 1 to 4, the (sub)investigator assessed application site reactions for the following

signs: perilesional erythema, perilesional dryness, perilesional erosion, and perilesional

oedema. The subject assessed the symptoms of application site burning or pain.

LP0053-1001 04-Mar-2014 of 315

The five assessments of local safety and tolerability are summarised by severity for each

treatment group and by visit in Table 10–6. The assessments are presented graphically in

Figure 10–1.

Local reactions were few and occurred with similar frequency in the two treatment groups.

The most frequently reported local reactions were erythema, dryness, and burning/pain

(Figure 10–1). The majority of local reactions were mild or moderate (Table 10–6).

LP0053-1001 04-Mar-2014 of 315

Table 10–6 Local Safety and Tolerability by Visit: Safety Analysis Set

LEO 90100(n=323)

Vehicle(n=103)

VisitAssessment



Perilesional erythemaBaseline

Absent 300 92.9 98 95.1 Mild 15 4.6 1 1.0 Moderate 8 2.5 4 3.9 Severe 0 0.0 0 0.0 Total 323 100.0 103 100.0 Week 1



Absent 307 98.1 97 98.0 Mild 6 1.9 2 2.0 Moderate 0 0.0 0 0.0 Severe 0 0.0 0 0.0 Total 313 100.0 99 100.0

Perilesional drynessBaseline



29NOV13:10:16:28 LP0053 1001 t14local.doc Continued...

LP0053-1001 04-Mar-2014 of 315

Table 10–6 Local Safety and Tolerability by Visit: Safety Analysis Set (Continued)

LEO 90100(n=323)

Vehicle(n=103)

LEO 90100(n=323)

Vehicle(n=103)

VisitAssessment



Perilesional drynessWeek 2



Perilesional erosionBaseline






LP0053-1001 04-Mar-2014 of 315


LEO 90100(n=323)

Vehicle(n=103)

VisitAssessment



Perilesional oedemaBaseline





Burning or painBaseline




LP0053-1001 04-Mar-2014 of 315


LEO 90100(n=323)

Vehicle(n=103)

VisitAssessment



Burning or painWeek 2



29NOV13:10:16:28 LP0053 1001 t14local.doc


LP0053-1001 04-Mar-2014 of 315

Figure 10–1 Local Safety and Tolerability – Safety Analysis Set

Cross-reference: EoT Figure 3-1

LEO 90100 Vehicle

15 <(

10 ~ w :I:

5 >= cr w

0

15

10 (/) (/) w z >-

5 0:: 0

(/) 0 --() 15 (1)

'E :J z (/) 10 - 0 0 u; (1) 0 0> 5 cr ('0 w 4J c (1) 0 () \... (1)

15 Q..

10 <( ~ w 0

5 w 0

0

15 z <(

10 Cl. -(!) z

5 z 0:: ::> m

0 T

~ % % % s~ % % % ~ ~ ~~ ~.f ~.f ~.f ~~ ~.f ~.f ~.f

"~ 7 .? v "~ 7 .;> v

Severe Moderate Mild

LP0053-1001 04-Mar-2014 of 315

10.4 Vital Signs

No clinically relevant changes in heart rate or blood pressure from baseline to Week 4 were

observed (EoT Table 3-15 and EoT Table 3-16).

10.5 Clinical Laboratory Evaluation

10.5.1 Laboratory Values Over Time

Albumin Corrected Serum Calcium

The mean values of albumin-corrected serum calcium were comparable between treatment

groups at baseline. Mean changes from baseline to Week 4 were small and comparable

between treatment groups (Table 10–7).

Table 10–7 Summary of Albumin-Corrected Serum Calcium and Change from Baseline: Safety Analysis Set

Albumin correctedserum calcium(mmol/L)

LEO 90100(n=323)

Vehicle(n=103)

Summary

Baseline Mean 2.307 2.295 SD 0.098 0.091 Median 2.300 2.300 Minimum 1.78 2.10 Maximum 2.83 2.70 Number 321 103

Week 4 / End of treatment Mean 2.296 2.270 SD 0.098 0.085 Median 2.280 2.280 Minimum 1.70 2.10 Maximum 2.78 2.55 Number 314 100

Change from Baseline

Week 4 / End of treatment Mean -0.011 -0.026 SD 0.085 0.087 Median 0.000 -0.030 Minimum -0.23 -0.35 Maximum 0.38 0.20 Number 312 100

28NOV13:12:12:27 LP0053 1001 t17sumcal.doc


LP0053-1001 04-Mar-2014 of 315

Urinary Calcium:Creatinine Ratio

Mean urinary calcium:creatinine ratios (from spot urine samples) were comparable between

treatment groups at baseline, and mean changes from baseline to Week 4 were small and

comparable between treatment groups (Table 10–8).

Table 10–8 Summary of Urinary Calcium:Creatinine Ratio and Change from Baseline: Safety Analysis Set

Urinary calcium:creatinine ratioLEO 90100(n=323)

Vehicle(n=103)

Summary




Week 4 / End of treatment Mean 0.032 -0.137 SD 2.207 1.879 Median 0.030 -0.100 Minimum -15.45 -6.55 Maximum 13.35 5.40 Number 311 99

28NOV13:16:04:11 LP0053 1001 t20sumcalcrea.doc

Cross-reference: EoT Table 3.20

10.5.2 Individual Changes in Laboratory Values

Albumin Corrected Serum Calcium

The albumin-corrected serum calcium was classified as ‘low’, ‘normal’ or ‘high’, depending

on whether the value was below, within or above the reference range (2.15 to 2.55 mmol/L).

A shift table showing the categories at baseline against those at Week 4 is presented in Table

10–9.

LP0053-1001 04-Mar-2014 of 315

In both treatment groups, the majority of subjects had normal albumin-corrected serum

calcium levels at baseline as well as at Week 4.

In the LEO 90100 group, 3 subjects shifted from ‘normal’ albumin-corrected serum calcium

levels at baseline to ‘high’ at Week 4. The measured levels of elevated serum calcium were

2.63 mmol/L, 2.58 mmol/L, and 2.60 mmol/L corresponding to 0.08 mmol/L, 0.03 mmol/L,

and 0.05 mmol/L, respectively, above the upper limit of the reference range (2.55 mmol/L)

(EoT Table 3-22). One of the cases was reported as an AE of mild intensity and evaluated as

possibly related to trial medication by the investigator (Appendix 2.7Listing 7-1). All 3 cases

returned to ‘normal’ or ‘low’ at follow-up. No subjects in the vehicle group developed

albumin-corrected serum calcium levels above the normal range. In the LEO 90100 group, 5

subjects shifted from ‘normal’ albumin-corrected serum calcium levels at baseline to ‘low’ at

Week 4, while this was recorded for 3 subjects in the vehicle group.

At baseline, 9 subjects in the LEO 90100 group and 3 subjects in the vehicle group had

albumin-corrected serum calcium levels lower than the normal reference limit. Of these, 8

subjects in the LEO 90100 group and 1 subject in the vehicle group recorded a shift to

‘normal’ at Week 4, while the remaining 3 subjects sustained at low levels at Week 4.

At baseline, 5 subjects in the LEO 90100 group and 1 subject in the vehicle group had

albumin-corrected serum calcium levels above the normal reference limit. Of these, 2 subjects

in the LEO 90100 group and the subject in the vehicle group recorded a shift to ‘normal’ at

Week 4, while the remaining 3 subjects sustained at high levels at Week 4.

Subjects with albumin-corrected serum calcium outside the reference range are presented in

EoT Table 3-22 and Appendix 2.8.

LP0053-1001 04-Mar-2014 of 315

Table 10–9 Shift Table for Albumin-Corrected Serum Calcium: Safety Analysis Set

LEO 90100(n=323)

End of treatment category1

Vehicle(n=103)


Laboratory parameter

Baseline category1 LOW NORMAL HIGH LOW NORMAL HIGH

Albumin corrected serum calcium

Low 1 8 0 2 1 0

Normal 5 290 3 3 93 0High 0 2 3 0 1 0

28NOV13:12:12:36 LP0053 1001 t18shalbu.doc

1) Number of subjects with laboratory parameters below, within or above the reference range (2.15 to 2.55

mmol/L).


A shift table as described above based on LEO defined clinically significant values is

presented in Table 10–10. According to this classification, 1 subject in the LEO 90100 group

had a ‘low’ albumin-corrected serum calcium value at baseline as well as at Week 4. All other

subjects had ‘normal’ values at baseline as well as at Week 4.

Table 10–10 Shift Table for Albumin-Corrected Serum Calcium Based on LEO Defined Clinically Significant Values: Safety Analysis Set

LEO 90100(n=323)


Vehicle(n=103)





Low 1 0 0 0 0 0

Normal 0 311 0 0 100 0High 0 0 0 0 0 0

28NOV13:12:12:47 LP0053 1001 t19leoshift.doc

1) Number of subjects with laboratory parameters below, within or above the reference range (2.0 mmol/L to 2.9

mmol/L)


Urinary Calcium:Creatinine Ratio

The calcium:creatinine ratio (from spot urine samples) was classified as ‘low’, ‘normal’ or

LP0053-1001 04-Mar-2014 of 315

‘high’, depending on whether the value was below, within or above the reference range (0.22

to 8.20 mmol/g for women and 0.30 to 6.10 mmol/g for men). A shift table showing the

categories at baseline against those at Week 4 is presented in Table 10–11.

In both treatment groups, the majority of subjects had a normal urinary calcium:creatinine

ratio at baseline as well as at Week 4. In the LEO 90100 group, 13 subjects and 2 subjects in

the vehicle group shifted from a ‘normal’ urinary calcium:creatinine ratio at baseline to ‘high’

at Week 4, while shifts from ‘normal’ at baseline to ‘low’ at Week 4 were recorded for 2

subjects in the LEO 90100 group and 1 subject in the vehicle group.

At baseline, 3 subjects in the LEO 90100 group and 2 subjects in the vehicle group had a

urinary calcium:creatinine ratio lower than the normal reference limit. All subjects recorded a

shift to ‘normal’ at Week 4.

At baseline, 15 subjects in the LEO 90100 group and 3 subjects in the vehicle group had a

urinary calcium:creatinine ratio above the normal reference limit. Of these, 10 subjects in the

LEO 90100 group and 1 subject in the vehicle group recorded a shift to ‘normal’ at Week 4,

while the remaining 7 subjects sustained at high levels at Week 4.

Table 10–11 Shift Table for Urinary Calcium:Creatinine Ratio: Safety Analysis Set

LEO 90100(n=323)


Vehicle(n=103)




Calcium/Creatinine Low 0 3 0 0 2 0Normal 2 277 13 1 91 2High 0 10 5 0 1 2

28NOV13:12:12:42 LP0053 1001 t21shcal.doc

1) Number of subjects with laboratory parameters below, within or above the reference range (0.22 to 8.20

mmol/g for women and 0.30 to 6.10 mmol/g for men).

Cross-reference: EoT Table 3.21

EoT Table 3-22 presents subjects with albumin-corrected serum calcium or calcium:creatinine

ratio outside the reference range for the safety analysis set. Subjects with calcium:creatinine

ratio outside the reference range are listed in Appendix 2.8.

LP0053-1001 04-Mar-2014 of 315

10.5.3 Pregnancies

No pregnancies occurred during the trial.

10.6 Safety Conclusions

There were no deaths in the trial. Two SAEs occurred in the trial and were reported in the

LEO 90100 group, both assessed as having no relation to investigational product. One of

the SAEs led to discontinuation of treatment. There were no AEs leading to withdrawal of

the subject from the trial. The vast majority of the AEs were mild or moderate and only 5

AEs were rated as severe. The severe AEs were reported in the LEO 90100 group.

The overall incidence of AEs was low and comparable between treatment groups, with 51

(15.8%) subjects in the LEO 90100 group and 12 (11.7%) subjects in the vehicle group.

ADRs (i.e. AEs for which the causal relationship to the drug cannot be ruled out) were

reported for 10 subjects (3.1%) in the LEO 90100 group and 2 subjects (1.9%) in the

vehicle group. Lesional/perilesional AEs were reported for 9 subjects (2.8%) in the LEO

90100 group and 3 subjects (2.9%) in the vehicle group. Local reactions, as assessed by

application site scores, were few and occurred with similar frequency in the 2 treatment

groups. The majority of local reactions were erythema, dryness, and burning/pain of mild

to moderate intensity.

There were no significant changes in albumin-corrected serum calcium and spot urinary

calcium:creatinine ratio.

LP0053-1001 04-Mar-2014 of 315

11 Discussion and Overall Conclusions

11.1 Discussion

The primary objective of this phase 3 trial was to compare the efficacy of treatment with

LEO 90100 to that of treatment with vehicle for up to 4 weeks in subjects with psoriasis

vulgaris. The trial was conducted to provide confirmatory evidence of efficacy and safety

results obtained in two phase 2 trials (LEO 90100-35 and LEO 90100-7).

The primary endpoint was subjects with ‘treatment success’, (‘clear’ or ‘almost clear’ for

subjects with at least moderate disease at baseline and ‘clear’ for subjects with mild disease at

baseline, equivalent to the term ‘controlled disease’ in the phase 2 trials) according to the IGA

at Week 4.

The trial was conducted as planned in the clinical study protocol. Demographics and subject

characteristics of the 426 randomised and treated subjects were well balanced between

treatment groups and complied with the targeted trial population. The completion rate was

high (above 96% in both treatment groups) and no bias as a result of subject withdrawals

would therefore be expected.

Overall, LEO 90100 was demonstrated to be effective in the treatment of psoriasis vulgaris on

the body (trunk and limbs) for all endpoints, with successive improvements in the disease

status of subjects during the course of the trial. In the primary analysis based on multiple

imputation of missing values, LEO 90100 was superior to vehicle in the proportion of

subjects achieving ‘treatment success’ at Week 4 (OR 30.3; 95% CI 9.7 to 94.3; p<0.001),

with response rates of 53.3% in the LEO 90100 groups and 4.8% in the vehicle group. These

results were supported by the m-PASI scores at Week 4 (secondary endpoint), which showed a

significantly greater improvement for LEO 90100 versus vehicle (p<0.001). Response to

treatment with LEO 90100 was rapid; with LEO 90100 being more effective than vehicle as

assessed by m-PASI as early as Week 1 (p<0.001). The results for PASI-50 and PASI-75 at

Week 4 also supported the results for the primary endpoint, as LEO 90100 was more effective

than vehicle for both these endpoints (p<0.001). Improvements for subjects treated with LEO

90100 were observed in all subgroups of baseline disease severity (IGA). In the LEO 90100

group, ‘treatment success’ rates at Week 4 were 30.6% in subjects with ‘mild’ severity at

baseline and 60.0% in subjects with ‘moderate’ disease severity at baseline, and even 37.9%

of subjects with ‘severe’ disease at baseline achieved ‘treatment success’, while the

corresponding rates in the vehicle group were only 0%, 4.2%, and 7.7%, respectively.

Finally, in the LEO 90100 group, the severity of the clinical signs of target lesions decreased

during the course of the trial and at Week 4, the redness, thickness, and scaliness of the target

LP0053-1001 04-Mar-2014 of 315

lesion had disappeared completely in 32.6%, 57.5%, and 70.0% subjects, respectively, while

the corresponding rates in the vehicle group were only 3.0%, 4.0%, and 18.2%, respectively,

BSA involvement of psoriasis on the trunk and limbs also decreased during the course of the

trial and at Week 4, the mean decrease from baseline in percentage BSA involvement was

3.7%-points in the LEO 90100 group and 1.0%-point in the vehicle group.

Overall, the results of subject’s assessments of disease severity were in line with those of the

investigator. Analyses of ‘treatment success’ demonstrated superiority of LEO 90100

compared to vehicle. Subjects assessed itching and itch-related sleep loss as increasingly less

severe during the course of the trial and LEO 90100 was superior to vehicle at all visits for

both VAS parameters. In the LEO 90100 group, a high proportion of subjects achieved the

treatment goal of a 70% itch reduction (from 36.8% on Day 3 to 83.5% on Week 4).

Comparable findings were achieved for itch-related sleep loss. There was a statistically

significantly greater improvement in quality of life (as measured by DLQI) for LEO 90100

versus vehicle at all visits (p<0.001) and for the EQ-5D-5L dimension pain/discomfort

(p<0.001).

The efficacy results in the present trial showed a high reproducibility of findings from the

phase 2 trials LEO 90100-35 and LEO 90100-7. The proportion of subjects achieving

‘treatment success’ (LOCF) in the LEO 90100 group was 52.0% in the present trial, while the

corresponding responder rates for controlled disease’ (equivalent to ‘treatment success’) was

54.6% and 45.0% in the phase 2 trials. Furthermore, at Week 4, the mean m-PASI (LOCF)

was 2.07 (1.99 and 2.37 in the phase 2 trials), the proportion of subjects with PASI-75

(LOCF) was 51.4% (50.4% and 49.0% in the phase 2 trials), and the mean change compared

to baseline in itch VAS score was -41.8 (-39.8 and -43.4 in the phase 2 trials).

The incidence of AEs, ADRs, local reactions, and lesional/perilesional AEs in this trial was

low and comparable between LEO 90100 and vehicle. AEs were most frequently reported in

the SOCs ‘Infections and infestations’, and ‘General disorders and administration site

conditions’. Two SAEs occurred in the trial, both in the LEO 90100 group, and both assessed

as having no relation to investigational product. One of the SAEs led to discontinuation of

treatment. There were no AEs leading to withdrawal of the subject from the trial.

A potential concern of systemic exposure to calcipotriol is its effects on calcium metabolism

including increased blood and urine calcium levels. In this trial, the majority of subjects had

albumin-corrected serum calcium levels as well as spot urinary calcium:creatinine ratios

within the normal range both at baseline and at Week 4. In the LEO 90100 group, 3 subjects

shifted from a ‘normal’ albumin-corrected serum calcium level at baseline to ‘high’ at Week 4.

LP0053-1001 04-Mar-2014 of 315

The levels were only 0.08 mmol/L, 0.03 mmol/L, and 0.05 mmol/L above the upper limit of

the reference range (2.55 mmol/L) and all returned to ‘normal’ or ‘low’ at follow-up. None of

these subjects experienced a concurrent increase in the urinary calcium/creatinine ratio Shifts

from a ‘normal’ urinary calcium/creatinine ratio at baseline to ‘high’ at Week 4 were observed

for 13 subjects in the LEO 90100 group and 2 subjects in the vehicle group, however, shifts in

the opposite direction (from ‘high’ at baseline to ‘normal’ at Week 4) were also observed in a

comparable number of subjects (10 subjects in the LEO 90100 group and 1 subject in the

vehicle group) suggesting that these changes may be non-specific rather than related to the

use of LEO 90100. In conclusion, the present trial did not indicate a significant effect of LEO

90100 on calcium homeostasis.

Vitamin D has a well-known role in calcium metabolism. In this trial levels of 25-hydroxy

vitamin D were measured at baseline and 73.5% of all randomised subjects had levels below

the normal reference range. This is not an unexpected finding given the fact that vitamin D

insufficiency is very common in the USA and Europe where its prevalence is estimated to be

as high as 50-80% in the general population, and there are studies to suggest that vitamin D

deficiency may be even more common in patients with psoriasis (26,27,28).

11.2 Overall Conclusions

Superiority of LEO 90100 compared to vehicle in the treatment of psoriasis vulgaris on

the trunk and limbs over 4 weeks was confirmed.

It was confirmed that LEO 90100 was safe and well tolerated in the treatment of psoriasis

vulgaris on the trunk and limbs over 4 weeks.

LP0053-1001 04-Mar-2014 of 315

12 References

1. ICH E3. Structure and Content of Clinical Study Reports. November 1995

2. ICH E3 (R1). ICH E3 Guideline: Structure and Content of Clinical Study Reports

Questions and Answers. July 2012

3. ICH E6 (R1). Guideline for Good Clinical Practice. June 1996

4. ICH E9. Statistical Principles for Clinical Trials. February 1998

5. M4E(R1). The Common Technical Document for the Registration of Pharmaceuticals

for Human Use Efficacy. September 2002

6. Menter A, Gottlieb A, Feldman SR, van Voorhees AS, Leonardi CL, Gordon KB et al.

Guidelines of care for the management of psoriasis and psoriatic arthritis. Section 1.

Overview of psoriasis and guidelines of care for the treatment of psoriasis with

biologics. J Am Acad Dermatol; 58: 826-50.

7. National Center for Health Statistics. Current estimates from the National Health Inter-

view Survey: United States, 1996, Vital Health Stat 1999; 10(200): 81-6.

8. Farber EM, Nall L. Epidemiology: Natural history and genetics. In: Roenigk HHJ,

Maibach HI, editors. Psoriasis. New York: Marcel Dekker, 1998: 107-57.

9. Gottlieb AB. Psoriasis. Dis Manag Clin Outcomes 1998; 1(6): 195-202.

10. Douglas WS, Poulin Y, Decroix J, Ortonne JP, Mrowietz U, Gulliver W et al. A new

calcipotriol/betamethasone formulation with rapid onset of action was superior to

monotherapy with BDP or calcipotriol in psoriasis vulgaris. Acta Derm Venereol.

2002;82(2):131-5.

11. Guenther L, van de Kerkhof PC, Snellman E, Kragballe K, Chu AC, Tegner E et al.

Efficacy and safety of a new combination of calcipotriol and betamethasone

dipropionate (one or twice daily) compared to calcipotriol (twice daily) in the treatment

of psoriasis vulgaris: a randomized, double-blind, vehicle-controlled clinical trial. Br J

Dermatol. 2002;147(2):316-23.

12. Kaufmann R, Bibby AJ, Bissonnette R, Cambazard F, Chu AC, Decroix J et al. A new

calcipotriol/betamethasone dipropionate formulation (Daivobet) is an effective once-

daily treatment for psoriasis vulgaris. Dermatology. 2002;205(4):389-93.

13. Papp KA, Guenther L, Boyden B, Larsen FG, Harvima RJ, Guilhou JJ et al. Early

onset of action and efficacy of a combination of calcipotriene and betamethasone

dipropionate in the treatment of psoriasis. J Am Acad Dermatol. 2003;48(1):48-54.

LP0053-1001 04-Mar-2014 of 315

14. Jemec GBE, Ganslandt C, Ortonne JP, Poulin Y, Burden AD, de Unamuno P et al. A

new scalp formulation of calcipotriene plus betamethasone compared with its active

ingredients and the vehicle in the treatment of scalp psoriasis. J Am Acad Dermatol

2008; 59 (3); 455-63.

15. van de Kerkhof PCM, Hoffman V, Anstey A, Barnes L, Bolduc C, Reich K et al. A

new scalp formulation of calcipotriol plus betamethasone dipropionate compared with

each of its active ingredients in the same vehicle for the treatment of scalp psoriasis: a

randomised, double-blind, controlled trial. Br J Dermatol 2009; 160; 170-76.

16. Kragballe K, Hoffmann V, Ortonne JP, Tan J, Nordin P, Segaert S. Efficacy and safety

of calcipotriol plus betamethasone dipropionate scalp formulation compared with

calcipotriol scalp solution in the treatment of scalp psoriasis. Br J Dermatol 2009; 161:

159-166 .

17. Fleming C, Ganslandt C, Guenther L, Johannesson A, Buckley C, Simon JC et al.

Calciopotriol plus betamethasone dipropionate gel compared with its active

components in the same vehicle and the vehicle alone in the treatment of psoriasis

vulgaris: a randomised, parallel group, double-blind, exploratory study. Eur J Dermatol

2010; 20 (4): 465-71.

18. Clinical Study Report. A phase 2 study comparing treatment with LEO 90100 with

betamethasone dipropionate in LEO 90100 vehicle and calcipotriol in LEO 90100

vehicle in subjects with psoriasis vulgaris. A multi-centre, prospective, randomised,

double-blind, 3-arm, parallel group, 4-week study in subjects with psoriasis vulgaris

Ballerup. Denmark: LEO Pharma, Clinical Development; LEO 90100-7. 19-Apr-2013.

19. Clinical Study Report. LEO 90100 Compared with Calcipotriol plus Betamethasone

Dipropionate Ointment, LEO 90100 Vehicle and Ointment Vehicle in Subjects with

Psoriasis Vulgaris. A phase 2 study comparing treatment with LEO 90100 with

calcipotriol plus betamethasone ointment, LEO 90100 vehicle and ointment vehicle in

subjects with psoriasis vulgaris. Ballerup. Denmark: LEO Pharma, Clinical

Development; LEO 90100-35. 10-Jun-2013.

20. CHMP, 18 November 2004: Guideline on Clinical Investigation of Medicinal Products

Indicated for the Treatment of Psoriasis.

21. Fitzpatrick TB: Soleil et peau. J Med Esthet 1975; 2:330-34.

22. Fredriksson T, Pettersson U. Dermatologica 1978;157:238-44.

23. Ratitch B, O'Kelly M, Tosiello R: Missing data in clinical trials: from clinical

assumptions to statistical analysis using pattern mixture models. Pharm. Stat 2013.

LP0053-1001 04-Mar-2014 of 315

24. Rubin D.B. 1987. Multiple Imputation for Nonresponse in Surveys. New York: John

Wiley and Sons.

25. Li, Meng et al.. 1991. Significance levels from repeated p-values with multiply-

imputed data. Statistica Sinica, 1 (1991), 65-92.

26. Van der Wielen RP, Lowik MR, Van den Berg H et al. Serum vitamin D concentrations

among elderly people in Europe. Lancet. 1995;346:207–10.

27. Thacher TD, Clarke BL. Vitamin D insufficiency. Mayo Clin Proc. 2011;86:50–60.

28. Adami S, Viapiana O, Gatti D et al. Relationship between serum parathyroid hormone,

vitamin D sufficiency, age, and calcium intake. Bone. 2008;42:267–70.

Trial ID: LP0053-1001 04-Mar-2014 of 315

1 Tables and Figures, Baseline Characteristics and Investigational Product

Data

List of Tables

Table 1–1: Reasons for withdrawal from trial: randomised subjects ..................................... 153

Table 1–2: Reasons for withdrawal from trial by last visit attended: randomised subjects ... 154

Table 1–3: Subject enrolment and randomisation by centre: enrolled and randomised subjects........................................................................................................................ 155

Table 1–4: Protocol deviations: randomised subjects ............................................................ 156

Table 1–5: Age, height, weight and BMI: randomised subjects ............................................ 157

Table 1–6: Sex, race, ethnicity and skin type: randomised subjects ...................................... 158

Table 1–7: Duration of psoriasis, BSA and baseline m-PASI: randomised subjects.............. 159

Table 1–8: Baseline IGA: randomised subjects ..................................................................... 160

Table 1–9: Other locations of psoriasis: randomised subjects ............................................... 161

Table 1–10: Previous psoriasis treatments: randomised subjects........................................... 162

Table 1–11: Concurrent diagnoses: randomised subjects....................................................... 163

Table 1–12: Concomitant medication at baseline: randomised subjects................................ 165

Table 1–13: Target lesion location: randomised subjects....................................................... 166

Table 1–14: 25-hydroxy vitamin D categorised as low, normal or high: randomised subjects........................................................................................................................ 167

Table 1–15: Vital signs at baseline: randomised subjects ...................................................... 168

Table 1–16: Age by centre: randomised subjects ................................................................... 169

Table 1–17: Sex by centre: randomised subjects.................................................................... 175

Table 1–18: Ethnicity by centre: randomised subjects........................................................... 179

Table 1–19: Race by centre: randomised subjects.................................................................. 183

Table 1–20: Baseline IGA by centre: randomised subjects.................................................... 188

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 1–21: Subjects with photographs by centre: randomised subjects ............................... 192

Table 1–22: Compliance with treatment instructions over the total trial period: randomised subjects ........................................................................................................... 196

Table 1–23: Compliance with treatment instructions by visit: randomised subjects ............. 197

Table 1–24: Baseline m-PASI: randomised subjects excluding site ................................. 199

List of Figures

Figure 1–1: Visit attendance by treatment: active .................................................................. 200

Figure 1–2: Visit attendance by treatment: vehicle ................................................................ 201

Figure 1–3: Trial analysis sets by treatment: active ............................................................... 202

Figure 1–4: Trial analysis sets by treatment: vehicle ............................................................. 203

Figure 1–5: Visit attendance: enrolled subjects...................................................................... 204

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 1–1: Reasons for withdrawal from trial: randomised subjects


LEO 90100(n=323)

Vehicle(n=103)

Reason for discontinuation




WithdrawalsVoluntary 4 0.9 2 0.6 2 1.9 Lost to follow-up 8 1.9 7 2.2 1 1.0 Other reason(s)1 2 0.5 1 0.3 1 1.0 Total number of withdrawn subjects

14 3.3 10 3.1 4 3.9

Completers2 412 96.7 313 96.9 99 96.1

28NOV13:12:13:39 LP0053 1001 t01wdr.doc

1) Other reasons: H return to college (subject ), moved to Canada (subject ).2) Attended Visit 4 4).

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 1–2: Reasons for withdrawal from trial by last visit attended: randomised subjects

Reason for


Visit

LEO 90100(n=323)

Visit

Vehicle(n=103)

Visit

discontinuation

1 2 3 4 1 2 3 4 1 2 3 4

Voluntary 2 0 2 0 2 0 0 0 0 0 2 0 Lost to follow-up 2 1 5 0 2 1 4 0 0 0 1 0 Other reason(s) 1 0 1 0 0 0 1 0 1 0 0 0 Total 5 1 8 0 4 1 5 0 1 0 3 0

28NOV13:13:18:33 LP0053 1001 t02wdrbylast.doc

Trial ID: LP0053-1001 04-Mar-2014 of315

Table 1-3: Subject emolment and randomisation by centre: emolled and randomised subjects

Total number of subject s a ssigne d t r eatment

Total numbe r Total numbe r of subje cts of subje cts

enrolle d randomise d LEO 90100 Vehicle Cent r e (n=4 91) (n=426) (n=323) (n=l03)

20 20 15 5 12 12 9 3 14 13 10 3 31 26 20 6 15 15 12 3 31 28 21 7 23 23 17 6 26 22 16 6 16 13 10 3 14 11 8 3

6 6 5 1 19 17 12 5 13 13 10 3 29 26 20 6

8 8 6 2 21 17 13 4 12 11 9 2 12 12 9 3 16 11 9 2 23 16 12 4

7 5 4 1 19 17 13 4 29 25 18 7 20 20 15 5 34 23 17 6 13 11 9 2

8 5 4 1

Tot al 4 91 426 323 1 03

28NOV13: 12 : 13 : 18 LP0053 1001 I 0 3enrol. doc

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 1–4: Protocol deviations: randomised subjects


LEO 90100(n=323)

Vehicle(n=103)

Deviation1Number of subjects %



Early withdrawal 14 3.3 10 3.1 4 3.9 Exclusionary medication taken

1 0.2 1 0.3 0 0.0

Incorrect kit dispensed2

1 0.2 1 0.3 0 0.0

Visit 4 conducted outside of window

12 2.8 9 2.8 3 2.9

Total number of deviations

28 21 7

Total number of subjects withdeviations

28 6.6 21 6.5 7 6.8

09DEC13:11:41:31 LP0053 1001 t04dev.doc

1) Only deviations leading to exclusion from per protocol analysis set are shown in table.2) Six other subjects were dispensed incorrect kit that however contained correct

medication.

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 1–5: Age, height, weight and BMI: randomised subjects

Baseline characteristic


LEO 90100(n=323)

Vehicle(n=103)

Age (years) Mean 50.0 51.2 46.0 SD 13.9 13.9 13.2 Median 51.0 52.0 46.0 Minimum 18 18 19 Maximum 87 87 79 Number 426 323 103 Height (cm) Mean 170.5 171.0 168.8 SD 10.6 10.9 9.7 Median 170.2 170.7 168.9 Minimum 135 137 135 Maximum 196 196 191 Number 424 323 101 Weight (kg) Mean 93.6 93.6 93.5 SD 23.0 23.0 22.9 Median 90.3 90.3 88.8 Minimum 43 43 59 Maximum 186 186 150 Number 426 323 103 BMI (kg/m²) Mean 32.3 32.0 33.1 SD 7.8 7.5 8.7 Median 30.7 30.6 30.7 Minimum 16 16 19 Maximum 62 62 59 Number 424 323 101

29NOV13:11:16:45 LP0053 1001 t05age.doc

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 1–6: Sex, race, ethnicity and skin type: randomised subjects


LEO 90100(n=323)

Vehicle(n=103)





SexMale 253 59.4 204 63.2 49 47.6 Female 173 40.6 119 36.8 54 52.4 Total 426 100.0 323 100.0 103 100.0

RaceWhite 366 85.9 276 85.4 90 87.4 Black or african american

30 7.0 24 7.4 6 5.8

Asian 13 3.1 10 3.1 3 2.9 American indian or alaska native

4 0.9 3 0.9 1 1.0

Native hawaiian or other pacificislander

3 0.7 2 0.6 1 1.0

Other 10 2.3 8 2.5 2 1.9 Total 426 100.0 323 100.0 103 100.0

EthnicicyNot hispanic or

latino 319 74.9 238 73.7 81 78.6


Skin typeType I = White:

always burns easily; nevertans

20 4.7 16 5.0 4 3.9

Type II = White: always burnseasily; tansminimally

108 25.4 83 25.7 25 24.3

Type III = White: burns moderately;tans gradually(light brown)

131 30.8 92 28.5 39 37.9

Type IV = White: burns minimally; alwaystans well (moderatebrown)

110 25.8 89 27.6 21 20.4

Type V = Brown: rarely burns; tansprofusely (darkbrown)

42 9.9 33 10.2 9 8.7

Type VI = Black: never burns; deeplypigmented

15 3.5 10 3.1 5 4.9

Total 426 100.0 323 100.0 103 100.0

29NOV13:11:17:21 LP0053 1001 t06_sex_race.doc

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 1–7: Duration of psoriasis, BSA and baseline m-PASI: randomised subjects



LEO 90100(n=323)

Vehicle(n=103)

Duration of Psoriasis Vulgaris (years) Mean 15.9 16.3 14.9 SD 13.8 14.4 11.4 Median 11.0 10.0 11.0 Minimum 1 1 1 Maximum 67 67 53 Number 426 323 103 BSA (%) Mean 7.5 7.4 8.0 SD 6.5 6.4 7.0 Median 5.0 5.0 5.0 Minimum 2 2 2 Maximum 30 30 30 Number 426 323 103 m-PASI Mean 7.5 7.4 7.9 SD 5.3 4.8 6.6 Median 6.0 6.0 6.1 Minimum 2 2 2 Maximum 47 37 47 Number 426 323 103

28NOV13:12:13:34 LP0053 1001 t07dur.doc

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 1–8: Baseline IGA: randomised subjects


LEO 90100(n=323)

Vehicle(n=103)

Baseline IGANumber of subjects %




28NOV13:12:13:50 LP0053 1001 t08baseiga.doc

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 1–9: Other locations of psoriasis: randomised subjects


LEO 90100(n=323)

Vehicle(n=103)

Location of Psoriasis Vulgaris




Psoriasis vulgaris on the faceYes 99 23.2 73 22.6 26 25.2 No 327 76.8 250 77.4 77 74.8 Total 426 100.0 323 100.0 103 100.0

Psoriasis vulgaris on the skin foldsYes 109 25.6 86 26.6 23 22.3 No 317 74.4 237 73.4 80 77.7 Total 426 100.0 323 100.0 103 100.0

Psoriasis vulgaris on the genitalsYes 68 16.0 53 16.4 15 14.6 No 358 84.0 270 83.6 88 85.4 Total 426 100.0 323 100.0 103 100.0

Psoriasis vulgaris on the nailsYes 114 26.8 88 27.2 26 25.2 No 312 73.2 235 72.8 77 74.8 Total 426 100.0 323 100.0 103 100.0

Psoriasis vulgaris on the scalpYes 219 51.4 167 51.7 52 50.5 No 207 48.6 156 48.3 51 49.5 Total 426 100.0 323 100.0 103 100.0

28NOV13:12:13:57 LP0053 1001 t09locations.doc

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 1–10: Previous psoriasis treatments: randomised subjects


LEO 90100(n=323)

Vehicle(n=103)

Previous treatmentsNumber of subjects %



Phototherapy 92 21.6 71 22.0 21 20.4 Systemic: any treatment (excludingbiologics)

53 12.4 39 12.1 14 13.6

Systemic: biologics 50 11.7 37 11.5 13 12.6 Topical: calcineurin inhibitors

10 2.3 7 2.2 3 2.9

Topical: coal tar 114 26.8 96 29.7 18 17.5 Topical: corticosteroids

320 75.1 244 75.5 76 73.8

Topical: fixed combinationcorticosteriod plusVitamin D analogues

70 16.4 56 17.3 14 13.6

Topical: Vitamin D analogues

69 16.2 56 17.3 13 12.6

Total number of subjects

373 87.6 287 88.9 86 83.5

06FEB14:09:30:15 LP0053 1001 t10prevtrt.doc

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 1–11: Concurrent diagnoses: randomised subjects


LEO 90100(n=323)

Vehicle(n=103)

System Organ Classification1Number ofdiagnoses

Number ofsubjects %

Number ofdiagnoses

Number ofsubjects %

Number ofdiagnoses

Number ofsubjects %

Blood and lymphatic system disorders

7 7 1.6 4 4 1.2 3 3 2.9

Cardiac disorders 23 22 5.2 14 13 4.0 9 9 8.7 Congenital, familial and genetic disorders

2 2 0.5 2 2 0.6 0 0 0.0

Ear and labyrinth disorders 4 3 0.7 3 2 0.6 1 1 1.0 Endocrine disorders 29 29 6.8 23 23 7.1 6 6 5.8 Eye disorders 27 21 4.9 22 17 5.3 5 4 3.9 Gastrointestinal disorders 73 65 15.3 59 52 16.1 14 13 12.6 General disorders and administration siteconditions

39 29 6.8 29 21 6.5 10 8 7.8

Immune system disorders 117 92 21.6 83 65 20.1 34 27 26.2 Infections and infestations 16 16 3.8 13 13 4.0 3 3 2.9 Injury, poisoning and procedural complications

8 8 1.9 7 7 2.2 1 1 1.0

Investigations 37 35 8.2 28 26 8.0 9 9 8.7 Metabolism and nutrition disorders

214 152 35.7 173 121 37.5 41 31 30.1

Musculoskeletal and connective tissue disorders

124 105 24.6 90 76 23.5 34 29 28.2

Neoplasms benign, malignant and unspecified (incl cysts andpolyps)

4 4 0.9 3 3 0.9 1 1 1.0

Nervous system disorders 49 48 11.3 32 32 9.9 17 16 15.5 Psychiatric disorders 92 66 15.5 71 50 15.5 21 16 15.5

28NOV13:12:14:11 LP0053 1001 t11diag.doc Continued...

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 1–11: Concurrent diagnoses: randomised subjects, continued


LEO 90100(n=323)

Vehicle(n=103)

System Organ Classification1Number ofdiagnoses

Number ofsubjects %

Number ofdiagnoses

Number ofsubjects %

Number ofdiagnoses

Number ofsubjects %

Renal and urinary disorders 7 7 1.6 7 7 2.2 0 0 0.0 Reproductive system and breast disorders

86 86 20.2 65 65 20.1 21 21 20.4

Respiratory, thoracic and mediastinal disorders

48 45 10.6 37 35 10.8 11 10 9.7

Skin and subcutaneous tissue disorders

59 53 12.4 49 44 13.6 10 9 8.7

Social circumstances 3 3 0.7 2 2 0.6 1 1 1.0 Surgical and medical procedures

172 133 31.2 133 102 31.6 39 31 30.1

Vascular disorders 139 136 31.9 111 110 34.1 28 26 25.2 Total number of diagnoses2

1379 1060 319 Total number of subjects

358 84.0 276 85.4 82 79.6

28NOV13:12:14:11 LP0053 1001 t11diag.doc

1) Classification according to MedDRA version 16.0.2) Different diagnoses within the same preferred term and involving the same subject have been counted as one. A

subject could appear in multiple classes.

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 1–12: Concomitant medication at baseline: randomised subjects


LEO 90100(n=323)

Vehicle(n=103)

ATC classificationindex level 11

Number of drugs

Number ofsubjects %

Number of drugs

Number ofsubjects %

Number of drugs

Number ofsubjects %

Alimentary tract and metabolism

266 150 35.2 199 113 35.0 67 37 35.9

Antiinfectives for systemic use

2 2 0.5 2 2 0.6 0 0 0.0

Antineoplastic and immunomodulating agents

2 2 0.5 1 1 0.3 1 1 1.0

Antiparasitic products, insecticides and repellent

1 1 0.2 1 1 0.3 0 0 0.0

Blood and blood forming organs 79 69 16.2 65 56 17.3 14 13 12.6 Cardiovascular system 293 160 37.6 239 129 39.9 54 31 30.1 Dermatologicals 5 5 1.2 4 4 1.2 1 1 1.0 Genito urinary system and sex hormones

30 28 6.6 24 22 6.8 6 6 5.8

Musculo-Skeletal system 83 72 16.9 61 50 15.5 22 22 21.4 Nervous system 163 106 24.9 121 78 24.1 42 28 27.2 Respiratory system 59 42 9.9 48 33 10.2 11 9 8.7 Sensory organs 6 5 1.2 6 5 1.5 0 0 0.0 Systemic hormonal preparations, excl. sex hormones

29 29 6.8 23 23 7.1 6 6 5.8

Various 41 33 7.7 30 26 8.0 11 7 6.8 Total number of drugs taken1 1059 824 235 Total number of subjects taking drugs

286 67.1 219 67.8 67 65.0

28NOV13:12:14:16 LP0053 1001 t12conmeds.doc

1) Drugs with the same Anatomical Therapeutic Chemical (ATC) classification level 4 code and generic name/preferred term name which have been taken by the same subject have been counted as one.

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 1–13: Target lesion location: randomised subjects


LEO 90100(n=323)

Vehicle(n=103)

Target lesion location




Elbow 35 8.2 25 7.7 10 9.7 Knee 16 3.8 14 4.3 2 1.9 Limbs 287 67.4 215 66.6 72 69.9 Trunk 88 20.7 69 21.4 19 18.4 Total 426 100.0 323 100.0 103 100.0

28NOV13:12:14:23 LP0053 1001 t13target.doc

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 1–14: 25-hydroxy vitamin D categorised as low, normal or high: randomised subjects


LEO 90100(n=323)

Vehicle(n=103)

25-hydroxy vitamin D level




Low 311 73.5 230 71.9 81 78.6 Normal 112 26.5 90 28.1 22 21.4 Total 423 100.0 320 100.0 103 100.0

28NOV13:12:14:32 LP0053 1001 t14vitd.doc

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 1–15: Vital signs at baseline: randomised subjects

Vital sign


LEO 90100(n=323)

Vehicle(n=103)

Heart Rate (Beats/Minute) Mean 73.6 73.2 74.8 SD 11.0 11.1 10.6 Median 73.0 72.0 74.0 Minimum 47 47 48 Maximum 106 106 98 Number 426 323 103 Systolic Blood Pressure (mmHg) Mean 129.9 130.0 129.8 SD 15.0 14.8 15.8 Median 130.0 130.0 130.0 Minimum 87 87 95 Maximum 185 185 182 Number 426 323 103 Diastolic Blood Pressure (mmHg) Mean 81.1 81.0 81.3 SD 9.1 8.8 10.2 Median 82.0 82.0 81.0 Minimum 54 56 54 Maximum 108 108 108 Number 426 323 103

29NOV13:13:06:11 LP0053 1001 t15vital.doc

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 1–16: Age by centre: randomised subjects

CentreAge (years)


LEO 90100(n=323)

Vehicle(n=103)

ean 49.7 50.1 48.4 SD 11.2 9.7 16.1 Median 53.0 51.0 53.0 Minimum 20 25 20 Maximum 68 68 59 Number 20 15 5





28NOV13:13:41:15 LP0053 1001 t16agebycntr.doc Continued...

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 1–16: Age by centre: randomised subjects, continued

CentreAge (years)


LEO 90100(n=323)

Vehicle(n=103)







Trial ID: LP0053-1001 04-Mar-2014 of 315


CentreAge (years)


LEO 90100(n=323)

Vehicle(n=103)

ean 62.3 62.4 62.0 SD 12.1 13.6 Median 64.5 65.0 62.0 Minimum 40 40 62 Maximum 77 77 62 Number 6 5 1






Trial ID: LP0053-1001 04-Mar-2014 of 315


CentreAge (years)


LEO 90100(n=323)

Vehicle(n=103)







Trial ID: LP0053-1001 04-Mar-2014 of 315


CentreAge (years)


LEO 90100(n=323)

Vehicle(n=103)



28NOV13:13:41:15 LP0053 1001 t16agebycntr.doc

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 1–17: Sex by centre: randomised subjects


LEO 90100(n=323)

Vehicle(n=103)

CentreSex




ale 13 65.0 8 53.3 5 100.0 Female 7 35.0 7 46.7 0 0.0 Total 20 100.0 15 100.0 5 100.0

ale 8 66.7 6 66.7 2 66.7 Female 4 33.3 3 33.3 1 33.3 Total 12 100.0 9 100.0 3 100.0

ale 9 69.2 8 80.0 1 33.3 Female 4 30.8 2 20.0 2 66.7 Total 13 100.0 10 100.0 3 100.0

ale 14 53.8 12 60.0 2 33.3 Female 12 46.2 8 40.0 4 66.7 Total 26 100.0 20 100.0 6 100.0

ale 8 53.3 6 50.0 2 66.7 Female 7 46.7 6 50.0 1 33.3 Total 15 100.0 12 100.0 3 100.0

ale 16 57.1 13 61.9 3 42.9 Female 12 42.9 8 38.1 4 57.1 Total 28 100.0 21 100.0 7 100.0

ale 11 47.8 11 64.7 0 0.0 Female 12 52.2 6 35.3 6 100.0 Total 23 100.0 17 100.0 6 100.0

ale 14 63.6 12 75.0 2 33.3 Female 8 36.4 4 25.0 4 66.7 Total 22 100.0 16 100.0 6 100.0

28NOV13:13:42:56 LP0053 1001 t17sexbycntr.doc Continued...

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 1–17: Sex by centre: randomised subjects, continued


LEO 90100(n=323)

Vehicle(n=103)

CentreSex




ale 7 53.8 6 60.0 1 33.3 Female 6 46.2 4 40.0 2 66.7 Total 13 100.0 10 100.0 3 100.0

ale 8 72.7 7 87.5 1 33.3 Female 3 27.3 1 12.5 2 66.7 Total 11 100.0 8 100.0 3 100.0

ale 5 83.3 4 80.0 1 100.0 Female 1 16.7 1 20.0 0 0.0 Total 6 100.0 5 100.0 1 100.0

ale 8 47.1 6 50.0 2 40.0 Female 9 52.9 6 50.0 3 60.0 Total 17 100.0 12 100.0 5 100.0

ale 10 76.9 9 90.0 1 33.3 Female 3 23.1 1 10.0 2 66.7 Total 13 100.0 10 100.0 3 100.0

ale 16 61.5 13 65.0 3 50.0 Female 10 38.5 7 35.0 3 50.0 Total 26 100.0 20 100.0 6 100.0

ale 5 62.5 3 50.0 2 100.0 Female 3 37.5 3 50.0 0 0.0 Total 8 100.0 6 100.0 2 100.0

ale 13 76.5 11 84.6 2 50.0 Female 4 23.5 2 15.4 2 50.0 Total 17 100.0 13 100.0 4 100.0


Trial ID: LP0053-1001 04-Mar-2014 of 315



LEO 90100(n=323)

Vehicle(n=103)

CentreSex




ale 6 54.5 5 55.6 1 50.0 Female 5 45.5 4 44.4 1 50.0 Total 11 100.0 9 100.0 2 100.0

ale 12 100.0 9 100.0 3 100.0 Total 12 100.0 9 100.0 3 100.0

ale 8 72.7 6 66.7 2 100.0 Female 3 27.3 3 33.3 0 0.0 Total 11 100.0 9 100.0 2 100.0

ale 13 81.3 10 83.3 3 75.0 Female 3 18.8 2 16.7 1 25.0 Total 16 100.0 12 100.0 4 100.0

ale 4 80.0 3 75.0 1 100.0 Female 1 20.0 1 25.0 0 0.0 Total 5 100.0 4 100.0 1 100.0

ale 10 58.8 7 53.8 3 75.0 Female 7 41.2 6 46.2 1 25.0 Total 17 100.0 13 100.0 4 100.0

ale 7 28.0 6 33.3 1 14.3 Female 18 72.0 12 66.7 6 85.7 Total 25 100.0 18 100.0 7 100.0

Male 5 25.0 4 26.7 1 20.0 Female 15 75.0 11 73.3 4 80.0 Total 20 100.0 15 100.0 5 100.0


Trial ID: LP0053-1001 04-Mar-2014 of 315



LEO 90100(n=323)

Vehicle(n=103)

CentreSex




ale 13 56.5 10 58.8 3 50.0 Female 10 43.5 7 41.2 3 50.0 Total 23 100.0 17 100.0 6 100.0

ale 8 72.7 7 77.8 1 50.0 Female 3 27.3 2 22.2 1 50.0 Total 11 100.0 9 100.0 2 100.0

ale 2 40.0 2 50.0 0 0.0 Female 3 60.0 2 50.0 1 100.0 Total 5 100.0 4 100.0 1 100.0

28NOV13:13:42:56 LP0053 1001 t17sexbycntr.doc

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 1–18: Ethnicity by centre: randomised subjects


LEO 90100(n=323)

Vehicle(n=103)

CentreEthnicity




ot hispanic or latino

2 10.0 1 6.7 1 20.0



12 100.0 9 100.0 3 100.0

Total 12 100.0 9 100.0 3 100.0


12 92.3 9 90.0 3 100.0



20 76.9 14 70.0 6 100.0



6 40.0 4 33.3 2 66.7



28 100.0 21 100.0 7 100.0

Total 28 100.0 21 100.0 7 100.0

Not hispanic or latino

21 91.3 16 94.1 5 83.3



15 68.2 10 62.5 5 83.3


28NOV13:13:48:53 LP0053 1001 t18ethbycentr.doc Continued...

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 1–18: Ethnicity by centre: randomised subjects, continued


LEO 90100(n=323)

Vehicle(n=103)

CentreEthnicity





12 92.3 9 90.0 3 100.0



11 100.0 8 100.0 3 100.0

Total 11 100.0 8 100.0 3 100.0


3 50.0 3 60.0 0 0.0



17 100.0 12 100.0 5 100.0

Total 17 100.0 12 100.0 5 100.0


11 84.6 8 80.0 3 100.0



25 96.2 19 95.0 6 100.0



8 100.0 6 100.0 2 100.0

Total 8 100.0 6 100.0 2 100.0


10 58.8 8 61.5 2 50.0



10 90.9 8 88.9 2 100.0


Trial ID: LP0053-1001 04-Mar-2014 of 315



LEO 90100(n=323)

Vehicle(n=103)

CentreEthnicity




ispanic or latino 1 9.1 1 11.1 0 0.0 Total 11 100.0 9 100.0 2 100.0


10 83.3 7 77.8 3 100.0



9 81.8 7 77.8 2 100.0



6 37.5 4 33.3 2 50.0



5 100.0 4 100.0 1 100.0

Total 5 100.0 4 100.0 1 100.0


12 70.6 9 69.2 3 75.0



9 36.0 6 33.3 3 42.9



10 50.0 9 60.0 1 20.0



21 91.3 16 94.1 5 83.3

Hispanic or latino 2 8.7 1 5.9 1 16.7


Trial ID: LP0053-1001 04-Mar-2014 of 315



LEO 90100(n=323)

Vehicle(n=103)

CentreEthnicity




otal 23 100.0 17 100.0 6 100.0


9 81.8 7 77.8 2 100.0



5 100.0 4 100.0 1 100.0

Total 5 100.0 4 100.0 1 100.0

28NOV13:13:48:53 LP0053 1001 t18ethbycentr.doc

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 1–19: Race by centre: randomised subjects


LEO 90100(n=323)

Vehicle(n=103)

CentreRace




hite 15 75.0 12 80.0 3 60.0 Black or african american

4 20.0 2 13.3 2 40.0

Other 1 5.0 1 6.7 0 0.0 Total 20 100.0 15 100.0 5 100.0

hite 11 91.7 8 88.9 3 100.0 Asian 1 8.3 1 11.1 0 0.0 Total 12 100.0 9 100.0 3 100.0

hite 12 92.3 9 90.0 3 100.0 American indian or alaska native

1 7.7 1 10.0 0 0.0

Total 13 100.0 10 100.0 3 100.0


4 15.4 3 15.0 1 16.7

Asian 2 7.7 2 10.0 0 0.0 Other 2 7.7 2 10.0 0 0.0 Total 26 100.0 20 100.0 6 100.0

hite 14 93.3 11 91.7 3 100.0 Asian 1 6.7 1 8.3 0 0.0 Total 15 100.0 12 100.0 3 100.0

hite 27 96.4 21 100.0 6 85.7 Native hawaiian or other pacific

islander

1 3.6 0 0.0 1 14.3

28NOV13:13:46:52 LP0053 1001 t19racbycntr.doc Continued...

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 1–19: Race by centre: randomised subjects, continued


LEO 90100(n=323)

Vehicle(n=103)

CentreRace




otal 28 100.0 21 100.0 7 100.0

White 20 87.0 15 88.2 5 83.3 Black or african american

3 13.0 2 11.8 1 16.7

Total 23 100.0 17 100.0 6 100.0

hite 18 81.8 14 87.5 4 66.7 Asian 2 9.1 0 0.0 2 33.3 Native hawaiian or other pacific

islander

1 4.5 1 6.3 0 0.0

Other 1 4.5 1 6.3 0 0.0 Total 22 100.0 16 100.0 6 100.0


1 7.7 1 10.0 0 0.0

Total 13 100.0 10 100.0 3 100.0


1 9.1 0 0.0 1 33.3

Total 11 100.0 8 100.0 3 100.0

hite 2 33.3 2 40.0 0 0.0 Native hawaiian or other pacific

islander

1 16.7 1 20.0 0 0.0

Other 3 50.0 2 40.0 1 100.0 Total 6 100.0 5 100.0 1 100.0


Trial ID: LP0053-1001 04-Mar-2014 of 315



LEO 90100(n=323)

Vehicle(n=103)

CentreRace




hite 17 100.0 12 100.0 5 100.0 Total 17 100.0 12 100.0 5 100.0

hite 13 100.0 10 100.0 3 100.0 Total 13 100.0 10 100.0 3 100.0


2 7.7 2 10.0 0 0.0

Asian 3 11.5 2 10.0 1 16.7 Total 26 100.0 20 100.0 6 100.0


1 12.5 1 16.7 0 0.0

Total 8 100.0 6 100.0 2 100.0

hite 14 82.4 11 84.6 3 75.0 Asian 2 11.8 2 15.4 0 0.0 Other 1 5.9 0 0.0 1 25.0 Total 17 100.0 13 100.0 4 100.0


1 9.1 1 11.1 0 0.0

American indian or alaska native

1 9.1 0 0.0 1 50.0

Other 1 9.1 1 11.1 0 0.0 Total 11 100.0 9 100.0 2 100.0


Trial ID: LP0053-1001 04-Mar-2014 of 315



LEO 90100(n=323)

Vehicle(n=103)

CentreRace




hite 12 100.0 9 100.0 3 100.0 Total 12 100.0 9 100.0 3 100.0


3 27.3 3 33.3 0 0.0

Total 11 100.0 9 100.0 2 100.0


2 12.5 1 8.3 1 25.0

American indian or alaska native

1 6.3 1 8.3 0 0.0

Total 16 100.0 12 100.0 4 100.0

hite 4 80.0 3 75.0 1 100.0 Other 1 20.0 1 25.0 0 0.0 Total 5 100.0 4 100.0 1 100.0


1 5.9 1 7.7 0 0.0

Total 17 100.0 13 100.0 4 100.0


1 4.0 1 5.6 0 0.0

Total 25 100.0 18 100.0 7 100.0


Trial ID: LP0053-1001 04-Mar-2014 of 315



LEO 90100(n=323)

Vehicle(n=103)

CentreRace





4 20.0 4 26.7 0 0.0

Asian 1 5.0 1 6.7 0 0.0 Total 20 100.0 15 100.0 5 100.0

hite 22 95.7 16 94.1 6 100.0 American indian or alaska native

1 4.3 1 5.9 0 0.0

Total 23 100.0 17 100.0 6 100.0


1 9.1 1 11.1 0 0.0

Asian 1 9.1 1 11.1 0 0.0 Total 11 100.0 9 100.0 2 100.0


1 20.0 1 25.0 0 0.0

Total 5 100.0 4 100.0 1 100.0

28NOV13:13:46:52 LP0053 1001 t19racbycntr.doc

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 1–20: Baseline IGA by centre: randomised subjects


LEO 90100(n=323)

Vehicle(n=103)

CentreIGA




ild 11 55.0 9 60.0 2 40.0 Moderate 9 45.0 6 40.0 3 60.0 Total 20 100.0 15 100.0 5 100.0

ild 1 8.3 1 11.1 0 0.0 Moderate 9 75.0 6 66.7 3 100.0 Severe 2 16.7 2 22.2 0 0.0 Total 12 100.0 9 100.0 3 100.0






28NOV13:13:53:57 LP0053 1001 t20igabycntr.doc Continued...

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 1–20: Baseline IGA by centre: randomised subjects, continued


LEO 90100(n=323)

Vehicle(n=103)

CentreIGA


Number ofsubjects %




oderate 10 90.9 7 87.5 3 100.0 Severe 1 9.1 1 12.5 0 0.0 Total 11 100.0 8 100.0 3 100.0

oderate 6 100.0 5 100.0 1 100.0 Total 6 100.0 5 100.0 1 100.0




ild 2 25.0 1 16.7 1 50.0 Moderate 6 75.0 5 83.3 1 50.0


Trial ID: LP0053-1001 04-Mar-2014 of 315



LEO 90100(n=323)

Vehicle(n=103)

CentreIGA




otal 8 100.0 6 100.0 2 100.0




oderate 11 100.0 9 100.0 2 100.0 Total 11 100.0 9 100.0 2 100.0


oderate 5 100.0 4 100.0 1 100.0 Total 5 100.0 4 100.0 1 100.0

Moderate 15 88.2 12 92.3 3 75.0 Severe 2 11.8 1 7.7 1 25.0 Total 17 100.0 13 100.0 4 100.0

Mild 4 16.0 3 16.7 1 14.3


Trial ID: LP0053-1001 04-Mar-2014 of 315



LEO 90100(n=323)

Vehicle(n=103)

CentreIGA







oderate 11 100.0 9 100.0 2 100.0 Total 11 100.0 9 100.0 2 100.0


28NOV13:13:53:57 LP0053 1001 t20igabycntr.doc

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 1–21: Subjects with photographs by centre: randomised subjects


LEO 90100(n=323)

Vehicle(n=103)

CentrePhotos taken




o 20 100.0 15 100.0 5 100.0 Total 20 100.0 15 100.0 5 100.0

o 12 100.0 9 100.0 3 100.0 Total 12 100.0 9 100.0 3 100.0

o 13 100.0 10 100.0 3 100.0 Total 13 100.0 10 100.0 3 100.0

es 22 84.6 17 85.0 5 83.3 No 4 15.4 3 15.0 1 16.7 Total 26 100.0 20 100.0 6 100.0

o 15 100.0 12 100.0 3 100.0 Total 15 100.0 12 100.0 3 100.0

o 28 100.0 21 100.0 7 100.0 Total 28 100.0 21 100.0 7 100.0

es 3 13.0 3 17.6 0 0.0 No 20 87.0 14 82.4 6 100.0 Total 23 100.0 17 100.0 6 100.0

o 22 100.0 16 100.0 6 100.0 Total 22 100.0 16 100.0 6 100.0

Yes 1 7.7 0 0.0 1 33.3 No 12 92.3 10 100.0 2 66.7 Total 13 100.0 10 100.0 3 100.0

28NOV13:12:49:04 LP0053 1001 t21photo.doc Continued...

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 1–21: Subjects with photographs by centre: randomised subjects, continued


LEO 90100(n=323)

Vehicle(n=103)

CentrePhotos taken




o 11 100.0 8 100.0 3 100.0 Total 11 100.0 8 100.0 3 100.0

es 6 100.0 5 100.0 1 100.0 Total 6 100.0 5 100.0 1 100.0

es 9 52.9 5 41.7 4 80.0 No 8 47.1 7 58.3 1 20.0 Total 17 100.0 12 100.0 5 100.0

o 13 100.0 10 100.0 3 100.0 Total 13 100.0 10 100.0 3 100.0

o 26 100.0 20 100.0 6 100.0 Total 26 100.0 20 100.0 6 100.0

es 5 62.5 4 66.7 1 50.0 No 3 37.5 2 33.3 1 50.0 Total 8 100.0 6 100.0 2 100.0

es 1 5.9 1 7.7 0 0.0 No 16 94.1 12 92.3 4 100.0 Total 17 100.0 13 100.0 4 100.0

o 11 100.0 9 100.0 2 100.0 Total 11 100.0 9 100.0 2 100.0

o 12 100.0 9 100.0 3 100.0 Total 12 100.0 9 100.0 3 100.0


Trial ID: LP0053-1001 04-Mar-2014 of 315


All randomisedsubjects(n=426)

LEO 90100(n=323)

Vehicle(n=103)

CentrePhotos taken




es 6 54.5 5 55.6 1 50.0 No 5 45.5 4 44.4 1 50.0 Total 11 100.0 9 100.0 2 100.0

o 16 100.0 12 100.0 4 100.0 Total 16 100.0 12 100.0 4 100.0

o 5 100.0 4 100.0 1 100.0 Total 5 100.0 4 100.0 1 100.0

es 7 41.2 4 30.8 3 75.0 No 10 58.8 9 69.2 1 25.0 Total 17 100.0 13 100.0 4 100.0

es 9 36.0 6 33.3 3 42.9 No 16 64.0 12 66.7 4 57.1 Total 25 100.0 18 100.0 7 100.0

es 2 10.0 2 13.3 0 0.0 No 18 90.0 13 86.7 5 100.0 Total 20 100.0 15 100.0 5 100.0

es 2 8.7 2 11.8 0 0.0 No 21 91.3 15 88.2 6 100.0 Total 23 100.0 17 100.0 6 100.0

o 11 100.0 9 100.0 2 100.0 Total 11 100.0 9 100.0 2 100.0


Trial ID: LP0053-1001 04-Mar-2014 of 315



LEO 90100(n=323)

Vehicle(n=103)

CentrePhotos taken




o 5 100.0 4 100.0 1 100.0 Total 5 100.0 4 100.0 1 100.0

28NOV13:12:49:04 LP0053 1001 t21photo.doc

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 1–22: Compliance with treatment instructions over the total trial period: randomised subjects


LEO 90100(n=323)

Vehicle(n=103)

Compliance1Number of subjects %



No applications missed

331 78.6 243 76.2 88 86.3


67 15.9 54 16.9 13 12.7


15 3.6 14 4.4 1 1.0


1 0.2 1 0.3 0 0.0


4 1.0 4 1.3 0 0.0


3 0.7 3 0.9 0 0.0

Total 421 100.0 319 100.0 102 100.0

28NOV13:14:21:52 LP0053 1001 t22cmptotal.doc

1) Percentage of applications missed between Visit 1 and last attended visit. Subjects withdrawn before Visit 2 not included in table.

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 1–23: Compliance with treatment instructions by visit: randomised subjects


LEO 90100(n=323)

Vehicle(n=103)

Visit intervalCompliance




Baseline to week 1No applications missed

402 96.2 305 96.5 97 95.1


1 0.2 1 0.3 0 0.0

>10% and <=20% applications

missed

14 3.3 9 2.8 5 4.9


missed

1 0.2 1 0.3 0 0.0

Total 418 100.0 316 100.0 102 100.0

Week 1 to week 2No applications missed

387 93.5 291 93.0 96 95.0


1 0.2 1 0.3 0 0.0


missed

24 5.8 19 6.1 5 5.0


missed

1 0.2 1 0.3 0 0.0


missed

1 0.2 1 0.3 0 0.0

Total 414 100.0 313 100.0 101 100.0

Week 2 to week 4No applications missed

338 82.8 248 80.0 90 91.8


41 10.0 36 11.6 5 5.1


missed

12 2.9 10 3.2 2 2.0

28NOV13:14:24:23 LP0053 1001 t23cmpbyvisit.doc Continued...

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 1–23: Compliance with treatment instructions by visit: randomised subjects, continued


LEO 90100(n=323)

Vehicle(n=103)

Visit intervalCompliance




Week 2 to week 4>20% and <=30% applications

missed

8 2.0 7 2.3 1 1.0


missed

1 0.2 1 0.3 0 0.0


missed

1 0.2 1 0.3 0 0.0


7 1.7 7 2.3 0 0.0

Total 408 100.0 310 100.0 98 100.0

28NOV13:14:24:23 LP0053 1001 t23cmpbyvisit.doc

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 1–24: Baseline m-PASI: randomised subjects excluding site 15



LEO 90100(n=303)

Vehicle(n=97)

m-PASI Mean 6.9 6.9 6.9 SD 3.7 3.9 3.1 Median 5.9 5.8 6.0 Minimum 2 2 2 Maximum 28 28 18 Number 400 303 97

28NOV13:12:49:13 LP0053 1001 t24pasi15.doc

Trial ID: LP0053-1001 04-Mar-2014 of 315

Figure 1–1: Visit attendance by treatment: active

316

315

313

4

1

Number of subjects

2 not attending

Primary reason for

withdrawal


Visit 2 (Week 1)

Visit 3 (Week 2)

Visit 4 (Week 4)


2 voluntary ( )

323

5


4 lost to follow-up )

1 other ( )

1 not attending

2 not attending

Trial ID: LP0053-1001 04-Mar-2014 of 315

Figure 1–2: Visit attendance by treatment: vehicle

102

101

99

1

Number of subjects

1 not attending

Primary reason for

withdrawal


Visit 2 (Week 1)

Visit 3 (Week 2)

Visit 4 (Week 4)

1 other reason(s) ( )

103

31 lost to follow-up ( )2 voluntary ( )

Trial ID: LP0053-1001 04-Mar-2014 of 315

Figure 1–3: Trial analysis sets by treatment: active

Randomised subjects

=Full analysis set



10 withdrew prior to visit 4

9 violate visit 4 visit window1 disallowed treatment

1 wrong kit dispensed302

323

Trial ID: LP0053-1001 04-Mar-2014 of 315

Figure 1–4: Trial analysis sets by treatment: vehicle

Randomised subjects

=Full analysis set



4 withdrew prior to visit 4

3 violate visit 4 visit window

96

103

Trial ID: LP0053-1001 04-Mar-2014

Figure 1-5: Visit attendance: enrolled subjects

Nmnber of subjects

Visit 1 (Enrolled)

.. 65


5

Visit 2 (Week 1) 2 not attending

1 not attending 1

Visit 3 (Week 2)

1---+ .. 8

Visit 4 (Week 4)

of 315

Primruy reason for withdrawal

6 S screen failure

1 lost to follow-up - )

Trial ID: LP0053-1001 04-Mar-2014 of 315

2 Tables and Figures, Efficacy Data

List of Tables

Table 2–1: Statistical analysis of treatment success according to the IGA at Week 4 (multiple imputation): full analysis set .......................................................................... 208

Table 2–2: Statistical analysis of treatment success according to the IGA at Week 4: per protocol analysis set ....................................................................................... 209

Table 2–3: Sensitivity analyses of treatment success according to the IGA at Week 4: full analysis set...................................................................................................... 210

Table 2–4: Treatment success according to the IGA by visit (observed cases): full analysis set........................................................................................................................ 211

Table 2–5: IGA by visit (observed cases): full analysis set.................................................... 212

Table 2–6: Treatment success according to the IGA at Week 4 by baseline disease severity (observed cases): full analysis set .................................................................. 213

Table 2–7: Treatment success according to the IGA at Week 4 by centre (observed cases): full analysis set...................................................................................................... 214

Table 2–8: Statistical analyses of m-PASI at Week 4 and Week 1 (multiple imputation): full analysis set...................................................................................................... 218

Table 2–9: Sensitivity analyses of m-PASI at Week 4: full analysis set ................................ 219

Table 2–10: Sensitivity analyses of m-PASI at Week 1: full analysis set .............................. 220

Table 2–11: m-PASI by visit (observed cases): full analysis set ............................................ 221

Table 2–12: m-PASI at Week 4 by centre (observed cases): full analysis set ........................ 222

Table 2–13: m-PASI at Week 1 by centre (observed cases): full analysis set ........................ 228

Table 2–14: Statistical analysis of PASI-50 at Week 4 (multiple imputation): full analysis set........................................................................................................................ 234

Table 2–15: Statistical analysis of PASI-75 at Week 4 (multiple imputation): full analysis set........................................................................................................................ 235

Table 2–16: PASI-50 by visit (observed cases): full analysis set ........................................... 236

Table 2–17: PASI-75 by visit (observed cases): full analysis set ........................................... 237

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 2–18: Statistical analysis of treatment success according to patient's global assessment at Week 4 (observed cases): full analysis set.................................................. 238

Table 2–19: Treatment success according to patient's global assessment by visit (observed cases): full analysis set ................................................................................... 239

Table 2–20: Patient's global assessment by visit (observed cases): full analysis set ............. 240

Table 2–21: Analysis of change in Subject's assessment of itch (VAS) by time point (observed cases): full analysis set ................................................................................... 241

Table 2–22: Analysis of change in Subject's assessment of itch-related sleep loss (VAS) by time point (observed cases): full analysis set ................................................. 243

Table 2–23: Change in BSA from baseline to each visit (observed cases): full analysis set . 245

Table 2–24: Redness, thickness and scaliness of target lesion by visit: full analysis set ....... 246

Table 2–25: Analysis of change in DLQI by visit (observed cases): full analysis set ........... 249

Table 2–26: Analysis of EQ-5D-5L dimensions at baseline and Week 4 (observed cases): full analysis set...................................................................................................... 250

Table 2–27: EQ VAS score at baseline and Week 4 and analysis of change from baseline (observed cases): full analysis set .................................................................. 253

Table 2–28: EQ-5D-5L index score at baseline and Week 4 and analysis of change from baseline (observed cases): full analysis set .................................................... 254

Table 2–29: Percentage change in m-PASI by visit (observed cases): full analysis set......... 255

Table 2–30: Analysis of subjects achieving 50 percent reduction in itch by time point (observed cases): full analysis set .................................................................. 256

Table 2–31: Analysis of subjects achieving 70 percent reduction in itch by time point (observed cases): full analysis set .................................................................. 257

Table 2–32: Analysis of subjects achieving 50 percent reduction in itch-related sleep loss by time point (observed cases): full analysis set ................................................. 258

Table 2–33: Analysis of subjects achieving 70 percent reduction in itch-related sleep loss by time point (observed cases): full analysis set ................................................. 259

Table 2–34: Statistical analyses of m-PASI at Week 4 and Week 1 (multiple imputation): full analysis set excluding site ......................................................................... 260

Table 2–35: m-PASI by visit (observed cases): full analysis set excluding site ............... 261

Table 2–36: Statistical analysis of PASI-50 at Week 4 (multiple imputation): full analysis set excluding site ............................................................................................. 262

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 2–37: Statistical analysis of PASI-75 at Week 4 (multiple imputation): full analysis set excluding site ............................................................................................. 263

Table 2–38: PASI-50 by visit (observed cases): full analysis set excluding site ............... 264

Table 2–39: PASI-75 by visit (observed cases): full analysis set excluding site ............... 265

Table 2–40: Percentage change in m-PASI by visit (observed cases): full analysis set excluding site ............................................................................................. 266

List of Figures

Figure 2–1: Treatment success (IGA) by visit (observed cases): full analysis set ................. 267

Figure 2–2: m-PASI by visit (observed cases): full analysis set ............................................ 268

Figure 2–3: m-PASI by visit (observed cases): full analysis set excluding site ................ 269

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 2–1: Statistical analysis of treatment success according to the IGA at Week 4 (multiple imputation): full analysis set

LEO 90100(n=323)

Vehicle(n=103)




94.30


06FEB14:09:31:20 LP0053 1001 t01 succ fas.doc

1) Mean number of subjects across imputations.2) Mantel-Haenszel odds of treatment success in LEO 90100 group

relative to vehicle group, adjusted for pooled centre.3) Breslow-Day test for homogeneity of odds ratios across pooled

centres.

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 2–2: Statistical analysis of treatment success according to the IGA at Week 4: per protocol analysis set

LEO 90100(n=302)

Vehicle(n=96)




87.02


06FEB14:09:39:19 LP0053 1001 t02 succ pp.doc

1) No imputation since all subjects in per protocol analysis set completed the study.2) Mantel-Haenszel odds of treatment success in LEO 90100 group


centres.

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 2–3: Sensitivity analyses of treatment success according to the IGA at Week 4: full analysis set

LEO 90100(n=323)

Vehicle(n=103)



Vehicle-based multiple imputation Treatment success: Yes1 168.1 52.0 4.7 4.5 Treatment success: No1 154.9 48.0 98.3 95.5 Total 323 100.0 103 100.0 Odds ratio2 29.34 95% CI 9.35 to

92.10

p-value < 0.001 Breslow-Day test p-value3 0.18 Observed cases Treatment success: Yes 167 53.4 4 4.0 Treatment success: No 146 46.6 95 96.0 Total 313 100.0 99 100.0 Odds ratio2 29.18 95% CI 9.44 to

90.15

p-value < 0.001 Breslow-Day test p-value3 0.084 Non-responder imputation Treatment success: Yes 167 51.7 4 3.9 Treatment success: No 156 48.3 99 96.1 Total 323 100.0 103 100.0 Odds ratio2 30.17 95% CI 9.65 to

94.38

p-value < 0.001 Breslow-Day test p-value3 0.14 LOCF Treatment success: Yes 168 52.0 5 4.9 Treatment success: No 155 48.0 98 95.1 Total 323 100.0 103 100.0 Odds ratio2 29.80 95% CI 9.49 to

93.61


06FEB14:09:33:29 LP0053 1001 t03_succ_sens.doc

1) Mean number of subjects across imputations.2) Mantel-Haenszel odds of treatment success in LEO 90100 group


centres.

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 2–4: Treatment success according to the IGA by visit (observed cases): full analysis set

LEO 90100(n=323)

Vehicle(n=103)

VisitTreatment success (IGA)






02DEC13:10:30:26 LP0053 1001 t04 succ vis.doc

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 2–5: IGA by visit (observed cases): full analysis set

LEO 90100(n=323)

Vehicle(n=103)

VisitIGA



BaselineMild 50 15.5 15 14.6 Moderate 244 75.5 75 72.8 Severe 29 9.0 13 12.6 Total 323 100.0 103 100.0




02DEC13:10:30:32 LP0053 1001 t05 iga vis.doc

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 2–6: Treatment success according to the IGA at Week 4 by baseline disease severity (observed cases): full analysis set

LEO 90100(n=323)

Vehicle(n=103)

Baseline IGATreatment success (IGA)



MildTreatment success: Yes 15 30.6 0 0.0 Treatment success: No 34 69.4 14 100.0 Total 49 100.0 14 100.0

ModerateTreatment success: Yes 141 60.0 3 4.2 Treatment success: No 94 40.0 69 95.8 Total 235 100.0 72 100.0

SevereTreatment success: Yes 11 37.9 1 7.7 Treatment success: No 18 62.1 12 92.3 Total 29 100.0 13 100.0

02DEC13:10:30:37 LP0053 1001 t06 succ bas.doc

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 2–7: Treatment success according to the IGA at Week 4 by centre (observed cases): full analysis set

LEO 90100(n=323)

Vehicle(n=103)

CentreTreatment success (IGA)



reatment success: Yes 3 20.0 0 0.0 Treatment success: No 12 80.0 5 100.0 Total 15 100.0 5 100.0







reatment success: Yes 10 62.5 0 0.0

02DEC13:10:30:43 LP0053 1001 t07 succ cen.doc Continued...

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 2–7: Treatment success according to the IGA at Week 4 by centre (observed cases): full

analysis set, continued

LEO 90100(n=323)

Vehicle(n=103)




reatment success: No 6 37.5 6 100.0 Total 16 100.0 6 100.0









Trial ID: LP0053-1001 04-Mar-2014 of 315



LEO 90100(n=323)

Vehicle(n=103)











reatment success: Yes 7 43.8 0 0.0


Trial ID: LP0053-1001 04-Mar-2014 of 315



LEO 90100(n=323)

Vehicle(n=103)




reatment success: No 9 56.3 7 100.0 Total 16 100.0 7 100.0





02DEC13:10:30:43 LP0053 1001 t07 succ cen.doc

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 2–8: Statistical analyses of m-PASI at Week 4 and Week 1 (multiple imputation): full analysis set


Vehicle(n=103)


02DEC13:13:21:17 LP0053 1001 t08 PASI mi.doc

1) Averaged across imputations.2) Adjusted for the effect of pooled centre and baseline m-PASI by

analysis of covariance.

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 2–9: Sensitivity analyses of m-PASI at Week 4: full analysis set

Mean m-PASI scoreLEO 90100(n=323)

Vehicle(n=103)

Vehicle-based multiple imputation

Week 41 2.06 5.50 Week 4 adjusted1,2 2.11 5.33 Difference2 -3.21 95% CI -3.85 to -2.57 p-value2 < 0.001 Observed cases Week 4 1.98 5.47 Week 4 adjusted2 2.03 5.31 Difference2 -3.28 95% CI -3.91 to -2.66 p-value2 < 0.001 Non-responder imputation Week 4 2.12 5.57 Week 4 adjusted2 2.18 5.40 Difference2 -3.22 95% CI -3.85 to -2.59 p-value2 < 0.001 LOCF Week 4 2.07 5.51 Week 4 adjusted2 2.13 5.34 Difference2 -3.21 95% CI -3.83 to -2.60 p-value2 < 0.001

19DEC13:10:23:08 LP0053 1001 t09 PASI4 sens.doc



Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 2–10: Sensitivity analyses of m-PASI at Week 1: full analysis set

Mean m-PASI scoreLEO 90100(n=323)

Vehicle(n=103)

Vehicle-based multiple imputation

Week 11 4.55 6.20 Week 1 adjusted1,2 4.68 5.92 Difference2 -1.24 95% CI -1.74 to -0.75 p-value2 < 0.001 Observed cases Week 1 4.54 6.23 Week 1 adjusted2 4.67 5.95 Difference2 -1.28 95% CI -1.77 to -0.78 p-value2 < 0.001 Non-responder imputation Week 1 4.57 6.20 Week 1 adjusted2 4.70 5.92 Difference2 -1.22 95% CI -1.71 to -0.73 p-value2 < 0.001 LOCF Week 1 4.57 6.20 Week 1 adjusted2 4.70 5.92 Difference2 -1.22 95% CI -1.71 to -0.73 p-value2 < 0.001

19DEC13:10:23:22 LP0053 1001 t10 PASI1 sens.doc



Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 2–11: m-PASI by visit (observed cases): full analysis set

Visitm-PASI

LEO 90100(n=323)

Vehicle(n=103)





02DEC13:10:30:48 LP0053 1001 t11_PASI_vis.doc

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 2–12: m-PASI at Week 4 by centre (observed cases): full analysis set

Centrem-PASI Week 4

LEO 90100(n=323)

Vehicle(n=103)

ean 2.39 5.06 SD 2.04 2.80 Median 3.00 3.80 Minimum 0.0 2.4 Maximum 5.6 9.5 Number 15 5




ean 0.13 4.50 SD 0.26 1.65 Median 0.00 3.60 Minimum 0.0 3.5 Maximum 0.8 6.4

02DEC13:10:30:56 LP0053 1001 t12 PASI4 cen.doc Continued...

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 2–12: m-PASI at Week 4 by centre (observed cases): full analysis set, continued

Centrem-PASI Week 4

LEO 90100(n=323)

Vehicle(n=103)

umber 12 3





ean 4.84 7.25 SD 5.64 0.64 Median 2.90 7.25 Minimum 0.0 6.8


Trial ID: LP0053-1001 04-Mar-2014 of 315


Centrem-PASI Week 4

LEO 90100(n=323)

Vehicle(n=103)

aximum 17.8 7.7 Number 8 2

ean 2.92 3.30 SD 2.41 Median 2.80 3.30 Minimum 0.4 3.3 Maximum 6.0 3.3 Number 5 1




ean 0.93 0.00 SD 0.98 Median 0.70 0.00


Trial ID: LP0053-1001 04-Mar-2014 of 315


Centrem-PASI Week 4

LEO 90100(n=323)

Vehicle(n=103)

inimum 0.0 0.0 Maximum 2.4 0.0 Number 6 1





ean 0.36 1.93 SD 0.44 1.37


Trial ID: LP0053-1001 04-Mar-2014 of 315


Centrem-PASI Week 4

LEO 90100(n=323)

Vehicle(n=103)

edian 0.10 1.30 Minimum 0.0 1.0 Maximum 1.2 3.5 Number 12 3





Mean 2.67 4.82


Trial ID: LP0053-1001 04-Mar-2014 of 315


Centrem-PASI Week 4

LEO 90100(n=323)

Vehicle(n=103)

D 3.11 0.84 Median 1.85 4.95 Minimum 0.0 3.6 Maximum 12.3 6.0 Number 16 6

Mean 2.03 3.50 SD 2.17 4.10 Median 1.20 3.50 Minimum 0.0 0.6 Maximum 6.4 6.4 Number 9 2


02DEC13:10:30:56 LP0053 1001 t12 PASI4 cen.doc

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 2–13: m-PASI at Week 1 by centre (observed cases): full analysis set

Centrem-PASI Week 1

LEO 90100(n=323)

Vehicle(n=103)





ean 2.71 4.17 SD 2.31 1.45 Median 2.20 4.20 Minimum 0.0 2.7 Maximum 6.7 5.6


Trial ID: LP0053-1001 04-Mar-2014 of 315


Centrem-PASI Week 1

LEO 90100(n=323)

Vehicle(n=103)

umber 12 3





ean 7.90 7.97 SD 7.05 0.55 Median 5.80 7.70 Minimum 2.6 7.6


Trial ID: LP0053-1001 04-Mar-2014 of 315


Centrem-PASI Week 1

LEO 90100(n=323)

Vehicle(n=103)

aximum 24.4 8.6 Number 8 3





ean 3.05 2.40 SD 1.69 Median 3.25 2.40


Trial ID: LP0053-1001 04-Mar-2014 of 315


Centrem-PASI Week 1

LEO 90100(n=323)

Vehicle(n=103)

inimum 0.0 2.4 Maximum 5.2 2.4 Number 6 1





ean 2.74 6.18 SD 1.76 4.52


Trial ID: LP0053-1001 04-Mar-2014 of 315


Centrem-PASI Week 1

LEO 90100(n=323)

Vehicle(n=103)

edian 2.30 5.05 Minimum 0.6 2.0 Maximum 7.4 12.6 Number 12 4





Mean 4.22 4.37


Trial ID: LP0053-1001 04-Mar-2014 of 315


Centrem-PASI Week 1

LEO 90100(n=323)

Vehicle(n=103)

D 2.81 1.28 Median 3.80 4.80 Minimum 1.0 2.4 Maximum 10.8 5.6 Number 17 6

Mean 3.41 3.20 SD 3.03 4.53 Median 2.40 3.20 Minimum 0.0 0.0 Maximum 9.4 6.4 Number 9 2


02DEC13:10:31:04 LP0053 1001 t13 PASI1 cen.doc

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 2–14: Statistical analysis of PASI-50 at Week 4 (multiple imputation): full analysis set

LEO 90100(n=323)

Vehicle(n=103)




25.73


02JAN14:15:19:28 LP0053 1001 t14 PASI50.doc

1) Mean number of subjects across imputations.2) Mantel-Haenszel odds of PASI-50 in LEO 90100 group relative to

vehicle group, adjusted for pooled centre.3) Breslow-Day test for homogeneity of odds ratios across pooled

centres.

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 2–15: Statistical analysis of PASI-75 at Week 4 (multiple imputation): full analysis set

LEO 90100(n=323)

Vehicle(n=103)




33.98


02JAN14:15:20:48 LP0053 1001 t15 PASI75.doc



centres.

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 2–16: PASI-50 by visit (observed cases): full analysis set

LEO 90100(n=323)

Vehicle(n=103)

VisitPASI-50



Week 1Yes 103 32.6 14 13.7 No 213 67.4 88 86.3 Total 316 100.0 102 100.0

Week 2Yes 207 65.7 21 20.8 No 108 34.3 80 79.2 Total 315 100.0 101 100.0

Week 4Yes 259 82.7 28 28.3 No 54 17.3 71 71.7 Total 313 100.0 99 100.0


Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 2–17: PASI-75 by visit (observed cases): full analysis set

LEO 90100(n=323)

Vehicle(n=103)

VisitPASI-75



Week 1Yes 29 9.2 1 1.0 No 287 90.8 101 99.0 Total 316 100.0 102 100.0

Week 2Yes 99 31.4 2 2.0 No 216 68.6 99 98.0 Total 315 100.0 101 100.0

Week 4Yes 166 53.0 8 8.1 No 147 47.0 91 91.9 Total 313 100.0 99 100.0


Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 2–18: Statistical analysis of treatment success according to patient's global assessment at Week 4 (observed cases): full analysis set

LEO 90100(n=323)

Vehicle(n=103)

Treatment success Week 4(Patients Global Assessment)




14.11


06FEB14:09:34:48 LP0053 1001 t18 succp.doc

1) Mantel-Haenszel odds of treatment success in LEO 90100 group relative to vehicle group, adjusted for pooled centre.2) Breslow-Day test for homogeneity of odds ratios across pooled

centres.

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 2–19: Treatment success according to patient's global assessment by visit (observed cases): full analysis set

LEO 90100(n=323)

Vehicle(n=103)

VisitTreatment success (Patients GlobalAssessment)



Week 1Yes 69 21.9 18 17.6 No 246 78.1 84 82.4 Total 315 100.0 102 100.0

Week 2Yes 133 42.2 22 21.8 No 182 57.8 79 78.2 Total 315 100.0 101 100.0

Week 4Yes 204 65.2 22 22.2 No 109 34.8 77 77.8 Total 313 100.0 99 100.0

02DEC13:10:32:17 LP0053 1001 t19 succp vis.doc

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 2–20: Patient's global assessment by visit (observed cases): full analysis set

LEO 90100(n=323)

Vehicle(n=103)

VisitPatients GlobalAssessment



BaselineVery mild 9 2.8 6 5.8 Mild 86 26.6 22 21.4 Moderate 167 51.7 53 51.5 Severe 61 18.9 22 21.4 Total 323 100.0 103 100.0




02DEC13:10:31:21 LP0053 1001 t20 pga vis.doc

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 2–21: Analysis of change in Subject's assessment of itch (VAS) by time point (observed cases): full analysis set


LEO 90100(n=323)

Vehicle(n=103)



Day 5 (change)Mean -30.8 -23.3 SD 26.2 24.7 Median -27.0 -20.0 Minimum -100 -76 Maximum 45 31 Number 310 98 Adjusted mean1 -31.5 -21.3 Difference1 -10.26 95% CI -14.94 to -5.58 p-value1 < 0.001


29JAN14:09:45:06 LP0053 1001 t21_itch_vas.doc Continued...

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 2–21: Analysis of change in Subject's assessment of itch (VAS) by time point (observed

cases): full analysis set, continued


LEO 90100(n=323)

Vehicle(n=103)



29JAN14:09:45:06 LP0053 1001 t21 itch vas.doc

1) Calculated from ANOVA adjusted for pooled centre and baseline score.

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 2–22: Analysis of change in Subject's assessment of itch-related sleep loss (VAS) by time point (observed cases): full analysis set


LEO 90100(n=323)

Vehicle(n=103)





29JAN14:09:42:12 LP0053 1001 t22 sleep vas.doc Continued...

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 2–22: Analysis of change in Subject's assessment of itch-related sleep loss (VAS) by

time point (observed cases): full analysis set, continued


LEO 90100(n=323)

Vehicle(n=103)



29JAN14:09:42:12 LP0053 1001 t22 sleep vas.doc


Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 2–23: Change in BSA from baseline to each visit (observed cases): full analysis set

VisitBSA/Change in BSA

LEO 90100(n=323)

Vehicle(n=103)


Week 1 (change)Mean -0.9 -0.3 SD 2.2 1.5 Median 0.0 0.0 Minimum -20 -11 Maximum 5 4 Number 316 102

Week 2 (change)Mean -2.0 -1.0 SD 3.3 2.9 Median -1.0 0.0 Minimum -28 -15 Maximum 4 12 Number 315 101

Week 4 (change)Mean -3.7 -1.0 SD 4.8 3.3 Median -2.0 0.0 Minimum -28 -15 Maximum 2 17 Number 313 99

02DEC13:10:31:39 LP0053 1001 t23 BSA.doc

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 2–24: Redness, thickness and scaliness of target lesion by visit: full analysis set

LEO 90100(n=323)

Vehicle(n=103)

Clinical Sign / VisitSeverity of Target Lesion



Redness / BaselineMild 19 5.9 5 4.9 Moderate 194 60.1 55 53.4 Severe 93 28.8 40 38.8 Very severe 17 5.3 3 2.9 Total 323 100.0 103 100.0

Redness / Week 1None 9 2.8 2 2.0 Mild 115 36.4 14 13.7 Moderate 153 48.4 59 57.8 Severe 37 11.7 25 24.5 Very severe 2 0.6 2 2.0 Total 316 100.0 102 100.0



02DEC13:10:31:46 LP0053 1001 t24 targetles.doc Continued...

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 2–24: Redness, thickness and scaliness of target lesion by visit: full analysis set,

continued

LEO 90100(n=323)

Vehicle(n=103)




Thickness / BaselineMild 29 9.0 7 6.8 Moderate 194 60.1 63 61.2 Severe 90 27.9 27 26.2 Very severe 10 3.1 6 5.8 Total 323 100.0 103 100.0

Thickness / Week 1None 45 14.2 2 2.0 Mild 133 42.1 26 25.5 Moderate 118 37.3 61 59.8 Severe 18 5.7 10 9.8 Very severe 2 0.6 3 2.9 Total 316 100.0 102 100.0



02DEC13:10:31:46 LP0053 1001 t24_targetles.doc Continued...

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 2–24: Redness, thickness and scaliness of target lesion by visit: full analysis set,

continued

LEO 90100(n=323)

Vehicle(n=103)




Scaliness / BaselineMild 44 13.6 8 7.8 Moderate 170 52.6 62 60.2 Severe 100 31.0 26 25.2 Very severe 9 2.8 7 6.8 Total 323 100.0 103 100.0

Scaliness / Week 1None 81 25.6 10 9.8 Mild 169 53.5 52 51.0 Moderate 57 18.0 35 34.3 Severe 9 2.8 4 3.9 Very severe 0 0.0 1 1.0 Total 316 100.0 102 100.0



02DEC13:10:31:46 LP0053 1001 t24_targetles.doc

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 2–25: Analysis of change in DLQI by visit (observed cases): full analysis set

VisitDLQI/Change in DLQI

LEO 90100(n=323)

Vehicle(n=103)





29JAN14:09:51:12 LP0053 1001 t25 DLQI.doc


Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 2–26: Analysis of EQ-5D-5L dimensions at baseline and Week 4 (observed cases): full analysis set

LEO 90100

(n=323)

Vehicle

(n=103)

EQ-5D dimensionVisit

Number of

subjects %

Number of

subjects %

Mobility

BaselineI have no problems walking 242 75.2 78 75.7 I have slight problems walking 45 14.0 12 11.7 I have moderate problems walking 25 7.8 9 8.7 I have severe problems walking 10 3.1 4 3.9 Total 322 100.0 103 100.0

Week 4 / End of treatmentI have no problems walking 251 81.0 82 82.0 I have slight problems walking 30 9.7 9 9.0 I have moderate problems walking 17 5.5 7 7.0 I have severe problems walking 11 3.5 1 1.0 I am unable to walk 1 0.3 1 1.0 Total 310 100.0 100 100.0

Treatment difference p-value1 0.80

Self-Care

BaselineI have no problems washing or dressing myself 292 90.7 96 93.2 I have slight problems washing or dressing

myself 25 7.8 3 2.9

I have moderate problems washing or dressing myself

4 1.2 3 2.9

I have severe problems washing or dressing myself

1 0.3 1 1.0

Total 322 100.0 103 100.0

Week 4 / End of treatmentI have no problems washing or dressing myself 286 92.3 94 94.0 I have slight problems washing or dressing

myself 14 4.5 4 4.0

I have moderate problems washing or dressing myself

7 2.3 2 2.0

I have severe problems washing or dressing myself

2 0.6 0 0.0

I am unable to wash or dress myself 1 0.3 0 0.0 Total 310 100.0 100 100.0


07JAN14:10:28:53 LP0053 1001 t26 EQ5D.doc Continued...

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 2–26: Analysis of EQ-5D-5L dimensions at baseline and Week 4 (observed cases): full

analysis set, continuedLEO 90100

(n=323)

Vehicle

(n=103)


Number of

subjects %

Number of

subjects %

Usual Activities

BaselineI have no problems doing my usual activities 229 71.1 78 75.7 I have slight problems doing my usual

activities 67 20.8 17 16.5

I have moderate problems doing my usual activities

19 5.9 5 4.9

I have severe problems doing my usual activities

6 1.9 3 2.9

I am unable to do my usual activities 1 0.3 0 0.0 Total 322 100.0 103 100.0

Week 4 / End of treatmentI have no problems doing my usual activities 267 86.1 78 78.0 I have slight problems doing my usual

activities 22 7.1 13 13.0

I have moderate problems doing my usual activities

15 4.8 7 7.0

I have severe problems doing my usual activities

5 1.6 1 1.0

I am unable to do my usual activities 1 0.3 1 1.0 Total 310 100.0 100 100.0


Pain/Discomfort

BaselineI have no pain or discomfort 97 30.1 36 35.0 I have slight pain or discomfort 121 37.6 40 38.8 I have moderate pain or discomfort 66 20.5 18 17.5 I have severe pain or discomfort 32 9.9 6 5.8 I have extreme pain or discomfort 6 1.9 3 2.9 Total 322 100.0 103 100.0

Week 4 / End of treatmentI have no pain or discomfort 212 68.4 43 43.0 I have slight pain or discomfort 63 20.3 36 36.0 I have moderate pain or discomfort 24 7.7 15 15.0 I have severe pain or discomfort 9 2.9 4 4.0 I have extreme pain or discomfort 2 0.6 2 2.0 Total 310 100.0 100 100.0

Treatment difference p-value1 <

0.001

07JAN14:10:28:53 LP0053 1001 t26 EQ5D.doc Continued...

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 2–26: Analysis of EQ-5D-5L dimensions at baseline and Week 4 (observed cases): full

analysis set, continuedLEO 90100

(n=323)

Vehicle

(n=103)


Number of

subjects %

Number of

subjects %

Anxiety/Depression

BaselineI am not anxious or depressed 176 54.7 57 55.3 I am slightly anxious or depressed 93 28.9 26 25.2 I am moderately anxious or depressed 38 11.8 19 18.4 I am severely anxious or depressed 7 2.2 1 1.0 I am extremely anxious or depressed 8 2.5 0 0.0 Total 322 100.0 103 100.0

Week 4 / End of treatmentI am not anxious or depressed 223 71.9 67 67.0 I am slightly anxious or depressed 60 19.4 24 24.0 I am moderately anxious or depressed 18 5.8 8 8.0 I am severely anxious or depressed 6 1.9 0 0.0 I am extremely anxious or depressed 3 1.0 1 1.0 Total 310 100.0 100 100.0


07JAN14:10:28:53 LP0053 1001 t26 EQ5D.doc

1) Proportional odds model.

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 2–27: EQ VAS score at baseline and Week 4 and analysis of change from baseline (observed cases): full analysis set

VisitEQ VAS score/Change in EQ VAS score

LEO 90100(n=323)

Vehicle(n=103)


Week 4 / End of treatmentMean 83.8 80.2 SD 15.3 16.3 Median 88.0 85.0 Minimum 12 0 Maximum 100 100 Number 311 99

Week 4 / End of treatment (change)Mean 5.3 0.4 SD 15.1 14.8 Median 5.0 0.0 Minimum -50 -80 Maximum 90 40 Number 311 99 Adjusted mean1 5.1 0.9 Difference1 4.26 95% CI 1.40 to 7.13 p-value1 0.004

07JAN14:10:28:47 LP0053 1001 t27 eq vas.doc


Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 2–28: EQ-5D-5L index score at baseline and Week 4 and analysis of change from baseline (observed cases): full analysis set

VisitEQ-5D-5L index value/Change in EQ-5D-5L index value

LEO 90100(n=323)

Vehicle(n=103)


Week 4 / End of treatmentMean 0.90 0.86 SD 0.14 0.15 Median 1.00 0.86 Minimum 0.18 0.00 Maximum 1.00 1.00 Number 310 100

Week 4 / End of treatment (change)Mean 0.08 0.04 SD 0.14 0.13 Median 0.08 0.00 Minimum -0.70 -0.53 Maximum 0.57 0.38 Number 310 100 Adjusted mean1 0.08 0.04 Difference1 0.04 95% CI 0.01 to 0.07 p-value1 0.005

07JAN14:10:29:03 LP0053 1001 t28 EQ5Dindex.doc


Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 2–29: Percentage change in m-PASI by visit (observed cases): full analysis set



Vehicle(n=103)




02DEC13:10:33:13 LP0053 1001 t29 pchg PASI.doc

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 2–30: Analysis of subjects achieving 50 percent reduction in itch by time point (observed cases): full analysis set

LEO 90100(n=323)

Vehicle(n=103)









14.27

p-value < 0.001

02DEC13:10:33:30 LP0053 1001 t30 itch50.doc

1) Subjects with no itch at baseline are excluded from table.2) Mantel-Haenszel odds of treatment response in LEO 90100 group

relative to vehicle group, adjusted for pooled centre.

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 2–31: Analysis of subjects achieving 70 percent reduction in itch by time point (observed cases): full analysis set

LEO 90100(n=323)

Vehicle(n=103)









11.74

p-value < 0.001

02DEC13:10:33:40 LP0053 1001 t31 itch70.doc

1) Subjects with no itch at baseline are excluded from table.2) Mantel-Haenszel odds of treatment response in LEO 90100 group


Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 2–32: Analysis of subjects achieving 50 percent reduction in itch-related sleep loss by time point (observed cases): full analysis set

LEO 90100(n=323)

Vehicle(n=103)









02DEC13:10:33:45 LP0053 1001 t32 sleep50.doc

1) Subjects with no itch-related sleep loss at baseline are excluded from table.2) Mantel-Haenszel odds of treatment response in LEO 90100 group


Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 2–33: Analysis of subjects achieving 70 percent reduction in itch-related sleep loss by time point (observed cases): full analysis set

LEO 90100(n=323)

Vehicle(n=103)









02DEC13:10:33:49 LP0053 1001 t33 sleep70.doc

1) Subjects with no itch-related sleep loss at baseline are excluded from table.2) Mantel-Haenszel odds of treatment response in LEO 90100 group


Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 2–34: Statistical analyses of m-PASI at Week 4 and Week 1 (multiple imputation): full analysis set excluding site 15


Vehicle(n=97)


02DEC13:13:32:39 LP0053 1001 t34 PASI mi15.doc



Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 2–35: m-PASI by visit (observed cases): full analysis set excluding site

Visitm-PASI

LEO 90100(n=303)

Vehicle(n=97)





02DEC13:10:33:54 LP0053 1001 t35_PASI_vis15.doc

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 2–36: Statistical analysis of PASI-50 at Week 4 (multiple imputation): full analysis set excluding site

LEO 90100(n=303)

Vehicle(n=97)




26.40


02JAN14:15:22:34 LP0053 1001 t36 PASI50 15.doc



centres.

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 2–37: Statistical analysis of PASI-75 at Week 4 (multiple imputation): full analysis set excluding site

LEO 90100(n=303)

Vehicle(n=97)




34.35


02JAN14:15:28:34 LP0053 1001 t37 PASI75 15.doc



centres.

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 2–38: PASI-50 by visit (observed cases): full analysis set excluding site

LEO 90100(n=303)

Vehicle(n=97)

VisitPASI-50



Week 1Yes 90 30.3 12 12.5 No 207 69.7 84 87.5 Total 297 100.0 96 100.0

Week 2Yes 190 64.2 18 18.9 No 106 35.8 77 81.1 Total 296 100.0 95 100.0

Week 4Yes 241 82.0 25 26.9 No 53 18.0 68 73.1 Total 294 100.0 93 100.0

02DEC13:10:34:05 LP0053 1001 t38 PASI50 vis15.doc

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 2–39: PASI-75 by visit (observed cases): full analysis set excluding site

LEO 90100(n=303)

Vehicle(n=97)

VisitPASI-75



Week 1Yes 23 7.7 1 1.0 No 274 92.3 95 99.0 Total 297 100.0 96 100.0

Week 2Yes 86 29.1 2 2.1 No 210 70.9 93 97.9 Total 296 100.0 95 100.0

Week 4Yes 150 51.0 7 7.5 No 144 49.0 86 92.5 Total 294 100.0 93 100.0

02DEC13:10:34:10 LP0053 1001 t39 PASI75 vis15.doc

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 2–40: Percentage change in m-PASI by visit (observed cases): full analysis set excluding site



Vehicle(n=97)




02DEC13:10:33:59 LP0053 1001 t40 pchg PASI15.doc

Trial ID: LP0053-1001 04-Mar-2014 of 315

Figure 2–1: Treatment success (IGA) by visit (observed cases): full analysis set

70

60 ~ LEO 90100 ------- Vehicle

50 bars show 95 pet. conf. int.

c 40 ~ Q) Q_ 30

20

10

t ~ ~ 0 1 2 4

weeks

Trial ID: LP0053-1001 04-Mar-2014 of 315

Figure 2–2: m-PASI by visit (observed cases): full analysis set

~ a: I E c ccs Q)

E

10

9

8

7

6

5

4

3

2 bars show 95 pet. coni. int.

7HHf LEO 90100 ---vehicle

1 L__o~~~1--~-2----~3-----4~~

weeks

Trial ID: LP0053-1001 04-Mar-2014 of 315

Figure 2–3: m-PASI by visit (observed cases): full analysis set excluding site

~ a: I E c ccs Q)

E

10

9

8

7

6

5

4

3

2 bars show 95 pet. coni. int.

7HHf LEO 90100 ---vehicle

1 L__o~~~1--~-2----~3-----4~~

weeks

I

Trial ID: LP0053-1001 04-Mar-2014 of 315

3 Tables and Figures, Safety Data

List of Tables

Table 3–1: Duration and extent of exposure to treatment: safety analysis set ....................... 272

Table 3–2: Average weekly amount of study medication used: safety analysis set ............... 273

Table 3–3: Total amount of study medication used: safety analysis set................................. 274

Table 3–4: Overall summary of adverse events: safety analysis set ...................................... 275

Table 3–5: Adverse events by SOC: safety analysis set......................................................... 276

Table 3–6: Adverse events by SOC and preferred term: safety analysis set .......................... 277

Table 3–7: Adverse drug reactions by SOC and preferred term: safety analysis set.............. 280

Table 3–8: Serious adverse events by SOC and preferred term: safety analysis set .............. 281

Table 3–9: Adverse events leading to withdrawal from trial by SOC and preferred term: safety analysis set...................................................................................................... 282

Table 3–10: Adverse events leading to discontinuation of treatment by SOC and preferred term: safety analysis set.................................................................................. 283

Table 3–11: Lesional/perilesional adverse events by SOC and preferred term: safety analysis set ................................................................................................................... 284

Table 3–12: Intensity of adverse events by SOC and preferred term: safety analysis set...... 285

Table 3–13: Relationship to study medication of adverse events by SOC and preferred term: safety analysis set ........................................................................................... 288

Table 3–14: Local safety and tolerability by visit: safety analysis set ................................... 291

Table 3–15: Vital signs by visit: safety analysis set ............................................................... 295

Table 3–16: Change in vital signs from baseline to Week 4: safety analysis set ................... 296

Table 3–17: Summary of albumin-corrected serum calcium and change from baseline: safety analysis set...................................................................................................... 297

Table 3–18: Shift table for albumin-corrected serum calcium: safety analysis set ................ 298

Table 3–19: Shift table for albumin-corrected serum calcium based on LEO defined clinically significant values: safety analysis set............................................................. 299

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 3–20: Summary of urinary calcium:creatinine ratio and change from baseline: safety analysis set...................................................................................................... 300

Table 3–21: Shift table for urinary calcium:creatinine ratio: safety analysis set ................... 301

Table 3–22: Subjects with albumin-corrected serum calcium or calcium: creatinine ratio outside the reference range: safety analysis set.............................................. 302

List of Figures

Figure 3–1: Local safety and tolerability by visit: safety analysis set ................................... 310

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 3–1: Duration and extent of exposure to treatment: safety analysis set

Exposure (weeks)LEO 90100(n=323)

Vehicle(n=103)

Mean 4.0 4.1 SD 0.6 0.6 Minimum 0.1 0.1 Maximum 6.0 6.3 Number 323 103 Extent of exposure to treatment(subject-treatment-weeks)

1290 418

28NOV13:12:11:54 LP0053 1001 t01expo.doc

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 3–2: Average weekly amount of study medication used: safety analysis set

IntervalAmount (grams per week)

LEO 90100(n=323)

Vehicle(n=103)





28NOV13:14:52:09 LP0053 1001 t02amount.doc

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 3–3: Total amount of study medication used: safety analysis set

IntervalAmount (grams)

LEO 90100(n=323)

Vehicle(n=103)





28NOV13:14:59:57 LP0053 1001 t03totamount.doc

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 3–4: Overall summary of adverse events: safety analysis set

LEO 90100(n=323)

Vehicle(n=103)

Adverse event categoryNumberof AEs1


Numberof AEs1


All adverse events 63 51 (15.8) 15 12 (11.7) Severe adverse events 5 5 ( 1.5) 0 0 ( 0.0) Adverse drug reactions 10 10 ( 3.1) 5 2 ( 1.9) AEs leading to withdrawal from trial

0 0 ( 0.0) 0 0 ( 0.0)

AEs leading to discontinuation of treatment

1 1 ( 0.3) 0 0 ( 0.0)

Lesional/perilesional AEs 9 9 ( 2.8) 6 3 ( 2.9) SAEs 2 2 ( 0.6) 0 0 ( 0.0)

14FEB14:09:01:54 LP0053 1001 t04overall.doc

1) Different adverse events within the same preferred term and system organ class and involving the same subject have been counted as one.

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 3–5: Adverse events by SOC: safety analysis set

LEO 90100(n=323)

Vehicle(n=103)

System Organ Class1Number of subjects %


Infections and infestations 15 4.6 3 2.9General disorders andadministration site conditions

11 3.4 3 2.9

Injury, poisoning and proceduralcomplications

4 1.2 2 1.9

Gastrointestinal disorders 4 1.2 1 1.0Musculoskeletal and connectivetissue disorders

4 1.2 1 1.0

Skin and subcutaneous tissuedisorders

4 1.2 1 1.0

Investigations 4 1.2 0 0.0Respiratory, thoracic andmediastinal disorders

4 1.2 0 0.0

Nervous system disorders 2 0.6 1 1.0Psychiatric disorders 2 0.6 0 0.0Vascular disorders 2 0.6 0 0.0Cardiac disorders 1 0.3 0 0.0Ear and labyrinth disorders 1 0.3 0 0.0Eye disorders 1 0.3 0 0.0Renal and urinary disorders 1 0.3 0 0.0Surgical and medical procedures 1 0.3 0 0.0 Total number of adverseevents2

63 15


20FEB14:08:37:09 LP0053 1001 t05soc.doc

1) Classification according to MedDRA version 16.0.2) Different adverse events within the same preferred term and system

organ class and involving the same subject have been counted as one. A single subject could appear in multiple classes.

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 3–6: Adverse events by SOC and preferred term: safety analysis set

LEO 90100(n=323)

Vehicle(n=103)




Infections and infestationsNasopharyngitis 6 1.9 0 0.0Cellulitis 1 0.3 0 0.0Eye infection 0 0.0 1 1.0Folliculitis 1 0.3 0 0.0Fungal skin infection 1 0.3 0 0.0Gastroenteritis viral 0 0.0 1 1.0Groin abscess 1 0.3 0 0.0Hordeolum 1 0.3 0 0.0Rhinitis 1 0.3 0 0.0Streptococcal infection 0 0.0 1 1.0Tinea cruris 1 0.3 0 0.0Tooth abscess 1 0.3 0 0.0Upper respiratory tractinfection

1 0.3 0 0.0

SOC total 15 4.6 3 2.9General disorders and administration siteconditionsApplication site pain 3 0.9 2 1.9Application sitediscolouration

1 0.3 0 0.0


0 0.0 1 1.0


1 0.3 0 0.0


1 0.3 0 0.0


1 0.3 0 0.0

Influenza like illness 1 0.3 0 0.0Oedema peripheral 1 0.3 0 0.0Pain 1 0.3 0 0.0Thirst 1 0.3 0 0.0SOC total 11 3.4 3 2.9


Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 3–6: Adverse events by SOC and preferred term: safety analysis set, continued

LEO 90100(n=323)

Vehicle(n=103)




Injury, poisoning and proceduralcomplicationsLigament sprain 1 0.3 1 1.0Sunburn 1 0.3 1 1.0Contusion 1 0.3 0 0.0Excoriation 1 0.3 0 0.0Laceration 1 0.3 0 0.0SOC total 4 1.2 2 1.9

Gastrointestinal disordersDiarrhoea 2 0.6 1 1.0Nausea 2 0.6 0 0.0SOC total 4 1.2 1 1.0

Musculoskeletal and connective tissuedisordersFlank pain 2 0.6 0 0.0Back pain 1 0.3 0 0.0Muscle spasms 1 0.3 0 0.0Pain in extremity 0 0.0 1 1.0SOC total 4 1.2 1 1.0

Skin and subcutaneous tissue disordersAngioedema 0 0.0 1 1.0Dermatitis contact 1 0.3 0 0.0Hyperhidrosis 1 0.3 0 0.0Psoriasis 1 0.3 0 0.0Skin irritation 1 0.3 0 0.0SOC total 4 1.2 1 1.0

InvestigationsBlood pressure increased 3 0.9 0 0.0Blood calcium increased 1 0.3 0 0.0SOC total 4 1.2 0 0.0


1 0.3 0 0.0

Cough 1 0.3 0 0.0Epistaxis 1 0.3 0 0.0Sinus congestion 1 0.3 0 0.0SOC total 4 1.2 0 0.0

Nervous system disordersDizziness 0 0.0 1 1.0


Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 3–6: Adverse events by SOC and preferred term: safety analysis set, continued

LEO 90100(n=323)

Vehicle(n=103)




Nervous system disordersHeadache 1 0.3 0 0.0Paraesthesia 1 0.3 0 0.0SOC total 2 0.6 1 1.0

Eye disordersBlepharitis 1 0.3 0 0.0Keratitis 1 0.3 0 0.0SOC total 1 0.3 0 0.0


1 0.3 0 0.0

SOC total 2 0.6 0 0.0Vascular disordersFlushing 1 0.3 0 0.0Hot flush 1 0.3 0 0.0SOC total 2 0.6 0 0.0

Cardiac disordersTachycardia 1 0.3 0 0.0SOC total 1 0.3 0 0.0

Ear and labyrinth disordersVertigo 1 0.3 0 0.0SOC total 1 0.3 0 0.0

Renal and urinary disordersDysuria 1 0.3 0 0.0SOC total 1 0.3 0 0.0

Surgical and medical proceduresTooth extraction 1 0.3 0 0.0SOC total 1 0.3 0 0.0


63 15


Fisher's exact test

P-value 0.34

14FEB14:08:56:03 LP0053 1001 t06socterm.doc



Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 3–7: Adverse drug reactions by SOC and preferred term: safety analysis set

LEO 90100(n=323)

Vehicle(n=103)





1 0.3 0 0.0


0 0.0 1 1.0


1 0.3 0 0.0


1 0.3 0 0.0


1 0.3 0 0.0

SOC total 6 1.9 2 1.9InvestigationsBlood calcium increased 1 0.3 0 0.0SOC total 1 0.3 0 0.0

Skin and subcutaneous tissue disordersPsoriasis 1 0.3 0 0.0Skin irritation 1 0.3 0 0.0SOC total 2 0.6 0 0.0

Infections and infestationsFolliculitis 1 0.3 0 0.0SOC total 1 0.3 0 0.0

Total number of drugreactions2

10 5


Fisher's exact test

P-value 0.74

14FEB14:09:02:25 LP0053 1001 t07adrs.doc

1) Classification according to MedDRA version 16.0.2) Different adverse drug reactions within the same preferred term

and system organ class and involving the same subject have been counted as one. A single subject could appear in multiple classes.

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 3–8: Serious adverse events by SOC and preferred term: safety analysis set

LEO 90100(n=323)

Vehicle(n=103)





1 0.3 0 0.0

SOC total 2 0.6 0 0.0

Total number of Seriousadverse events2

2 0


28NOV13:15:20:32 LP0053 1001 t08serious.doc



Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 3–9: Adverse events leading to withdrawal from trial by SOC and preferred term: safety analysis set

No data for this table.

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 3–10: Adverse events leading to discontinuation of treatment by SOC and preferred term: safety analysis set

LEO 90100(n=323)

Vehicle(n=103)




Psychiatric disordersSubstance-inducedpsychotic disorder

1 0.3 0 0.0

SOC total 1 0.3 0 0.0


1 0


28NOV13:15:29:15 LP0053 1001 t10drgdisc.doc



Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 3–11: Lesional/perilesional adverse events by SOC and preferred term: safety analysis set

LEO 90100(n=323)

Vehicle(n=103)





1 0.3 0 0.0


0 0.0 1 1.0


1 0.3 0 0.0


1 0.3 0 0.0

SOC total 6 1.9 3 2.9Skin and subcutaneous tissue disordersPsoriasis 1 0.3 0 0.0Skin irritation 1 0.3 0 0.0SOC total 2 0.6 0 0.0

Injury, poisoning and proceduralcomplicationsSunburn 1 0.3 0 0.0SOC total 1 0.3 0 0.0


9 6


28NOV13:12:11:39 LP0053 1001 t11lesional.doc



Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 3–12: Intensity of adverse events by SOC and preferred term: safety analysis set

LEO 90100(n=323)

Vehicle(n=103)

System Organ Class(SOC)Preferred Term1 Mild Moderate Severe Mild Moderate Severe

Infections and infestationsNasopharyngitis 5 1 0 0 0 0Cellulitis 0 0 1 0 0 0Eye infection 0 0 0 1 0 0Folliculitis 1 0 0 0 0 0Fungal skin

infection 0 1 0 0 0 0

Gastroenteritis viral

0 0 0 1 0 0

Groin abscess 1 0 0 0 0 0Hordeolum 1 0 0 0 0 0Rhinitis 1 0 0 0 0 0Streptococcalinfection

0 0 0 0 1 0

Tinea cruris 1 0 0 0 0 0Tooth abscess 1 0 0 0 0 0Upper respiratorytract infection

1 0 0 0 0 0

General disorders and administration siteconditionsApplication site

pain 3 0 0 1 1 0

Application sitediscolouration

1 0 0 0 0 0

Application sitedryness

0 0 0 1 0 0

Application siteerosion

0 0 0 1 0 0

Application siteerythema

0 0 0 0 1 0


0 1 0 0 0 0

Application siteoedema

0 0 0 1 0 0

Application sitepruritus

1 0 0 0 0 0


1 0 0 0 0 0

Influenza likeillness

0 1 0 0 0 0

Oedema peripheral 0 0 1 0 0 0Pain 1 0 0 0 0 0Thirst 0 1 0 0 0 0

14FEB14:08:56:28 LP0053 1001 t12aeint.doc Continued...

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 3–12: Intensity of adverse events by SOC and preferred term: safety analysis set,

continued

LEO 90100(n=323)

Vehicle(n=103)


Injury, poisoning and proceduralcomplicationsLigament sprain 1 0 0 1 0 0Sunburn 1 0 0 1 0 0Contusion 1 0 0 0 0 0Excoriation 1 0 0 0 0 0Laceration 0 1 0 0 0 0

Gastrointestinal disordersDiarrhoea 1 1 0 1 0 0Nausea 2 0 0 0 0 0

Musculoskeletal and connective tissuedisordersFlank pain 2 0 0 0 0 0Back pain 1 0 0 0 0 0Muscle spasms 1 0 0 0 0 0Pain in extremity 0 0 0 0 1 0

Skin and subcutaneous tissue disordersAngioedema 0 0 0 0 1 0Dermatitis contact 0 1 0 0 0 0Hyperhidrosis 0 1 0 0 0 0Psoriasis 0 0 1 0 0 0Skin irritation 0 1 0 0 0 0

InvestigationsBlood pressureincreased

1 2 0 0 0 0

Blood calciumincreased

1 0 0 0 0 0


1 0 0 0 0 0

Cough 1 0 0 0 0 0Epistaxis 1 0 0 0 0 0Sinus congestion 1 0 0 0 0 0

Nervous system disordersDizziness 0 0 0 1 0 0Headache 1 0 0 0 0 0Paraesthesia 1 0 0 0 0 0

Eye disordersBlepharitis 1 0 0 0 0 0

14FEB14:08:56:28 LP0053 1001 t12aeint.doc Continued...

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 3–12: Intensity of adverse events by SOC and preferred term: safety analysis set,

continued

LEO 90100(n=323)

Vehicle(n=103)


Eye disordersKeratitis 1 0 0 0 0 0

Psychiatric disordersBipolar disorder 0 0 1 0 0 0Substance-inducedpsychotic disorder

0 0 1 0 0 0

Vascular disordersFlushing 1 0 0 0 0 0Hot flush 1 0 0 0 0 0

Cardiac disordersTachycardia 1 0 0 0 0 0

Ear and labyrinth disordersVertigo 1 0 0 0 0 0

Renal and urinary disordersDysuria 1 0 0 0 0 0

Surgical and medical proceduresTooth extraction 1 0 0 0 0 0

Total number ofadverse events

46 12 5 10 5 0

14FEB14:08:56:28 LP0053 1001 t12aeint.doc



Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 3–13: Relationship to study medication of adverse events by SOC and preferred term: safety analysis set

LEO 90100(n=323)

Vehicle(n=103)

System Organ Class(SOC)Preferred Term1

Not related Possible Probable


Infections and infestationsNasopharyngitis 6 0 0 0 0 0Cellulitis 1 0 0 0 0 0Eye infection 0 0 0 1 0 0Folliculitis 0 1 0 0 0 0Fungal skin

infection 1 0 0 0 0 0

Gastroenteritis viral

0 0 0 1 0 0

Groin abscess 1 0 0 0 0 0Hordeolum 1 0 0 0 0 0Rhinitis 1 0 0 0 0 0Streptococcalinfection

0 0 0 1 0 0

Tinea cruris 1 0 0 0 0 0Tooth abscess 1 0 0 0 0 0Upper respiratorytract infection

1 0 0 0 0 0

General disorders and administration siteconditionsApplication site

pain 1 0 2 1 1 0

Application sitediscolouration

0 0 1 0 0 0

Application sitedryness

0 0 0 0 1 0

Application siteerosion

0 0 0 0 1 0

Application siteerythema

0 0 0 0 1 0


0 0 1 0 0 0

Application siteoedema

0 0 0 0 1 0

Application sitepruritus

0 1 0 0 0 0


0 1 0 0 0 0

Influenza likeillness

1 0 0 0 0 0

Oedema peripheral 1 0 0 0 0 0Pain 1 0 0 0 0 0

14FEB14:09:02:55 LP0053 1001 t13aerel.doc Continued...

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 3–13: Relationship to study medication of adverse events by SOC and preferred term:

safety analysis set, continued

LEO 90100(n=323)

Vehicle(n=103)




General disorders and administration siteconditionsThirst 1 0 0 0 0 0

Injury, poisoning and proceduralcomplicationsLigament sprain 1 0 0 1 0 0Sunburn 1 0 0 1 0 0Contusion 1 0 0 0 0 0Excoriation 1 0 0 0 0 0Laceration 1 0 0 0 0 0

Gastrointestinal disordersDiarrhoea 2 0 0 1 0 0Nausea 2 0 0 0 0 0

Musculoskeletal and connective tissuedisordersFlank pain 2 0 0 0 0 0Back pain 1 0 0 0 0 0Muscle spasms 1 0 0 0 0 0Pain in extremity 0 0 0 1 0 0

Skin and subcutaneous tissue disordersAngioedema 0 0 0 1 0 0Dermatitis contact 1 0 0 0 0 0Hyperhidrosis 1 0 0 0 0 0Psoriasis 0 1 0 0 0 0Skin irritation 0 0 1 0 0 0

InvestigationsBlood pressureincreased

3 0 0 0 0 0

Blood calciumincreased

0 1 0 0 0 0


1 0 0 0 0 0

Cough 1 0 0 0 0 0Epistaxis 1 0 0 0 0 0Sinus congestion 1 0 0 0 0 0

Nervous system disordersDizziness 0 0 0 1 0 0Headache 1 0 0 0 0 0Paraesthesia 1 0 0 0 0 0

14FEB14:09:02:55 LP0053 1001 t13aerel.doc Continued...

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 3–13: Relationship to study medication of adverse events by SOC and preferred term:

safety analysis set, continued

LEO 90100(n=323)

Vehicle(n=103)




Eye disordersBlepharitis 1 0 0 0 0 0Keratitis 1 0 0 0 0 0

Psychiatric disordersBipolar disorder 1 0 0 0 0 0Substance-inducedpsychotic disorder

1 0 0 0 0 0

Vascular disordersFlushing 1 0 0 0 0 0Hot flush 1 0 0 0 0 0

Cardiac disordersTachycardia 1 0 0 0 0 0

Ear and labyrinth disordersVertigo 1 0 0 0 0 0

Renal and urinary disordersDysuria 1 0 0 0 0 0

Surgical and medical proceduresTooth extraction 1 0 0 0 0 0

Total number ofadverse events

53 5 5 10 5 0

14FEB14:09:02:55 LP0053 1001 t13aerel.doc



Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 3–14: Local safety and tolerability by visit: safety analysis set

LEO 90100(n=323)

Vehicle(n=103)

VisitAssessment



Perilesional erythemaBaseline





Perilesional drynessBaseline




Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 3–14: Local safety and tolerability by visit: safety analysis set, continued

LEO 90100(n=323)

Vehicle(n=103)

VisitAssessment



Perilesional drynessWeek 2



Perilesional erosionBaseline






Trial ID: LP0053-1001 04-Mar-2014 of 315


LEO 90100(n=323)

Vehicle(n=103)

VisitAssessment



Perilesional oedemaBaseline





Burning or painBaseline




Trial ID: LP0053-1001 04-Mar-2014 of 315


LEO 90100(n=323)

Vehicle(n=103)

VisitAssessment



Burning or painWeek 2



29NOV13:10:16:28 LP0053 1001 t14local.doc

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 3–15: Vital signs by visit: safety analysis set

VisitVital sign

LEO 90100(n=323)

Vehicle(n=103)

Baseline

Systolic Blood Pressure (mmHg) Mean 130.0 129.8 SD 14.8 15.8 Median 130.0 130.0 Minimum 87 95 Maximum 185 182 Number 323 103

Diastolic Blood Pressure (mmHg) Mean 81.0 81.3 SD 8.8 10.2 Median 82.0 81.0 Minimum 56 54 Maximum 108 108 Number 323 103

Heart Rate (Beats/Minute) Mean 73.2 74.8 SD 11.1 10.6 Median 72.0 74.0 Minimum 47 48 Maximum 106 98 Number 323 103

Week 4 / End of treatment

Systolic Blood Pressure (mmHg) Mean 131.0 128.5 SD 14.4 14.9 Median 130.0 128.0 Minimum 97 91 Maximum 184 172 Number 314 101

Diastolic Blood Pressure (mmHg) Mean 80.6 81.8 SD 9.2 10.0 Median 80.0 82.0 Minimum 58 58 Maximum 114 120 Number 314 101

Heart Rate (Beats/Minute) Mean 73.8 76.3 SD 11.4 11.3 Median 72.0 75.0 Minimum 48 42 Maximum 109 116 Number 314 101

29NOV13:11:13:18 LP0053 1001 t15vitals.doc

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 3–16: Change in vital signs from baseline to Week 4: safety analysis set

Change from baselineLEO 90100(n=323)

Vehicle(n=103)

Systolic Blood Pressure (mmHg)Mean 1.0 -1.4 SD 13.1 12.0 Median 0.0 -1.0 Minimum -32 -41 Maximum 46 36 Number 314 101

Diastolic Blood Pressure (mmHg)Mean -0.4 0.4 SD 8.4 9.7 Median 0.0 -1.0 Minimum -29 -26 Maximum 34 33 Number 314 101

Heart Rate (Beats/Minute)Mean 0.5 1.4 SD 10.1 9.9 Median 1.0 2.0 Minimum -31 -29 Maximum 30 30 Number 314 101

29NOV13:11:18:25 LP0053 1001 t16vitalchg.doc

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 3–17: Summary of albumin-corrected serum calcium and change from baseline: safety analysis set

Albumin correctedserum calcium(mmol/L)

LEO 90100(n=323)

Vehicle(n=103)

Summary




Week 4 / End of treatment Mean -0.011 -0.026 SD 0.085 0.087 Median 0.000 -0.030 Minimum -0.23 -0.35 Maximum 0.38 0.20 Number 312 100

28NOV13:12:12:27 LP0053 1001 t17sumcal.doc

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 3–18: Shift table for albumin-corrected serum calcium: safety analysis set

LEO 90100(n=323)


Vehicle(n=103)





Low 1 8 0 2 1 0

Normal 5 290 3 3 93 0High 0 2 3 0 1 0

28NOV13:12:12:36 LP0053 1001 t18shalbu.doc

1) Number of subjects with laboratory parameters below, within or above the reference range.

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 3–19: Shift table for albumin-corrected serum calcium based on LEO defined clinically significant values: safety analysis set

LEO 90100(n=323)


Vehicle(n=103)





Low 1 0 0 0 0 0

Normal 0 311 0 0 100 0High 0 0 0 0 0 0

28NOV13:12:12:47 LP0053 1001 t19leoshift.doc


Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 3–20: Summary of urinary calcium:creatinine ratio and change from baseline: safety analysis set

Urinary calcium:creatinine ratioLEO 90100(n=323)

Vehicle(n=103)

Summary




Week 4 / End of treatment Mean 0.032 -0.137 SD 2.207 1.879 Median 0.030 -0.100 Minimum -15.45 -6.55 Maximum 13.35 5.40 Number 311 99

28NOV13:16:04:11 LP0053 1001 t20sumcalcrea.doc

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 3–21: Shift table for urinary calcium:creatinine ratio: safety analysis set

LEO 90100(n=323)


Vehicle(n=103)




Calcium/Creatinine Low 0 3 0 0 2 0Normal 2 277 13 1 91 2High 0 10 5 0 1 2

28NOV13:12:12:42 LP0053 1001 t21shcal.doc


Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 3-22: Subjects with albumin-con ected sennn calcium or calcium: creatinine ratio outside the reference range: safety analysis set

Uni que subje ct

Ce ntr ident ifi e Laboratory Da t e of Re fere nce e r pa rame t e r Test Vi sit r a nge Result1

LEO 90100

I - Calcium/Creatinine - Baseli ne (0 .22 - 8 . 2) 1 0 . 700 H (mmol/g)

Week 4 (0 .22 - 8 . 2) 1 0 . 150 H - Albumi n corrected Baseline (2 .15 - 2 . 30 serum calci um 2 . 55) (mmol/L) - Week 4 (2 .15 - 2 . 13 L

2 . 55) - Albumi n cor rected - Baseline (2 .15 - 2 . 83 H serum calci um 2 . 55) (mmol/L) - Week 4 (2 .15 - 2 . 78 H

2 . 55) - Calcium/Creatinine - Baseline (0 .3 - 6 . 1) 7 . 850 H (mmol/g) - Week 4 (0 .3 - 6 . 1) 8 . 150 H

I - Albumi n cor rected - Baseline (2 .15 - 2 . 18 serum calci um 2 . 55) (mmol/L) - Week 4 (2 .15 - 2 . 13 L

2 . 55) Calcium/Creatinine - Baseline (0 .3 - 6 . 1) 0 . 175 L (mmol/g) - Week 4 (0 .3 - 6 . 1) 0 . 400

I - Calcium/Creatinine - Baseline (0 .3 - 6 . 1) 1 . 400 (mmol/g)

Week 4 (0 .3 - 6 . 1) 6 . 450 H - Calcium/Creatinine Baseline (0 .3 - 6 . 1) 7 . 950 H (mmol/g)

Week 4 (0 .3 - 6 . 1) 7 . 800 H - Calcium/Creatinine Baseline (0 .3 - 6 . 1) 1 0 . 0 75 H (mmol/g)

Week 4 (0 .3 - 6 . 1) 3 . 300 - Calcium/Creatinine Baseline (0 .3 - 6 . 1) 4 . 050 (mmol/g) - Wee k 4 (0 .3 - 6 . 1) 6 . 575 H

I - Albumi n cor rected - Baseline (2 .15 - 2 . 10 L serum calci um 2 . 55) (mmol/L)

13DEC13:14 : 09:26 LPOOS3 1001 t 22out side.doc Cont i nued .. •

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table 3- 22: Subjects with albumin-con ected sennn calcium or calcium: creatinine ratio

outside the reference range: safety analysis set, continued Uni que subje ct

Ce ntr ident ifi e Laboratory Da t e o f Re ference e r parame t er Te st Vi sit range Result1

EO 90

I - Albumi n corrected - Week 4 (2 .15 - 2 . 18 serum calci um 2 . 55) (mmol/L)

I - Albumi n corrected - Baseline (2 .15 - 2 . 10 L serum calci um 2 . 55) (mmol/L) - Week 4 (2 .15 - 2 . 25

2 . 55) - Calcium/Creat ini ne - Baseline (0 . 3 - 6 . 1) 5 . 950 (mmol/g) - Week 4 (0 . 3 - 6 . 1) 1 0 . 075 H

I - Albumi n corrected - Baseline (2 .15 - 2 . 05 L serum calci um 2 . 55) (mmol/L) - Week 4 (2 .15 - 2 . 20

2 . 55) Calcium/Creat ini ne - Baseline (0 .22 - 8 . 2) 3 . 800 (mmol/g)

Week 4 (0 .22 - 8 . 2) 8 . 700 H - Albumi n corrected Baseline (2 .15 - 2 . 25 serum calci um 2 . 55) (mmol/L) - Week 4 (2 .15 - 2 . 63 H

2 . 55) - Follow- up (2 .15 - 2 . 13 L 2 . 55) - Albumi n corrected - Baseline (2 .15 - 2 . 13 L

serum calci um 2 . 55) (mmol/L) - Week 4 (2 .15 - 2 . 15

2 . 55) - Albumi n corrected - Baseline (2 .15 - 1. 78 L serum calci um 2 . 55) (mmol/L) - Week 4 (2 .15 - 1 . 70 L

2 . 55) Calcium/Creat ini ne - Week 4 (0 . 3 - 6 . 1) 0 . 2 75 L (mmol/g)

I - Albumi n corrected - Baseline (2 .15 - 2 . 20 serum calci um 2 . 55) (mmol/L)

13DEC13:14:09:26 LPOOS3 1001 t 22outsi de. doc Cont i nued .. .

Trial ID: LP0053-1001 04-Mar-2014 of 315



Ce ntr ident ifi e Laboratory Da t e o f Re ference e r parame t er Test Vi sit range Result1

EO 90

I - Albumi n cor rected - Week 4 (2 .15 - 2 . 13 L serum calci um 2 . 55) (mmol/L) - Albumi n cor rected - Baseline (2 .15 - 2 . 25 serum calci um 2 . 55) (mmol/L) - Week 4 (2 .15 - 2 . 13 L

2 . 55)

I - Albumi n cor rected - Baseline (2 .15 - 2 . 10 L serum calci um 2 . 55) (mmol/L) - Week 4 (2 .15 - 2 . 23

2 . 55) - Calcium/Creatinine - Baseline (0 . 3 - 6 . 1) 5 . 200 (mmol/g) - Week 4 (0 . 3 - 6 . 1) 7 . 2 75 H

I - Albumi n cor rected - Baseline (2 .15 - 2 . 13 L serum calci um 2 . 55) (mmol/L) - Week 4 (2 .15 - 2 . 20

2 . 55)

I - Calcium/Creatinine - Baseline (0 . 3 - 6 . 1) 6 . 300 H (mmol/g) - Week 4 (0 . 3 - 6 . 1) 3 . 675


Week 4 (0 .22 - 8 . 2) 8 . 425 H - Albumi n cor rected Baseline (2 .15 - 2 . 40 serum calci um 2 . 55) (mmol/L) - Week 4 (2 .15 - 2 . 58 H

2 . 55) - Follow- up (2 .15 - 2 . 35 2 . 55) - Calcium/Creatinine - Baseline (0 . 3 - 6 . 1) 6 . 050

(mmol/g) Week 4 (0 . 3 - 6 . 1) 8 . 750 H - Calcium/Creatinine Baseline (0 . 3 - 6 . 1) 2 . 750

(mmol/g) - Week 4 (0 . 3 - 6 . 1) 6 . 175 H

13DEC13:14 : 09:26 LPOOS3 1001 t 22out s i de.doc Cont i nued .. .

Trial ID: LP0053-1001 04-Mar-2014 of 315




EO 90

I - Calcium/Creat ini ne - Baseli ne (0.3 - 6 . 1) 1 0 . 825 H (mmol/g)

Week 4 (0 . 3 - 6 . 1) 4 . 375 - Albumi n corrected Baseline (2 .15 - 2 . 13 L serum calci um 2 . 55) (mmol/L) - Week 4 (2 .15 - 2 . 23

2 . 55)

I - Albumi n corrected - Baseline (2 .15 - 2 . 20 serum calci um 2 . 55) (mmol/L) - Week 4 (2 .15 - 2 . 13 L

2 . 55)

I - Albumi n corrected - Baseline (2 .15 - 2 . 38 serum calci um 2 . 55) (mmol/L) - Week 4 (2 .15 - 2 . 60 H

2 . 55) - Follow- up (2 .15 - 2 . 35 2 . 55) - Calcium/Creatinine - Baseline (0 .22 - 8 . 2) 8 . 675 H

(mmol/g) - Week 4 (0 .22 - 8 . 2) 6 . 950

I - Calcium/Creatinine - Baseline (0 .22 - 8 . 2) 0 . 200 L (mmol/g)

Week 4 (0 .22 - 8 . 2) 0 . 900 - Calcium/Creatinine Baseline (0 . 3 - 6 . 1) 7 . 550 H (mmol/g) - Week 4 (0 . 3 - 6 . 1) 9 . 475 H

I - Calcium/Creatinine - Baseline (0 .22 - 8 . 2) 4 . 900 (mmol/g) - Week 4 (0 .22 - 8 . 2) 8 . 250 H

I - Albumi n corrected - Baseline (2 .15 - 2 . 80 H serum calci um 2 . 55) (mmol/L) - Week 4 (2 .15 - 2 . 75 H

2 . 55) Calcium/Creatinine - Baseline (0 . 3 - 6 . 1) 4 . 900 (mmol/g)

13DEC13:14:0 9 :26 LPOOS3 1001 t 22outsi de.doc Cont i nued .. .

Trial ID: LP0053-1001 04-Mar-2014 of 315




EO 90

I - Calcium/Creat ini ne - Week 4 (0.3 - 6 . 1) 6 . 200 H (mmol/g)

I - Calcium/Creat ini ne - Baseli ne (0 . 3 - 6 . 1) 5 . 125 (mmol/g)

Week 4 (0 . 3 - 6 . 1) 6 . 775 H - Calcium/Creatinine Baseli ne (0 . 3 - 6 . 1) 7 . 900 H (mmol/g) - Week 4 (0 . 3 - 6 . 1) 5 . 875

I - Calcium/Creatinine - Baseli ne (0 . 3 - 6 . 1) 0 . 875 (mmol/g)

Week 4 (0 . 3 - 6 . 1) 0 . 275 L - Calcium/Creat ini ne Baseli ne (0 . 3 - 6 . 1) 7 . 700 H (mmol/g) - Week 4 (0 . 3 - 6 . 1) 1 . 800

I - Calcium/Creat ini ne - Baseli ne (0 . 3 - 6 . 1) 6 . 875 H (mmol/g)

Week 4 (0 . 3 - 6 . 1) 2 . 550 - Calcium/Creat ini ne Baseli ne (0 .22 - 8 . 2) 1 0 . 150 H (mmol/g) - Week 4 (0 .22 - 8 . 2) 4 . 275

I - Calcium/Creatinine - Baseli ne (0 . 3 - 6 . 1) 4 . 475 (mmol/g) - Week 4 (0 . 3 - 6 . 1) 7 . 050 H

I - Calcium/Creatinine - Baseli ne (0 .22 - 8 . 2) 1 0 . 850 H (mmol/g)

Week 4 (0 .22 - 8 . 2) 1 . 350 - Calcium/Creatinine Baseli ne (0 . 3 - 6 . 1) 0 . 225 L (mmol/g)

Week 4 (0 . 3 - 6 . 1) 1 . 050 - Albumi n cor rected Baseli ne (2 .15 - 2 . 60 H serum calci um 2 . 55) (mmol/L)

13DEC13:14 : 09 : 26 LPOOS3 1001 t 22out s i de . doc Cont i nued .. .

Trial ID: LP0053-1001 04-Mar-2014 of 315




EO 90

I - Albumi n corrected - Week 4 (2 .15 - 2 . 50 serum calci um 2 . 55) (mmol/L)


Week 4 (0 .3 - 6 . 1) 0 . 175 L - Albumi n corrected Baseline (2 .15 - 2 . 60 H serum calci um 2 . 55) (mmol/L) - Week 4 (2 .15 - 2 . 48

2 . 55)

I - Albumi n corrected - Week 4 (2 .15 - 2 . 13 L serum calci um 2 . 55) (mmol/L) Calcium/Creatinine - Baseline (0 .22 - 8 . 2) 1 7 . 775 H (mmol/g)

Week 4 (0 .22 - 8 . 2) 2 . 325 - Albumi n corrected Baseline (2 .15 - 2 . 13 L serum calci um 2 . 55) (mmol/L) - Week 4 (2 .15 - 2 . 20

2 . 55) - Albumi n corrected - Baseline (2 .15 - 2 . 68 H serum calci um 2 . 55) (mmol/L) - Week 4 (2 .15 - 2 . 58 H

2 . 55) - Follow- up (2 .15 - 2 . 58 H 2 . 55) - Calcium/Creatinine - Baseline (0 .3 - 6 . 1) 53 . 325 H

(mmol/g) - Week 4 (0 .3 - 6 . 1) 66 . 675 H

I - Calcium/Creatinine - Baseline (0 .3 - 6 . 1) 1 . 700 (mmol/g) - Week 4 (0 .3 - 6 . 1) 7 . 325 H

ehicle

I - Calcium/Creatinine - Baseline (0 .3 - 6 . 1) 8 . 700 H (mmol/g) - Week 4 (0 .3 - 6 . 1) 7 . 500 H

13DEC13:14:0 9 :26 LPOOS3 1001 t 22outsi de.doc Cont i nued .. .

Trial ID: LP0053-1001 04-Mar-2014 of 315




ehicle

I - Calcium/Creatinine - Baseli ne (0 .22 - 8 . 2) 1 0 . 450 H (mmol/g) - Week 4 (0 .22 - 8 . 2) 4 . 425

I - Albumi n corrected - Baseli ne (2 .15 - 2 . 23 serum calci um 2 . 55) (mmol/L) - Week 4 (2 .15 - 2 . 10 L

2 . 55)


Week 4 (0 .3 - 6 . 1) 7 . 275 H - Albumi n corrected Baseline (2 .15 - 2 . 10 L serum calci um 2 . 55) (mmol/L) - Week 4 (2 .15 - 2 . 18

2 . 55)

I - Calcium/Creatinine - Baseline (0 .3 - 6 . 1) 1 1.125 H (mmol/g)

Week 4 (0 .3 - 6 . 1) 9 . 125 H - Calcium/Creatinine Baseline (0 .3 - 6 . 1) 0 . 125 L (mmol/g) - Week 4 (0 .3 - 6 . 1) 1 . 200


2 . 55)

I - Albumi n corrected - Baseline (2 .15 - 2 . 70 H serum calci um 2 . 55) (mmol/L) - Week 4 (2 .15 - 2 . 35

2 . 55)


2 . 55)

13DEC13:14:09:26 LPOOS3 1001 t 22outsi de.doc Cont i nued .. .

Trial ID: LP0053-1001 04-Mar-2014 of 315




ehicle

I - Calcium/Creatinine - Baseli ne (0 . 3 - 6 . 1) 0 . 200 L (mmol/g) - Week 4 (0 . 3 - 6 . 1) 0 . 525

I - Albumi n cor rected - Baseli ne (2 .15 - 2 . 10 L serum calci um 2 . 55) (mmol/L) - Week 4 (2 .15 - 2 . 10 L

2 . 55)


Week 4 (0 .3 - 6 . 1) 6 . 300 H - Calcium/Creatinine Baseline (0 .3 - 6 . 1) 1 . 750 (mmol/g) - Week 4 (0 .3 - 6 . 1) 0 . 225 L

I - Albumi n cor rected - Baseline (2 .15 - 2 . 13 L serum calci um 2 . 55) (mmol/L) - Week 4 (2 .15 - 2 . 10 L

2 . 55)

13DEC13:14 : 0 9 : 26 LP00 53 1001 t.22out.si de.doc

Trial ID: LP0053-1001 04-Mar-2014 of 315

Figure 3–1: Local safety and tolerability by visit: safety analysis set

15 -

10 -

5 -

0 -

15 -

10 -

5 -

en 0 -...... ()

15 -Q)

E ::::l en 10 -'+-0 Q) 0) 5 -co ...... c Q) 0 -() I-Q)

15 -D...

10 -

5 -

0 -

15 -

10 -

5 -

0 -

LEO 90100 Vehicle

• Severe • Moderate D Mild

-

<( ~ w I I>-0::: w

(/) (/) w z >-0::: 0

z 0 (/)

0 0::: w

<( ~ w 0 w 0

z <{ 0... (5 z z 0::: ::J en

Trial ID: LP0053-1001 04-Mar-2014 of 315

0 End-of-Text Listings

Trial ID: LP0053-1001 04-Mar-2014 of 315

Table of Contents

0-1 Subjects Withdrawn due to AE .........................................................................................................................................................................313

0-2 Deaths..............................................................................................................................................................................................................................314

0-3 Serious Adverse Events .......................................................................................................................................................................................315

Treatment group=LEO 90100..........................................................................................................................................................................................315

Trial ID: LP0053-1001 04-Mar-2014 of 315

Listing 0-1: Subjects Withdrawn due to AE

Date of program execution Empty List04FEB2014:09:16:12 No data for this listing

04FEB2014:09:16:12 Programs-Listings empty Page 313 of 5

Trial ID: LP0053-1001 04-Mar-2014 of 315

Listing 0-2: Deaths

Date of program execution Empty List04FEB2014:09:16:12 No data for this listing

04FEB2014:09:16:12 Programs-Listings ae(where=aeout='FATAL') Page 314 of 5

Trial ID: LP0053-1001

Listing 0-3 : Serious Adverse Events

Treatment group=LEO 90100

Centre/ Subjec t ID Location

•

Preferred term/ rted term

BIPOLAR DI SORDER/ Bipo l ar d i sorder exac erb ati on

SUBSTANCE- INDUCED PSYCHOTIC DISORDER/ Acute psychiatric event with drug overdose

04-Mar-2014

Duratio n

-04FEB2014 : 09 :1 6:12 PrograJDS-Listinqs a e 1001 (where=first(upcase(aeser) ) = 'Y' )

Rela- In ten-tion s Not Severe rel ated

Not Severe rel ated

of315

Action taken Days since with Other first/ lates study a c tion Seriou t

taken Outcome s dose Dose not Concomi ta Recovered Yes 28/15 changed nt

medicatio n

Drug None Unknown Yes 21/6 withdrawn

Page 315 o f 5

clinical study report leo 90100 compared to vehicle in...

Documents