LEO80185-G23 Clinical Study Report...

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1 REPORT STATEMENTS

APPROVAL STATEMENT On behalf of LEO, only the Head of International Clinical Development and the Head of Biostatistics, LEO head quarters (HQ) are authorised to approve the main Clinical Study Report. All LEO approvers will be identified on a signature page automatically generated as the last page of the pdf-file of the final main Clinical Study Report, when the last LEO approval is obtained. The time and date of their e-signatures are likewise presented on the approval page. The following persons have approved this main Clinical Study Report (including appendices) by use of electronic signatures:

, LEO HQ

APPROVAL STATEMENT, INVESTIGATORS The International Co-ordinating Investigator approves the main Clinical Study Report (including appendices) 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 main Clinical Study Report (including appendices):

, MD International Co-ordinating Investigator

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COMPLIANCE WITH GOOD CLINICAL PRACTICE This Clinical Study Report is designed to comply with the standards issued by the Interna-tional Conference on Harmonisation (ICH) (E3 Structure and Content of Clinical Study Reports; E6 Good Clinical Practice; E9 Statistical Principles for Clinical Trials and M4 Common Technical Document). DISCLOSURE OF CLINICAL TRIAL RESULTS Results from this clinical trial will be posted on www.clinicaltrials.gov which is a publicly accessible database.

2 SYNOPSIS

The synopsis of this Clinical Study Report exists as a separately approved document. LEO 80185-G23 Clinical Study Report Synopsis

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3 TABLE OF CONTENTS

1 REPORT STATEMENTS .................................................................................................... 2 2 SYNOPSIS ............................................................................................................................. 3 3 TABLE OF CONTENTS ...................................................................................................... 4 LIST OF IN-TEXT TABLES .................................................................................................. 8 LIST OF IN-TEXT FIGURES .............................................................................................. 13 4 LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .................................... 14 5 ETHICS ................................................................................................................................ 19 5.1 INDEPENDENT ETHICS COMMITTEE (IEC) OR INSTITUTIONAL REVIEW

BOARD (IRB) .................................................................................................................. 19 5.2 ETHICAL CONDUCT OF THE TRIAL ........................................................................... 19 5.3 SUBJECT INFORMATION AND INFORMED CONSENT ........................................... 19 6 INVESTIGATORS AND TRIAL ADMINISTRATIVE STRUCTURE ....................... 21 7 INTRODUCTION ............................................................................................................... 24 7.1 PSORIASIS VULGARIS ................................................................................................... 24 7.2 INVESTIGATIONAL PRODUCT DESCRIPTION ......................................................... 25 7.3 TRIAL RATIONALE ........................................................................................................ 28 8 TRIAL OBJECTIVES ........................................................................................................ 31 8.1 PRIMARY OBJECTIVE ................................................................................................... 31 8.2 SECONDARY OBJECTIVES ........................................................................................... 31 9 INVESTIGATIONAL PLAN ............................................................................................. 32 9.1 OVERALL TRIAL DESIGN AND PLAN - DESCRIPTION .......................................... 32 TRIAL DESIGN ...................................................................................................................... 32 9.2 DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF CONTROL

GROUPS ........................................................................................................................... 35 9.3 SELECTION OF TRIAL POPULATION ......................................................................... 38 9.3.1 Inclusion Criteria ............................................................................................................. 39 9.3.2 Exclusion Criteria ............................................................................................................ 40 9.3.3 Removal of Subjects from Therapy or Assessment ........................................................ 41 9.4 TREATMENTS ................................................................................................................. 42 9.4.1 Treatments Administered ................................................................................................ 42 9.4.2 Identity of Investigational Product(s) .............................................................................. 42 9.4.3 Method of Assigning Subjects to Treatment Groups ...................................................... 45 9.4.4 Selection of Doses in the Trial ........................................................................................ 46

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9.4.5 Selection and Timing of Dose for each Subject .............................................................. 47 9.4.6 Blinding ........................................................................................................................... 47 9.4.7 Prior and Concomitant Therapy ...................................................................................... 49 9.4.8 Treatment Compliance .................................................................................................... 50 9.5 EFFICACY AND SAFETY VARIABLES ....................................................................... 52 9.5.1 Efficacy and Safety Measurements Assessed and Flow Chart ....................................... 52 9.5.1.1 Flow Chart .................................................................................................................... 52 9.5.1.2 Subject Eligibility ......................................................................................................... 53 9.5.1.3 Clinical Assessments .................................................................................................... 54 9.5.1.4 Subject Assessments .................................................................................................... 57 9.5.1.5 Safety Assessments ...................................................................................................... 58 9.5.2 Appropriateness of Measurements .................................................................................. 64 9.5.3 Primary Efficacy Variable(s) .......................................................................................... 65 9.5.4 Drug Concentration Measurements ................................................................................. 65 9.6 DATA QUALITY ASSURANCE ..................................................................................... 65 9.7 STATISTICAL METHODS PLANNED IN THE PROTOCOL AND

DETERMINATION OF SAMPLE SIZE ......................................................................... 67 9.7.1 Statistical and Analytical Plans ....................................................................................... 67 9.7.1.1 Reasons for Leaving the Study ..................................................................................... 68 9.7.1.2 Baseline Characteristics ............................................................................................... 68 9.7.1.3 Analysis of Efficacy ..................................................................................................... 68 9.7.1.4 Analysis of Safety ........................................................................................................ 71 9.7.1.5 General Principles ........................................................................................................ 73 9.7.2 Determination of Sample Size ......................................................................................... 74 9.8 CHANGES IN THE CONDUCT OF THE TRIAL OR PLANNED ANALYSES ........... 75 10 TRIAL POPULATION .................................................................................................... 76 10.1 DISPOSITION OF SUBJECTS ....................................................................................... 76 10.2 PROTOCOL DEVIATIONS ............................................................................................ 87 11 EFFICACY EVALUATION ............................................................................................ 90 11.1 DATA SETS ANALYSED .............................................................................................. 90 11.2 DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ........................... 94 11.3 MEASUREMENT OF TREATMENT COMPLIANCE ............................................... 103 11.4 EFFICACY RESULTS AND TABULATION OF INDIVIDUAL SUBJECT DATA . 106 11.4.1 Analysis of Efficacy .................................................................................................... 106 11.4.1.1 Primary Endpoint – Controlled Disease According to the Investigator’s Global

Assessment of Disease Severity (IGA) at Weeks 4 and 8 .............................................. 106

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11.4.1.2 Secondary Endpoint - Percentage Change in PASI at Weeks 4 and 8 ..................... 120 11.4.1.3 Tertiary endpoints .................................................................................................... 134 11.4.2 Statistical/Analytical Issues ......................................................................................... 138 11.4.2.1 Adjustments for Covariates ...................................................................................... 138 11.4.2.2 Handling of Dropouts or Missing Data .................................................................... 138 11.4.2.3 Interim Analyses and Data Monitoring .................................................................... 139 11.4.2.4 Multi-site Clinical Trials .......................................................................................... 139 11.4.2.5 Multiple Comparison/multiplicity ............................................................................ 139 11.4.2.6 Use of an “Efficacy Subset” of Subjects .................................................................. 139 11.4.2.7 Active-control Studies Intended to Show Equivalence ............................................ 139 11.4.2.8 Examination of Subgroups ....................................................................................... 139 11.4.3 Tabulation of Individual Response Data ..................................................................... 139 11.4.4 Drug Dose, Drug Concentration, and Relationships to Response ............................... 139 11.4.5 Drug-Drug and Drug-Disease Interactions ................................................................. 140 11.4.6 By-Subject Displays .................................................................................................... 140 11.4.7 Efficacy Conclusions ................................................................................................... 140 12 SAFETY EVALUATION ............................................................................................... 141 12.1 EXTENT OF EXPOSURE ............................................................................................. 141 12.2 ADVERSE EVENTS ..................................................................................................... 144 12.2.1 Brief Summary of Adverse Events .............................................................................. 144 12.2.2 Display of Adverse Events .......................................................................................... 144 12.2.3 Analysis of Adverse Events ........................................................................................ 161 12.2.4 Listing of Adverse Events by Subject ......................................................................... 161 12.3 DEATHS, OTHER SERIOUS ADVERSE EVENTS AND OTHER SIGNIFICANT

ADVERSE EVENTS ...................................................................................................... 162 12.3.1 Listing of Deaths, Other Serious Adverse Events and Other Significant Adverse

Events .............................................................................................................................. 162 12.3.1.1 Deaths ....................................................................................................................... 162 12.3.1.2 Other Serious Adverse Events .................................................................................. 162 12.3.1.3 Other Significant Adverse Events ............................................................................ 165 12.3.2 Narratives of Deaths, Other Serious Adverse Events and Other Significant

Adverse Events ................................................................................................................ 165 12.3.2.1 Serious Adverse Event Narratives ............................................................................ 165 12.3.2.2 Pregnancy Narratives ............................................................................................... 171 12.3.2.3 Narratives ................................................................................................................. 172

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12.3.3 Analysis and Discussion of Deaths, other Serious Adverse Events and Other Significant Adverse Events ............................................................................................. 177

12.4 CLINICAL LABORATORY EVALUATION .............................................................. 178 12.4.1 Listing of Individual Laboratory Measurements by Subject and Each Abnormal

Laboratory Value ............................................................................................................ 178 12.4.2 Evaluation of Each Laboratory Parameter .................................................................. 178 12.5 VITAL SIGNS, PHYSICAL FINDINGS AND OTHER OBSERVATIONS

RELATED TO SAFETY ................................................................................................ 204 12.6 SAFETY CONCLUSIONS ............................................................................................ 204 13 DISCUSSION AND OVERALL CONCLUSIONS...................................................... 206 14 TABLES, FIGURES AND GRAPHS REFERRED TO BUT NOT INCLUDED

IN THE TEXT ............................................................................................................... 210 14.1 DEMOGRAPHIC DATA .............................................................................................. 211 14.2 EFFICACY DATA ........................................................................................................ 224 14.3 SAFETY DATA ............................................................................................................. 291 15 REFERENCES ................................................................................................................ 344 16 LIST OF APPENDICES................................................................................................. 348 16.1 STUDY INFORMATION .............................................................................................. 348 16.2 SUBJECT DATA LISTINGS ........................................................................................ 348 16.3 CASE REPORT FORMS ............................................................................................... 349

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LIST OF IN-TEXT TABLES Table 1: Study period: enrolled subjects .................................................................................. 77 Table 2: Subject enrolment and randomisation: enrolled subjects and randomised subjects .. 79 Table 3: Reasons for withdrawal: randomised subjects ........................................................... 81 Table 4: Protocol deviations ..................................................................................................... 88 Table 5: Age: randomised subjects .......................................................................................... 94 Table 6: Sex: randomised subjects ........................................................................................... 95 Table 7: Race: randomised subjects ......................................................................................... 96 Table 8: Ethnicity: randomised subjects .................................................................................. 97 Table 9: Skin type: randomised subjects .................................................................................. 99 Table 10: Duration of psoriasis vulgaris: randomised subjects .............................................. 100 Table 11: Disease severity (IGA) at baseline: randomised subjects ...................................... 101 Table 12: PASI at baseline: randomised subjects .................................................................. 102 Table 13: BSA involvement of psoriasis vulgaris at baseline: randomised subjects ............. 102 Table 14: Adherence to treatment instructions over the total study period: full analysis set 104 Table 15: Adherence to treatment instructions over the total study period: per protocol

analysis set ...................................................................................................................... 105 Table 16: Percentage of subjects with ‘Controlled disease’ (IGA) at Week 4: full analysis

set .................................................................................................................................... 109 Table 17: Percentage of subjects with ‘Controlled disease’ (IGA) at Week 8: full analysis

set .................................................................................................................................... 110 Table 18: Percentage of subjects with ‘Controlled disease’ (IGA) at Week 4: full analysis

set Site excluded .................................................................................................. 111 Table 19: Percentage of subjects with ‘Controlled disease’ (IGA) at Week 8: full analysis

set Site excluded .................................................................................................. 112 Table 20: Percentage of subjects with ‘Controlled disease’ (IGA) at Week 4: per protocol

analysis set ...................................................................................................................... 113 Table 21: Percentage of subjects with ‘Controlled disease’ (IGA) at Week 8: per protocol

analysis set ...................................................................................................................... 114 Table 22: Percentage of subjects with ‘Controlled disease’ (IGA) at Weeks 1, 2, 4, 6 and

8: full analysis set ............................................................................................................ 118 Table 23: Mean Percentage change in PASI from baseline to Week 4: full analysis set ....... 121 Table 24: Mean Percentage change in PASI from baseline to Week 8: full analysis set ....... 122 Table 25: Mean Percentage change in PASI from baseline to Week 4: full analysis set site

excluded .............................................................................................................. 123

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Table 26: Mean Percentage change in PASI from baseline to Week 8: full analysis set site excluded .............................................................................................................. 124

Table 27: Mean Percentage change in PASI from baseline to Week 4: per protocol set ....... 125 Table 28: Mean Percentage change in PASI from baseline to Week 8: per protocol set ....... 126 Table 29: Mean Percentage change in PASI from baseline to Weeks 1, 2, 4, 6 and 8: full

analysis set ...................................................................................................................... 130 Table 30: Percentage of subjects with PASI 75 at Weeks 4 and 8: full analysis set .............. 132 Table 31: Percentage of subjects with PASI 50 at Weeks 4 and 8: full analysis set .............. 133 Table 32: Summary change in DLQI score at baseline at Weeks 2, 4 and 8: full analysis

set .................................................................................................................................... 135 Table 33: Duration and extent of exposure to treatment: safety analysis set ......................... 142 Table 34: Amount of study medication used between visits: safety analysis set ................... 143 Table 35: AEs occurring in ≥1% of subjects in any treatment group: safety analysis set ..... 148 Table 36: AEs by MedDRA primary system organ class: safety analysis set ....................... 152 Table 37: ADRs by MedDRA primary SOC and preferred term: safety analysis set ............ 155 Table 38: AEs in the treatment area by MedDRA primary SOC and preferred term: safety

analysis set ...................................................................................................................... 159 Table 39: SAEs by MedDRA primary SOC and preferred term: safety analysis set ............. 163 Table 40: Summary of albumin-corrected serum calcium and change from baseline at

Weeks 4 and 8: safety analysis set .................................................................................. 179 Table 41: Shift tables for albumin-corrected serum calcium from baseline to Weeks 4 and

8: safety analysis set ........................................................................................................ 182 Table 42: Summary of serum phosphate and change from baseline at Weeks 4 and 8:

safety analysis set ............................................................................................................ 184 Table 43: Shift tables for serum phosphate from baseline to Weeks 4 and 8: safety

analysis set ...................................................................................................................... 186 Table 44: Summary of serum alkaline phosphatase and change from baseline at Weeks 4

and 8: safety analysis set ................................................................................................. 188 Table 45: Shift tables for serum alkaline phosphatase from baseline to Weeks 4 and 8:

safety analysis set ............................................................................................................ 190 Table 46: Summary of plasma parathyroid hormone and change from baseline at Weeks 4

and 8: safety analysis set ................................................................................................. 192 Table 47: Shift tables for plasma parathyroid hormone from baseline to Weeks 4 and 8:

safety analysis set ............................................................................................................ 195 Table 48: Summary of urinary calcium:creatinine ratio and change from baseline at

Weeks 4 and 8: safety analysis set .................................................................................. 197

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Table 49: Shift tables for Urinary calcium:creatinine ratio from baseline to Weeks 4 and 8: safety analysis set ........................................................................................................ 199

Table 50: Summary of urinary phosphate:creatinine ratio and change from baseline at Weeks 4 and 8: safety analysis set .................................................................................. 201

Table 51: Shift tables for urinary phosphate:creatinine ratio from baseline to Weeks 4 and 8: safety analysis set ........................................................................................................ 203

Table 52: Reasons for withdrawal by last on-treatment visit for which data are recorded: randomised subjects ........................................................................................................ 211

Table 53: Investigator’s assessment of clinical signs at baseline: randomised subjects ....... 212 Table 54: Physical examination (weight, height, blood pressure): randomised subjects ...... 217 Table 55: Relevant medical history and concurrent diagnoses at baseline by MedDRA

primary SOC: randomised subjects ................................................................................. 219 Table 56: Concomitant medication at baseline: randomised subjects ................................... 222 Table 57: Sensitivity analysis of Percentage of subjects with “Controlled disease” (IGA)

at Week 4 – missing values set to “Controlled disease”: full analysis set ...................... 224 Table 58: Sensitivity analysis of Percentage of subjects with “Controlled disease” (IGA)

at Week 4 – missing values set to “Non-controlled disease”: full analysis set ............... 225 Table 59: Sensitivity analysis of Percentage of subjects with “Controlled disease” (IGA)

at Week 4 – missing values set to “Non-controlled disease” for LEO80185 and to “Controlled disease” for the other treatments: full analysis set ...................................... 226

Table 60: Sensitivity analysis of Percentage of subjects with “Controlled disease” (IGA) at week 8 – missing values set to “Controlled disease”: full analysis set ....................... 227

Table 61: Sensitivity analysis of Percentage of subjects with “Controlled disease” (IGA) at week 8 – missing values set to “Non-controlled disease”: full analysis set ................ 228

Table 62: Sensitivity analysis of Percentage of subjects with “Controlled disease” (IGA) at week 8 – missing values set to “Non-controlled disease” for LEO80185 and to “Controlled disease” for the other treatments: full analysis set ...................................... 229

Table 63: Percentage of subjects with “Controlled disease” (IGA) at Weeks 4 and 8 by centre: full analysis set .................................................................................................... 230

Table 64: Centre specific odds ratio including 95% CI ranked from lowest to highest – DAIVOBET/DOVOBET vs each of the other treatments: full analysis set ................... 246

Table 65: Percentage of subjects with “Controlled disease” (IGA) at Weeks 4 and 8 by sex: full analysis set ........................................................................................................ 248

Table 66: Percentage of subjects with “Controlled disease” (IGA) at Weeks 4 and 8 by age group: full analysis set .............................................................................................. 249

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Table 67: Percentage of subjects with “Controlled disease” (IGA) at Weeks 4 and 8 by ethnicity: full analysis set ................................................................................................ 251

Table 68: Percentage of subjects with “Controlled disease” (IGA) at Weeks 4 and 8 by race: full analysis set ....................................................................................................... 252

Table 69: Percentage of subjects with “Controlled disease” (IGA) at Weeks 4 and 8 by baseline disease severity (IGA): full analysis set ............................................................ 255

Table 70: Percentage of subjects in each IGA-category at weeks 1, 2, 4, 6 and 8: full analysis set ...................................................................................................................... 256

Table 71: Mean percentage change in PASI from baseline to Weeks 4 and 8 by centre: full analysis set ............................................................................................................... 258

Table 72: Summary of mean absolute change in PASI from baseline to weeks 1, 2, 4, 6 and 8: full analysis set ..................................................................................................... 282

Table 73: Percentage of subjects with “Controlled disease” (Patient’s Global Assessment of disease severity) at weeks 1, 2, 4, 6 and 8: full analysis set ....................................... 284

Table 74: Percentage of subjects in each category of Patient’s Global Assessment of disease severity at weeks 1, 2, 4, 6 and 8: full analysis set ............................................ 285

Table 75: Summary of change in plaque discomfort score from baseline to week 1, 2, 4, 6 and 8: full analysis set ..................................................................................................... 287

Table 76: Summary of DLQI score at baseline, week 2, 4 and 8: full analysis set ................ 289 Table 77: AEs by MedDRA primary SOC and preferred term: safety analysis set ............... 291 Table 78: Causal relationship of AEs by MedDRA primary SOC and preferred term:

safety analysis set ............................................................................................................ 301 Table 79: Intensity of AEs by MedDRA primary SOC and preferred term: safety analysis

set .................................................................................................................................... 311 Table 80: Intensity of ADRs by MedDRA primary SOC and preferred term: safety

analysis set ...................................................................................................................... 321 Table 81: Intensity of AEs in treatment area by MedDRA primary SOC and preferred

term: safety analysis set .................................................................................................. 324 Table 82: Summary of serum calcium and change from baseline at baseline and Weeks 4

and 8: safety analysis set ................................................................................................. 326 Table 83: Shift tables for serum calcium from baseline to Weeks 4 and 8: safety analysis

set .................................................................................................................................... 328 Table 84: Summary of serum albumin and change from baseline at baseline and Weeks 4

and 8: safety analysis set ................................................................................................. 329 Table 85: Shift tables for serum albumin from baseline to Weeks 4 and 8: safety analysis

set .................................................................................................................................... 331

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Table 86: Summary of urinary calcium and change from baseline at baseline and Weeks 4 and 8: safety analysis set ................................................................................................. 332

Table 87: Shift tables for urinary calcium from baseline to Weeks 4 and 8: safety analysis set .................................................................................................................................... 334

Table 88: Summary of urinary phosphate and change from baseline at baseline and Weeks 4 and 8: safety analysis set .................................................................................. 335

Table 89: Shift tables for urinary phosphate from baseline to Weeks 4 and 8: safety analysis set ...................................................................................................................... 337

Table 90: Summary of urinary creatinine and change from baseline at baseline and Weeks 4 and 8: safety analysis set .............................................................................................. 338

Table 91: Shift tables for urinary creatinine from baseline to Weeks 4 and 8: safety analysis set ...................................................................................................................... 340

Table 92: AEs leading to discontinuation .............................................................................. 341

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LIST OF IN-TEXT FIGURES Figure 1: Overall chart of study design .................................................................................... 35 Figure 2: Schedule/chart of trial procedures ............................................................................ 52 Figure 3: Subject recruitment: number of enrolled subjects vs time ........................................ 76 Figure 4: Visit attendance by treatment: randomised subjects ................................................. 83 Figure 5: Trial analysis sets by treatment: randomised subjects .............................................. 90 Figure 6: Centre specific odds ratio including 95% CI ranked from lowest to highest –

DAIVOBET/DOVOBET gel vs betamethasone gel: full analysis set ............................ 107 Figure 7: Percentage of subjects with “Controlled disease” (IGA) at weeks 1, 2, 4, 6 and

8: full analysis set ............................................................................................................ 115 Figure 8: Percentage of subjects in each IGA category at Weeks 1, 2, 4, 6 and 8: full

analysis set ...................................................................................................................... 116 Figure 9: Summary of percentage change in PASI from baseline to weeks 1, 2, 4, 6 and 8:

full analysis set ................................................................................................................ 127 Figure 10: Summary of mean absolute change in PASI from baseline to weeks 1, 2, 4, 6

and 8: full analysis set ..................................................................................................... 128 Figure 11: Percentage of subjects with ‘Controlled disease’ (PGA) at weeks 1, 2, 4, 6 and

8: full analysis set ............................................................................................................ 137 Figure 12: Summary of change in plaque discomfort score from baseline to Week 1, 2, 4,

6 and 8: full analysis set .................................................................................................. 138

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4 LIST OF ABBREVIATIONS AND DEFINITION OF TERMS

LIST OF ABBREVIATIONS

ACE Angiotensin-converting enzyme

ADR Adverse Drug Reaction

AE Adverse Event

ALP Alkaline Phosphatase

ANOVA Analysis of Variance

APC Antigen Presenting Cell

BSA Body Surface Area

CI Confidence Interval

CRF Case Report Form

CRO Contract Research Organisation

CTS Clinical Trial Supplies

DLQI Dermatology Life Quality Index

EU European Union

FDA Food and Drug Administration

GCP Good Clinical Practice

GPV Global Pharmacovigilance

HPA Hypothalamic-pituitary-adrenal axis

HQ Head Quarters

ICH International Conference on Harmonisation

ICTM International Clinical Trial Manager

IGA Investigator’s Global Assessment of disease severity

IND Investigational New Drug

INN International Non-proprietary Name

IRB Institutional Review Board

IWRS Interactive Web Response System

LAD Left Anterior Descending (Artery)

LOCF Last Observation Carried Forward

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MedDRA Medical Dictionary for Regulatory Activities

NCTM National Clinical Trial Manager

OR Odds Ratio

PASI Psoriasis Area and Severity Index

PGA Patient’s Global Assessment of disease severity

PTH Parathyroid hormone

PUVA Psoralen plus Ultraviolet light A

QA Quality Assurance

QoL Quality of Life

RDC Remote Data Capture

SAE Serious Adverse Event

SAPU Statistical Analysis Plan Update

SD Standard Deviation

SOP Standard Operating Procedure

STP Subject Treatment Pack

SUSAR Suspected Unexpected Serious Adverse Reaction

USAN US Adopted Name

UVA Ultraviolet light A

UVB Ultraviolet light B

VAS Visual Analogue Scale

WHO World Health Organisation

WMA World Medical Assembly DEFINITION OF TERMS Terms defined by International Conference on Harmonisation (ICH) Guidelines are not mentioned here. Assessment A (cluster of) characteristic(s) measured and/or recorded for a subject.

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Certified Copy A certified copy is a copy of original information that has been verified, as indicated by a dated signature, as an exact copy having all of the same attributes and information as the original (Food and Drug Administration, FDA, Guidance for Industry, Computerized Systems Used in Clinical Investigations, May 2007). Clinical Lead The person appointed by LEO to be responsible for the oversight of clinical monitoring performed by the Clinical CRO. Concomitant Medication Any medication taken by a subject during a clinical trial apart from the trial medication. CRF Number A unique identifier allocated to a subject. This number is used to identify subjects without using personal data and is synonymous with the term Subject Number as used by the Clinical-CRO. Enrolled Subject A subject for whom informed consent has been obtained and a CRF number assigned. Fraud Fabrication of data, selective and undisclosed rejection of undesired results, substitution with fictitious data, deliberately incorrect use of statistical methods for the purposes of reaching other conclusions than those warranted by the data, misinterpretation of results and conclu-sions, plagiarism of results or entire articles from other researchers, misrepresentation of other researchers’ results, unwarranted authorship, and misleading application for positions or funds. International Clinical Trial Manager (ICTM) The person appointed by LEO to be the main international representative responsible for all aspects of a clinical trial as outlined in Clinical Development SOPs. Investigator Agreement A contract between LEO and an investigator specifying the conditions for the co-operation in the clinical trial and the investigators’ responsibilities.

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Investigator Staff Signature Form A form used: 1. for the investigator to delegate trial-related tasks/duties 2. for trial site staff to sign and date to accept delegation 3. for trial site staff to document signatures and initials 4. for the investigator to authorise tasks/duties delegated. Investigator Trial File The collection of trial documents required by LEO GCP SOPs, ICH Guidelines and/or regulatory requirements to be on file at the trial site.

LEO LEO (no suffix): Refers to the corporate organisation of LEO Pharma. Monitor A person appointed by LEO to carry out monitoring of a clinical trial. 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). Response Criterion 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.

Subject Identification List A summary list kept by the investigator in the Investigator Trial File that records the names of all subjects enrolled and the date of enrolment in the trial at that trial site, with the subject’s corresponding CRF Book Number, to allow the investigator/institution to reveal the identity of any subject, if required.

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Subject Study Card A card given to a subject by the trial site at the time trial medication is first dispensed to a subject, to identify that the subject is having treatment with an investigational product.

Subject Screening Log A document kept by the investigator which identifies patients/subjects who entered pre-trial screening. Subject Screening Log is synonymous with Patient Screening Log.

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5 ETHICS

5.1 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/received favourable opinion from 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 16.1.3.

5.2 ETHICAL CONDUCT OF THE TRIAL

The clinical trial was conducted to conform to the principles of the Declaration of Helsinki as adopted by the 18th World Medical Assembly, 1964, and subsequent amendments. The clinical trial was conducted in accordance with the principles of Good Clinical Practice (GCP). Subjects were asked to consent that data could be recorded, collected, processed and trans-ferred to European Union (EU) and non-EU countries in accordance with any national legislation implementing the EU Data Protection Directive (95/46/EC). 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 (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.

5.3 SUBJECT INFORMATION AND INFORMED CONSENT

All subjects received written and verbal information concerning the clinical trial. This information emphasised that participation in the trial was voluntary and that the subject could

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withdraw from the trial at any time and for any reason. All subjects were given an opportu-nity to ask questions and were given sufficient time to consider all relevant issues before consenting. 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. A representative subject information sheet and informed consent form is provided in Appen-dix 16.1.3. All investigators signed an Investigator Agreement before the clinical trial is initiated to confirm the above.

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6 INVESTIGATORS AND TRIAL ADMINISTRATIVE STRUCTURE

LEO Pharma A/S 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. Role Name, title, affiliation International Co-ordinating Investigator:

, MD,

USA.

:

, MD, , LEO Pharma A/S, Industriparken 55, DK-2750

Ballerup, Denmark.

, LEO HQ:

, MSc, , LEO Pharma A/S, Industriparken 55, DK-2750 Ballerup, Denmark.

Trial Statistician: , MSc (stat), , Biostatistics Department, LEO Pharma A/S, Industriparken 55, DK-2750 Ballerup, Denmark.

International Clinical Trial Manager (ICTM):

, BSc (Hons), , LEO Pharma, Longwick Road, Princes Risborough, Buckingham-shire, HP27 9RR U.K.

Sponsor’s Medical Expert: , MD, , Medical Department, LEO Pharma A/S, Industriparken 55, DK-2750 Ballerup, Denmark.

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Central Laboratory: , U.K.,

Contract Research Organisation (CRO):

Clinical CRO

, USA.

, USA.

, USA.

, USA.

, USA,

USA

United Kingdom.

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7 INTRODUCTION

This was a phase 3 clinical study of LEO 80185 topical suspension (herein referred to as DAIVOBET/DOVOBET gel), a fixed combination product containing calcipotriol plus betamethasone dipropionate in a gel vehicle, in subjects with psoriasis vulgaris on non-scalp regions of the body (trunk and/or limbs). The study was conducted in accordance with applicable national regulatory requirements and under a US Investigational New Drug (IND).

7.1 PSORIASIS VULGARIS

Psoriasis vulgaris is a chronic and recurrent skin disorder with up to 30% of patients developing psoriatic arthritis. It is characterised by sharply marginated areas of affected skin which appear thickened, red and scaly. The scalp, elbows, knees, lower back, hands, feet and nails are commonly affected sites. About 80% of affected subjects complain about itching (1). The psoriatic appearance of the skin is initiated by an antigen presenting cell (APC) – T-cell interaction leading to the liberation of multiple inflammatory cytokines. This in time leads to an increased rate of epidermal proliferation with impaired differentiation of kerati-nocytes resulting in a thickened, undulating epidermis covered by a thickened, parakeratotic stratum corneum. Dermal capillaries become tortuous and dilated and there is infiltration of both epidermis and dermis with immunologically active cells (2, 3). There is currently no cure for psoriasis vulgaris and treatment is targeted at reducing the signs of erythema, scaling and infiltration and associated symptoms such as pruritus. Topical corticosteroids and vitamin D analogues are effective and the most commonly used therapies for treating psoriasis vulgaris. Adverse reactions associated with used topical therapies include skin atrophy, irreversible striae, telangiectasia, perioral dermatitis, glau-coma and acne. Additionally, continued corticosteroid therapy may result in tachyphylaxis (a condition with decreasing response to treatment). Rebound of disease may also occur if corticosteroid therapy is abruptly withdrawn. The most common adverse reaction associated with topical Vitamin D therapy (calcipotriol and calcitriol) is skin irritation. Phototherapy (psoralen combined with ultraviolet radiation A (PUVA), broad-band or narrow-band ultraviolet radiation B (UVB) and systemic treatments (methotrexate, oral retinoids and ciclosporine) are generally required in more extensive, therapy-resistant and socially disabling disease and in the serious forms of erythrodermic and pustular psoriasis (4,

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1). Among the newest therapies for the treatment of moderate to severe chronic plaque psoriasis are biological agents (e.g. alefacept, etanercept, infliximab, adalimumab and ustekinumab), which reduce the pathogenic effects of T-cells, either by a direct effect on the T-cells or by inhibition of their secreted cytokines.

7.2 INVESTIGATIONAL PRODUCT DESCRIPTION

Calcipotriol Calcipotriol (International Non –proprietary name INN; identical to calcipotriene (US Adopted Name USAN)) is a Vitamin D analogue manufactured by LEO Pharma A/S. It is the active component of DAIVONEX/DOVONEX, which has been widely available world-wide for treatment of psoriasis vulgaris since it was first approved in 1991. Due to its main effects of inhibition of cell proliferation, stimulation of cell differentiation and regulation of inflammatory response, calcipotriol reverses the signs and symptoms associated with psoriasis vulgaris. Calcipotriol has been thoroughly investigated in preclini-cal safety studies and clinical trials involving use for up to 1 year (5, 6, 7, 8, 9, 10, 11, 12) and extensive post-marketing experience is available. A number of short term studies have been conducted with calcipotriol ointment 50 mcg/g applied twice daily in psoriasis vulgaris of trunk and limbs (5, 6, 7, 8). Calcipotriol is well tolerated, adverse events (AEs) being mainly application related; lesional/perilesional irritation that tended to be mild and subside despite continuation of treatment. The long term efficacy and safety of calcipotriol for up to 1 year has also been established (9, 10, 11, 12). The most frequent treatment related AE is burning/stinging/tingling which is usually mild in severity. Laboratory test results showed no treatment related changes on blood parameters. Overdosage with calcipotriol can cause systemic side effects in the form of hypercalcaemia, attributable to the effect of Vitamin D analogues on the calcium metabolism. However, extensive experience with topical use of calcipotriol in psoriasis has demonstrated no impact on calcium metabolism, when used in amounts of up to 100 g DAIVONEX/DOVONEX per week. Furthermore a broad safety margin has been demonstrated (13).

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Betamethasone dipropionate Betamethasone dipropionate is a synthetic fluorinated corticosteroid classified as a potent (World Health Organisation, WHO Group III) steroid. It has been available on prescription world-wide for many years for treating various dermatological disorders including psoriasis vulgaris (14, 15, 16). Like other corticosteroids it exerts its effect by suppressing various components of the inflammatory reaction of the disease. Betamethasone dipropionate has been shown to have metabolic and toxicological effects typical of corticosteroids. The safety profile of betamethasone dipropionate is well estab-lished and an extensive clinical database demonstrates that it is a safe product for topical treatment of psoriasis. Adverse events with topical corticosteroids are generally local and include itching, skin atrophy and striae of the skin. Excessive and prolonged use may result in suppression of the Hypothalamic-Pituitary-Adrenal (HPA) axis which is generally reversible. Calcipotriol plus betamethasone dipropionate) gel/topical suspension The gel/topical suspension formulation containing calcipotriol 50 mcg/g (as hydrate) and betamethasone 0.5 mg/g (as dipropionate) has been developed as an alternative to the ointment formulation (DAIVOBET/DOVOBET/TACLONEX) for topical treatment of psoriasis on the scalp and on the body. DAIVOBET/DOVOBET/TACLONEX ointment, which is approved for topical treatment of psoriasis vulgaris once daily, contains the same active substances (calcipotriol and be-tamethasone dipropionate) in the same concentration. As the strengths of calcipotriol and betamethasone dipropionate are identical in the two products the pharmacological and toxicological behaviour of the two well-established drug substances in DAIVOBET/DOVOBET gel is expected to be similar to that observed with DAIVOBET/DOVOBET ointment. Clinical knowledge of DAIVOBET/DOVOBET gel A phase 1 programme consisting of seven studies on local tolerability and systemic safety of DAIVOBET/DOVOBET gel has been finalised. In summary, the studies showed that DAIVOBET/DOVOBET gel was not phototoxic or irritant. No sensitisation or photo allergic potential was identified. The atrophogenic potential of betamethasone dipropionate in DAIVOBET/DOVOBET gel was not statistically significantly different from a marketed potent (WHO group III) corticosteroid, DIPROSONE ointment. When

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DAIVOBET/DOVOBET gel was applied to extensive psoriasis on the scalp concomitant with application of DAIVOBET/DOVOBET ointment to extensive psoriasis on the non-scalp regions of the body (trunk and/or limbs) there was no effect on serum calcium but a possible weak effect on the HPA axis, consistent with some degree of systemic exposure to a potent steroid (as found with other topical products containing potent steroids). DAIVOBET/DOVOBET gel has been tested in six phase 2 and 3 studies in scalp psoriasis (17, 18, 19, 20, 21, 22) and two clinical studies in subjects with psoriasis on the non-scalp regions of the body (trunk and/or limbs) (23, 24). The results from these clinical studies showed that DAIVOBET/DOVOBET gel is statistically significantly more effective than monotherapy with betamethasone dipropionate in the gel vehicle, calcipotriol (in the gel vehicle or as the marketed scalp solution) and the gel vehicle alone when used to treat psoriasis vulgaris on the body and the scalp. When compared with a marketed comparator product in a phase 3 study in psoriasis vulgaris on the body, results also show that DAIVOBET/DOVOBET gel was statistically significantly more effective compared with the topical suspension vehicle and tacalcitol ointment and had a significantly lower incidence of adverse drug reactions (ADRs) and lesional/perilesional AEs (24). DAIVOBET/DOVOBET gel was approved for use in scalp psoriasis in the US in May 2008 under the trade name TACLONEX SCALP Topical Suspension and was later approved within the EU in September 2008 and in Canada in November 2008 under the trade name XAMIOL gel. In addition the indication of the combination gel was extended to include treatment of non-scalp areas in the EU in July 2009 under the trade names DAIVOBET/DOVOBET gel. The gel (topical suspension) formulation A study of subject preference for topical psoriasis formulations (gel, cream or ointment) has provided data on the immediate response when placebo formulations were applied to psoriatic skin (25). Overall, 93% of subjects found the gel easy to apply, as compared to 85% for the cream and 84% for the ointment. The subjects also reported that the gel required the least effort to apply and was equal to the cream in terms of the time required to apply, whereas the ointment was preferred less for these criteria. For those criteria relating to the cosmetic properties of the formulation such as greasiness and the perceived rate of absorp-tion, the subjects ranked the cream first, the gel second with the ointment ranked third. In conclusion, the evidence suggests that the ease of use and cosmetic properties of cream and gel formulations are preferred by psoriasis patients over ointments (25). It is therefore

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expected that the majority of patients will find the gel formulation more cosmetically appealing and easier to use than the ointment formulation, which might increase adherence and thereby the real life treatment response.

7.3 TRIAL RATIONALE

Although originally developed for use on the scalp, DAIVOBET/DOVOBET gel has physical properties suitable for the treatment of psoriasis on non-scalp regions of the body (trunk and/or limbs) and may be a more cosmetically acceptable alternative to the ointment formulation which has been available for a number of years. Calcipotriol plus betamethasone dipropionate (DAIVOBET/DOVOBET/TACLONEX) ointment has proven highly effective in the treatment of psoriasis vulgaris on trunk and limbs with an improved benefit/safety profile compared to each active component used as mono-therapy. The assumption is that the same constituents (calcipotriol plus betamethasone dipropionate) combined in a topical suspension/gel vehicle would also be effective in the treatment of psoriasis vulgaris - a hypothesis supported by the results of a proof-of-concept study (23) and a phase 3 study in psoriasis vulgaris on non-scalp regions of the body (trunk and/or limbs) (24). Scientific rationale Calcipotriol exerts its effect on psoriasis by inhibiting cell proliferation, stimulating cell differentiation and suppressing components of the inflammatory response, thereby reversing the signs and symptoms associated with the disease. Betamethasone dipropionate exerts its effect on psoriasis by suppressing various components of the inflammatory response. Using calcipotriol and betamethasone dipropionate in combination has been shown to result in an additive effect in the treatment of psoriasis vulgaris on the trunk and limbs (26, 27, 28, 29). By simultaneous use of the two active components it is expected that betamethasone dipropionate counteracts the local skin irritation that calcipotriol exhibits in some subjects, thereby allowing calcipotriol to exert its beneficial effects. On the other hand calcipotriol may reduce the amount of corticosteroid required due to a possible additive effect and thus reduce the risk of steroid-related adverse effects. Combining the two compounds in a topical suspension/gel vehicle with favourable cosmetic properties might improve subject adherence as compared to a more greasy ointment vehicle.

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The proof-of-concept study in psoriasis vulgaris on non-scalp regions of the body (trunk and/or limbs) (23), was a randomised, double-blind, 4-arm parallel group study in which once daily DAIVOBET/DOVOBET gel was compared with vehicle gel and both its compo-nents (calcipotriol and betamethasone dipropionate) in the same gel formulation applied as monotherapy for 8 weeks. Subjects were randomised in a 4:2:2:1 ratio and the primary endpoint was ‘Controlled disease’ according to the Investigator’s global assessment of disease severity (IGA) at Weeks 4 and 8 (Last observation carried forward; LOCF). The percentages of subjects with ‘Controlled disease’ at Weeks 4 and 8 respectively were 16.0% and 27.2% for DAIVOBET/DOVOBET gel, 9.6% and 16.9% for betamethasone gel, 3.8% and 11.4% for calcipotriol gel and 2.5% and 0.0% for the gel vehicle. At Week 8, DAIVOBET/DOVOBET gel was statistically significantly more efficacious than all three treatment groups (P=0.006, P=0.027 and P<0.001 for calcipotriol gel, betamethasone gel and the gel vehicle, respectively). At Week 4, statistical significance was achieved versus calcipotriol gel and the gel vehicle (P=0.006 and P=0.027 respectively) but the comparison with betamethasone gel did not reach statistical significance (P=0.11). The percentage change in Psoriasis Area and Severity Index (PASI) from baseline to Weeks 4 and 8 (LOCF) were secondary endpoints. Similarly, DAIVOBET/DOVOBET gel was statistically signifi-cantly more efficacious than calcipotriol gel and the gel vehicle at both time points (P<0.001 for all comparisons). However statistical significance versus betamethasone gel was achieved at Week 4 (P=0.04) but not at Week 8 (P=0.13). A phase 3 study in psoriasis vulgaris on the body showed that DAIVOBET/DOVOBET gel was statistically significantly more effective and had a significantly lower incidence of adverse drug reactions (ADRs) and lesional/perilesional AEs resulting in a more favourable benefit/risk ratio compared with gel vehicle and tacalcitol ointment (24). For a fixed combination drug (30, 31) each component should make a contribution to the efficacy of the fixed combination and the combination should be safe and effective for a significant patient population requiring such concurrent therapy. The combination of calcipotriol and betamethasone dipropionate formulated in an ointment vehicle (the approved DAIVOBET/DOVOBET/TACLONEX ointment) has been shown to be superior to mono-therapy with calcipotriol or betamethasone formulated in the same ointment vehicle and to the ointment vehicle alone (28). DAIVOBET/DOVOBET gel (the approved XAMIOL gel /TACLONEX SCALP Topical Suspension) has been shown to be superior to monotherapy with calcipotriol or betamethasone formulated in the same gel vehicle and to the gel vehicle alone when treating scalp psoriasis (17, 18). Thus the use of calcipotriol and betamethasone

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dipropionate in combination has been approved in a different dosage form (ointment) and in a closely related disease variant (scalp psoriasis) (32). The proof-of concept study in subjects with psoriasis on non-scalp regions of the body (trunk and/or limbs), described previously, did confirm the consistent and highly significant efficacy of DAIVOBET/DOVOBET gel versus both calcipotriol in gel vehicle and the gel vehicle alone (23). This was shown for the two primary endpoints as well as for the secon-dary endpoints. However, the proof-of-concept study was not sufficiently powered to confirm the efficacy of DAIVOBET/DOVOBET gel versus betamethasone gel for both primary endpoints. Thus further data is required to confirm the efficacy of DAIVOBET/DOVOBET gel versus betamethasone gel. The purpose of the present study was to investigate the comparative efficacy of DAIVOBET/DOVOBET gel, the gel vehicle alone and the active components (calcipotriol and betamethasone dipropionate) in the gel vehicle in a larger phase 3 study in subjects with psoriasis vulgaris on non-scalp regions of the body (trunk and/or limbs). This will enable a more informed assessment of the benefit/risk ratio of DAIVOBET/DOVOBET gel in comparison to the betamethasone component of the gel, while providing further evidence for superiority of the combination product over calcipotriol and the vehicle alone as displayed in the phase 2 study.

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8 TRIAL OBJECTIVES

8.1 PRIMARY OBJECTIVE

To compare the efficacy of once daily treatment for up to 8 weeks of DAIVOBET/DOVOBET gel (calcipotriol 50 mcg/g plus betamethasone dipropionate 0.5 mg/g) with betamethasone gel (betamethasone 0.5 mg/g as dipropionate), calcipotriol gel (calcipotriol 50 mcg/g) and the gel vehicle alone in subjects with psoriasis vulgaris on the non-scalp regions of the body (trunk and/or limbs).

8.2 SECONDARY OBJECTIVES

To compare the safety of DAIVOBET/DOVOBET gel with betamethasone gel, calcipotriol gel and the gel vehicle alone in subjects with psoriasis vulgaris on the non-scalp regions of the body (trunk and/or limbs).

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9 INVESTIGATIONAL PLAN

The entire Clinical Study Protocol and any amendments are presented in Appendix 16.1.1 and the unique pages of the case report form (CRF) are presented in Appendix 16.1.2.

9.1 OVERALL TRIAL DESIGN AND PLAN - DESCRIPTION

TRIAL DESIGN

1. Overall Design A national, multi-centre, prospective, randomised, double-blind, 4-arm, parallel group, 8-week study in subjects with psoriasis vulgaris on the non-scalp regions of the body (trunk and/or limbs). The trunk and limbs included the arms (including hands) and/or trunk (including neck) and/or the legs (including buttocks and feet). The scalp, face, flexures and genitals were not treated with the investigational product or assessed as part of the efficacy analysis.

Subjects with mild or moderate disease severity (according to the IGA) were enrolled. Eligible subjects were randomised, using a central Interactive Web Response System (IWRS), to receive once daily treatment for up to 8 weeks with either: 1. DAIVOBET/DOVOBET gel (calcipotriol 50 mcg/g plus betamethasone 0.5 mg/g (as dipropionate) 2. Betamethasone 0.5 mg/g (as dipropionate) in the gel vehicle 3. Calcipotriol 50mcg/g in the gel vehicle 4. The gel vehicle alone The IWRS system stratified the randomisation of subjects according to baseline disease severity (mild:moderate) as determined by the IGA. Randomisation to treatment arms 1-4 took place in a 5:5:1:1 ratio within each stratum of baseline disease severity. 2. Individual Phases Washout phase Prior to randomisation, the subject entered a washout phase (if required) where anti-psoriatic treatments and other relevant medication were discontinued as defined by the exclusion criteria (see section 9.3.2). The washout was to ensure that no other treatment could interfere with the response to the investigational products obtained in the study. The duration of the

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washout period was limited for logistical reasons to a maximum of 4 weeks. The length of washout was up to 4 weeks depending on which treatment the subject was receiving. Some prohibited medications should not have been used for a period greater than the maximum 4 week duration of the washout period, therefore subjects were not eligible for the study if they had been recently treated with biologics other than etanercept that required more than a 4 week washout period (e.g., ustekinumab should not have been used for 4 months prior to commencing the study. Because the maximum washout was 4 weeks, the product should not have been used during the 3 months prior to eligibility consideration). Assessment of subject eligibility was made (following Informed Consent) at a Screening Visit, prior to commencing a washout period (see Figure 2). On completion of the washout period, confirmation of the subject’s ongoing eligibility for the study was made at Visit 1. Treatment Phase The treatment phase of the study started at Day 0 (Visit 1, baseline) when the subject was randomised to one of the four treatment groups. The treatment period was 56 days (8 weeks) and included six visits: Days 0, 7 (± 2), 14 (± 2), 28 (± 2), 42 (± 2) and 56 (± 2) (Visits 1-6). Subjects classified as ‘clear’ according to the IGA at any of Visits 2-5 were allowed to stop treatment at the (sub)investigator’s discretion. The subjects remained in the study and were to attend all scheduled visits. Investigational product was dispensed and they were advised to reinitiate treatment if required based on the subject’s own judgement, due to reappearance of psoriasis vulgaris on the treatment areas. More than one discontinuation/restart cycle was allowed. The subject was not allowed to discontinue treatment themselves between study visits. Study treatment was only stopped on the advice of the (sub)investigator at a sched-uled visit. Investigators were asked to comply with the scheduled visit days. The Week 4 and Week 8 dates were particularly important because these are the time points to be analysed for the primary endpoint. If the visit window of ± 2 days for any of the Visits 2 to 6 and/or Follow-up was not met, the investigator was to record the reason in the subject’s medical record. LEO did not need to be notified that a subject was outside the visit window. For the duration of the study, female subjects of childbearing potential were to agree to use a highly effective method of birth control. A highly effective method of birth control was defined as one which results in a low failure rate (less than 1% per year). Examples of those methods of birth control which are generally considered acceptable for use in clinical trials

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are detailed in the relevant inclusion criteria (1.10) and furthermore were provided to the subjects in the Subject Information Sheet. The subjects should have used the contraceptive method continually for at least 1 month prior to the pregnancy test, and continued using the contraceptive method for at least 1 week after the last application of study 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 liga-tion/section, hysterectomy or bilateral ovariectomy). Follow-up Phase A follow-up phase took place if there was an ongoing (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 follow-up visit/contact was conducted 14 (± 2) days after the last on-treatment visit, unless the final outcome of the event had been deter-mined before then. The follow-up visit was also performed if albumin-corrected serum calcium was above reference range at the last on-treatment visit or if any other laboratory parameter result was abnormal and judged as clinically significant at the last on treatment visit. The follow-up visit/contact was made either by telephone call or as a regular visit according to the investigator’s discretion, as applicable. Serious adverse events (SAEs) were followed up until final outcome, and details for follow-up requirements for SAEs in general are given in section 0.

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preferable. Thus subjects with severe and very severe disease were not included in the population to be studied. In addition, to ensure an equal distribution of the two disease severities in each of the treatment groups, subjects were stratified by disease severity (mild and moderate) prior to randomisation, see sections 9.7.2 and 9.4.3. Treatment duration The treatment duration of 8 weeks is considered appropriate to obtain sufficient data on the efficacy and safety of the evaluated investigational products. This treatment duration is based on the results of the phase 2, proof-of-concept study (23), which showed continuous improvement in the IGA of disease severity up to Week 8. This duration of treatment with the DAIVOBET/DOVOBET gel is further supported by the results obtained in the phase 3 comparator study (24). Furthermore, a treatment duration of 8 weeks has been shown to be safe and effective in several studies of DAIVOBET/DOVOBET gel used on the scalp (17, 18, 19, 20, 21, 22) and in a study of DAIVOBET/DOVOBET/TACLONEX ointment on the trunk and limbs (33). Subjects in whom the psoriasis was judged as clear according to the IGA at any of the on-treatment visits (2 – 5) were allowed to stop treatment at the investigator’s discretion. They were to continue in the study and attend all scheduled visits. The subjects had investigational product dispensed and were advised to restart treatment if required based on the subject’s own judgement, due to reappearance of psoriasis vulgaris on the treatment areas. More than one discontinuation /restart cycle was allowed up to Week 8 of the study. Study treatment should only have been stopped on the advice of the (sub)investigator at a scheduled visit, thus providing an assessment of the subject throughout the study up to Week 8. Dosing A once daily treatment regimen was chosen as this is considered more convenient for the subject and has shown to be effective in previous studies. It decreases drug exposure and time spent on application and is thus expected to enhance subject adherence. Assessments The IGA was chosen as the primary efficacy assessment. The IGA is a static skin scoring system, consisting of a six point scale from clear to very severe. The primary endpoint is subjects with ‘Controlled disease’ according to the IGA. ‘Con-trolled disease’ is defined as clear or almost clear for subjects with moderate disease at

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baseline and clear for subjects with mild disease at baseline. The percentage of subjects who achieve a disease status of clear and/or almost clear is regarded as the best evidence of efficacy (34). Comparison of the percentage of subjects with ‘Controlled disease’ between the treatment arms reflects the difference in the effect of the treatments. In order 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 PASI, used as a secondary response criterion, is a well established assessment that has been used in all previous studies of psoriasis on the trunk and/or limbs conducted by LEO. The PASI was included to enable comparison of results across several studies and to assess the development of response to treatment over time. To support the clinical decision-making when treating psoriasis patients, it is important to consider quality of life issues. Therefore, evaluation of quality of life (QoL) was included in this study by means of the Dermatology Life Quality Index (DLQI) questionnaire which is a validated dermatology specific questionnaire which measures specific factors influencing the quality of life for patients with skin disease. Subjects were invited to give assessment of their psoriasis by means of a global assessment of disease severity and an assessment of plaque discomfort. The patient assessment of plaque discomfort recorded changes in discomfort which comprises domains such as itching, stinging and burning which are secondary characteristics of the condition other than those primary domains measured in the PASI (redness, thickness and scaliness). Because of the potential effect of the vitamin D analogue containing investigational products on calcium metabolism and homeostasis, safety analysis of parameters of calcium metabolism were made following sampling of venous blood and urine collected at Day 0, Week 4 and Week 8 (or the last on-treatment visit as applicable). Concomitant treatments During the course of the study, subjects were prohibited from using any concomitant treatments that have a possible effect on the psoriasis on the trunk and/or limbs. This included various systemic treatments (e.g. systemic corticosteroids, retinoids, methotrexate, ciclosporin and other immunosuppressants and biological therapies).

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Topical treatments which might have a systemic effect on the psoriasis lesions on trunk and/or limbs if used to treat psoriasis or other skin conditions (e.g. eczema) in other locations were also disallowed (i.e. vitamin D analogues and class 1-5 corticosteroids on the face, flexures and scalp and prescription shampoos on the scalp). Treatment options for psoriasis or other dermatological disorders on the face, flexures and scalp were therefore limited to the immumomodulators such as tacrolimus or pimecrolimus or class 6 and 7 corticosteroids. 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 study and to allow use of the study medication up to the maximum recommended level. A stable concomitant treatment regimen (no start or change of dosage during the study) with drugs that have a potential effect on psoriasis (e.g., beta blockers, anti-malarials, angiotensin-converting enzyme, ACE, inhibitors and lithium) was allowed during the study. Although these drugs have a potential effect on psoriasis, they are not known to cause fluctuations in the disease severity and therefore should not affect the subject’s response to study medica-tion. Prior to randomisation, a washout period was completed if the patient was being treated, or had recently been treated with anti-psoriatic treatments or other relevant medication that could influence the outcome of the trial.

9.3 SELECTION OF TRIAL POPULATION

A total of 1152 subjects were to be enrolled in the study and randomised in a 5:5:1:1 ratio: 480 subjects in the DAIVOBET/DOVOBET gel treatment group, 480 subjects in the betamethasone gel treatment group, 96 in the calcipotriol gel treatment group and 96 in the gel vehicle alone group. Following receipt of verbal and written information about the trial, the subject provided signed and dated informed consent before any trial related activity was carried out, including activities relating to washout periods.

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Any implementation of national requirements/law for the trial subject’s participation in the clinical trial was ensured and was described in submission documentation to authori-ties/IRBs, as applicable.

9.3.1 Inclusion Criteria

1.1 Signed and dated informed consent was obtained prior to any trial related activities (including any washout period).

1.2 Aged 18 years or above. 1.3 Either sex. 1.4 Any race or ethnicity. 1.5 Attending a hospital outpatient clinic or the private practice of a board certified

dermatologist. 1.6 Clinical diagnosis of stable plaque psoriasis vulgaris of at least 6 months duration

involving the non-scalp regions of the body (trunk and/or limbs) amenable to treatment with a maximum of 100 g of topical medication per week.

1.7 An IGA of mild or moderate on the body (trunk and/or limbs) at Day 0 (Visit 1). 1.8 A minimum modified PASI score for extent of 2 in at least one body region (i.e.

psoriasis affecting at least 10% of arms, and/or 10% of trunk, and/or 10% of legs). 1.9 Females of childbearing potential had to have a negative pregnancy test at Day 0

(Visit 1). 1.10 Females of childbearing potential had to agree to use a highly effective method of birth

control during the study. A highly effective method of birth control was defined as one with a low failure rate (less than 1% per year) such as implants, injectables, com-bined oral contraceptives, some intra-uterine devices, sexual abstinence or vasec-tomised partner. The subjects must have used the contraceptive method continuously for at least 1 month prior to the pregnancy test, and must continue using the contracep-tive method for at least 1 week after the last application of study 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 liga-tion/section, hysterectomy or bilateral ovariectomy).

1.11 Able to communicate with the investigator and understand and comply with the requirements of the study.

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9.3.2 Exclusion Criteria

2.1 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 • adalimumab, alefacept, infliximab – within 2 months prior to randomisation • ustekinumab – within 4 months prior to randomisation • experimental products – within 4 weeks/5 half-lives (whichever was longer) prior

to randomisation. 2.2 Systemic treatment with all other therapies with a possible effect on psoriasis vulgaris

(e.g., corticosteroids, retinoids, methotrexate, ciclosporin and other immunosuppres-sants) within 4 weeks prior to randomisation.

2.3 PUVA or Grenz ray therapy within 4 weeks prior to randomisation.

2.4 UVB therapy within 2 weeks prior to randomisation.

2.5 Any topical treatment of the trunk and/or limbs (except for emollients) within 2 weeks prior to randomisation.

2.6 Topical treatment for other relevant skin disorders on the face and flexures (e.g., facial and flexural psoriasis, eczema) with class 1-5 corticosteroids or vitamin D analogues within 2 weeks prior to randomisation.

2.7 Topical treatment for other relevant skin disorders on the scalp (e.g. scalp psoriasis) with class 1-5 corticosteroids, vitamin D analogues or prescription shampoos within 2 weeks prior to randomisation.

2.8 Planned initiation of, or changes to, concomitant medication that could affect psoriasis vulgaris (e.g. beta blockers, anti-malarials, lithium, ACE inhibitors) during the study.

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

2.10 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 infections, skin manifestations in relation to syphilis or tuberculosis, rosacea, perioral dermatitis, acne vulgaris, atrophic skin, striae atrophicae, fragility of skin veins, ic-thyosis, acne rosacea, ulcers and wounds.

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

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

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

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2.14 Current participation in any other interventional clinical study.

2.15 Subjects who had received treatment with any non-marketed drug substance (i.e. an agent which had not yet been made available for clinical use following registration) within the 4-week period prior to randomisation or longer, if the class of substance re-quired a longer washout as defined above (e.g. biological treatments).

2.16 Planned excessive exposure to the sun during the study that could affect the psoriasis vulgaris.

2.17 Previously randomised in this study.

2.18 Females who were pregnant, have a positive pregnancy test at Day 0 (Visit 1), or were breast-feeding. Females of child-bearing potential wishing to become pregnant during the study, or not using an adequate method of contraception during the study.

9.3.3 Removal of Subjects from Therapy or Assessment

Subjects could leave the study for any of the following reasons: 1. Subject completed treatment according to the Clinical Study Protocol. 2. Unacceptable treatment efficacy: the investigator was free to withdraw the subject at any

time for medical reasons. 3. Unacceptable adverse events: any AE that the investigator or the subject considered

unacceptable. 4. Exclusion criteria: any exclusion criteria which emerged/became apparent during the

subject’s participation in the clinical trial. 5. Voluntary withdrawal: subjects were free to withdraw from the clinical trial at any time

and for any reason. 6. Other reasons: other reasons than stated above which required the subject to (be) with-

draw(n) were specified (see section 9.5.1.5). Subjects who were discovered, after enrolment/randomisation, not to have fulfilled all in/exclusion criteria at time of enrolment, were withdrawn from treatment unless the investigator, based on clinical and ethical evaluation, found withdrawal inappropriate. The final efficacy assessment (at the correct scheduled time) should, however, have been attempted to be completed for all subjects. Such deviation(s) from the (Consolidated)

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Clinical Study Protocol had to be reported to LEO (and IEC/IRB, as appropriate) and recorded in the Clinical Study Report. Subjects, who withdrew from treatment for any other reasons, should likewise, as a mini-mum, have been asked to complete the final efficacy assessment (at the correct scheduled time). Reasons for withdrawals were recorded in the CRF. Subjects withdrawn were not substituted.

9.4 TREATMENTS

9.4.1 Treatments Administered

Subjects were to receive one of the following treatments: 1. Calcipotriol 50 mcg/g plus betamethasone 0.5 mg/g (as dipropionate) gel

(DAIVOBET/DOVOBET gel ) 2. Betamethasone 0.5 mg/g (as dipropionate) in the gel vehicle 3. Calcipotriol 50mcg/g in the gel vehicle 4. The gel vehicle alone

9.4.2 Identity of Investigational Product(s)

Identity of DAIVOBET/DOVOBET gel

Finished product (brand) name (if avail-able)/name investigational product

DAIVOBET/DOVOBET gel

Formulation Gel/topical suspension

Active ingredient name/concentration Calcipotriol (as hydrate) 50 mcg/g Betamethasone (as dipropionate) 0.5 mg/g

Excipients Paraffin, liquid Polyoxypropylene-15-stearyl ether Castor oil (hydrogenated) Butylhydroxytoluene (E321) (added to Polyoxypropylene-15-Stearyl Ether by the

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supplier) All-rac-α-tocopherol (added to Paraffin liquid by the supplier)

Pack size(s) 50 g gel in 120 ml bottle

Manufacturer’s name of bulk medication (IP)

LEO Pharma A/S

Certifier’s name of bulk medication (IP) LEO Pharma A/S

Supplier’s name LEO Pharma A/S

Manufacturer’s name of subject treatment packages

Certifier’s name of subject treatment packages

Lot number/expiry date Jun 2012, Jun 2012

Identity of betamethasone gel


Betamethasone 0.5 mg/g (as dipropionate) in the gel vehicle


Active ingredient name/concentration Betamethasone (as dipropionate) 0.5 mg/g

Excipients Paraffin, liquid Polyoxypropylene-15-stearyl ether Castor oil (hydrogenated) Butylhydroxytoluene (E321) (added to Polyoxypropylene-15-Stearyl Ether by the supplier) All-rac-α-tocopherol (added to Paraffin liquid by the supplier)



LEO Pharma A/S



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Lot number (s)/expiry dates Jul 2012, Sep 2012

Identity of calcipotriol gel


Calciptriol 50 mcg/g in the gel vehicle


Active ingredient name/concentration Calcipotriol 50 mcg/g




LEO Pharma A/S





Lot number (s)/expiry dates Jul 2012

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Identity of gel vehicle


DAIVOBET/DOVOBET gel vehicle


Active ingredient name/concentration Not applicable




LEO Pharma A/S





Lot number (s)/expiry dates Jun 2012

9.4.3 Method of Assigning Subjects to Treatment Groups

Subjects who were found to comply with all the protocol’s inclusion and exclusion criteria were randomised to receive one of the four study treatments. Treatment was assigned via a central IWRS system in accordance with a pre-planned, computer generated randomisation schedule in a 5:5:1:1 ratio for treatment arms 1-4. Two separate randomization code lists were used, one for subjects with mild disease and one for subjects with moderate disease. In order to meet the assumption of a 1:3 ratio for mild:moderate for disease severity at baseline, a maximum of 30% was set for subjects with

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a mild disease and a maximum of 80% for subjects with a moderate disease. Thus, recruit-ment of subjects with mild or moderate disease would have been stopped if a total of 347 mild or 922 moderate subjects, respectively, were recruited. At Visit 1 (Day 0), once the subject’s eligibility was confirmed, the (sub)investigator was required to supply the IWRS system with the subject’s CRF Number and baseline disease severity (IGA). In return, the site was informed which randomisation number (corresponding to a subject treatment pack) should be assigned to the subject for the duration of the study. Each randomisation number was exclusive to a Subject Treatment Pack (STP) and deter-mined the treatment group to which a subject was assigned (the Randomisation Code Number and CRF Number are distinct from each other). The randomisation code lists were generated by the Clinical CRO. These files were not shared with LEO during the study, and were stored securely by the Clinical CRO, inaccessi-ble to staff involved with the conduct and administration of the clinical trial until the clinical trial was un-blinded. A hard copy was filed in a sealed envelope within the Clinical CRO Quality Assurance (QA) Department while the electronic version was saved on a separate server location which is inaccessible to all staff apart from the independent statistician.

9.4.4 Selection of Doses in the Trial

The concentrations of calcipotriol and betamethasone in DAIVOBET/DOVOBET (cal-cipotriol 50 mcg/g plus betamethasone 0.5 mg/g as dipropionate) are the same as in the approved DAIVOBET/DOVOBET/TACLONEX ointment. DAIVOBET/DOVOBET gel (the approved XAMIOL gel /TACLONEX SCALP Topical Suspension) has been shown to be superior to monotherapy with calcipotriol or betamethasone formulated in the same gel vehicle and to the gel vehicle alone when treating scalp psoriasis (17, 18). Also DAIVOBET/DOVOBET/TACLONEX ointment has been shown to be superior to monother-apy with calcipotriol or betamethasone formulated in the same ointment vehicle and to the ointment vehicle alone (28). Thus the use of calcipotriol and betamethasone dipropionate in combination has been approved in a different dosage form (ointment) and in a closely related disease variant (scalp psoriasis) (32).

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9.4.5 Selection and Timing of Dose for each Subject

A once daily treatment regimen was chosen as this is considered more convenient for the subject and has been shown to be effective in previous studies. It decreases drug exposure and time spent on application and is thus expected to enhance subject adherence.

9.4.6 Blinding

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 were expected which would reveal the identity of the individual treatment allocations. Consequently, it was expected that the subjects and the (sub)investigators would remain unaware of the individual treatment assignment during the conduct of the clinical trial. Emergency un-blinding of individual subject treatment could be made via the IWRS system. An emergency un-blinding request could be made only by the (sub)investigators and drug safety personnel (i.e., Global Pharmacovigilance at LEO Pharma A/S) [known collectively as requesters]. This functionality was controlled by the allocation of appropriate credentials by the IWRS CRO. Drug safety personnel were permitted to un-blind any subject on the study, while (sub)investigators access was limited to the subjects enrolled at their site. The requester needed to log into the IWRS system and provide the CRF Number (synony-mous with Subject Number) and/or Randomisation Code Number. The requester would then be prompted to provide the reason for un-blinding the individual subject. Upon confirming the reason the requester would enter their unique username and password. An email confirmation containing the following information would be automatically sent by the IWRS to the requester: • Protocol code number • Trial site code • Principal Investigator’s name • CRF book number • Subject’s date of birth • Subject’s gender • Un-blinding user name (requester) • Date/time of un-blinding (local) • Name of treatment

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• A note stating: Confidential note: The information transmitted in this communication is intended only for the person to whom it is addressed and contains confidential data.

Where the requester was the (sub)investigator, Global Pharmacovigilance at LEO Pharma A/S would be included as a recipient of the email confirmation. A back-up system which did not use on-line technology and that was fully validated against the randomisation code list was also implemented. The same principles as above would be used to provide un-blinding services, via a helpdesk, to those permitted requesters. Where emergency un-blinding was required for scenarios outside of the study conduct (i.e. the subject presented to an emergency room), this healthcare professional would be able to receive the treatment allocation of the subject by contacting the emergency contact numbers contained on the study card. The subject study card included a statement regarding the subject’s participation in the study and the allocated CRF Number and Randomisation Code Number. Un-blinding initiated by the investigator during the conduct of the clinical trial was only to be performed in an emergency situation where investigational product identification was considered necessary. In such an event the date and the reason for the un-blinding was recorded on the appropriate page of the CRF. If code break was considered necessary for other safety concerns, for example due to signals of important ADRs, un-blinding could be performed by Global Pharmacovigilance at LEO Pharma A/S, and the reason for un-blinding documented. For un-blinding of suspected, unexpected serious adverse reactions (SUSARS), see section 9.5.1.5. The clinical trial was un-blinded when a final validated database had been produced, the statistical analysis specified in the protocol had been reviewed in relation to the blinded data actually obtained and the Statistical Analysis Plan Update (SAPU) had been approved.

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9.4.7 Prior and Concomitant Therapy

Prior to the Study Treatment Phase Treatments requiring washout • Systemic treatment with biological therapies, whether marketed or not, with a potential

effect on psoriasis vulgaris (e.g. alefacept, etanercept, infliximab, adalimumab and ustekinumab (up to 4 months*, see exclusion criterion 2.1).

• 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 or Grenz ray therapy (4 weeks).

• UVB therapy (2 weeks).

• Topical anti-psoriatic treatment on the trunk and/or limbs (2 weeks)**. • Topical treatment with class 1-5*** corticosteroids on the face, flexures and scalp (2

weeks. • Topical treatment with vitamin D analogues on the face, flexures and scalp (2 weeks). • Use of prescription shampoos on the scalp (2 weeks). • Use of non-marketed Investigational Products (4 weeks). *) Note: duration of the washout phase should not have exceed 30 days **) Note: use of emollients was allowed on treatment areas during this 2-week period ***) Please see Appendix III of the study protocol (Appendix 16.1.1) for Potency Classifica-tion of Topical Corticosteroids During the Study Treatment Phase Concomitant treatment for conditions other than psoriasis vulgaris (with no potential effect on psoriasis vulgaris) could be continued throughout the trial without any change in dosage whenever possible. Use of concomitant treatment was recorded in the subject’s medical record and the CRF (treatment/drug name, dose, indication and dates of start and stop).

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Use of non-marketed/other investigational products was not permitted during the trial. Changes in doses (including starting) of drugs that, while not specifically indicated for treatment of the indication being studied, are known to have an effect (positive or negative) on the indication, were not permitted. This included, but was not limited to beta-blockers, anti-malarial drugs, lithium and ACE inhibitors. Inhaled steroids, bath oils and moisturising soaps were allowed during the study. Except for some topical treatments on the scalp, face and skin folds (see below), use of any drug except the investigational product for the treatment of psoriasis vulgaris was not allowed. Accordingly, only the following concomitant topical anti-psoriatic treatments were permitted during the study: Face, Flexures (Skin Folds) and Scalp • All topical medications were allowed except class 1 to 5 corticosteroids, vitamin D

analogues and prescription shampoos for the scalp. • Unlimited use of emollients was allowed.

9.4.8 Treatment Compliance

The Investigator was fully responsible for the investigational product at the trial site. Dispensing of trial medication may have been delegated to, e.g., a hospital pharmacy as locally applicable. The person responsible for dispensing the trial medication was responsible for maintaining adequate control of the investigational products and for documenting all transactions with them. Investigational products were to be stored in a safe and secure place, and proper dispensing arrangements were made. All investigational products supplied by the Clinical Trial Supplies Contract Research Organisation (CTS CRO) on behalf of LEO were returned to the CTS CRO and fully

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accounted for by the monitor with the help of the person responsible for dispensing the medication. Accountability was documented using drug accountability forms. Trial medication was returned from the trial site directly to the CTS CRO by the Clinical CRO responsible for the running the clinical trial. At each of Visits 1-5, investigational product was dispensed to the subjects. At Visits 2-6, the investigational products, including empty bottles, dispensed at the previous visit should have been returned by the subject. An inventory (Individual Drug Accountability Form) was kept of all trial medication given to and returned by each subject randomised in the trial. This inventory was made available for inspection during monitoring visits and was checked by the monitor to ensure correct dispensing of investigational product. All investigational product supplies returned to the CTS CRO were reconciled with the Individual Drug Accountability Forms. All returned bottles were subsequently weighed by the CTS CRO to determine the amount of investigational product used. At all on-treatment visits, the subject was asked if s/he has used the medication as prescribed. If this was not the case, the degree and nature of non-adherence was specified.

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9.5 EFFICACY AND SAFETY VARIABLES

9.5.1 Efficacy and Safety Measurements Assessed and Flow Chart

9.5.1.1 Flow Chart

Figure 2: Schedule/chart of trial procedures Visit SVa) 1 2 3 4 5 6 FU f) Week up to -4 0 1 2 4 6 8 10 Visit Window / Day up to −28 0 7 ±2 14 ±2 28 ±2 42 ±2 56 ±2 +14 ±2 Informed consent (x)b) xb) Inclusion / Exclusion criteria (x) x Demographics (x) x Physical examination (x) x Concomitant medication (x) x x x x x x x Concurrent diagnoses (x) x Pregnancy test x c) Biochemistry / urinalysis x h) x h) x g) h) x d) Randomisation x Investigator’s global assessment of disease severity (IGA)

x x x x x x

Investigator’s assessment of body surface area (BSA) involvement

x

Investigator’s assessment of extent and severity of clinical signs (PASI)

x x x x x x

Patient’s global assessment of disease severity

x x x x x x

Patient’s assessment of plaque discomfort x x x x x x Dermatology Life Quality Index (DLQI) – Quality of life questionnaire

x x x x g)

Dispensing of investigational product x x x x x Return of investigational product x x x x x Adherence x x x x x Adverse Event(s) x e) x x x x x x a) A washout period of up to 4 weeks had to be 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 had to be reviewed at a Screening Visit prior to commencing a washout, to asses if the subject was otherwise eligible. Such items had to be checked for any change in eligibility status at Visit 1 if a washout was completed.

b) Informed consent had to be signed both by subject and (sub)investigator before any study related procedures were carried out. For subjects requiring a washout period informed consent had to be completed prior to washout.

c) If female of childbearing potential. d) If albumin-corrected serum calcium was above the reference range at the last on-treatment visit, a follow up test was to be performed. e) AEs were to be collected from the date of signing the informed consent form i.e. during the washout period

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f) If an AE (serious or non-serious) classified as possibly or probably related to the study treatment or not assessable in relation to the study treatment was ongoing at the last on-treatment visit.

g) Assessment had to be made at the last on-treatment visit should the subject not complete all study visits. h) If a laboratory result was abnormal and judged as significant, the (sub)investigator had to follow-up as clinically appropriate (this could involve

requesting repeat samples)

9.5.1.2 Subject Eligibility

Subject’s eligibility for the clinical trial was to be checked according to the inclusion and exclusion criteria at visits specified in the flowchart (Figure 2). Subject’s demographic details and duration of psoriasis vulgaris were recorded. Demographic data Demographic data comprised: • Date of birth • Gender • Ethnic origin • Race. The subjects were asked to self-report their ethnicity (Hispanic or Latino, not Hispanic nor Latino) and race (Native American or Alaska Native, Asian, Black or African American, Native Hawaiian or Other Pacific Islander, White, Other). Skin type In addition, the skin type of the subjects was recorded using the following classification:

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

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Duration of psoriasis The duration of psoriasis vulgaris was to be recorded, to the nearest whole year. Medical History Concomitant medication and concurrent diagnoses were recorded. Physical Examination A routine medical examination was made. Any findings either prevented eligibility for the trial or were to be documented as concurrent diagnoses, as appropriate. Specifically, the following assessments were also to be made: • Weight (with indoor clothing and without shoes) • Height (without shoes) • Blood pressure (subjects in the sitting position with 5 minutes rest prior to measurement.

The same arm was to be used for all measurements).

9.5.1.3 Clinical Assessments

9.5.1.3.1 Investigator Assessments Definition of the body areas to be assessed The treatment areas which were to be assessed were the non-scalp regions of the body (trunk and/or limbs). The trunk and limbs included the arms (including hands) and/or trunk (including neck) and/or the legs (including buttocks and feet) The scalp, face, flexures and genitals 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 At all treatment phase visits (1 to 6) the (sub)investigator made a global assessment of the disease severity of the psoriasis on the trunk, arms and legs by use of the 6-point scale below. This assessment was to represent the average lesion severity on trunk, arm and legs. The assessment was to be based on the condition of the disease at the time of evaluation, and not in relation to the condition at a previous visit.

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Clear Plaque thickening = no elevation or thickening over normal skin

Scaling = no evidence of scaling Erythema = none (no residual red colouration but post-inflammatory hyperpigmentation may be present)

Almost clear Plaque thickening = none or possible thickening but difficult to ascertain whether there is a slight elevation above normal skin level Scaling = none or residual surface dryness and scaling Erythema = light pink colouration

Mild Plaque thickening = slight but definite elevation Scaling = fine scales partially or mostly covering lesions Erythema = light red colouration

Moderate Plaque thickening = moderate elevation with rounded or sloped edges Scaling = most lesions at least partially covered Erythema = definite red colouration

Severe Plaque thickening = marked elevation typically with hard or sharp edges Scaling = non-tenacious scale predominates, covering most or all of the lesions Erythema = very bright red colouration

Very severe Plaque thickening = very marked elevation typically with hard or sharp edges Scaling = thick tenacious scale covers most or all of the lesions Erythema = extreme red colouration; deep red colouration.

Subjects classified as clear at any of Visits 2-5 were allowed to stop the treatment at the (sub)investigator’s discretion. They were to remain in the study and attend all visits up to and including Week 8 (Visit 6). Although classified as clear, the subject was still to have study medication dispensed at each visit and was to restart treatment if required, based on their own judgement. More than one discontinuation/restart cycle was allowed. The subject was not allowed to discontinue treatment themselves between visits, but instead was only to stop using the treatment on the advice of the (sub)investigator at a scheduled visit.

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Investigator’s assessment of the extent and severity of clinical signs (Redness, Thick-ness, Scaliness) At all treatment phase visits (1 to 6) the (sub)investigator made an assessment of the extent and severity of clinical signs of the subject’s psoriasis using a modified PASI scoring system (excluding scalp, face and flexures), in terms of three clinical signs: redness, thickness and scaliness. The extent of psoriatic involvement was to be 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% 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 signs of redness, thickness and scaliness. For each clinical sign, a single score, reflecting the average severity of all psoriatic lesions on given body region, was to be determined accord-ing to the scale below: Redness 0 = none (no erythema) 1 = mild (faint erythema, pink to very light red) 2 = moderate (definite light red erythema) 3 = severe (dark red erythema) 4 = very severe (very dark red erythema). Thickness 0 = none (no plaque elevation) 1 = mild (slight, barely perceptible elevation) 2 = moderate (definite elevation but not thick) 3 = severe (definite elevation, thick plaque with sharp edge) 4 = very severe (very thick plaque with sharp edge).

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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 body surface area involvement of psoriasis vulgaris at baseline In order to obtain baseline data of psoriatic severity for all the subjects enrolled in the study, the (sub)investigator was also to assess the extent of the subject’s total psoriatic involvement at Day 0 (Visit 1). The total psoriatic involvement on the arms, legs and trunk was recorded as a percentage of the total body surface area (BSA), estimating that the surface of a full, flat palm (including the five digits) correlates to approximately 1% of the total BSA. The purpose of this was to obtain an estimate of the total area to be treated with study medication.

9.5.1.4 Subject Assessments

Patient’s global assessment of disease severity (PGA) This assessment was to be made at all treatment phase visits (1 to 6), based on the condition of the disease at the time of the evaluation and not in relation to the condition at a previous visit, using the scale below. The subject’s assessment was made prior to the investigator assessments. The (sub)investigator explained the categories of the scale to the subject and the subject was to tell the (sub)investigator which category to mark. Clear No psoriasis symptoms at all Very mild Very slight psoriasis symptoms, does not interfere with daily life Mild Slight psoriasis symptoms, interferes with daily life only occasionally Moderate Definite psoriasis symptoms, interferes with daily life frequently Severe Intense psoriasis symptoms, interferes or restricts daily life very fre-

quently.

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Patient’s assessment of plaque discomfort This assessment was to be made by the subject at all treatment phase visits (1 to 6), based on the level of discomfort felt on the psoriasis plaques. Discomfort comprised various compo-nents such as itching, stinging and burning. The assessment was to be based on the condition of the disease at the time of evaluation and used a validated visual analogue scale. This assessment was made prior to the IGA and used the subject’s mark on an arbitrary scale of 0 – 100 graduated in 10 unit intervals. Quality of Life Assessments The subject’s assessments of quality of life was performed at Day 0 (Visit 1 / Baseline) and at Week 2, Week 4 and Week 8 (Visits 2, 4 and 6 respectively) [or the last on-treatment visit as applicable] by means of the DLQI which is a validated dermatology specific question-naire. The questionnaire was to be completed by the subject while at the investigator site, before the subject had been assessed by the (sub)investigator.

9.5.1.5 Safety Assessments

9.5.1.5.1 Laboratory Analysis Samples for analysis of the parameters listed below were taken as scheduled in the flowchart (Figure 2) or on withdrawal from or early completion of the treatment phase of the clinical trial. A urine pregnancy test was performed locally at the trial site at Day 0 (Visit 1), prior to randomisation, in female subjects of child-bearing potential. The test kits were provided by the Central Laboratory. All other laboratory analysis was performed centrally. A sample of venous blood and a spot urine sample were taken at Day 0 (Visit 1 / Baseline) and at Week 4 and Week 8 (Visit 4 and visit 6, respectively). If at the last on-treatment visit the albumin-corrected serum calcium was above the reference range or if any other labora-tory parameter result was abnormal and judged as clinically significant, a follow-up visit was required for further sampling. The Central Laboratory provided the materials and instruc-tions necessary for the collections and transport of the samples. Biochemistry The following analysis was performed on the blood samples: Serum biochemisty: calcium, albumin, alkaline phosphatase (ALP), phosphate.

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Albumin-corrected serum calcium was calculated in mmol/L using the formula: serum calcium (total) in mmol/L + (0.02 x [40-serum albumin in g/L]). Plasma biochemistry: parathyroid hormone (PTH). Urinalysis The laboratory reported: calcium, phosphate and creatinine. Calcium:creatinine and phosphate:creatinine ratios were calculated. Review of laboratory results If any laboratory results were abnormal and judged as clinically significant, the (sub)investigator was to follow-up with the subject as clinically appropriate (this may 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 to be performed for repeat sampling. 9.5.1.5.2 Adverse Event (AE) An adverse event (AE) is any untoward medical occurrence in a subject or clinical investiga-tion occurring after the subject has signed the informed consent form. The AE does not necessarily have a causal relationship with the trial treatment or trial procedures. Conse-quently, AEs include ADRs, significant abnormal laboratory values and intercurrent diseases. A serious adverse event (SAE) is any untoward medical occurrence that • results in death • is life-threatening • requires inpatient hospitalisation or prolongation of existing hospitalisation • results in persistent or significant disability/incapacity or • 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 outcomes listed in the definition above. Examples of such events are allergic broncospasm, blood dyscrasias, and convulsions.

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Global Pharmacovigilance was responsible for the assessment of headquarter expectedness according to LEO procedures. The relevant reference document for this clinical trial was Investigator’s Brochure, edition 9 and subsequent updates as agreed between the Head of International Clinical Development and the Medical Director, Global Pharmacovigilance. 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, then “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 irritancy and AEs associated with the use of topical corticosteroids. Only medically qualified personnel assessed AEs. Reporting of Adverse Events Events reported by the subject, or observed by the (sub)investigator, that fell into any of the above definitions were to be recorded on the AE page of the CRF and described in the following manner: The nature of the event was to be described in precise, English medical terminology (i.e., not necessarily the exact words used by the subject). Whenever possible, a specific diagnosis had to be stated (e.g., allergic contact dermatitis). For cutaneous AEs the location was to be part of the AE description described as either: • lesional/perilesional (≤2 cm from the border of lesion(s) treated with investigational

product) or • distant (>2 cm from the lesion border).

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However, this was not captured in the CRF (see section 9.8 for details). 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: Probable: • 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. Possible: • Follows a reasonable temporal sequence from administration of the investigational

product • Could also be reasonably explained by the subject’s clinical state, environmental or toxic

factors or other therapies administered to the subject • Follows a known pattern of response to the investigational product. Not related: • Does not follow a reasonable temporal sequence from administration of the investiga-

tional product

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• Is better explained by other factor like the subject’s clinical state, environmental or toxic factors or other therapies administered to the subject

• Does not follow a known pattern of response to the investigational product. Not assessable: • The AE cannot be judged otherwise because the information is insufficient or contradic-

tory. All attempts to obtain more information have been in vain during the course of 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 was

to 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 was required until final outcome has been established.

• Not recovered/not resolved: Event is still ongoing. Follow-up on the event was required until final outcome has been 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 was to be recorded.

• Fatal: The subject has died as a consequence of the event. Date of death was recorded as stop date for the AE.

• Unknown: Unknown to investigator, e.g., subject lost to follow-up.

Once a subject had completed the trial, the investigator was to follow-up for outcome on all non-serious AEs classified as possibly/probably related to the investigational product or not assessable for 14 (±2) days or until final outcome was determined, whichever came first. 9.5.1.5.3 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 to be reported to LEO within one working day.

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Note: Planned hospitalisation or planned prolonged of hospitalisation did not fulfil the criteria for being an SAE. The elective nature of the event must have been clearly documented in the subject’s medical record.

All SAEs were to be reported on the AE form of the CRF book. Additionally reports were to be made using the paper SAE Form – Clinical Trial, supplied by LEO. Apart from the 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 had to contain a comprehen-sive narrative description of the course of the event. The completed SAE Form – Clinical Trial was to be faxed or scanned and emailed to both the Sponsor and the Clinical CRO: • Global Pharmacovigilance, LEO Pharma A/S.

•

All other relevant reports of diagnostic procedures, hospital records, autopsy reports etc. were to be included, as applicable or upon request from Global Pharmacovigilance. The IRB(s), regulatory authorities and concerned investigators were to be notified of SAEs according to current regulation and local requirements. All SUSARs were subject to expedited reporting to regulatory authorities. Global Pharma-covigilance was to unblind such cases prior to reporting. Investigators remained blinded. SAEs were to be followed indefinitely until a final outcome had been established i.e., the follow-up may have continued beyond the end of the clinical trial.

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9.5.1.5.4 Other Events to be Reported

Pregnancy Pregnancy, which occurred during a clinical trial with an investigational product, was to be reported to LEO within one working day of first knowledge using the Pregnancy Follow-up Form supplied by LEO. All pregnancies were to be followed-up until delivery or termination. 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 in the overdose were to be documented on a separate line. Aggravation of Condition Any clinically significant aggravation/exacerbation/worsening of the initially treated condi-tion compared to baseline, judged by an overall medical assessment, was to be reported as an AE.

9.5.2 Appropriateness of Measurements

The IGA of disease severity was chosen as the primary efficacy assessment because it is a well known assessment of psoriasis vulgaris that has been used widely in the clinical trial setting and is accepted as a standard by regulatory authorities. The IGA is a static skin scoring system, consisting of a six point scale from clear to very severe. In order 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 PASI, used as a secondary response criterion, is a well established assessment that has been used in all previous studies of psoriasis on the trunk and/or limbs 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. To support clinical decision-making when treating psoriasis patients, it is important to consider quality of life issues. Therefore, evaluation of QoL was included in this study by means of the DLQI questionnaire which is a validated dermatology specific questionnaire which measures specific factors influencing the quality of life for patients with skin disease.

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Subjects were invited to give assessment of their psoriasis by means of a global assessment of disease severity and an assessment of plaque discomfort. The patient assessment of plaque discomfort recorded changes in discomfort which comprised of domains such as itching, stinging and burning which are secondary characteristics of the condition other than those primary domains measured in the modified PASI (redness, thickness and scaliness). Because of the potential effect of the vitamin D analogue containing investigational products on calcium metabolism and homeostasis, the safety analysis included parameters of calcium metabolism following sampling of venous blood and urine collected at Day 0, Week 4 and Week 8 (or the last on-treatment visit as applicable).

9.5.3 Primary Efficacy Variable(s)

The primary endpoint was subjects with ‘Controlled disease’ according to the IGA. ‘Con-trolled disease’ is defined as clear or almost clear for subjects with moderate disease at baseline and clear for subjects with mild disease at baseline. The percentage of subjects who achieve a disease status of clear and/or almost clear is regarded as the best evidence of efficacy (34). Comparison of the percentage of subjects with ‘Controlled disease’ between the treatment arms will reflect the difference in the effect of the treatments.

9.5.4 Drug Concentration Measurements

Not applicable.

9.6 DATA QUALITY ASSURANCE

LEO has implemented a system of quality assurance, including all the elements described in this report. Within this system company Standard Operating Procedures (SOPs) are imple-mented to ensure that clinical studies are conducted in compliance with regulatory require-ments 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, six site audits were conducted. The audit certificate(s) are provided in Appen-dix 16.1.8.

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Data Handling LEO, as sponsor of this trial, is responsible to the authorities for assuring the proper conduct of the trial with regard to protocol adherence and validity of the data recorded on the CRFs. Monitors were assigned to serve as the principal link between (sub)investigators and LEO and to advise the investigators on the collection and maintenance of complete, legible, well organised, and easily retrievable data for the trial. In addition, they were to explain to the investigators any aspect of the (conduct of the) trial, including interpretation of the protocol, and purpose of collection of the specified data and reporting responsibilities to the investiga-tors. In this trial data were collected by means of Remote Data Capture. The investigator, or staff authorised by the investigator, were to enter subject data into an electronic CRF. A uniquely numbered CRF was used for each subject enrolled. Data recorded in the electronic CRF were accessible to site staff through a secure internet connection immediately after entry of data had taken place. The CRFs were to be maintained in an up-to-date condition at all times by the investigator. The investigator, or sub-investigator(s) authorised by the investigator, were to electronically sign all sections of CRFs used. This signature information (including date of signature) was kept in an audit trail and could not be altered. Only medically qualified (sub)investigators were to sign data on clinical assessments/safety. Any correction(s) to data in the CRF, made by the investigator or authorised site staff, after original entry, were documented in the audit trail. Changes to data already approved, required the re-signature of investigator or author-ised staff. The person making the change and the date, time and reason for the change were identified in the audit trail. Subject data were to be entered into the electronic CRF by authorised site staff in a timely manner. Data were to be entered by site staff and systematic data validation was performed through the discrepancy management system within the data collection software. Queries for discrepant data were generated either 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 electronic format. This systematic validation was made to ensure that a clean and consistent database was provided prior to the statistical analysis being performed.

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Data were and are handled in accordance with the general terms and conditions of the authorisation granted by the Danish Data Protection Agency to LEO Pharma A/S, as required, according to the Danish Personal Act and any national legislation implementing the Data Protection Directive (95/46/EC). LEO HQ is considered data responsible for all international clinical trials sponsored by LEO.

9.7 STATISTICAL METHODS PLANNED IN THE PROTOCOL AND DETERMINATION OF SAMPLE SIZE

9.7.1 Statistical and Analytical Plans

The statistical analysis was planned in the clinical study protocol and further detailed in the SAPU dated 28-JUN-2011. All subjects enrolled in the study (i.e. signed informed consent obtained and CRF book started) were to be accounted for. All randomised subjects were to be included in the full analysis set (intention-to-treat analysis set) and analysed for efficacy. All subjects who received any treatment with trial medication and for whom the presence or confirmed absence of AEs was available were included in the safety analysis set and analysed for safety. 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 trial medication throughout the treatment phase of the trial and/or who did not fulfil the disease defining inclusion criteria (i.e. inclusion criteria 1.6, 1.7 and 1.8 see section 9.3.1 ). Further exclusion of subjects or subject data were decided upon after the blind review of the data, reviewing all the remaining in- and exclusion criteria, but focusing on concomitant medication that may affect psoriasis and also considering adherence. The decisions regarding inclusion/exclusion of subjects and/or subject data from the trial analysis sets were documented in the SAPU before breaking the blind.

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9.7.1.1 Reasons for Leaving the Study

The reasons for leaving the study were presented for all randomised subjects and by treat-ment group.

9.7.1.2 Baseline Characteristics

Descriptive statistics of demographics and other baseline characteristics were presented for all randomised subjects and by treatment group, country and centre. Demographics included age, sex, race, ethnicity and skin type. Physical examination included weight, height and blood pressure. Other baseline characteristics included duration of psoriasis, concurrent diagnoses, concomitant medication, IGA, PASI (calculated from the investigator’s assessment of extent and severity of the clinical signs) and the investigator’s assessment of the 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.

9.7.1.3 Analysis of Efficacy

The statistical analysis of efficacy was based on the defined response criteria. 9.7.1.3.1 Primary Efficacy Criteria The primary response criteria 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 to be supportive. Two co-primary end points were defined: • Subjects with ‘Controlled disease’ according to the IGA at Week 4 • Subjects with ‘Controlled disease’ according to the IGA at Week 8 The analysis of the primary response criteria consisted of testing the following hypotheses at each time point (Week 4 and Week 8) using the Hochberg correction (35) to control for multiplicity in terms of testing two primary response criteria. In terms of testing three

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hypotheses for each response criterion, no adjustment for multiplicity was to be made, since no claims were to be made unless all three tests were significant. In clinical terms the hypotheses were as follows: 1. DAIVOBET/DOVOBET gel is superior to betamethasone gel with respect to the

percentage of subjects with ‘Controlled disease’ according to the IGA 2. DAIVOBET/DOVOBET gel is superior to calcipotriol gel with respect to the percentage

of subjects with ‘Controlled disease’ according to the IGA 3. DAIVOBET/DOVOBET gel is superior to vehicle gel with respect to the percentage of

subjects with ‘Controlled disease’ according to the IGA. In statistical terms the hypotheses tested and the alternatives were as follows: H01: µDAIVOBET/DOVOBET= µbetamathasone HA1: µDAIVOBET/DOVOBET ≠ µbetamethasone H02: µDAIVOBET/DOVOBET = µcalcipotriol HA2: µDAIVOBET/DOVOBET ≠ µcalcipotriol H03: µDAIVOBET/DOVOBET = µvehicle HA3: µDAIVOBET/DOVOBET ≠ µvehicle where µ is the odds of percentage Controlled disease to percentage non-controlled disease. The percentage of subjects who achieved ‘Controlled disease’ according to the IGA at Weeks 4 and 8 (both LOCF) were compared between DAIVOBET/DOVOBET gel and each of the other three treatments using the Cochran-Mantel-Haenszel test adjusting for the effect of (pooled) centre. Prior to this, an analysis of the effect of baseline IGA (stratum) on the odds as well as (pooled) centre effects was attempted. The Cochran-Mantel-Haenszel adjusted odds ratios (odds of ‘Controlled disease’ for DAIVOBET/DOVOBET gel relative to that for betamethasone, calcipotriol and vehicle gel), corresponding 95% confidence interval (CI) and p-values were calculated. The Breslow-Day test for homogeneity of the odds ratio across (pooled) centres was performed at a 10% level; if significant, a sensitivity analysis omitting centres with the smallest and highest odds ratios respectively was to be performed to identify possible extreme centres. To further describe the treatment by centre interaction, the centre specific odds ratios including CIs were estimated and listed in a table ranking from the lowest to the highest odds ratio. The percentage of subjects who achieved ‘Controlled disease’ at Weeks 4 and 8 were tabulated by treatment group, by centre and by country, by age group (≤35, 36-50, 51-64, ≥65 years), by sex, by ethnicity, by race, and by baseline disease severity according to the IGA. The number and percentage of subjects in each of the six categories (clear to very

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severe) was tabulated for each of the treatments pooling all centres together. These tabula-tions were intended for descriptive purposes only and no statistical analyses of these data were undertaken. 9.7.1.3.2 Secondary Efficacy Criteria The secondary efficacy response criteria were analysed at Week 4 and Week 8 for the full analysis set. The analyses were to use the Hochberg correction to account for multiplicity (35) using the same principles as described for the primary efficacy criteria. The 95% CIs may thus not reflect the conclusions of the analyses. The percentage change in PASI from baseline to Week 4 and 8, respectively were expected to be approximately normally distributed. Thus the treatment groups were compared using analysis of variance (ANOVA) including centre, baseline disease severity and treatment in the model as design variables. The presence of a treatment by centre interaction was tested but not included in the model. For each of the treatment comparisons, the difference (DAIVOBET/DOVOBET gel – betamethasone/calcipotriol/vehicle gel), its 95% CI and a p-value were calculated from the ANOVA. The analyses for the percentage change in PASI from baseline to Week 4 and 8 were also performed for the per-protocol analysis set. The percentage change in PASI from baseline to Week 4 and 8 was presented for each centre by treatment group. 9.7.1.3.3 Tertiary Response criteria Investigator’s global assessment of disease severity The percentage of subjects who achieved ‘Controlled disease’ according to the IGA was tabulated at Weeks 1, 2, 4, 6 and 8 by treatment group. The number and percentage of subjects in each of the six categories (clear to very severe) was tabulated for each of the treatments pooling all centres together. The percentage of subjects who achieved Controlled disease was tabulated at each visit for each of the treatments pooling all centres together. PASI The change in PASI (actual and percentage) from baseline to each visit was summarised as mean, median, SD, minimum and maximum for each of the treatments pooling all centres together.

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PASI 75 The percentage of subjects at each visit, who achieved at least 75% reduction in PASI from baseline, was tabulated for each of the treatments pooling all centres together. PASI 50 The percentage of subjects at each visit, who achieved at least 50% reduction in PASI from baseline, was tabulated for each of the treatments pooling all centres together. Patient’s global assessment of disease severity (PGA) The percentage of subjects who achieved ‘Controlled disease’ according to the patient’s global assessment of disease severity was tabulated at Weeks 1, 2, 4, 6 and 8 by treatment group. The number and percentage of subjects in each of the five categories (clear to severe) at each visit was tabulated for each of the treatments pooling all centres together. Patient’s assessment of plaque discomfort The change in discomfort score (actual) from baseline to each visit was summarised as mean, median, SD, minimum and maximum for each of the treatments pooling all centres together.

9.7.1.4 Analysis of Safety

The analysis of safety was based on the safety analysis set. 9.7.1.4.1 Adverse Events Any AEs were coded during the course of the trial in accordance with the current version of the MedDRA dictionary. The AEs were presented by Preferred Terms and Primary System Organ Class. All AEs recorded during the course of the study were included in the subject data listings. An event was considered emergent with the study treatment if started after the first applica-tion or if started before the first application (applicable if subject had a wash-out) and worsened in intensity after. The tabulations described in the following only included the AEs that were emergent with study treatment. The number of subjects experiencing each type of AE (according to MedDRA Preferred Terms within Primary System Organ Class) was tabulated by treatment group regardless of

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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. The causal relationship to trial medication for each type of AE (according to the coding system) was tabulated by treatment group. Where there were several recordings of causal relationship to trial medication 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 was when the investigator was in possession of most information and so best able to judge causal relationship. Where there were several recordings of intensity for a given type of AE, intensity was taken as the worst ever recording of that AE. Adverse drug reactions were defined as AEs for which the investigator had not described the causal relationship to trial medication as ‘not related’. The number of subjects experiencing each type of ADR was tabulated and compared by treatment group by the same principles as described for AEs. The intensity for each type of ADR was tabulated by treatment group. Serious adverse events were evaluated separately, and a narrative for each given. 9.7.1.4.2 Laboratory Safety Examinations For all serum biochemistry (calcium, albumin, phosphate, ALP and albumin-corrected serum calcium), plasma PTH and urinalysis (calcium, phosphate, creatinine, calcium:creatinine and phosphate:creatinine ratios) parameters, the absolute value by visit and the change from baseline (Day 0) to Week 4 and Week 8 (or the last on-treatment visit as applicable) was summarised. For the serum biochemistry parameters, the albumin-corrected serum calcium, and the urinary calcium:creatinine and phosphate:creatinine ratios, the values were to be categorised as ‘low’, ‘normal’ or ‘high’ depending on whether they were below, within or above the laboratory reference range, respectively. Shift tables were produced showing the categories at baseline (Day 0) against those at Week 4 and Week 8 (or the last on-treatment visit as applicable). The albumin-corrected serum calcium, phosphate, PTH, ALP, urinary cal-cium:creatinine ratio and phosphate creatinine were listed by visit for all subjects. Any values outside the reference range were flagged.

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9.7.1.5 General Principles

All significance tests were two-sided. In the analyses where centre was adjusted for, the validity of the statistical tests would depend on there being a sufficient number of subjects recruited in each treatment group at each centre. If this was not achieved in all centres, pooling of small centres could be done for analyses purposes. In order to avoid introducing bias through knowledge of study results, the pooling strategy was determined before the study was unblinded and is described below. The actual pooling of centres is described in the SAPU which was created after the blind review of data. For the treatment comparisons small centres, were pooled aiming at a minimum of 24 subjects. This was achieved by ordering all centres within a country with less than 24 subjects and then pairing the largest centre with the smallest centres until the size of the pooled centre was larger than or equal to 24. This was then repeated for the next-to-largest centre until all pooled centres had 24 or more subjects. In the case of a final centre (pooled or not) with less than 24 subjects, this was pooled with the smallest centre (pooled or not). All efficacy data was tabulated by visit using an observed cases approach (i.e. involving only those subjects who attended each specific visit). Last observation carried forward (LOCF) data at relevant visits was used for efficacy data that was statistically analysed (using the last non-missing value for subjects with missing data at a particular visit). As a supplement to the LOCF handling of missing data for the primary efficacy criterion, three sensitivity analyses were to be carried out: 1) all missing set to ‘Controlled disease’, 2) all missing set to ‘non-controlled disease’ and 3) all missing in the DAIVOBET/DOVOBET gel treatment group set to ‘non-controlled disease’ and in the other treatment groups set to ‘controlled disease’. Drop-outs and missing values were accounted for by the analysis of last observation values and by the definition of trial analysis sets prior to unblinding. The definition of methods to handle drop-outs and missing values could be refined, before breaking the randomisation code, by updating this aspect in the SAPU during the blind review of data actually obtained. All the analyses specified in the protocol were reviewed in relation to the blinded data actually obtained and the SAPU which was finalised before breaking the randomisation code.

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9.7.2 Determination of Sample Size

A total of 1152 subjects were to be enrolled in the study and randomised in a 5:5:1:1 ratio: 480 subjects in the DAIVOBET/DOVOBET gel treatment group, 480 subjects in the betamethasone gel treatment group, 96 in the calcipotriol gel treatment group and 96 in the gel vehicle alone group. In a phase 2 study with DAIVOBET/DOVOBET gel (23) with a design similar to the design of this study the following estimates were obtained: the percentage of subjects having ‘Controlled disease’ at Week 8 according to the IGA was approximately 30% in the DAIVOBET/DOVOBET gel group, 20% in the betamethasone gel group, 13% in the calcipotriol gel group and 0% in the group treated with the gel vehicle alone for subjects with mild or moderate disease severity at baseline. Likewise the estimates were 20%, 10%, 4.5% and 3% respectively at Week 4. With 480 subjects in the DAIVOBET/DOVOBET gel as well as betamethasone gel treatment groups, Fisher's exact test would have 90% power to reject the null hypothesis of no differ-ence between the two treatment groups regarding the primary response criterion, subjects with ‘Controlled disease’ according to the IGA at Week 8 and more than 90% power for the endpoint at Week 4. With 480 subjects in DAIVOBET/DOVOBET gel and betamethasone groups the sample size of the calcipotriol and the vehicle groups was fixed at 96. The test of no difference between the DAIVOBET/DOVOBET gel and the calcipotriol groups in the primary response criterion has a power of at least 89%. For comparison to the vehicle group the power has not been calculated, but is greater than 90% because the value of the primary response criterion is smaller. The sample size calculation assumed that the true percentages of subjects with ‘Controlled disease’ were the same as the observed percentages in the phase 2 study mentioned above and that a two-tailed significance level was used. A further assumption was that the ratio of mild:moderate (IGA) was approximately 1:3. Adjustment of the significance level to 0.025 was used in the calculations to adjust for multiplicity where the two co-primary end points of ‘Controlled disease’ at Week 4 and at Week 8 were tested independently (see section 9.7.1.3 for details about the primary analysis). Each centre was to recruit a minimum of 12 subjects. Due to the disproportionate allocation ratio, centres may have been pooled when comparing the DAIVOBET/DOVOBET gel group to either calcipotriol or vehicle groups to allow estimation of the odds ratio within pooled centres. No centres were allowed to recruit more than 100 subjects (approximately 10% of the total sample size).

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The sample size calculations were carried out using the Proc Power in SAS®, version 9.2.

9.8 CHANGES IN THE CONDUCT OF THE TRIAL OR PLANNED ANALYSES

The protocol was amended once and the changes were incorporated into the Consolidated Clinical Study Protocol dated 15-OCT-2010. The main change was to remove an incorrect number from the SAE section, which had no impact on the conduct of the trial or planned analyses. Some minor administrative corrections were also made during this amendment. Since AEs were not recorded in the CRF as lesional/perilesional or distant as described in the protocol, but as ‘in treatment area’ or ‘not in treatment area’, AEs categorised as ‘in treatment area’ were tabulated rather than ‘lesional/perilesional AEs’. The category of ‘not assessable’ was not included on the CRF for AE causality so it was not possible for any AEs to have this causality recorded. On 22-MAR-2011, the Sponsor became aware that all subjects at site had been unblinded and 144 data points had been altered. The unblinding occurred after the source data for the last visit had been obtained for all subjects randomised at the site except one. This subject ( ) had the last visit 3 days after the unblinding occurred and the data recorded at the clinic for this visit was therefore excluded from the analyses. The data points that were altered in connection with the unblinding were recreated and 100% source data verified. Therefore all data recorded from the site, except for the last visit of Subject

, were considered valid. The analysis of data for the primary and secondary endpoints therefore consisted of the analysis originally planned but supplemented with a sensitivity analysis with site excluded. A figure of ‘Centre specific odds ratio including 95% CI ranked from lowest to highest – DAIVOBET/DOVOBET gel vs each of the other treatment’ was planned for the full analysis set. This figure is presented for DAIVOBET/DOVOBET gel versus betamethasone gel only because too few odds ratios were available for DAIVOBET/DOVOBET gel versus cal-cipotriol gel and the gel vehicle to give information on variation among sites. Furthermore, due to the wide range of odds ratios (0.018 to 88.2) this figure (Figure 6) shows the logarithm of the odds ratio and CIs.

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10 TRIAL POPULATION

10.1 DISPOSITION OF SUBJECTS

A total of 1423 subjects from 59 centres in the USA were enrolled into the study (i.e. informed consent form signed and CRF number assigned). Figure 3 summarises subject recruitment over time. The first subject’s first visit was on 27-SEP-2010 and the last subject’s last visit was on 29-MAR-2011 (Table 1). Hence the study had a duration of 26 weeks.

Figure 3: Subject recruitment: number of enrolled subjects vs time

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Table 1: Study period: enrolled subjects

Centre

Date of first subject visit

Date of last subject visit

Duration of

study (weeks)

11NOV2010 17MAR2011 18.0 13OCT2010 20JAN2011 14.1 15OCT2010 26JAN2011 14.7 06OCT2010 09FEB2011 18.0 14OCT2010 09MAR2011 20.9 29NOV2010 08FEB2011 10.1 07OCT2010 09MAR2011 21.9 12OCT2010 21MAR2011 22.9 29SEP2010 15MAR2011 23.9 16NOV2010 28MAR2011 18.9 29SEP2010 02MAR2011 22.0 11NOV2010 16MAR2011 17.9 27SEP2010 29MAR2011 26.1 29NOV2010 22MAR2011 16.1 07OCT2010 15FEB2011 18.7 15OCT2010 31JAN2011 15.4 17JAN2011 23MAR2011 9.3 13OCT2010 16MAR2011 22.0 05OCT2010 15FEB2011 19.0 16NOV2010 21MAR2011 17.9 12OCT2010 01MAR2011 20.0 12OCT2010 01MAR2011 20.0 19JAN2011 24MAR2011 9.1 08OCT2010 07MAR2011 21.4 04OCT2010 02FEB2011 17.3 04OCT2010 15MAR2011 23.1 12OCT2010 14MAR2011 21.9 07OCT2010 21MAR2011 23.6 29SEP2010 16FEB2011 20.0 13OCT2010 12JAN2011 13.0 17NOV2010 10MAR2011 16.1 11OCT2010 04MAR2011 20.6 18NOV2010 22MAR2011 17.7 19OCT2010 03MAR2011 19.3 26OCT2010 17MAR2011 20.3 04OCT2010 22MAR2011 24.1 25OCT2010 22MAR2011 21.1 15NOV2010 16FEB2011 13.3 29SEP2010 21MAR2011 24.7

06JUL11:15:29:27 LEO80185 G23 t01.doc Continued...

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Table 1: Study period: enrolled subjects, continued

Centre

Date of first subject visit

Date of last subject visit

Duration of

study (weeks)

11OCT2010 22MAR2011 23.1 18OCT2010 28MAR2011 23.0 22OCT2010 09MAR2011 19.7 28SEP2010 24MAR2011 25.3 07OCT2010 25JAN2011 15.7 14OCT2010 22MAR2011 22.7 08OCT2010 14MAR2011 22.4 12OCT2010 17MAR2011 22.3 11OCT2010 21MAR2011 23.0 15OCT2010 21MAR2011 22.4 16NOV2010 15MAR2011 17.0 15OCT2010 21MAR2011 22.4 17NOV2010 15FEB2011 12.9 30DEC2010 17MAR2011 11.0 23NOV2010 03FEB2011 10.3 13OCT2010 29MAR2011 23.9 13OCT2010 03FEB2011 16.1 11OCT2010 15FEB2011 18.1 22NOV2010 16MAR2011 16.3 11NOV2010 24MAR2011 19.0

All enrolled subjects 27SEP2010 29MAR2011 26.1 06JUL11:15:29:27 LEO80185 G23 t01.doc

A total of 1152 subjects were randomised in the study (Table 2). The treatment groups followed the 5:5:1:1 randomisation pattern, 482 subjects were randomised to DAIVOBET/DOVOBET gel, 479 to betamethasone gel, 96 to calcipotriol gel and 95 to the gel vehicle).

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Table 2: Subject enrolment and randomisation: enrolled subjects and randomised subjects Total number of subjects assigned treatment

Centre

Total number of subjects enrolled (n=1423)

Daivobet® gel(n=482)

Betamethasone gel

(n=479)

Calcipotriol gel

(n=96) Vehicle (n=95)

30 11 11 5 2 16 3 5 0 2 16 6 8 0 2 25 7 8 0 3 24 6 5 1 1 2 1 1 0 0 34 9 8 4 3 20 12 8 0 0 22 7 5 2 2 20 6 9 0 2 31 7 7 5 0 21 9 5 0 1 63 26 25 4 2 13 3 2 0 0 12 1 3 2 2 19 8 9 0 0 4 2 0 0 1 16 7 5 1 2 22 4 7 0 0 25 13 9 1 1 16 5 9 1 0 31 11 11 2 4 15 3 8 1 2 14 5 6 2 1 44 17 13 4 6 26 7 3 1 1 31 12 13 3 2 20 8 11 0 1 16 5 10 0 1 20 13 6 0 1 8 3 2 1 1 3 2 0 1 0 22 8 9 0 1 10 3 5 1 0 38 11 15 3 0 50 8 17 1 1 28 15 8 4 1 16 5 7 0 2 36 12 18 3 3 63 19 20 4 6 29 13 8 2 3

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Table 2: Subject enrolment and randomisation: enrolled subjects and randomised subjects, continued

Total number of subjects assigned treatment

Centre

Total number of subjects enrolled (n=1423)


Betamethasone gel

(n=479)

Calcipotriol gel


20 9 8 1 1 29 7 11 1 2 18 8 7 1 1 26 10 8 3 1 45 12 13 3 2 54 14 17 6 3 43 13 11 3 4 23 7 7 1 3 12 5 1 1 1 28 12 10 5 1 6 1 1 2 1 13 3 5 3 1 5 1 3 0 1 39 18 12 2 4 24 8 9 2 3 26 6 4 2 2 18 6 2 0 1 23 9 11 1 0

Total 1423 482 479 96 95 06JUL11:15:29:33 LEO80185 G23 t02.doc

Table 3 summarises the reasons for withdrawal. There were 132 subjects (11.5%) who withdrew from the study overall. The lowest rate of withdrawals was in the DAIVOBET/DOVOBET gel group where 38 subjects (7.9%) withdrew compared with 62 (12.9%) in the betamethasone gel group, 14 (14.6%) in the calcipotriol gel group and 18 (18.9%) in the gel vehicle group. The most common reason for withdrawal was ‘lost to follow-up; this was reported most frequently in gel vehicle group (9.5%) followed by the betamethasone gel group (6.3%) the calcipotriol gel group (4.2%) and the DAIVOBET/DOVOBET gel group (3.1%). ‘Unacceptable adverse events’ was also a common reason for withdrawal in the calcipotriol gel group, leading to the withdrawal of 4 subjects (4.2%). There were 3 withdrawals due to ‘Unacceptable adverse events’ each in the DAIVOBET/DOVOBET gel and betamethasone gel groups (0.6% each), and none in the gel vehicle group. ‘Unacceptable treatment efficacy’ was more common in the calcipotriol gel and gel vehicle groups (3.1% and 4.2%, respectively) than for the other treatments groups (0.6% each). It was noted that, 1 subject in the betamethasone gel group was recorded as withdrawing due to other reasons (developed guttate psoriasis), which was recorded as an AE.

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Table 3: Reasons for withdrawal: randomised subjects

All randomised subjects (n=1152)

Daivobet® gel (n=482)

Betamethasone gel (n=479)

Calcipotriol gel (n=96)

Vehicle (n=95)

Reason for disconti-nuance

Number of subjects

%

Number of subjects

%

Number of subjects

%

Number of subjects

%

Number of subjects

%

Unacceptable treat-ment efficacy

13 1.1 3 0.6 3 0.6 3 3.1 4 4.2

Unacceptable adverse event

10 0.9 3 0.6 3 0.6 4 4.2 0 0.0

Exclusion criteria emerging during study

6 0.5 4 0.8 2 0.4 0 0.0 0 0.0

Voluntary (and no other reason)

27 2.3 6 1.2 16 3.3 2 2.1 3 3.2

Lost to follow-up 58 5.0 15 3.1 30 6.3 4 4.2 9 9.5 Other reason(s)1,2,3,4 18 1.6 7 1.5 8 1.7 1 1.0 2 2.1 Total number of withdrawn subjects

132 11.5 38 7.9 62 12.9 14 14.6 18 18.9

Completers5 1020 88.5 444 92.1 417 87.1 82 85.4 77 81.1 22JUL11:14:14:37 LEO80185 G23 t03.doc

1) Other reasons: Investigator decision (subject ), Transportation problems (subjects and ), Clinically significant PTH levels at baseline (subject 2) and ), Work commitments (subjects and ), Pregnancy (subject ), Non-compliance (subjects , and ), 3) Personal reasons (subjects , and ), Schedule conflicts (subject ), Developed GUTTATE PSORIASIS (subject ), 4) Enrolled in error (subjects and ) 5) A completer is defined as a subject who had not withdrawn

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The reasons for withdrawal are summarised by last on-treatment visit for which data were recorded in Table 52. Figure 4 summarises visit attendance. See Appendix 16.2.1 for individual subject data on discontinued subjects (Listing 5) and actual study period (Listing 4). A subject index is available in Appendix 16.1.7 Listing 3 and individual data on the randomisation and treatment number is shown in Listing 2.

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10.2 PROTOCOL DEVIATIONS

Table 4 summarises the protocol deviations that lead to the exclusion of data from the per protocol analysis set. The most common protocol deviation was violation of visit windows (67 subjects) which accounted for the exclusion of some data from a similar percentage of subjects in all the treatment groups; 26 subjects (5.4%) in the DAIVOBET/DOVOBET gel group, 32 (6.7%) in the betamethasone gel group, 4 (4.2%) in the calcipotriol gel group and 5 (5.3%) in the gel vehicle group. The second most frequent protocol deviation was withdrawal after Visit 1 (25 subjects) which meant that no efficacy data post baseline were obtained. The percentage of subjects who had data excluded for this reason was higher in the betamethasone gel and gel vehicle groups (2.9% and 4.2% respectively) than in the DAIVOBET/DOVOBET gel and calcipotriol gel groups (1.2% and 1.0% respectively). The number of subjects who had protocol deviations at baseline and whose data were excluded was low (7 subjects who had baseline extent of clinical signs <10%, 5 who had disallowed medications and 1 with disallowed diagnosis at baseline). Section 11.1 gives more details of the protocol deviations that excluded subjects and visit data from the per protocol analysis set. Protocol deviations are listed in Appendix 16.2.2 Listing 6

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Table 4: Protocol deviations

All randomised

subjects (n=1152)

Daivobet® gel

(n=482)

Betamethasone gel

(n=479)

Calcipotriol gel

(n=96)

Vehicle (n=95)

Protocol deviation1

Number of subjects

%

Number of subjects

%

Number of subjects

%

Number of subjects

%

Number of subjects

%

Extent of all clinical signs <10% at baseline

7 0.6 3 0.6 2 0.4 2 2.1 0 0.0

Disallowed medication at baseline

5 0.4 4 0.8 1 0.2 0 0.0 0 0.0

Disallowed diagnosis at baseline

1 0.1 0 0.0 0 0.0 1 1.0 0 0.0

Withdrew after Visit 1

25 2.2 6 1.2 14 2.9 1 1.0 4 4.2

Non-adherence 4 0.3 1 0.2 3 0.6 0 0.0 0 0.0 Disallowed medication started after baseline

11 1.0 5 1.0 3 0.6 2 2.1 1 1.1

Other protocol violations

5 0.4 3 0.6 1 0.2 1 1.0 0 0.0

19AUG11:12:18:31 LEO80185 G23 t04.doc Continued...

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Table 4: Protocol deviations, continued

All randomised

subjects (n=1152)

Daivobet® gel

(n=482)

Betamethasone gel

(n=479)

Calcipotriol gel

(n=96)

Vehicle (n=95)

Protocol deviation1

Number of subjects

%

Number of subjects

%

Number of subjects

%

Number of subjects

%

Number of subjects

%

Violation of visit windows

67 5.8 26 5.4 32 6.7 4 4.2 5 5.3

Total number of deviations

125 48 56 11 10

Total number of subjects

123 10.7 47 9.8 55 11.5 11 11.5 10 10.5

19AUG11:12:18:31 LEO80185 G23 t04.doc

1) Only deviations that led to exclusion of data from the per protocol analysis are included in this table.

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provided efficacy data after start of treatment and who met the inclusion/exclusion criteria described in the protocol. Reasons for excluding subject data from the per protocol analysis set were: use of therapies or medicines not allowed, disallowed diagnoses and non-compliance, including violation of visit windows. Seven subjects ( , , , , ,

and ) did not have a minimum PASI score for extent of 2 in at least one body region (i.e. did not have psoriasis affecting at least 10% of arms or trunk or legs) at baseline. Five subjects ( , , , and

) had used disallowed medication and one subject ( ) had acne on the treatment area. These 13 subjects violated inclusion or exclusion criteria and were excluded from the per protocol analysis set. A total of 25 subjects (including who had used disallowed medication) withdrew after Visit 1 and did not contribute any efficacy data and were therefore excluded from the per protocol analysis set. Four subjects ( , , and ) missed more than 50% of the applications during the treatment period and were excluded from per protocol analysis set. Overall, 41 subjects were excluded from the per protocol analysis set. Subject data excluded from particular visits Due to emerging exclusion criteria regarding disallowed medication the following subjects had efficacy data excluded at some visits in the per protocol analysis • (Visit 6) • (Visits 3-6) • (Visit 4) • (Visits 5-6) • (Visits 5-6) • (Visit 4-5) • (Visit 5) • (Visit 6) • (Visits 5-6) • (Visit 6)

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• (Visits 3-6). Due to protocol violations the following subjects had efficacy data excluded at some visits from the per protocol analysis • (Visits 5-6), discontinued dosing at own discretion • (Visit 2), did not apply during the first week • (Visits 3-6), investigator recommended the subject not to use trial medica-

tion on the treatment area. Subject had the treatment kit of Subject between Visits 4 and 5, as the treatments were not the same for these subjects, data from Visit 4 and onwards for Subject

were excluded from the per protocol analysis. Subject had the wrong kit dispensed at Visit 5 and as the kit did not contain the same treatment as the subject had been randomised to, Visit 6 data were excluded from the per protocol analysis for subject . The medication pack number should have been dispensed to , but this subject was given two bottles from Visit 3 that had not been used and two from Visit 4. This does not exclude from the per protocol analysis set because the subject had sufficient correct medication available to treat the psoriasis. Visit windows After a review of the visit window violations it was decided that for Visit 4 (Week 4) a difference of ±5 days and for Visit 6 (Week 8) ±7 days would be allowed in the per protocol analysis because the efficacy data would still be clinically reliable. For the per protocol LOCF analyses, data were not excluded from subjects with early visits. This resulted in 997 subjects (95.3%) being inside the window and 49 subjects (4.7%) being outside the window at Visit 4. For Visit 6, the corresponding numbers were 998 (97.5%) inside and 26 subjects (2.5%) outside the window. See Appendix 16.2.3 Listing 7 for individual subject data on subjects and observations excluded from the analysis sets.

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11.2 DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS

Demographic and baseline characteristics, concurrent diagnoses and concomitant drug treatment are presented for all the randomised subjects. Table 5 summarises age. The overall mean age was similar among the treatment groups and was 48.7 (range 18 to 82) years in the DAIVOBET/DOVOBET gel group, 48.5 (range 19 to 88) years in the betamethasone gel group, 48.0 (range 18 to 82) years in the calcipotriol gel group and 49.4 (range 22 to 76) years in the gel vehicle group. The distribution of age was similar among the groups.

Table 5: Age: randomised subjects

Age(years)

All rando-

mised subjects (n=1152)

Daivobet® gel

(n=482)

Betamethasone

gel (n=479)

Calcipotriol

gel (n=96)

Vehicle (n=95)

Mean 48.6 48.7 48.5 48.0 49.4 SD 13.5 13.4 13.8 13.7 13.0 Median 49.0 49.0 50.0 48.0 49.0 Minimum 18 18 19 18 22 Maximum 88 82 88 82 76 Number 1152 482 479 96 95 06JUL11:15:29:08 LEO80185 G23 t05 age.doc

The distribution of sex is shown in Table 6. The overall distribution of sex was similar in all treatment groups and was consistent with the overall distribution of approximately 60% males and 40% females. The distributions of race and ethnicity are summarised in Table 7 and Table 8, respectively. Nearly all the subjects (89.1%) were White and self-reported Not Hispanic or Latino ethnicity (85.3%). Black or African American subjects accounted for 6.2% of randomised subjects and Asian subjects accounted for 2.6% of randomised subjects. American Indian or Alaska native subjects and native Hawaiian or other Pacific Islander subjects each accounted for only 0.3% of randomised subjects. The distributions of race and ethnicity were similar among the groups.

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Table 6: Sex: randomised subjects

All randomised

subjects (n=1152)

Daivobet® gel

(n=482)

Betamethasone gel

(n=479)

Calcipotriol gel

(n=96)

Vehicle (n=95)

Sex

Number of subjects

%

Number of subjects

%

Number of subjects

%

Number of subjects

%

Number of subjects

%

Male 690 59.9 284 58.9 286 59.7 60 62.5 60 63.2 Female 462 40.1 198 41.1 193 40.3 36 37.5 35 36.8 Total 1152 100.0 482 100.0 479 100.0 96 100.0 95 100.0 06JUL11:15:29:18 LEO80185 G23 t06 sex.doc

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Table 7: Race: randomised subjects

All randomised

subjects (n=1152)

Daivobet® gel

(n=482)

Betamethasone gel

(n=479)

Calcipotriol gel

(n=96)

Vehicle (n=95)

Race

Number of subjects

%

Number of subjects

%

Number of subjects

%

Number of subjects

%

Number of subjects

%

White 1027 89.1 435 90.2 425 88.7 83 86.5 84 88.4 Black or African American

71 6.2 27 5.6 28 5.8 9 9.4 7 7.4

Asian 30 2.6 11 2.3 15 3.1 1 1.0 3 3.2 American Indian or Alaska Native

4 0.3 2 0.4 1 0.2 1 1.0 0 0.0

Native Hawaiian or Other Pacific Islander

4 0.3 2 0.4 2 0.4 0 0.0 0 0.0

Other 16 1.4 5 1.0 8 1.7 2 2.1 1 1.1 Total 1152 100.0 482 100.0 479 100.0 96 100.0 95 100.0 06JUL11:15:29:43 LEO80185 G23 t07.doc

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Table 8: Ethnicity: randomised subjects

All randomised

subjects (n=1152)

Daivobet® gel

(n=482)

Betamethasone gel

(n=479)

Calcipotriol gel

(n=96)

Vehicle (n=95)

Ethnicity

Number of subjects

%

Number of subjects

%

Number of subjects

%

Number of subjects

%

Number of subjects

%

Hispanic or Latino 169 14.7 69 14.3 64 13.4 20 20.8 16 16.8 Not Hispanic or Latino

983 85.3 413 85.7 415 86.6 76 79.2 79 83.2

Total 1152 100.0 482 100.0 479 100.0 96 100.0 95 100.0 06JUL11:15:29:53 LEO80185 G23 t08.doc

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Skin type is shown in Table 9. Most subjects recorded skin types II (white; always burns easily; tans minimally) 27.7% of randomised subjects, III (white; burns moderately; tans gradually) 32.0% of randomised subjects or IV (white; burns minimally; always tans well) 23.3% of randomised subjects. The distribution of skin type was similar among the groups.

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Table 9: Skin type: randomised subjects

All randomised

subjects (n=1152)

Daivobet® gel

(n=482)

Betamethasone gel

(n=479)

Calcipotriol gel

(n=96)

Vehicle (n=95)

Skintype

Number of subjects

%

Number of subjects

%

Number of subjects

%

Number of subjects

%

Number of subjects

%

I 66 5.7 30 6.2 20 4.2 10 10.4 6 6.3 II 319 27.7 134 27.8 148 30.9 19 19.8 18 18.9 III 369 32.0 158 32.8 144 30.1 30 31.3 37 38.9 IV 268 23.3 109 22.6 117 24.4 21 21.9 21 22.1 V 82 7.1 33 6.8 29 6.1 13 13.5 7 7.4 VI 48 4.2 18 3.7 21 4.4 3 3.1 6 6.3 Total 1152 100.0 482 100.0 479 100.0 96 100.0 95 100.0 06JUL11:15:30:03 LEO80185 G23 t09.doc

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The duration of psoriasis vulgaris is shown in Table 10. The mean duration of psoriasis vulgaris was similar among treatment groups and was 17.8 (range 1 to 71) years in the DAIVOBET/DOVOBET gel group, 15.8 (range 1 to 63) years in the betamethasone gel group, 15.9 (range 1 to 56) years in the calcipotriol gel group, and 17.8 (range 1 to 60) years in the gel vehicle group.

Table 10: Duration of psoriasis vulgaris: randomised subjects

Duration (years)

All rando-


Daivobet® gel

(n=482)

Betamethasone

gel (n=479)

Calcipotriol

gel (n=96)

Vehicle (n=95)

Mean 16.8 17.8 15.8 15.9 17.8 SD 13.1 13.3 12.5 13.3 14.4 Median 14.0 15.0 12.0 10.5 13.0 Minimum 1 1 1 1 1 Maximum 71 71 63 56 60 Number 1152 482 479 96 95 06JUL11:15:30:13 LEO80185 G23 t10.doc

The disease severity (according to the IGA) at baseline is presented in Table 11, PASI at baseline in Table 12 and BSA involvement at baseline in Table 13. As stipulated in the protocol, all subjects had an IGA of mild or moderate disease on the body at baseline. The distribution of the IGA was similar among the four treatment groups. In each group, moder-ate disease severity accounted for approximately 78% of subjects. Overall the mean scores for the PASI were similar for the four groups although the mean score for the calcipotriol gel group was slightly higher 8.5 than for the other three groups (7.8 to 7.9). The mean baseline extent of psoriasis was similar among the four treatment groups; 12.3% of the BSA (range 2 to 90%) in the DAIVOBET/DOVOBET gel group, 12.2% (range 2 to 84%) in the be-tamethasone gel group, 12.6% in the calcipotriol gel group (range 1 to 60%) and 11.1% (range 2 to 40%) in the gel vehicle group.

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Table 11: Disease severity (IGA) at baseline: randomised subjects

All randomised

subjects (n=1152)

Daivobet® gel

(n=482)

Betamethasone gel

(n=479)

Calcipotriol gel

(n=96)

Vehicle (n=95)

IGA at baseline

Number of subjects

%

Number of subjects

%

Number of subjects

%

Number of subjects

%

Number of subjects

%

Mild 253 22.0 107 22.2 105 21.9 20 20.8 21 22.1 Moderate 899 78.0 375 77.8 374 78.1 76 79.2 74 77.9 Total 1152 100.0 482 100.0 479 100.0 96 100.0 95 100.0 06JUL11:15:30:23 LEO80185 G23 t11.doc

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Table 12: PASI at baseline: randomised subjects

PASI at baseline

All rando-


Daivobet® gel

(n=482)

Betamethasone

gel (n=479)

Calcipotriol

gel (n=96)

Vehicle (n=95)


The investigator’s assessment of clinical signs which are used for calculating the PASI score is given in Table 53.

Table 13: BSA involvement of psoriasis vulgaris at baseline: randomised subjects

BSA at baseline

All rando-


Daivobet® gel

(n=482)

Betamethasone

gel (n=479)

Calcipotriol

gel (n=96)

Vehicle (n=95)


Table 54 shows that the groups were balanced for weight, height and blood pressure at baseline. Table 55 summarises the concurrent diagnoses which includes the relevant medical history recorded at baseline and Table 56 summarises concomitant medication at baseline. The most common relevant medical history and concurrent diagnoses were surgical and medical procedures, followed by vascular disorders and metabolic and nutritional disorders. The distribution of concurrent diagnoses at baseline was considered similar across the four treatment groups. The most common concomitant medications at baseline were for the cardiovascular system, the alimentary tract and metabolism, and the nervous system. Apart from medications for the genitourinary system and sex hormones, which were twice as common in the gel vehicle group than in the other three groups, the use of concomitant medication at baseline was similar across the treatment groups.

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See Appendix 16.2.4 Listing 8 for individual subject demographic data and Listing 9 for data on physical examiniation. See Appendix 16.2.6 for individual subject data on the investiga-tor’s assessment of extent and severity of clinical signs (Listing 13) and IGA (Listing 14)

11.3 MEASUREMENT OF TREATMENT COMPLIANCE

Compliance with treatment instructions for the prescribed study medication is shown in Table 14 for the full analysis set and in Table 15 for the per protocol analysis set. Twenty-five subjects withdrew after Visit 1 and did not contribute compliance data. For the full analysis set, compliance data were available for 475 subjects in the DAIVOBET/DOVOBET gel group, 463 subjects in the betamethasone gel group, 94 subjects in the calcipotriol gel group and 91 subjects in the gel vehicle group. For two subjects in the betamethasone gel group and one each in the DAVOBET gel and calcipotriol gel groups, compliance was unknown although the subjects did not withdraw after Visit 1. During the study, 317 subjects (66.6%) in the DAIVOBET/DOVOBET gel group, 301 (64.7%) in the betamethasone gel group, 54 (56.8%) in the calcipotriol gel group, and 61 (67.0%) in the gel vehicle group applied the treatment as instructed and were fully compliant. A further 128 subjects (26.9%) in the DAIVOBET/DOVOBET gel group, 132 (28.4%) in the be-tamethasone gel group, 31 (32.6%) in the calcipotriol gel group, and 23 (25.3%) in the gel vehicle group missed 10% or less of applications. Thus, 445 (93.5%) in the DAIVOBET/DOVOBET gel group, 433 (93.1%) in the in the betamethasone gel group, 85 (89.5%) in the calcipotriol gel group, and 84 (92.3%) in the gel vehicle group either applied medication as instructed or missed 10% or less of applications. For the per protocol analysis set, 440 (93.8%) in the DAIVOBET/DOVOBET gel group, 430 (93.7%) in the betamethasone gel group, 82 (89.1%) in the calcipotriol gel group, and 84 (92.3%) in the gel vehicle group either applied medication as instructed or missed 10% or less of applications. See Appendix 16.2.5 for individual subject data on drug accountability (Listing 11) and adherence (Listing 12).

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Table 14: Adherence to treatment instructions over the total study period: full analysis set

Daivobet® gel

(n=482) Betamethasone gel

(n=479) Calcipotriol gel


Did subject miss any doses?1

Number of subjects

%

Number of subjects

%

Number of subjects

%

Number of subjects

%

No 317 66.6 301 64.7 54 56.8 61 67.0 Yes: <= 10% applica-tions missed

128 26.9 132 28.4 31 32.6 23 25.3

>10% and <=20% applications missed

19 4.0 18 3.9 5 5.3 6 6.6


6 1.3 7 1.5 2 2.1 1 1.1


3 0.6 2 0.4 1 1.1 0 0.0


1 0.2 0 0.0 1 1.1 0 0.0

>50% applications missed

1 0.2 3 0.6 0 0.0 0 0.0

Unknown 1 0.2 2 0.4 1 1.1 0 0.0 Total 476 100.0 465 100.0 95 100.0 91 100.0 22JUL11:10:56:34 LEO80185 G23 t14.doc

1) 25 subjects withdrawing after visit 1 do not contribute to this table

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Table 15: Adherence to treatment instructions over the total study period: per protocol analysis set

Daivobet® gel




Did subject miss any doses?

Number of subjects

%

Number of subjects

%

Number of subjects

%

Number of subjects

%

No 312 66.5 298 64.9 52 56.5 61 67.0 Yes: <= 10% applica-tions missed

128 27.3 132 28.8 30 32.6 23 25.3


19 4.1 18 3.9 5 5.4 6 6.6


5 1.1 7 1.5 2 2.2 1 1.1


3 0.6 2 0.4 1 1.1 0 0.0


1 0.2 0 0.0 1 1.1 0 0.0

Unknown 1 0.2 2 0.4 1 1.1 0 0.0 Total 469 100.0 459 100.0 92 100.0 91 100.0 20JUL11:11:53:43 LEO80185 G23 t15.doc

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11.4 EFFICACY RESULTS AND TABULATION OF INDIVIDUAL SUBJECT DATA

11.4.1 Analysis of Efficacy

11.4.1.1 Primary Endpoint – Controlled Disease According to the Investigator’s Global Assessment of Disease Severity (IGA) at Weeks 4 and 8

The percentage of subjects with ‘Controlled disease’ at Week 4 (LOCF) is shown in Table 16 and at Week 8 (LOCF) in Table 17 for the full analysis set, in Table 18 and Table 19, respectively, for the full analysis set excluding centre and in Table 20 and Table 21 for the per protocol analysis set. For the full analysis set, the proportion of subjects who achieved ‘Controlled disease’ (according to the IGA) at Week 4 (LOCF) in the DAIVOBET/DOVOBET gel group was 13.3% compared with 12.5% in the betamethasone gel group, 5.2% in the calcipotriol gel group and 2.1% in the gel vehicle group. At Week 8 (LOCF), the corresponding numbers with ‘Controlled disease’ were: 29.0% in the DAIVOBET/DOVOBET gel group compared with 21.5% in the betamethasone gel group, 14.6% in the calcipotriol gel group and 6.3% in the gel vehicle group. The primary analysis was to test for superiority of DAIVOBET/DOVOBET gel versus betamethasone gel, calcipotriol gel and the gel vehicle using the full analysis set. To be considered superior, all three tests had to be statistically significant. At Week 4 (LOCF), DAIVOBET/DOVOBET gel was statistically significantly more effective than calcipotriol gel (OR 3.0; 95% CI: 1.1 to 7.6; p=0.019) and the gel vehicle (OR 8.4; 95% CI: 1.9 to 37.1; p=0.001) but not betamethasone gel (OR 1.0; 95% CI: 0.7 to 1.5; p=0.82) (Table 16). At Week 8 (LOCF), DAIVOBET/DOVOBET gel was statistically significantly more effective than betamethasone gel (OR 1.5; 95% CI: 1.1 to 2.0; p=0.008), calcipotriol gel (OR 2.8; 95% CI: 1.5 to 5.3; p=0.002) and the gel vehicle (OR 7.5; 95% CI: 3.0 to 18.8; p<0.001) (Table 17). At both timepoints, the analyses of the full analysis set excluding site supported these results (Table 18 and Table 19). Figure 6 presents the centre specific odds ratios for the full analysis set. This figure intended to present these data for all treatments but is presented for DAIVOBET/DOVOBET gel versus betamethasone gel only because too few odds ratios were available for DAIVOBET/DOVOBET gel versus calcipotriol gel and the gel vehicle.

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Figure 6: Centre specific odds ratio including 95% CI ranked from lowest to highest – DAIVOBET/DOVOBET gel vs betamethasone gel: full analysis set Week 4

Week 8

Note: At Week 4, 13 centres had at least one treatment group without any responders (hence no OR was defined), compared with 3 centres at Week 8.

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The per protocol analysis set supported the results of the full analysis set at Week 8. As shown in Table 20 and Table 21, the proportion of subjects in the per protocol analysis set who achieved ‘Controlled disease’ (IGA) at Week 4 (LOCF) in the DAIVOBET/DOVOBET gel group was 12.4% compared with 12.9% in the betamethasone gel group, 5.4% in the calcipotriol gel group and 2.2% in the gel vehicle group. At Week 8 (LOCF), the correspond-ing numbers with ‘Controlled disease’ were: 29.2% in the DAIVOBET/DOVOBET gel group compared with 22.4% in the betamethasone gel group, 15.2% in the calcipotriol gel group and 6.6% in the gel vehicle group. In the per protocol analysis at Week 4 (LOCF), DAIVOBET/DOVOBET gel was statistically significantly more effective than the gel vehicle (OR 7.3; 95% CI: 1.7 to 32.0; p=0.003) but not betamethasone gel (OR 0.9; 95% CI: 0.6 to 1.4; p=0.71) or calcipotriol gel (OR 2.5; 95% CI: 1.0 to 6.5; p=0.053) . At Week 8 (LOCF), DAIVOBET/DOVOBET gel was statistically significantly more effective than betamethasone gel (OR 1.4; 95% CI: 1.1 to 1.9; p=0.020), calcipotriol gel (OR 2.7; 95% CI: 1.4 to 5.3; p=0.003) and the gel vehicle (OR 7.7; 95% CI: 3.0 to 19.7; p<0.001). For all of the above analyses, the Breslow-Day test to investigate the consistency of the response across centres was not statistically significant at the 10% level which means that no treatment by centre interactions were found indicating a consistent reponse among centres.

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Table 16: Percentage of subjects with ‘Controlled disease’ (IGA) at Week 4: full analysis set

Daivobet® gel




Controlled Disease

Number of subjects

%

Number of subjects

%

Number of subjects

%

Number of subjects

%

Controlled 64 13.3 60 12.5 5 5.2 2 2.1 Non-controlled 418 86.7 419 87.5 91 94.8 93 97.9 Total 482 100.0 479 100.0 96 100.0 95 100.0 Statistical analysis Difference (%) 0.8 8.1 11.2 95% CI -3.5 to 5.0 2.7 to 13.4 7.0 to 15.4 Odds ratio1 1.0 3.0 8.4 95% CI 0.7 to 1.5 1.1 to 7.6 1.9 to 37.1 CMH test p-value2 0.82 0.019 0.001 Breslow-Day test p-value3

0.65 0.43 0.96

15JUL11:13:32:10 LEO80185 G23 t16.doc

1) Cochran-Mantel-Haenszel odds ratio for Controlled disease (Daivobet gel relative to Betamethasone gel/Calcipotriol gel/Vehicle) adjusted for pooled centre 2) Cochran-Mantel-Haenszel test for the hypothesis of odds ratio equal to 1 3) Breslow-Day test for homogeneity of odds ratios across pooled centres

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Table 17: Percentage of subjects with ‘Controlled disease’ (IGA) at Week 8: full analysis set

Daivobet® gel




Controlled Disease

Number of subjects

%

Number of subjects

%

Number of subjects

%

Number of subjects

%

Controlled 140 29.0 103 21.5 14 14.6 6 6.3 Non-controlled 342 71.0 376 78.5 82 85.4 89 93.7 Total 482 100.0 479 100.0 96 100.0 95 100.0 Statistical analysis Difference (%) 7.5 14.5 22.7 95% CI 2.1 to 13.0 6.3 to 22.6 16.4 to 29.1 Odds ratio1 1.5 2.8 7.5 95% CI 1.1 to 2.0 1.5 to 5.3 3.0 to 18.8 CMH test p-value2 0.008 0.002 < 0.001 Breslow-Day test p-value3

0.56 0.94 0.98

15JUL11:13:32:00 LEO80185 G23 t17.doc


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Table 18: Percentage of subjects with ‘Controlled disease’ (IGA) at Week 4: full analysis set Site excluded

Daivobet® gel




Controlled Disease5

Number of subjects

%

Number of subjects

%

Number of subjects

%

Number of subjects

%


0.73 0.42 0.96

15JUL11:13:32:21 LEO80185 G23 t18.doc

1) Cochran-Mantel-Haenszel odds ratio for Controlled disease (Daivobet gel relative to Betamethasone gel/Calcipotriol gel/Vehicle) adjusted for pooled centre 2) Cochran-Mantel-Haenszel test for the hypothesis of odds ratio equal to 1 3) Breslow-Day test for homogeneity of odds ratios across pooled centres 4) Centre originally pooled with centre has not been pooled with other centres in this table

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Table 19: Percentage of subjects with ‘Controlled disease’ (IGA) at Week 8: full analysis set Site excluded

Daivobet® gel




Controlled Disease5

Number of subjects

%

Number of subjects

%

Number of subjects

%

Number of subjects

%


0.56 0.93 0.98

15JUL11:13:32:36 LEO80185 G23 t19.doc

1) Cochran-Mantel-Haenszel odds ratio for Controlled disease (Daivobet gel relative to Betamethasone gel/Calcipotriol gel/Vehicle) adjusted for pooled centre 2) Cochran-Mantel-Haenszel test for the hypothesis of odds ratio equal to 1 3) Breslow-Day test for homogeneity of odds ratios across pooled centres 4) Centre originally pooled with centre has not been pooled with other centres in this table

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Table 20: Percentage of subjects with ‘Controlled disease’ (IGA) at Week 4: per protocol analysis set

Daivobet® gel




Controlled Disease

Number of subjects

%

Number of subjects

%

Number of subjects

%

Number of subjects

%

Controlled 58 12.4 59 12.9 5 5.4 2 2.2 Non-controlled 411 87.6 400 87.1 87 94.6 89 97.8 Total 469 100.0 459 100.0 92 100.0 91 100.0 Statistical analysis Difference (%) -0.5 6.9 10.2 95% CI -4.8 to 3.8 1.4 to 12.4 5.9 to 14.4 Odds ratio1 0.9 2.5 7.3 95% CI 0.6 to 1.4 1.0 to 6.5 1.7 to 32.0 CMH test p-value2 0.71 0.053 0.003 Breslow-Day test p-value3

0.68 0.48 0.91

02AUG11:11:17:02 LEO80185 G23 t20.doc


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Table 21: Percentage of subjects with ‘Controlled disease’ (IGA) at Week 8: per protocol analysis set

Daivobet® gel




Controlled Disease

Number of subjects

%

Number of subjects

%

Number of subjects

%

Number of subjects

%


0.71 0.95 0.99

02AUG11:11:22:12 LEO80185 G23 t21.doc


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The percentage of subjects with ‘Controlled disease’ (IGA) at Weeks 1, 2, 4, 6 and 8 is shown in Table 22 and Figure 7. In each treatment group, the proportion of subjects with ‘Controlled disease’ increased as the study progressed; from 1.7% at Week 1 to 30.9% at Week 8 in the DAIVOBET/DOVOBET gel group, from 0.9% to 23.9% in the betamethasone gel group, from 1.1% to 17.1% in the calcipotriol gel group and from 0.0% to 7.8% in the gel vehicle group.

Figure 7: Percentage of subjects with “Controlled disease” (IGA) at weeks 1, 2, 4, 6 and 8: full analysis set

The percentage of subjects in each category is provided in Figure 8.

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Figure 8: Percentage of subjects in each IGA category at Weeks 1, 2, 4, 6 and 8: full analysis set

Three sensitivity analyses were performed, in the first, missing values were set to ‘Controlled disease’ for all treatments, in the second missing values were set to ‘Non-controlled disease’ for all treatments, and in the third missing values were set to ‘Non-controlled disease’ for DAIVOBET/DOVOBET gel and ‘Controlled disease’ for the other treatments. The results are summarised in Table 57, Table 58 and Table 59, respectively for Week 4, and in Table 60, Table 61 and Table 62 at Week 8. When all missing values were set to ‘Non-controlled disease’ the results supported those of the primary analysis. When all missing values were set to ‘Controlled disease’ there was no difference between DAIVOBET/DOVOBET gel and any of the other treatments at Week 4, and the only treatment comparison of statistical signifi-cance was between DAIVOBET/DOVOBET gel and gel vehicle at Week 8 (OR 1.8; 95% CI: 1.1, 3.1; p=0.024). Using the worst case scenario, when missing values were set to ‘Non-controlled disease’ for DAIVOBET/DOVOBET gel and ‘Controlled disease’ for the other treatments, the comparison between DAIVOBET/DOVOBET gel and betamethasone gel was significant in favour of betamethasone gel at Week 4 (OR 0.5; 95% CI: 0.4, 0.7, p<0.001) but there were no significant differences at Week 8.

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The percentages of subjects with ‘Controlled disease’ at Weeks 4 and 8 are summarised by sex in Table 65, by age group in Table 66, by ethnicity in Table 67, by race in Table 68 and by baseline IGA in Table 69. There was no pattern to suggest an effect of sex, race or ethnicity on the percentages of subjects with Controlled disease in the DAIVOBET/DOVOBET gel group. In the DAIVOBET/DOVOBET gel group, there was a higher percentage of subjects aged over 65 years with ‘Controlled disease’ than for the younger age groups (50.0% versus 23.6% to 30.7% at Week 8). In the DAIVOBET/DOVOBET gel and betamethasone gel groups, the percentage of subjects with ‘Controlled disease’ was approximately three times higher for those with moderate disease at baseline than for those with mild disease at baseline at both Weeks 4 and 8. However, for the calcipotriol gel and gel vehicle groups, there was no apparent difference in the percentage of subjects with ‘Controlled disease’ by baseline disease severity. The percentage of subjects in each IGA category at Weeks 1, 2, 4, 6 and 8 is summarised for the full analysis set in Table 70. See Appendix 16.2.6 for individual subject data on the IGA (Listing 14).

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Table 22: Percentage of subjects with ‘Controlled disease’ (IGA) at Weeks 1, 2, 4, 6 and 8: full analysis set

Daivobet® gel




Visit Controlled disease

Number of subjects

%

Number of subjects

%

Number of subjects

%

Number of subjects

%

Week 1 Controlled 8 1.7 4 0.9 1 1.1 0 0.0 Non-controlled 453 98.3 452 99.1 92 98.9 89 100.0 Total 461 100.0 456 100.0 93 100.0 89 100.0 Week 2 Controlled 31 6.7 21 4.7 1 1.1 1 1.1 Non-controlled 431 93.3 430 95.3 89 98.9 87 98.9 Total 462 100.0 451 100.0 90 100.0 88 100.0 Week 4 Controlled 63 14.1 60 13.9 5 5.9 2 2.4 Non-controlled 383 85.9 371 86.1 80 94.1 80 97.6 Total 446 100.0 431 100.0 85 100.0 82 100.0 Week 6 Controlled 105 23.7 79 18.8 11 13.6 3 3.7 Non-controlled 338 76.3 342 81.2 70 86.4 78 96.3 Total 443 100.0 421 100.0 81 100.0 81 100.0 15JUL11:13:33:10 LEO80185 G23 t22.doc Continued...

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Table 22: Percentage of subjects with ‘Controlled disease’ (IGA) at Weeks 1, 2, 4, 6 and 8: full analysis set, continued

Daivobet® gel




Visit Controlled disease

Number of subjects

%

Number of subjects

%

Number of subjects

%

Number of subjects

%

Week 8 Controlled 137 30.9 100 23.9 14 17.1 6 7.8 Non-controlled 306 69.1 318 76.1 68 82.9 71 92.2 Total 443 100.0 418 100.0 82 100.0 77 100.0 15JUL11:13:33:10 LEO80185 G23 t22.doc

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11.4.1.2 Secondary Endpoint - Percentage Change in PASI at Weeks 4 and 8

Percentage change in PASI from baseline is summarised at Week 4 (LOCF) in Table 23 and at Week 8 (LOCF) in Table 24 for the full analysis set, in Table 25 and Table 26, respectively, for the full analysis set excluding site and in Table 27 and Table 28 for the per protocol analysis set. For the full analysis set, the mean percentage change in PASI from baseline to Week 4 (LOCF) was -46.4 in the DAIVOBET/DOVOBET gel group, compared with -42.7 in the betamethasone gel group, -32.2 in the calcipotriol gel group and -17.4 in the gel vehicle group. The corresponding numbers at Week 8 (LOCF) were: -55.8 in the DAIVOBET/DOVOBET gel group, compared with -48.6 in the betamethasone gel group, -43.6 in the calcipotriol gel group and -20.9 in the gel vehicle group. Each of the three treatment comparisons versus DAIVOBET/DOVOBET gel were statisti-cally significant at both Weeks 4 and 8. At Week 4 (LOCF), DAIVOBET/DOVOBET gel was statistically significantly more effective than betamethasone gel (mean difference -3.9; 95% CI: -7.6 to -0.2; p=0.038), calcipotriol gel (mean difference -16.3; 95% CI: -22.7 to -9.8; p<0.001) and the gel vehicle (mean difference -28.9; 95% CI: -35.4 to -22.5; p<0.001). At Week 8 (LOCF), DAIVOBET/DOVOBET gel was statistically significantly more effective then betamethasone gel (mean difference -7.6; 95% CI: -12.1 to -3.1; p<0.001), calcipotriol gel (mean difference -14.9; 95% CI: -22.7 to -7.0; p<0.001) and the gel vehicle (mean difference -34.2; 95% CI: -42.0 to -26.4; p<0.001). At both timepoints, the analyses of the full analysis set excluding site supported these results. For the per protocol analysis set, the treatment comparison between DAIVOBET/DOVOBET gel and betamethasone gel was not statistically significant at Week 4 (LOCF) but at Week 8 (LOCF) the results sup-ported those of the full analysis set.

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Table 23: Mean Percentage change in PASI from baseline to Week 4: full analysis set

Percentage change in PASI




Vehicle (n=95)

Mean -46.4 -42.7 -32.2 -17.4 SD 30.2 29.4 27.3 36.8 Median -50.0 -42.6 -33.3 -16.7 Minimum -100 -100 -94 -98 Maximum 73 62 59 173 Number 482 479 96 95 Statistical analysis Difference1,2 -3.9 -16.3 -28.9 95% CI -7.6 to -0.2 -22.7 to -9.8 -35.4 to -22.5 P-value3 0.038 < 0.001 < 0.001 15JUL11:13:33:19 LEO80185 G23 t23.doc

1) Daivobet gel minus Betamethasone gel/Calcipotriol gel/Vehicle 2) Adjusted for the effect of centre and baseline disease severity 3) T-test for adjusted difference

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Table 24: Mean Percentage change in PASI from baseline to Week 8: full analysis set





Vehicle (n=95)

Mean -55.8 -48.6 -43.6 -20.9 SD 34.4 35.8 34.1 49.1 Median -63.0 -53.7 -45.9 -20.3 Minimum -100 -100 -100 -100 Maximum 73 83 59 173 Number 482 479 96 95 Statistical analysis Difference1,2 -7.6 -14.9 -34.2 95% CI -12.1 to -3.1 -22.7 to -7.0 -42.0 to -26.4 P-value3 < 0.001 < 0.001 < 0.001 15JUL11:13:33:29 LEO80185 G23 t24.doc


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Table 25: Mean Percentage change in PASI from baseline to Week 4: full analysis set site excluded

Percentage change in PASI4




Vehicle (n=93)

Mean -46.4 -42.9 -32.7 -19.7 SD 30.3 29.3 27.2 31.3 Median -50.0 -42.9 -33.3 -17.5 Minimum -100 -100 -94 -98 Maximum 73 62 59 93 Number 475 468 95 93 Statistical analysis Difference1,2 -3.9 -15.6 -26.8 95% CI -7.6 to -0.3 -22.0 to -9.3 -33.2 to -20.3 P-value3 0.036 < 0.001 < 0.001 15JUL11:13:33:39 LEO80185 G23 t25.doc

1) Daivobet gel minus Betamethasone gel/Calcipotriol gel/Vehicle 2) Adjusted for the effect of centre and baseline disease severity 3) T-test for adjusted difference 4) Centre originally pooled with centre has not been pooled with other centres in this table

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Table 26: Mean Percentage change in PASI from baseline to Week 8: full analysis set site excluded

Percentage change in PASI4




Vehicle (n=93)

Mean -56.2 -48.9 -44.1 -23.2 SD 34.0 35.4 33.9 45.3 Median -63.9 -53.9 -47.0 -21.0 Minimum -100 -100 -100 -100 Maximum 73 79 59 146 Number 475 468 95 93 Statistical analysis Difference1,2 -7.9 -14.7 -32.4 95% CI -12.3 to -3.4 -22.4 to -7.0 -40.1 to -24.6 P-value3 < 0.001 < 0.001 < 0.001 15JUL11:13:33:49 LEO80185 G23 t26.doc

1) Daivobet gel minus Betamethasone gel/Calcipotriol gel/Vehicle 2) Adjusted for the effect of centre and baseline disease severity 3) T-test for adjusted difference 4) Centre originally pooled with centre has not been pooled with other centres in this table

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Table 27: Mean Percentage change in PASI from baseline to Week 4: per protocol set





Vehicle (n=91)

Mean -46.7 -44.1 -34.0 -19.8 SD 29.3 28.2 25.8 31.8 Median -50.0 -42.9 -33.3 -18.2 Minimum -100 -100 -94 -98 Maximum 73 62 15 93 Number 469 459 92 91 Statistical analysis Difference1,2 -2.7 -15.0 -27.2 95% CI -6.3 to 0.9 -21.3 to -8.8 -33.5 to -21.0 P-value3 0.14 < 0.001 < 0.001 02AUG11:11:31:42 LEO80185 G23 t27.doc


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Table 28: Mean Percentage change in PASI from baseline to Week 8: per protocol set





Vehicle (n=91)

Mean -56.9 -50.6 -45.6 -21.5 SD 33.5 34.7 31.8 50.6 Median -64.7 -54.5 -47.1 -22.4 Minimum -100 -100 -100 -100 Maximum 73 83 29 186 Number 469 459 92 91 Statistical analysis Difference1,2 -6.7 -14.3 -35.5 95% CI -11.1 to -2.2 -22.1 to -6.6 -43.3 to -27.8 P-value3 0.003 < 0.001 < 0.001 02AUG11:11:41:16 LEO80185 G23 t28.doc


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The mean percentage change in PASI at Weeks 1, 2, 4, 6 and 8 is shown in Table 29 and Figure 9. In each active treatment group, the mean percentage change in PASI increased as the study progressed; from -23.0 at Week 1 to -58.9 at Week 8 in the DAIVOBET/DOVOBET gel group, from -22.0 to -52.8 in the betamethasone gel group, and from -17.8 to -49.5 in the calcipotriol gel group. In the gel vehicle group, the mean percentage change in PASI was similar at Weeks 1, 2, 4 and 6, ranging between -15.1 and -18.6 but was slightly greater at Week 8 (-25.0). Figure 10 shows actual change in PASI from baseline at each visit.

Figure 9: Summary of percentage change in PASI from baseline to weeks 1, 2, 4, 6 and 8: full analysis set

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Figure 10: Summary of mean absolute change in PASI from baseline to weeks 1, 2, 4, 6 and 8: full analysis set

The percentage of subjects with a 75% reduction in the PASI is summarised at Week 4 and 8 in Table 30 for the full analysis set. At each timepoint, the proportion of subjects with a 75% reduction in PASI was greater for the DAIVOBET/DOVOBET gel group than for the other treatments. At Week 4, 23.1% of subjects in the DAIVOBET/DOVOBET gel group had a reduction of 75% compared with 18.1% in the betamethasone gel group, 5.9% in the cal-cipotriol gel group and 2.4% in the gel vehicle group. At Week 8, the corresponding numbers were: 40.8% in the DAIVOBET/DOVOBET gel group compared with 34.9% in the be-tamethasone gel group, 20.7% in the calcipotriol gel group and 15.6% in the gel vehicle group. A similar pattern was observed for the percentage of subjects with a 50% reduction in the PASI (Table 31). At each timepoint, the proportion of subjects with a 50% reduction in PASI was greater for the DAIVOBET/DOVOBET gel group than for the other treatments. At Week 4, 53.6% of subjects in the DAIVOBET/DOVOBET gel group had a reduction of 50% compared with 46.2% in the betamethasone gel group, 31.8% in the calcipotriol gel group and 24.4% in the gel vehicle group. At Week 8, the corresponding numbers were: 67.1% in the

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DAIVOBET/DOVOBET gel group compared with 58.6% in the betamethasone gel group, 54.9% in the calcipotriol gel group and 33.8% in the gel vehicle group. Mean percentage change in PASI from baseline to Weeks 4 and 8 is summarised by centre in Table 71. Mean absolute change in PASI from baseline to Weeks 1, 2, 4, 6 and 8 is presented in Table 72. See Appendix 16.2.6 for individual subject data on the investigator’s assessment of extent and severity of clinical signs (Listing 13).

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Table 29: Mean Percentage change in PASI from baseline to Weeks 1, 2, 4, 6 and 8: full analysis set Visit Percentage change in PASI




Vehicle (n=95)

Week 1 Mean -23.0 -22.0 -17.8 -15.1 SD 23.5 21.9 19.0 21.3 Median -21.4 -20.0 -16.7 -8.3 Minimum -89 -100 -90 -80 Maximum 123 78 33 21 Number 461 456 93 89 Week 2 Mean -38.9 -35.1 -26.7 -17.7 SD 26.7 25.3 26.7 27.2 Median -37.5 -34.4 -27.9 -15.0 Minimum -100 -100 -90 -92 Maximum 123 38 59 93 Number 462 451 90 88 Week 4 Mean -48.6 -45.8 -35.3 -18.6 SD 29.2 28.7 25.6 38.9 Median -50.0 -45.7 -33.7 -19.1 Minimum -100 -100 -94 -98 Maximum 73 62 15 173 Number 446 431 85 82 15JUL11:13:34:19 LEO80185 G23 t29.doc Continued...

´

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Table 29: Mean Percentage change in PASI from baseline to Weeks 1, 2, 4, 6 and 8: full analysis set, continued Visit Percentage change in PASI




Vehicle (n=95)

Week 6 Mean -55.9 -50.4 -43.9 -16.4 SD 30.2 32.5 29.4 51.1 Median -60.8 -54.5 -46.2 -16.7 Minimum -100 -100 -100 -100 Maximum 71 70 29 186 Number 443 421 81 81 Week 8 Mean -58.9 -52.8 -49.5 -25.0 SD 32.4 34.7 30.9 50.0 Median -66.1 -58.8 -55.2 -29.2 Minimum -100 -100 -100 -100 Maximum 73 83 29 173 Number 444 418 82 77 15JUL11:13:34:19 LEO80185 G23 t29.doc

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Table 30: Percentage of subjects with PASI 75 at Weeks 4 and 8: full analysis set

Daivobet® gel




Visit PASI 75

Number of subjects

%

Number of subjects

%

Number of subjects

%

Number of subjects

%

Week 4 >= 75% PASI reduction

103 23.1 78 18.1 5 5.9 2 2.4

< 75% PASI reduction

343 76.9 353 81.9 80 94.1 80 97.6

Total 446 100.0 431 100.0 85 100.0 82 100.0 Week 8 >= 75% PASI reduction

181 40.8 146 34.9 17 20.7 12 15.6


263 59.2 272 65.1 65 79.3 65 84.4

Total 444 100.0 418 100.0 82 100.0 77 100.0 15JUL11:13:34:29 LEO80185 G23 t30.doc

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Table 31: Percentage of subjects with PASI 50 at Weeks 4 and 8: full analysis set

Daivobet® gel




Visit PASI 50

Number of subjects

%

Number of subjects

%

Number of subjects

%

Number of subjects

%

Week 4 >= 50% PASI reduction

239 53.6 199 46.2 27 31.8 20 24.4


207 46.4 232 53.8 58 68.2 62 75.6

Total 446 100.0 431 100.0 85 100.0 82 100.0 Week 8 >= 50% PASI reduction

298 67.1 245 58.6 45 54.9 26 33.8


146 32.9 173 41.4 37 45.1 51 66.2

Total 444 100.0 418 100.0 82 100.0 77 100.0 15JUL11:13:34:39 LEO80185 G23 t31.doc

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11.4.1.3 Tertiary endpoints

11.4.1.3.1 DLQI The scores for the DLQI range between 0 and 30 and a reduction in the DQLI score indicates an improvement. The DLQI scores at baseline and Weeks 2, 4 and 8 are summarised in Table 76 and the changes in the DLQI scores are summarised in Table 32. At baseline, the scores were largely similar across all the groups and were between 9.8 in the betamethasone gel group and 11.6 in the calcipotriol gel group. At Weeks 2, 4 and 8, a greater improvement in DLQI was observed in the DAIVOBET/DOVOBET gel group compared with the other three treatment groups. At Week 8, the DAIVOBET/DOVOBET gel group had a mean change in score of -6.4 compared with -5.4 in the betamethasone gel group, -5.9 in the calcipotriol gel group and -2.7 in the gel vehicle group. See Appendix 16.2.6 for individual subject data on the DLQI (Listing 19)

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Table 32: Summary change in DLQI score at baseline at Weeks 2, 4 and 8: full analysis set Visit change in DLQI score




Vehicle (n=95)

Week 2 Mean -4.8 -4.1 -3.9 -1.9 SD 4.6 4.6 4.6 3.8 Median -4.0 -3.0 -3.0 -1.0 Minimum -26 -27 -16 -16 Maximum 9 9 5 12 Number 460 443 90 86 Week 4 Mean -5.8 -4.9 -5.1 -2.2 SD 5.2 4.9 6.0 4.4 Median -5.0 -4.0 -4.0 -2.0 Minimum -26 -27 -22 -12 Maximum 7 12 9 13 Number 444 431 86 82 Week 8 Mean -6.4 -5.4 -5.9 -2.7 SD 5.6 5.6 5.4 5.2 Median -5.0 -4.0 -5.0 -3.0 Minimum -26 -29 -21 -15 Maximum 8 11 4 12 Number 442 418 80 77 22JUL11:14:51:28 LEO80185 G23 t32.doc

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11.4.1.3.2 Patient’s Global Assessment of Disease Severity The percentage of subjects with ‘Controlled disease’ according to the Patient’s Global Assessment of disease severity (PGA) at Weeks 1, 2, 4, 6 and 8 is summarised for the full analysis set in Table 73 and in Figure 11. The definition of ‘Controlled disease’ for the PGA was clear or very mild disease. The percentage of subjects in each category is provided in Table 74. The proportion of subjects who achieved ‘Controlled disease’ (patient’s global assessment) was higher in the DAIVOBET/DOVOBET gel group than in the calcipotriol gel and gel vehicle groups throughout the study and similar to that in the betamethasone group until Week 6, afterwhich it was also higher than in the betamethasone gel group. The proportion of subjects who achieved ‘Controlled disease’ (patient’s global assessment) increased during the course of the study in all the treatment groups from Week 2 onwards. At Week 4, 35.4% of subjects in the DAIVOBET/DOVOBET gel group had ‘Controlled disease’ according to the patient’s global assessment, compared with 34.3% in the betamethasone gel group, 18.6% in the calcipotriol gel group and 15.9% in the gel vehicle group. At Week 8, these figures had increased to 47.6% of subjects in the DAIVOBET/DOVOBET gel group, 41.4% in the betamethasone gel group, 34.1% in the calcipotriol gel group and 20.8% in the gel vehicle group. See Appendix 16.2.6 for individual subject data on the patient’s global assessment (Listing 15)

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Figure 11: Percentage of subjects with ‘Controlled disease’ (PGA) at weeks 1, 2, 4, 6 and 8: full analysis set

11.4.1.3.3 Patient’s Assessment of Plaque Discomfort The change in plaque discomfort score from baseline to Week 1, 2, 4, 6 and 8 is summarised for the full analysis set in Table 75 and Figure 12. In each of the active treatment groups the plaque discomfort score decreased as the study progressed and the DAIVOBET/DOVOBET gel group was associated with the greatest decreases in scores from Week 2 onwards. The changes in mean scores ranged from -13.8 at Week 1 to -28.6 at Week 8 in the DAIVOBET/DOVOBET gel group, from -13.9 at Week 1 to -25.8 at Week 8 in the betamethasone gel group and from -6.1 at Week 1 to -18.8 at Week 8 in the calcipotriol gel group. In the gel vehicle group the changes in mean scores were smaller and generally similar throughout the study, ranging between -5.8 at Week 1 and -9.3 at Week 8. See Appendix 16.2.6 for individual subject data on the patients’s assessment of plaque discomfort (Listing 16)

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Figure 12: Summary of change in plaque discomfort score from baseline to Week 1, 2, 4, 6 and 8: full analysis set

11.4.2 Statistical/Analytical Issues

The analyses were conducted according to the protocol and the SAPU as summarised in section 9.7.1 and further changes as described in section 9.8.

11.4.2.1 Adjustments for Covariates

Not applicable.

11.4.2.2 Handling of Dropouts or Missing Data

For the co-primary endpoint and the secondary endpoint, percentage change in PASI, the statistical analysis was carried out using LOCF. This means that an IGA-value missing at Week 4 was imputed by the last non-missing IGA-value prior to Week 4. The same approach was used for Week 8.

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11.4.2.3 Interim Analyses and Data Monitoring

No interim analysis was planned nor performed.

11.4.2.4 Multi-site Clinical Trials

The centres with less than 24 subjects were sorted by descending number of subjects. The largest centre was combined with the smallest centre and this continued down the list. In the event of an uneven number of centres with less than 24 subjects, the middle centre was to be pooled with the smallest centre (pooled or not). This resulted in site being pooled with site

11.4.2.5 Multiple Comparison/multiplicity

For each comparison, the Hochberg correction for the p-values for the two endpoints means that the largest of the two p-values must be <5% for both to be statistically significant. If the largest p-value is ≥5% then the corresponding hypothesis cannot be rejected. If the smaller p-value is <2.5%, then it is statistically significant and the corresponding hypothesis is rejected, otherwise it cannot be rejected. This means that both p-values must be <5% for DAIVOBET/DOVOBET gel to be superior to the comparators at both Week 4 and Week 8. If DAIVOBET/DOVOBET gel is superior to all three comparators at Weeks 4 and 8, then superiority can be claimed for both timepoints. If statistical significance is obtained for all three comparators only at Week 4 or only at Week 8 only, then superiority can be claimed at for that timepoint only (i.e. only Week 4 or only Week 8).

11.4.2.6 Use of an “Efficacy Subset” of Subjects

Not applicable.

11.4.2.7 Active-control Studies Intended to Show Equivalence

Not applicable.

11.4.2.8 Examination of Subgroups

No subgroup analyses were planned nor performed but summaries are available by age, sex, race, ethnicity and baseline disease severity and are provided in Section 14.2.

11.4.3 Tabulation of Individual Response Data

Not applicable.

11.4.4 Drug Dose, Drug Concentration, and Relationships to Response

Not applicable.

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11.4.5 Drug-Drug and Drug-Disease Interactions

Not applicable.

11.4.6 By-Subject Displays

Not applicable.

11.4.7 Efficacy Conclusions

The primary endpoint, analysis of the proportion of subjects who achieved ‘Controlled disease’ according to the IGA at Week 8 (LOCF) showed that DAIVOBET/DOVOBET gel was superior to betamethasone gel, calcipotriol gel and the gel vehicle (p≤0.008). The proportion of subjects who achieved ‘Controlled disease’ was: 29.0% in the DAIVOBET/DOVOBET gel group compared with 21.5% in the betamethasone gel group, 14.6% in the calcipotriol gel group and 6.3% in the gel vehicle group. At Week 4 (LOCF) similar percentages of subjects had ‘Controlled disease’ in the DAIVOBET/DOVOBET gel group and in the betamethasone gel group, (13.3% and 12.5%, respectively, p=0.81). How-ever, the response rate for DAIVOBET/DOVOBET gel was statistically significantly higher than for calcipotriol gel (5.2%, p=0.019) and the gel vehicle group (2.1%, p=0.001). Due to the lack of statistical significance in the comparison with betamethasone, a formal claim of superiority could not be made at Week 4 for any of the three pair-wise comparisons. However, at Week 8, DAIVOBET/DOVOBET gel was confirmed as superior to each of the other three treatments. For the secondary endpoint, mean percentage change in PASI, DAIVOBET/DOVOBET gel was superior to betamethasone gel, calcipotriol gel and gel vehicle at both Week 4 (p≤0.038) and Week 8 (p<0.001). The mean percentage change in PASI from baseline to Week 4 (LOCF) was -46.4 in the DAIVOBET/DOVOBET gel group, compared with -42.7 in the betamethasone gel group, -32.2 in the calcipotriol gel group and -17.4 in the gel vehicle group. The corresponding numbers at Week 8 (LOCF) were: -55.8 In the DAIVOBET/DOVOBET gel group, compared with -48.6 in the betamethasone gel group, -43.6 in the calcipotriol gel group and -20.9 in the gel vehicle group.

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12 SAFETY EVALUATION

12.1 EXTENT OF EXPOSURE

For individual subject data on study medication used see Appendix 16.2.5 Listing 10. Subjects receiving IMP from specific batches where more than one batch was used are listed in Appendix 16.1.6 Listing 1. The duration and extent of exposure to treatment are summarised in Table 33 for the safety analysis set and the average amount of study medication used per week during the study is shown in Table 34. The mean duration of treatment was similar for all treatment groups (7.7 weeks for the DAIVOBET/DOVOBET gel group, 7.4 weeks for the betamethasone gel group, 7.2 weeks for the calcipotriol gel group and 7.1 weeks for the gel vehicle group). The overall extent of exposure (treatment weeks) was similar for the DAIVOBET/DOVOBET gel and be-tamethasone gel groups and markedly higher than for the calcipotriol gel and gel vehicle groups due to the randomization ratio used (5:5:1:1). Extent of exposure was 3688 subject treatment weeks for the DAIVOBET/DOVOBET gel group, 3556 subject treatment weeks for the betamethasone gel group, 687 subject treatment weeks for the calcipotriol gel group and 672 subject treatment weeks for the gel vehicle group. The mean amount of study medication used per week over the total treatment period was similar in the DAIVOBET/DOVOBET gel, betamethasone gel and gel vehicle groups (31.9 g, 27.7 g and 30.9 g respectively) but higher in the calcipotriol gel group (37.2 g). In all the groups the mean amount of study meducation used per week increased as the study pro-gressed. It must be noted that the amounts reflect actual use and include data from subjects who achieved ‘clear’ who were allowed to use the treatment ‘as needed’.

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Table 33: Duration and extent of exposure to treatment: safety analysis set

Duration (weeks)




Vehicle (n=95)

Mean 7.7 7.4 7.2 7.1 SD 1.7 2.1 2.2 2.7 Minimum 0.1 0.1 0.1 0.1 Maximum 11.3 12.7 9.0 13.7 Number1 482 479 96 95 Extent of exposure to treatment(subject-treatment-weeks)

3688 3556 687 672

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1) Two subjects received wrong trial medication during the study, subject from visit 4 and subject from visit 5.

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Table 34: Amount of study medication used between visits: safety analysis set Visit interval Trial medication used(g per week)1

Daivobet® gel

(n=482)

Betamethasone gel

(n=479)

Calcipotriol gel

(n=96)

Vehicle (n=95)

Visit 1 to Visit 2 (1 week) Mean 27.2 24.5 32.9 26.6 SD 23.8 22.7 24.4 25.5 Median 19.5 16.3 25.8 16.4 Minimum 0.7 0.0 3.0 2.0 Maximum 107.4 93.6 99.8 95.0 Number 432 434 85 82 Visit 2 to Visit 3 (1 week) Mean 28.9 25.4 35.5 28.2 SD 26.2 24.2 25.9 27.2 Median 19.8 16.4 28.5 15.3 Minimum 0.0 0.0 2.5 0.1 Maximum 130.9 106.6 110.4 95.6 Number 438 431 86 85 Visit 3 to Visit 4 (2 weeks) Mean 32.3 29.1 40.4 33.0 SD 26.2 25.0 27.7 27.1 Median 24.7 21.1 34.3 22.6 Minimum 0.0 0.0 0.0 1.8 Maximum 155.0 101.8 134.9 92.0 Number 426 405 79 77 Visit 4 to Visit 5 (2 weeks) Mean 32.7 30.4 41.2 32.4 SD 26.7 27.5 29.1 28.6 Median 25.9 21.2 38.1 22.8 Minimum 0.4 0.0 0.0 1.9 Maximum 124.9 157.4 154.1 103.4 Number 415 400 76 78 Visit 5 to Visit 6 (2 weeks) Mean 35.7 32.7 42.2 34.7 SD 30.4 27.9 33.2 33.3 Median 26.2 23.3 39.7 22.8 Minimum 0.0 0.0 0.0 1.7 Maximum 181.5 116.9 167.9 178.7 23AUG11:13:17:34 LEO80185 G23 t34.doc Continued...

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Table 34: Amount of study medication used between visits: safety analysis set, continued Visit interval Trial medication used(g per week)1

Daivobet® gel

(n=482)

Betamethasone gel

(n=479)

Calcipotriol gel

(n=96)

Vehicle (n=95)

Visit 5 to Visit 6 (2 weeks) Number 429 402 77 75 Visit 1 to End of Treatment (total treatment period) Mean 31.9 27.7 37.2 30.9 SD 24.2 22.5 23.9 25.9 Median 25.8 20.6 34.5 22.2 Minimum 1.0 0.7 1.1 1.9 Maximum 101.6 90.8 93.9 91.8 Number 396 376 73 77 23AUG11:13:17:34 LEO80185 G23 t34.doc


12.2 ADVERSE EVENTS

12.2.1 Brief Summary of Adverse Events

The incidence of AEs was generally similar for the four treatment groups. Overall 169 AEs were reported by 125 subjects (26.0%) in the DAIVOBET/DOVOBET gel group, compared with 144 AEs reported by 96 subjects (20.0%) in the betamethasone gel group, 28 AEs reported by 22 subjects (23.2%) in the calcipotriol gel group and 35 AEs reported by 22 subjects (23.2%) in the gel vehicle group.

12.2.2 Display of Adverse Events

The AEs at the preferred term level reported by ≥1% of subjects in any treatment group are summarised in Table 35 and all AEs reported are summarised at the system organ class level in Table 36. Table 77 presents all AEs by MedDRA system organ class and preferred term. Most commonly, AEs were: infections or infestations, skin and subcutaneous tissue disorders, or affected the investigations system organ class. These events were all reported at similar incidences across the treatments groups. Infections and infestations were the most common type of AE in each treatment group: reported for 13.3% of subjects in the DAIVOBET/DOVOBET gel group, 9.4% in the betamethasone gel group, 13.7% in the calcipotriol gel group and 9.5% in the gel vehicle

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group. The most common individual infection and infestation AEs in the DAIVOBET/DOVOBET gel group were nasopharyngitis, upper respiratory tract infection and sinusitis, which were reported by 2.9%, 2.9% and 2.1% of subjects, respectively. The incidence of each of these individual events was considered similar across the four groups. Skin and subcutaneous tissue disorders were the next most common types of AEs and were reported by 3.1% of subjects for the DAIVOBET/DOVOBET gel group, 2.5% in the be-tamethasone gel group, 4.2% in the calcipotriol gel group and 3.2% in the gel vehicle group. In the DAIVOBET/DOVOBET gel group, there was no individual AE reported at an inci-dence of ≥1%. The most common skin and subcutaneous tissue AE in the DAIVOBET/DOVOBET gel group was pruritus reported for 0.6% of subjects, the incidence of pruritus was 0.2% in the betamethasone gel group, 1.1% in the calcipotriol group and 2.1% in the gel vehicle group. Apart from rash, reported for 2 subjects (0.4%), all other skin and subcutaneous tissue AEs in the DAIVOBET/DOVOBET gel group were reported for only a single subject (0.2%). It must be noted that the incidence of the AE psoriasis was lower in the DAIVOBET/DOVOBET gel and betamethasone gel groups (0.2% and 0.2%, respectively) than in the calcipotriol gel and gel vehicle groups (1.1% and 1.1%, respectively). Adverse events coded to the investigations system organ class were reported by 3.1% of subjects in the DAIVOBET/DOVOBET gel group, 2.1% in the betamethasone gel group, 0% in the calcipotriol gel group and 2.1% in the gel vehicle group. These events were most commonly blood PTH increased, which was more common in the DAIVOBET/DOVOBET gel group than in the other groups, reported for 13 subjects (2.7%) in the DAIVOBET/DOVOBET gel group, 9 (1.9%) in the betamethasone gel group, 0% in the calcipotriol gel group and 1 (1.1%) in the gel vehicle group. For the subjects who reported AEs of blood parathyroid increased, the plasma PTH values as well as the corresponding albumin-corrected serum calcium values are listed below. Those AEs also considered to be related to study medication (ADRs) are shown in bold.

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Subject# Visit 1 Visit 4 Visit 6

PTH

(pmol/L)

Albumin corrected calcium (mmol/L)

PTH

(pmol/L)

Albumin corrected calcium

(mmol/L)

PTH

(pmol/L)

Albumin crrected calcium

(mmol/L)

DAIVOBET/DOVOBET gel

8.06 H 2.18 N 6.89 N 2.20 N 6.47 N 2.20 N

8.90 H 2.30 N 8.69 H 2.15 N 8.69 H 2.25 N

10.60 H 2.20 N 11.34 H 2.13 L 9.65 H 2.18 N

10.49 H 2.18 N 6.36 N 2.23 N 7.42 N 2.30 N

9.86 H 2.38 N 9.22 H 2.45 N 9.75 H 2.35 N

9.33 H 2.15 N 6.25 N 2.23 N 7.10 N 2.20 N

6.89 N 2.33 N 9.65 H 2.15 N 8.69 H 2.13 L

4.66 N 2.18 N 4.24 N 2.10 L 7.84 H 2.08 L

9.01 H 2.20 N 7.53 N 2.23 N 8.16 H 2.25 N

7.10 N 2.15 N 9.01 H 2.13 L 6.47 N 2.30 N

6.68 N 2.18 N 11.45 H 2.25 N 13.04 H 2.20 N

6.68 N 2.30 N 6.47 N 2.18 N 9.43 H 2.28 N

6.89 N 2.15 N 6.25 N 2.15 N 9.43 H 2.23 N

Betamethasone gel

10.39 H 2.13 L 9.12 H 2.23 N 11.55 H 2.18 N

11.55 H 2.30 N 10.71 H 10.28 H 2.18 N

8.59 H 2.13 L 5.09 N 2.28 N 3.71 N 2.33 N

3.50 N 2.35 N 7.84 H 2.20 N 7.53 N 2.15 N

6.47 N 2.25 N 11.66 H 2.18 N 4.13 N 2.18 N

7.63 N 2.13 L 7.53 N 2.05 L 10.28 H 2.15 N

4.35 N 2.45 N 10.92 H 2.15 N 10.28 H 2.13 L

2.23 N 12.08 H 2.20 N 7.95 H 2.28 N

6.57 N 2.20 N 9.86 H 2.23 N 7.53 N 2.18 N

Gel vehicle

10.81 H 2.10 L 9.33 H 2.13 L 11.66 H 2.15 N

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It is interesting to note that 20 of the 23 AEs were reported by two sites ( ). Of the 13 subjects with AEs of blood PTH increased in the DAIVOBET/DOVOBET gel group, seven subjects had high values at baseline and all the subsequent values on treatment were lower than the high baseline value for six of these subjects. For the seventh subject

), the value at Week 4 (11.34 pmol/L) was higher than at baseline (10.60 pmol/L) but at the end of study, a lower vale (9.65 pmol/L) was reported. Six subjects with plasma PTH within the normal range at baseline had high values after starting treatment, for two subjects the high values were reported at Week 4 and Week 8, for one subject only at Week 4 and for three only at Week 8. Of the nine subjects with AEs of blood PTH increased in the betamethasone gel group, three subjects had high values at baseline and for two of these subjects all the subsequent values on treatment were lower than the high baseline value. For the third subject ( ), the value at Week 8 (11.55 pmol/L) was higher than at baseline (10.39 pmol/L) but at Week 4, a lower value (9.12 pmol/L) was reported. One subject had missing baseline PTH, which makes interpretation of the high values difficult. However, it was noted that this subject (

) had a decrease in PTH at Week 8 (7.95 pmol/L) compared with the first value available at Week 4 (12.08 pmol/L) both of these values were above the normal range. Five subjects with plasma PTH within the normal range at baseline had high values after starting treatment, for one subject the high values were reported at Week 4 and Week 8, and for three subjects only at Week 4 and for one only at Week 8 only. In the gel vehicle group one subject had a high PTH at baseline (10.81 pmol/L) which remained high at Weeks 4 and 8 (9.33 and 11.66 pmol/L, respectively). As shown in Table 46, the mean PTH values were similar across the treatment groups and changes from baseline were small. However, individual values showed wide variation at baseline and Weeks 4 and 8 in all treatment groups. Each treatment group showed a small decrease from baseline in mean PTH during treatment and the pattern of shifts from normal at baseline to high during treatment were similar among the groups (Table 47). Thus there was no evidence to indicate that treatment with DAIVOBET/DOVOBET gel, betamethasone gel or calcipotriol gel had a different safety profile with respect to PTH than the gel vehicle.

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Table 35: AEs occurring in ≥1% of subjects in any treatment group: safety analysis set

Daivobet® gel




System Organ Class Preferred Term1

Number of subjects %




Cardiac disorders Angina pectoris 1 0.2 0 0.0 0 0.0 1 1.1 Ear and labyrinth disorders Cerumen impaction 0 0.0 0 0.0 0 0.0 1 1.1 Vertigo 0 0.0 0 0.0 0 0.0 1 1.1 Eye disorders Conjunctivitis 1 0.2 0 0.0 0 0.0 1 1.1 Erythema of eyelid 0 0.0 0 0.0 1 1.1 0 0.0 Gastrointestinal disorders Diarrhoea 2 0.4 1 0.2 1 1.1 1 1.1 Nausea 1 0.2 2 0.4 1 1.1 0 0.0 Toothache 1 0.2 0 0.0 0 0.0 1 1.1 Vomiting 2 0.4 1 0.2 0 0.0 1 1.1 General disorders and administration siteconditions Application site pain 2 0.4 1 0.2 0 0.0 1 1.1 Pyrexia 0 0.0 0 0.0 0 0.0 1 1.1 Infections and infestations Bronchitis 5 1.0 1 0.2 1 1.1 1 1.1 22JUL11:13:23:01 LEO80185 G23 t35.doc Continued...

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Table 35: AEs occurring in ≥1% of subjects in any treatment group: safety analysis set, continued

Daivobet® gel









Infections and infestations Candidiasis 0 0.0 0 0.0 1 1.1 1 1.1 Eye infection 0 0.0 0 0.0 0 0.0 1 1.1 Gastroenteritis viral 2 0.4 3 0.6 1 1.1 0 0.0 Influenza 5 1.0 4 0.8 1 1.1 1 1.1 Nasopharyngitis 14 2.9 15 3.1 5 5.3 3 3.2 Sinusitis 10 2.1 3 0.6 1 1.1 1 1.1 Tooth infection 1 0.2 0 0.0 0 0.0 2 2.1 Upper respiratory tract infection 14 2.9 8 1.7 3 3.2 0 0.0 Vulvovaginal mycotic infection 0 0.0 1 0.2 0 0.0 1 1.1 Injury, poisoning and proceduralcomplications Animal bite 0 0.0 1 0.2 0 0.0 1 1.1 Cartilage injury 0 0.0 0 0.0 1 1.1 0 0.0 Investigations Angiogram 0 0.0 0 0.0 0 0.0 1 1.1 Blood parathyroid hormone increased

13 2.7 9 1.9 0 0.0 1 1.1

Musculoskeletal and connective tissuedisorders Arthralgia 0 0.0 1 0.2 0 0.0 2 2.1 22JUL11:13:23:01 LEO80185 G23 t35.doc Continued...

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Daivobet® gel









Musculoskeletal and connective tissuedisorders Joint swelling 0 0.0 0 0.0 1 1.1 0 0.0 Psoriatic arthropathy 0 0.0 0 0.0 1 1.1 0 0.0 Nervous system disorders Amnesia 0 0.0 0 0.0 1 1.1 0 0.0 Headache 4 0.8 5 1.0 0 0.0 0 0.0 Tunnel vision 0 0.0 0 0.0 1 1.1 0 0.0 Psychiatric disorders Depression 0 0.0 0 0.0 0 0.0 1 1.1 Suicide attempt 0 0.0 0 0.0 0 0.0 1 1.1 Respiratory, thoracic and mediastinaldisorders Cough 4 0.8 3 0.6 1 1.1 0 0.0 Oropharyngeal pain 1 0.2 0 0.0 1 1.1 2 2.1 Respiratory tract congestion 1 0.2 0 0.0 1 1.1 0 0.0 Sinus congestion 4 0.8 1 0.2 0 0.0 1 1.1 Skin and subcutaneous tissue disorders Dermatitis contact 1 0.2 1 0.2 1 1.1 0 0.0 Pruritus 3 0.6 1 0.2 1 1.1 2 2.1 Psoriasis 1 0.2 1 0.2 1 1.1 1 1.1 22JUL11:13:23:01 LEO80185 G23 t35.doc Continued...

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Daivobet® gel









Skin and subcutaneous tissue disorders Rash papular 1 0.2 0 0.0 0 0.0 1 1.1 Skin irritation 0 0.0 1 0.2 1 1.1 0 0.0 Surgical and medical procedures Surgery 0 0.0 0 0.0 0 0.0 1 1.1 Total number of adverse events2 94 64 28 35 Total number of subjects3 82 17.0 55 11.5 22 23.2 22 23.2 22JUL11:13:23:01 LEO80185 G23 t35.doc

1) Classification according to MedDRA version 13.0 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 3) Subjects and received wrong trial medication during the study and are excluded from body of table, incl denominator of randomised treatment. They reported no adverse events.

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Table 36: AEs by MedDRA primary system organ class: safety analysis set




Vehicle (n=95)

System Organ Class1 Number of subjects %




Blood and lymphatic system disorders

0 0.0 1 0.2 0 0.0 0 0.0

Cardiac disorders 1 0.2 0 0.0 0 0.0 1 1.1 Ear and labyrinth disorders 0 0.0 0 0.0 0 0.0 2 2.1 Endocrine disorders 0 0.0 2 0.4 0 0.0 0 0.0 Eye disorders 1 0.2 0 0.0 1 1.1 1 1.1 Gastrointestinal disorders 7 1.5 5 1.0 1 1.1 2 2.1 General disorders and administra-tion site conditions

5 1.0 2 0.4 0 0.0 2 2.1

Hepatobiliary disorders 0 0.0 1 0.2 0 0.0 0 0.0 Immune system disorders 2 0.4 1 0.2 0 0.0 0 0.0 Infections and infestations 64 13.3 45 9.4 13 13.7 9 9.5 Injury, poisoning and procedural complications

8 1.7 12 2.5 1 1.1 1 1.1

Investigations 15 3.1 10 2.1 0 0.0 2 2.1 Metabolism and nutrition disorders 3 0.6 4 0.8 0 0.0 0 0.0 Musculoskeletal and connective tissue disorders

6 1.2 5 1.0 2 2.1 2 2.1

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

1 0.2 0 0.0 0 0.0 0 0.0

Nervous system disorders 8 1.7 8 1.7 1 1.1 0 0.0 Psychiatric disorders 0 0.0 1 0.2 0 0.0 2 2.1 Renal and urinary disorders 0 0.0 2 0.4 0 0.0 0 0.0 22JUL11:13:32:52 LEO80185 G23 T36.doc Continued...

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Table 36: AEs by MedDRA primary system organ class: safety analysis set, continued




Vehicle (n=95)

System Organ Class1 Number of subjects %




Reproductive system and breast disorders

0 0.0 2 0.4 0 0.0 0 0.0

Respiratory, thoracic and medias-tinal disorders

14 2.9 8 1.7 2 2.1 2 2.1

Skin and subcutaneous tissue disorders

15 3.1 12 2.5 4 4.2 3 3.2

Surgical and medical procedures 2 0.4 3 0.6 0 0.0 1 1.1 Vascular disorders 4 0.8 4 0.8 0 0.0 0 0.0 Total number of adverse events2 169 144 28 35 Total number of subjects4 125 26.0 96 20.0 22 23.2 22 23.2 Statistical analysis P-value³ 0.028 0.56 0.56 22JUL11:13:32:52 LEO80185 G23 T36.doc

1) Classification according to MedDRA version 13.0 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 3) Chi-squared test 4) Subjects and received wrong trial medication during the study and are excluded from body of table, incl denominator of randomised treatment. They reported no adverse events.

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The majority of AEs were not considered related to study treatment by the investigators. Table 37 summarises the ADRs reported during the study. Overall 26 ADRs were reported by 24 subjects (5.0%) in the DAIVOBET/DOVOBET gel group, compared with 15 ADRs reported by 15 subjects (3.1%) in the betamethasone gel group, 5 ADRs reported by 5 subjects (5.3%) in the calcipotriol gel group and 6 ADRs reported by 4 subjects (4.2%) in the gel vehicle group. The most common ADR reported was blood PTH increased, which was reported for 7 subjects (1.5%) in the DAIVOBET/DOVOBET gel group, 6 (1.3%) in the betamethasone gel group, none in the calcipotriol gel group and 1 (1.1%) in the gel vehicle group. In the DAIVOBET/DOVOBET gel group, 3 subjects (0.6%) experienced ADRs of pruritus. There were no ADRs of pruritus in the betamethasone gel group but 1 subject (1.1%) in the calcipotriol gel group and 2 (2.1%) in the gel vehicle group had ADRs of pruritus reported. Treatment-related dizziness and application site pain were each reported as ADRs for 2 subjects (0.4%) in the DAIVOBET/DOVOBET gel group. Dizziness was not reported as an ADR for any subjects in the other three treatment groups whereas application site pain was reported as an ADR for 1 subject (0.2%) in the betamethasone gel group and 1 (1.1%) in the gel vehicle group. No other ADRs were reported by more than a single case in any treatment group. Table 78 presents a summary of AEs by relationship to study treatment (not related, possible and probable relationships).

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Table 37: ADRs by MedDRA primary SOC and preferred term: safety analysis set

DAIVOBET/DOVOBET® gel









Ear and labyrinth disorders Vertigo 0 0.0 0 0.0 0 0.0 1 1.1 Gastrointestinal disorders Nausea 0 0.0 1 0.2 0 0.0 0 0.0 General disorders and administration siteconditions Application site pain 2 0.4 1 0.2 0 0.0 1 1.1 Feeling of body temperature change

1 0.2 0 0.0 0 0.0 0 0.0

Infections and infestations Bronchitis 0 0.0 1 0.2 0 0.0 0 0.0 Candidiasis 0 0.0 0 0.0 1 1.1 0 0.0 Cellulitis 1 0.2 1 0.2 0 0.0 0 0.0 Folliculitis 1 0.2 0 0.0 0 0.0 0 0.0 Sinusitis 1 0.2 0 0.0 0 0.0 0 0.0 Investigations Blood parathyroid hormone increased

7 1.5 6 1.3 0 0.0 1 1.1

Blood phosphorus decreased 1 0.2 0 0.0 0 0.0 0 0.0 22JUL11:13:33:07 LEO80185 G23 t37.doc Continued...

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Table 37: ADRs by MedDRA primary SOC and preferred term: safety analysis set, continued

Daivobet® gel









Nervous system disorders Dizziness 2 0.4 0 0.0 0 0.0 0 0.0 Headache 0 0.0 1 0.2 0 0.0 0 0.0 Paraesthesia 0 0.0 1 0.2 0 0.0 0 0.0 Renal and urinary disorders Nephrolithiasis 0 0.0 1 0.2 0 0.0 0 0.0 Skin and subcutaneous tissue disorders Dermatitis 1 0.2 0 0.0 0 0.0 0 0.0 Dermatitis contact 1 0.2 0 0.0 1 1.1 0 0.0 Guttate psoriasis 1 0.2 0 0.0 0 0.0 0 0.0 Pruritus 3 0.6 0 0.0 1 1.1 2 2.1 Psoriasis 1 0.2 0 0.0 1 1.1 0 0.0 Rash 1 0.2 0 0.0 0 0.0 0 0.0 Rash papular 1 0.2 0 0.0 0 0.0 1 1.1 Skin fissures 0 0.0 1 0.2 0 0.0 0 0.0 Skin irritation 0 0.0 1 0.2 1 1.1 0 0.0 Vascular disorders Flushing 1 0.2 0 0.0 0 0.0 0 0.0 22JUL11:13:33:07 LEO80185 G23 t37.doc Continued...

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Table 37: ADRs by MedDRA primary SOC and preferred term: safety analysis set, continued

Daivobet® gel









Total number of drug reactions2

26 15 5 6

Total number ofsubjects4

24 5.0 15 3.1 5 5.3 4 4.2

Statistical analysis P-value³ 0.14 0.91 0.74 22JUL11:13:33:07 LEO80185 G23 t37.doc

1) Classification according to MedDRA version 13.0 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. 3) Chi-squared test 4) Subjects and received wrong trial medication during the study and are excluded from body of table, incl denominator of randomised treatment. They reported no adverse events.

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The AEs reported to be in the treatment area are summarised in Table 38. Overall 13 AEs were reported in the treatment area for 13 subjects (2.7%) in the DAIVOBET/DOVOBET gel group, compared with 13 AEs reported by 11 subjects (2.3%) in the betamethasone gel group, 4 AEs reported by 4 subjects (4.2%) in the calcipotriol gel group and 4 AEs reported by 4 subjects (4.2%) in the gel vehicle group. The only AEs in the treatment area reported by more than a single case in any treatment group were pruritus, application site pain and paresthesia. In the DAIVOBET/DOVOBET gel group, 2 subjects (0.4%) experienced AEs of pruritus in the treatment area. There were no AE of pruritus in the treatment area in the betamethasone gel group but 1 subject (1.1%) in the calcipotriol gel group and 2 (2.1%) in the gel vehicle group had AEs of pruritus reported in the treatment area. Application site pain was reported as an AE in the treatment area for 2 subjects (0.4%) in the DAIVOBET/DOVOBET gel group, for 1 subject (0.2%) in the betamethasone gel group and 1 (1.1%) in the gel vehicle group. Paraesthesia was reported as an AE in the treatment area for 2 subjects (0.4%) in the be-tamethasone gel group but was not reported as an AE in the treatment area for any subjects in the other treatment groups.

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Table 38: AEs in the treatment area by MedDRA primary SOC and preferred term: safety analysis set

Daivobet® gel









General disorders and administration siteconditions Application site pain 2 0.4 1 0.2 0 0.0 1 1.1 Cyst 1 0.2 0 0.0 0 0.0 0 0.0 Infections and infestations Candidiasis 0 0.0 0 0.0 1 1.1 0 0.0 Cellulitis 1 0.2 1 0.2 0 0.0 0 0.0 Otitis media acute 0 0.0 1 0.2 0 0.0 0 0.0 Injury, poisoning and proceduralcomplications Arthropod bite 1 0.2 0 0.0 0 0.0 0 0.0 Contusion 0 0.0 1 0.2 0 0.0 0 0.0 Excoriation 1 0.2 1 0.2 0 0.0 0 0.0 Wrist fracture 1 0.2 0 0.0 0 0.0 0 0.0 Nervous system disorders Hypoaesthesia 0 0.0 1 0.2 0 0.0 0 0.0 Paraesthesia 0 0.0 2 0.4 0 0.0 0 0.0 Skin and subcutaneous tissue disorders Dermatitis contact 1 0.2 0 0.0 1 1.1 0 0.0 Erythema 0 0.0 1 0.2 0 0.0 0 0.0 22JUL11:13:33:27 LEO80185 G23 t38.doc Continued...

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Table 38: AEs in the treatment area by MedDRA primary SOC and preferred term: safety analysis set, continued

Daivobet® gel









Skin and subcutaneous tissue disorders Guttate psoriasis 1 0.2 1 0.2 0 0.0 0 0.0 Pruritus 2 0.4 0 0.0 1 1.1 2 2.1 Psoriasis 1 0.2 1 0.2 1 1.1 1 1.1 Rash 0 0.0 1 0.2 0 0.0 0 0.0 Rash papular 1 0.2 0 0.0 0 0.0 0 0.0 Skin fissures 0 0.0 1 0.2 0 0.0 0 0.0 Total number of adverse events2

13 13 4 4


13 2.7 11 2.3 4 4.2 4 4.2

22JUL11:13:33:27 LEO80185 G23 t38.doc


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Table 79 presents a summary of AEs by intensity, Table 80 presents ADRs by intensity and Table 81 presents the AEs in the treatment area by intensity. In the DAIVOBET/DOVOBET gel group, 116 AEs were mild, 40 were moderate and 13 were severe in intensity. In the betamethasone gel group, 87 were mild, 49 were moderate and 8 were severe, in the calcipotriol gel group, 20 were mild, 7 were moderate and 1 was severe, and in the gel vehicle group 17 were mild, 15 were moderate and 3 were severe. Thus in each of the active treatment groups, 60% to 71% of the AEs reported were mild in intensity and 24% to 34% were moderate in intensity. In the gel vehicle group, the distribution of mild and moderate events was similar 49% and 43%, respectively. The incidence of severe events ranged from 3.6% to 8.6% of the events reported and there was no individual preferred term reported as severe by more than 1 subject in any of the treatment groups. The severe AEs reported in the DAIVOBET/DOVOBET gel group were: diarrhoea, vomiting, bronchitis, ear infection, nasopharyngitis, pneumonia, muscle strain, wrist fracture, muscu-loskeletal pain, epistaxis, dermatitis (ADR not in the treatment area), abortion induced, and hypertension. The severe AEs in the betamethasone gel group were: kidney infection, rib fractrure, arthralgia, tendonitis, nephrolithiasis (ADR), Bartholin’s cyst, acute respiratory failure and stent placement. The severe AE in the calcipotriol gel group was dermatitis contact (ADR in the treatment area) and in the vehicle gel group were: eye infection, animal bite and sinusitis.

12.2.3 Analysis of Adverse Events

Statistical comparisons of the incidence of AEs in each treatment group showed a signifi-cantly lower incidence of AEs in the betamethasone gel group (20.0%) compared with the DAIVOBET/DOVOBET gel group (26.0%, p=0.028) but there were no statistically signifi-cant differences between DAIVOBET/DOVOBET gel and calcipotriol gel or gel vehicle (Table 36). No statistically significant differences were detected between DAIVOBET/DOVOBET gel and betamethasone gel, calcipotriol gel and gel vehicle for the incidence of ADRs (Table 37).

12.2.4 Listing of Adverse Events by Subject

All AE data are listed in Appendix 16.2.7 Listing 17.

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12.3 DEATHS, OTHER SERIOUS ADVERSE EVENTS AND OTHER SIGNIFICANT ADVERSE EVENTS

12.3.1 Listing of Deaths, Other Serious Adverse Events and Other Significant Adverse Events

All AE data are listed in Appendix 16.2.7 Listing 17.

12.3.1.1 Deaths

There were no deaths during the study.

12.3.1.2 Other Serious Adverse Events

The incidence of SAEs was low. Overall 1 SAE was reported by 1 subject (0.2%) in the DAIVOBET/DOVOBET gel group, compared with 8 SAEs reported by 7 subjects (1.5%) in the betamethasone gel group, no SAEs reported in the calcipotriol gel group and 1 SAE reported by 1 subject (1.1%) in the gel vehicle group. The SAEs are summarised in Table 39 by MedDRA system organ class and preferred term. There was no individual preferred term reported by more than one subject.

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Table 39: SAEs by MedDRA primary SOC and preferred term: safety analysis set

Daivobet® gel









Hepatobiliary disorders Cholecystitis acute 0 0.0 1 0.2 0 0.0 0 0.0 Infections and infestations Cellulitis 0 0.0 1 0.2 0 0.0 0 0.0 Injury, poisoning and proceduralcomplications Alcohol poisoning 0 0.0 1 0.2 0 0.0 0 0.0 Psychiatric disorders Suicidal ideation 0 0.0 1 0.2 0 0.0 0 0.0 Suicide attempt 0 0.0 0 0.0 0 0.0 1 1.1 Renal and urinary disorders Haematuria 0 0.0 1 0.2 0 0.0 0 0.0 Nephrolithiasis 0 0.0 1 0.2 0 0.0 0 0.0 Respiratory, thoracic and mediastinaldisorders Acute respiratory failure 0 0.0 1 0.2 0 0.0 0 0.0 Surgical and medical procedures Stent placement 0 0.0 1 0.2 0 0.0 0 0.0 Vascular disorders Hypertension 1 0.2 0 0.0 0 0.0 0 0.0 22JUL11:13:33:47 LEO80185 G23 t39.doc Continued...

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Table 39: SAEs by MedDRA primary SOC and preferred term: safety analysis set, continued

Daivobet® gel









Total number of Serious adverse events 2

1 8 1


1 0.2 7 1.5 0 0.0 1 1.1

22JUL11:13:33:47 LEO80185 G23 t39.doc


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12.3.1.3 Other Significant Adverse Events

Table 92 presents a listing of the subjects who withdrew due to AEs. Although not necessarily recorded as the reason for withdrawal at the end of the study, there were 6 subjects in the DAIVOBET/DOVOBET gel group, and 5 each in the betamethasone gel and calcipotriol gel groups who withdrew due to AEs. No subjects withdrew due to AEs in the gel vehicle group. In the DAIVOBET/DOVOBET gel group, the AEs that led to discontinuation were bronchitis ( ), application site pain ( ), abortion induced ( ), psoriasis ( ), dermatitis contact ( ), and dyspnoea ( ). The AEs that led to discontinuation in the betamethasone gel group were haematuria ( ), stent placement ( ), acute respiratory failure ( ), hypertension (

) and hypoparathyroidism ( ). In the calcipotriol gel group the AEs that led to withdrawal were candidiasis ( ), dermatitis contact ( ), pruritus ( ), psoriasis ( ) and diarrhoea, nausea, skin irritation, amnesia and tunnel vision ( ). An additional subject ( ) in the betamethasone gel group discontinued due to guttate psoriasis recorded the reason for withdrawal as ‘other’. There were 2 cases of abortion induced; in the DAIVOBET/DOVOBET gel group one subject ( ) found she was pregnant during the study and was discontinued and in the betamethasone gel group one subject ( ) found she was pregnant a week after she last applied study treatment.

12.3.2 Narratives of Deaths, Other Serious Adverse Events and Other Significant Adverse Events

12.3.2.1 Serious Adverse Event Narratives

DAIVOBET/DOVOBET gel group CRF Number: Event: Hypertension

-

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12.4 CLINICAL LABORATORY EVALUATION

12.4.1 Listing of Individual Laboratory Measurements by Subject and Each Abnormal Laboratory Value

For individual subject data on laboratory parameters see Appendix 16.2.8 Listing 18.

12.4.2 Evaluation of Each Laboratory Parameter

Albumin-corrected serum calcium at each visit and change from baseline is summarised for the safety analysis set in Table 40. Mean albumin-corrected serum calcium was similar across the treatment groups at all visits and mean changes from baseline were small (range -0.019 to -0.006 mmol/L across the groups and visits).

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Table 40: Summary of albumin-corrected serum calcium and change from baseline at Weeks 4 and 8: safety analysis set Albumin corrected serum calcium (mmol/L)

Daivobet® gel

(n=482)

Betamethasone gel

(n=479)

Calcipotriol gel

(n=96)

Vehicle (n=95)

Summary1 Baseline Mean 2.238 2.225 2.241 2.233 SD 0.088 0.089 0.085 0.092 Median 2.250 2.225 2.250 2.225 Minimum 2.03 1.68 2.05 2.03 Maximum 2.55 2.58 2.53 2.70 Number 474 465 93 91 Week 4 Mean 2.220 2.215 2.228 2.222 SD 0.091 0.086 0.082 0.100 Median 2.225 2.200 2.225 2.200 Minimum 1.98 1.98 2.05 2.03 Maximum 2.53 2.70 2.48 2.55 Number 436 416 85 79 Week 8 Mean 2.224 2.213 2.234 2.223 SD 0.084 0.082 0.087 0.080 Median 2.200 2.200 2.225 2.225 Minimum 2.03 2.00 2.03 2.03 Maximum 2.50 2.53 2.50 2.50 Number 435 403 82 74 End of Treatment Mean 2.222 2.213 2.235 2.221 SD 0.083 0.082 0.089 0.088 Median 2.200 2.200 2.225 2.225 Minimum 2.03 2.00 2.03 2.03 Maximum 2.50 2.53 2.50 2.53 Number 460 434 91 83 Change from Baseline Week 4 Mean -0.019 -0.010 -0.016 -0.012 SD 0.091 0.093 0.077 0.098 Median -0.025 0.000 -0.025 0.000 Minimum -0.33 -0.30 -0.23 -0.28 23SEP11:12:00:04 LEO80185 G23 t40.doc Continued...

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Table 40: Summary of albumin-corrected serum calcium and change from baseline at Weeks 4 and 8: safety analysis set, continued Albumin corrected serum calcium (mmol/L)

Daivobet® gel

(n=482)

Betamethasone gel

(n=479)

Calcipotriol gel

(n=96)

Vehicle (n=95)

Change from Baseline Week 4 Maximum 0.28 0.48 0.18 0.25 Number 433 410 82 76 Week 8 Mean -0.016 -0.014 -0.012 -0.006 SD 0.088 0.086 0.087 0.083 Median 0.000 -0.025 0.000 -0.025 Minimum -0.25 -0.33 -0.25 -0.20 Maximum 0.25 0.30 0.25 0.20 Number 432 397 79 71 End of Treatment Mean -0.016 -0.013 -0.006 -0.013 SD 0.087 0.086 0.090 0.085 Median 0.000 -0.025 0.000 -0.025 Minimum -0.25 -0.33 -0.25 -0.20 Maximum 0.25 0.30 0.25 0.20 Number 457 427 88 80 23SEP11:12:00:04 LEO80185 G23 t40.doc


The majority of subjects in all treatment groups had albumin-corrected serum calcium values within the normal reference range at baseline (2.15 to 2.55 mmol/L) and did not record a shift at Weeks 4 and 8 or the end of treatment. For the minority of subjects that recorded a shift the pattern of shifts from low to normal values and normal to low values was similar across the treatment groups. Only one subject shifted to a high albumin-corrected serum calcium value. This subject was in the betamethasone group and recorded a shift from normal at baseline to high at Week 4 only. A further subject, also in the betamethasone group, recorded an albumin-corrected serum calcium above the normal refererence range at baseline which was normal at all the other timepoints. One subject in the gel vehicle group shifted from high at baseline to normal at Week 4, and missing at Week 8. It is interesting to note that a high proportion of subjects across all treatment groups (approximately 13% overall) reported a low value at baseline (Table 41).

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Mean serum calcium values and changes from baseline are summarised in Table 82 and shifts in serum calcium are summarised in Table 83. Likewise, mean serum albumin values and changes from baseline are summarised in Table 84 and shifts in serum albumin are summa-rised in Table 85.

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Table 41: Shift tables for albumin-corrected serum calcium from baseline to Weeks 4 and 8: safety analysis set


End of Period catego-

ry1


End of Period category1

Calcipotriol gel(n=96)


ry1

Vehicle(n=95)


ry1 Albumin corrected serum calcium

Baseline category1,2 Low Normal Low Normal High Low Normal Low Normal

Week 4 LOW 20 34 26 37 0 4 5 3 8 NORMAL 47 332 41 304 1 7 66 10 54 HIGH 0 0 0 1 0 0 0 0 1 Week 8 LOW 23 33 24 34 0 4 4 2 8 NORMAL 47 329 37 301 0 5 66 7 54 HIGH 0 0 0 1 0 0 0 0 0 End of Treatment LOW 23 37 27 36 0 4 6 2 9 NORMAL 50 347 40 323 0 5 73 10 58 HIGH 0 0 0 1 0 0 0 0 1 23SEP11:12:00:45 LEO80185 G23 t41.doc

1) Number of subjects with laboratory parameters below, within or above the reference range. 2) Two subjects received wrong trial medication during the study, subject from visit 4 and subject from visit 5.

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Serum phosphate is summarised at each visit together with change from baseline for the safety analysis set in Table 42. Serum phosphate was similar across the treatment groups at all visits and mean changes from baseline were small (range -0.029 to 0.009 mmol/L across groups and visits).

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Table 42: Summary of serum phosphate and change from baseline at Weeks 4 and 8: safety analysis set

Serum phosphate (mmol/L)

Daivobet® gel

(n=482)

Betamethasone gel

(n=479)

Calcipotriol gel

(n=96)

Vehicle (n=95)

Summary1 Baseline Mean 1.162 1.151 1.152 1.130 SD 0.191 0.184 0.177 0.178 Median 1.160 1.130 1.160 1.130 Minimum 0.68 0.61 0.68 0.74 Maximum 2.39 2.10 1.52 1.55 Number 474 463 93 90 Week 4 Mean 1.141 1.146 1.141 1.108 SD 0.191 0.170 0.182 0.165 Median 1.130 1.130 1.130 1.130 Minimum 0.55 0.68 0.65 0.74 Maximum 1.78 1.71 1.58 1.62 Number 433 414 85 78 Week 8 Mean 1.139 1.154 1.147 1.151 SD 0.187 0.180 0.178 0.196 Median 1.130 1.130 1.130 1.145 Minimum 0.48 0.74 0.71 0.48 Maximum 1.81 1.78 1.65 1.71 Number 433 401 81 74 End of Treatment Mean 1.141 1.153 1.141 1.136 SD 0.187 0.180 0.184 0.196 Median 1.130 1.130 1.130 1.130 Minimum 0.48 0.74 0.65 0.48 Maximum 1.81 1.78 1.65 1.71 Number 460 434 91 83 Change from Baseline Week 4 Mean -0.024 -0.005 -0.003 -0.029 SD 0.210 0.194 0.191 0.177 Median 0.000 -0.030 0.000 0.000 Minimum -1.49 -0.68 -0.45 -0.36 23SEP11:11:59:55 LEO80185 G23 t42.doc Continued...

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Table 42: Summary of serum phosphate and change from baseline at Weeks 4 and 8: safety analysis set, continued

Serum phosphate (mmol/L)

Daivobet® gel

(n=482)

Betamethasone gel

(n=479)

Calcipotriol gel

(n=96)

Vehicle (n=95)

Change from Baseline Week 4 Maximum 0.68 0.55 0.48 0.45 Number 430 407 82 74 Week 8 Mean -0.021 0.006 0.003 0.009 SD 0.204 0.199 0.180 0.194 Median -0.030 0.000 0.000 0.015 Minimum -1.45 -0.59 -0.55 -0.49 Maximum 0.68 0.68 0.45 0.51 Number 430 394 78 70 End of Treatment Mean -0.021 0.003 0.001 0.000 SD 0.202 0.200 0.176 0.207 Median -0.030 0.000 0.000 0.000 Minimum -1.45 -0.68 -0.55 -0.49 Maximum 0.68 0.68 0.45 0.51 Number 457 426 88 79 23SEP11:11:59:55 LEO80185 G23 t42.doc


The majority of subjects in all treatment groups had serum phosphate values within the normal reference range at baseline (0.81 to 1.45 mmol/L) and did not record a shift at Weeks 4 and 8 or the end of treatment. For the minority of subjects that recorded a shift the pattern of shifts was similar across the treatment groups (Table 43).

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Table 43: Shift tables for serum phosphate from baseline to Weeks 4 and 8: safety analysis set







Vehicle(n=95)


Serum Phos-phate

Baseline catego-ry1,2 Low Normal High Low Normal High Low Normal High Low Normal High

Week 4 LOW 2 9 0 2 7 0 1 3 0 1 2 0 NORMAL 13 371 15 3 372 10 2 72 2 1 65 0 HIGH 0 17 3 0 12 1 0 2 0 0 4 1 Week 8 LOW 3 8 0 3 6 0 1 3 0 0 3 0 NORMAL 7 378 14 2 352 17 1 70 1 3 57 2 HIGH 0 15 5 0 12 2 0 1 1 0 4 1 End of Treatment

LOW 3 8 0 3 6 0 1 3 0 0 3 0

NORMAL 8 404 14 2 380 19 2 79 1 3 66 2 HIGH 0 15 5 0 14 2 0 1 1 0 4 1 23SEP11:12:01:06 LEO80185 G23 t43.doc


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Serum alkaline phosphatase is summarised at each visit together with change from baseline for the safety analysis set in Table 44. Serum alkaline phosphatase was similar across the treatment groups at all visits and mean changes from baseline were small (range -1.1 to 2.9 U/L across groups and visits).

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Table 44: Summary of serum alkaline phosphatase and change from baseline at Weeks 4 and 8: safety analysis set

Serum ALP (U/L)

Daivobet® gel

(n=482)

Betamethasone gel

(n=479)

Calcipotriol gel

(n=96)

Vehicle (n=95)

Summary1 Baseline Mean 79.0 81.8 79.6 78.6 SD 24.1 28.7 22.6 25.3 Median 74.0 78.0 75.0 74.0 Minimum 40 34 33 20 Maximum 251 356 146 154 Number 474 465 93 91 Week 4 Mean 78.1 80.3 80.0 78.7 SD 24.1 27.1 24.2 24.8 Median 76.0 76.5 79.0 76.0 Minimum 40 33 34 27 Maximum 279 349 154 156 Number 436 416 85 79 Week 8 Mean 79.7 81.3 82.2 78.9 SD 23.5 25.3 23.6 25.7 Median 77.0 80.0 78.0 76.0 Minimum 39 32 36 28 Maximum 240 282 152 194 Number 435 403 82 74 End of Treatment Mean 79.6 81.2 82.6 79.8 SD 23.8 25.2 24.8 25.8 Median 76.5 80.0 78.0 77.0 Minimum 39 32 36 28 Maximum 240 282 176 194 Number 460 434 91 83 Change from Baseline Week 4 Mean -0.6 -1.1 0.3 -1.1 SD 10.8 9.7 7.5 10.4 Median 0.0 -1.0 0.0 -1.5 Minimum -87 -64 -16 -44 23SEP11:12:00:15 LEO80185 G23 t44.doc Continued...

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Table 44: Summary of serum alkaline phosphatase and change from baseline at Weeks 4 and 8: safety analysis set, continued

Serum ALP (U/L)

Daivobet® gel

(n=482)

Betamethasone gel

(n=479)

Calcipotriol gel

(n=96)

Vehicle (n=95)

Change from Baseline Week 4 Maximum 46 48 25 43 Number 433 410 82 76 Week 8 Mean 0.9 -0.1 2.8 1.5 SD 11.3 11.0 10.2 8.4 Median 1.0 1.0 1.0 1.0 Minimum -101 -74 -21 -17 Maximum 55 40 51 40 Number 432 397 79 71 End of Treatment Mean 1.0 -0.2 2.9 0.3 SD 11.6 10.9 10.6 9.8 Median 1.0 1.0 1.5 0.0 Minimum -101 -74 -21 -36 Maximum 74 40 51 40 Number 457 427 88 80 23SEP11:12:00:15 LEO80185 G23 t44.doc

1) Two subjects received wrong trial medication during the study, subject from visit 4 and subject from visit 5. The majority of subjects in all treatment groups had serum alkaline phosphatase values within the normal reference range at baseline (53 to 129 U/L for males and 42 to 98 U/L for females) and did not record a shift at Weeks 4 and 8 or the end of treatment. For the minority of subjects that recorded a shift, the pattern of shifts was similar across the treatment groups. It is interesting to note that a high proportion of subjects across all treatment groups (approxi-mately 9%) reported a high value at baseline (Table 45).

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Table 45: Shift tables for serum alkaline phosphatase from baseline to Weeks 4 and 8: safety analysis set







Vehicle(n=95)


Serum ALP



LOW 12 11 0 11 7 0 4 1 0 4 1 0



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Plasma PTH is summarised at each visit together with change from baseline for the safety analysis set in Table 46. In all treatment groups there was a small decrease in mean PTH values during treatment (range -0.760 to -0.194 pmol/L across groups and visits).

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Table 46: Summary of plasma parathyroid hormone and change from baseline at Weeks 4 and 8: safety analysis set

Plasma PTH (pmol/L)

Daivobet® gel

(n=482)

Betamethasone gel

(n=479)

Calcipotriol gel

(n=96)

Vehicle (n=95)

Summary1 Baseline Mean 5.903 5.713 6.437 6.374 SD 2.824 2.743 3.663 4.004 Median 5.410 5.140 5.940 5.620 Minimum 0.95 0.11 0.53 2.12 Maximum 20.67 24.59 28.51 27.77 Number 467 446 91 89 Week 4 Mean 5.490 5.431 5.799 6.005 SD 2.899 2.634 2.982 4.208 Median 4.880 4.880 5.245 5.035 Minimum 0.85 0.64 0.11 1.48 Maximum 31.59 19.72 22.47 26.92 Number 423 403 82 78 Week 8 Mean 5.471 5.542 5.822 5.592 SD 2.643 4.082 3.963 3.948 Median 5.090 4.980 5.190 4.660 Minimum 0.42 0.74 0.11 0.11 Maximum 20.88 68.37 33.18 28.09 Number 429 396 75 73 End of Treatment Mean 5.458 5.568 5.794 5.789 SD 2.660 3.980 3.715 3.992 Median 4.980 5.090 5.190 4.880 Minimum 0.42 0.74 0.11 0.11 Maximum 20.88 68.37 33.18 28.09 Number 454 429 88 83 Change from Baseline Week 4 Mean -0.387 -0.346 -0.356 -0.450 SD 2.533 2.203 2.192 2.643 Median -0.320 -0.425 -0.210 -0.640 Minimum -7.95 -13.99 -6.26 -5.20 23SEP11:12:00:25 LEO80185 G23 t46.doc Continued...

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Table 46: Summary of plasma parathyroid hormone and change from baseline at Weeks 4 and 8: safety analysis set, continued

Plasma PTH (pmol/L)

Daivobet® gel

(n=482)

Betamethasone gel

(n=479)

Calcipotriol gel

(n=96)

Vehicle (n=95)

Change from Baseline Week 4 Maximum 27.67 7.95 4.98 14.09 Number 413 384 77 73 Week 8 Mean -0.415 -0.194 -0.369 -0.760 SD 2.248 3.883 3.320 2.414 Median -0.320 -0.320 -0.533 -0.740 Minimum -7.84 -9.33 -13.56 -8.17 Maximum 9.96 62.22 18.34 4.55 Number 418 377 70 69 End of Treatment Mean -0.367 -0.213 -0.542 -0.551 SD 2.231 3.783 3.207 2.392 Median -0.320 -0.320 -0.640 -0.425 Minimum -7.84 -9.33 -13.56 -8.17 Maximum 9.96 62.22 18.34 4.55 Number 443 405 83 78 23SEP11:12:00:25 LEO80185 G23 t46.doc

1) Two subjects received wrong trial medication during the study, subject from visit 4 and subject from visit 5. The majority of subjects in all treatment groups had plasma PTH values within the normal reference range at baseline (1.48 to 7.63 pmol/L) and did not record a shift at Weeks 4 and 8 or the end of treatment. For the minority of subjects that recorded a shift, the pattern of shifts was largely similar across the treatment groups. Based on the numbers of subjects who had baseline and end of treatment values (443, 405, 83 and 78, respectively for DAIVOBET/DOVOBET gel, betamethasone gel, calcipotriol gel and the gel vehicle), 35 subjects (approximately 8%) in the DAIVOBET/DOVOBET gel group shifted from normal to high values of PTH and 44 (approximately 10%) shifted from high to normal values. In the betamethasone gel, calcipotriol gel and gel vehicle groups the corresponding numbers shifting from normal to high PTH values were 25, 5 and 5 subjects, respectively (approximately 6% each) and from high to normal were 40, 10 and 7 subjects (approximately 10%, 12% and 9%)

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respectively (Table 47). It is interesting to note that a high proportion of subjects across all treatment groups (approximately 20% overall) reported a high value at baseline and a similar number in all groups shifted from high to normal values after treatment.

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Table 47: Shift tables for plasma parathyroid hormone from baseline to Weeks 4 and 8: safety analysis set







Vehicle(n=95)


Plasma PTH



LOW 0 3 0 0 0 0 1 0 0 0 0 0



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Urinary calcium:creatinine ratio is summarised at each visit together with change from baseline for the safety analysis set in Table 48. Urinary calcium:creatinine ratio was similar across the treatment groups at all visits and mean changes from baseline were small (range -0.31 to 0.07 mmol/g across groups and visits).

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Table 48: Summary of urinary calcium:creatinine ratio and change from baseline at Weeks 4 and 8: safety analysis set Urinary Cal-cium/Creatinine (mmol/g)

Daivobet® gel

(n=482)

Betamethasone gel

(n=479)

Calcipotriol gel

(n=96)

Vehicle (n=95)

Summary1 Baseline Mean 3.21 3.25 2.77 2.84 SD 2.44 2.43 1.87 2.42 Median 2.60 2.70 2.38 2.30 Minimum 0.2 0.1 0.3 0.3 Maximum 15.4 19.7 8.3 12.5 Number 468 468 95 91 Week 4 Mean 2.98 3.12 2.56 2.78 SD 2.17 2.81 2.34 2.03 Median 2.40 2.43 1.88 2.29 Minimum 0.2 0.1 0.3 0.2 Maximum 12.5 26.3 14.5 10.3 Number 427 415 83 78 Week 8 Mean 3.01 3.14 2.86 2.55 SD 2.27 2.49 2.02 1.56 Median 2.49 2.63 2.35 2.39 Minimum 0.1 0.2 0.3 0.0 Maximum 15.4 18.3 11.8 6.9 Number 434 405 81 74 End of Treatment Mean 2.99 3.05 2.87 2.64 SD 2.27 2.44 2.00 1.57 Median 2.46 2.53 2.35 2.48 Minimum 0.1 0.2 0.3 0.0 Maximum 15.4 18.3 11.8 6.9 Number 458 434 91 83 Change from Baseline Week 4 Mean -0.31 -0.11 -0.20 -0.08 SD 2.22 2.55 2.33 2.38 Median -0.13 -0.15 -0.24 0.00 Minimum -8.0 -8.3 -5.0 -8.1 10OCT11:15:07:30 LEO80185 G23 t48.doc Continued...

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Table 48: Summary of urinary calcium:creatinine ratio and change from baseline at Weeks 4 and 8: safety analysis set, continued Urinary Cal-cium/Creatinine (mmol/g)

Daivobet® gel

(n=482)

Betamethasone gel

(n=479)

Calcipotriol gel

(n=96)

Vehicle (n=95)

Change from Baseline Week 4 Maximum 7.3 22.2 12.2 7.0 Number 418 410 82 75 Week 8 Mean -0.22 -0.18 0.07 -0.28 SD 2.36 2.36 1.85 2.28 Median -0.10 -0.20 0.10 -0.25 Minimum -9.2 -8.5 -4.4 -8.2 Maximum 13.7 11.4 7.9 4.6 Number 427 400 80 72 End of Treatment Mean -0.23 -0.22 0.04 -0.29 SD 2.34 2.34 1.80 2.28 Median -0.14 -0.18 0.13 -0.16 Minimum -9.2 -8.5 -4.4 -8.2 Maximum 13.7 11.4 7.9 4.6 Number 448 429 90 80 10OCT11:15:07:30 LEO80185 G23 t48.doc

1) Two subjects received wrong trial medication during the study, subject from visit 4 and subject from visit 5. The majority of subjects in all treatment groups had urinary calcium:creatinine ratio values within the normal reference range at baseline (0.300 to 6.100 mmol/g in males and 0.225 to 8.200 mmol/g in females) and did not record a shift at Weeks 4 and 8 or the end of treatment. For the minority of subjects that recorded a shift, the pattern of shifts was largely similar across the treatment groups (Table 49).

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Table 49: Shift tables for Urinary calcium:creatinine ratio from baseline to Weeks 4 and 8: safety analysis set






End of Period

category1

Vehicle (n=95)


Urinary Cal-cium/Creatinine

Baseline catego-ry1,2 Low Normal High Low Normal High Normal High Low Normal High

Week 4 LOW 1 4 0 0 3 0 1 0 0 2 0 NORMAL 6 356 14 6 354 19 73 5 2 62 3 HIGH 0 29 8 0 18 10 3 0 0 4 2 Week 8 LOW 1 4 0 0 3 0 1 0 0 2 0 NORMAL 3 369 15 1 350 17 73 2 1 64 0 HIGH 0 28 7 0 18 11 2 2 0 5 0 End of Treat-ment

LOW 1 4 0 0 3 0 1 0 0 2 0

NORMAL 3 387 16 1 377 17 82 2 1 70 0 HIGH 0 30 7 0 20 11 3 2 0 7 0 23SEP11:12:01:35 LEO80185 G23 t49.doc


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Urinary phosphate:creatinine ratio is summarised at each visit together with change from baseline for the safety analysis set in Table 50. Urinary phosphate:creatinine ratio was similar across the treatment groups at all visits and at the end of treatment.

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Table 50: Summary of urinary phosphate:creatinine ratio and change from baseline at Weeks 4 and 8: safety analysis set Urinary Phos-phate/Creatinine (mg/mg)

Daivobet® gel

(n=482)

Betamethasone gel

(n=479)

Calcipotriol gel

(n=96)

Vehicle (n=95)

Summary1 Baseline Mean 0.499 0.509 0.503 0.465 SD 0.263 0.254 0.247 0.244 Median 0.473 0.485 0.479 0.440 Minimum 0.00 0.05 0.04 0.05 Maximum 1.59 1.82 1.15 1.55 Number 468 468 95 91 Week 4 Mean 0.519 0.536 0.517 0.517 SD 0.258 0.244 0.269 0.260 Median 0.501 0.513 0.488 0.475 Minimum 0.03 0.02 0.02 0.05 Maximum 1.64 1.53 1.32 1.48 Number 427 415 83 78 Week 8 Mean 0.517 0.546 0.564 0.542 SD 0.244 0.266 0.255 0.253 Median 0.493 0.511 0.562 0.545 Minimum 0.01 0.03 0.01 0.01 Maximum 1.29 1.50 1.55 1.20 Number 434 405 81 74 End of Treatment Mean 0.513 0.542 0.546 0.529 SD 0.247 0.265 0.248 0.249 Median 0.487 0.508 0.524 0.520 Minimum 0.01 0.02 0.01 0.01 Maximum 1.29 1.50 1.55 1.20 Number 458 434 91 83 Change from Baseline Week 4 Mean 0.009 0.026 0.013 0.022 SD 0.283 0.273 0.256 0.249 Median 0.016 0.027 0.003 0.018 Minimum -1.20 -1.41 -0.88 -0.51 10OCT11:15:07:50 LEO80185 G23 t50.doc Continued...

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Table 50: Summary of urinary phosphate:creatinine ratio and change from baseline at Weeks 4 and 8: safety analysis set, continued Urinary Phos-phate/Creatinine (mg/mg)

Daivobet® gel

(n=482)

Betamethasone gel

(n=479)

Calcipotriol gel

(n=96)

Vehicle (n=95)

Change from Baseline Week 4 Maximum 0.84 0.81 0.63 1.08 Number 418 410 82 75 Week 8 Mean 0.011 0.037 0.056 0.047 SD 0.283 0.306 0.261 0.251 Median 0.011 0.037 0.059 0.077 Minimum -1.27 -1.65 -0.61 -0.63 Maximum 1.00 1.12 0.94 0.51 Number 427 400 80 72 End of Treatment Mean 0.010 0.031 0.044 0.044 SD 0.282 0.302 0.255 0.249 Median 0.010 0.033 0.056 0.077 Minimum -1.27 -1.65 -0.61 -0.63 Maximum 1.00 1.12 0.94 0.51 Number 448 429 90 80 10OCT11:15:07:50 LEO80185 G23 t50.doc

1) Two subjects received wrong trial medication during the study, subject from visit 4 and subject from visit 5. The majority of subjects in all treatment groups had urinary phosphate:creatinine ratio values within the normal reference range at baseline (males <40 years: 0.036 to 1.770 and ≥40 years 0.054 to 0.860; females <40 years: 0.111 to 0.927 and ≥40 years 0.105 to 1.081 mg/mg) and did not record a shift at Weeks 4 and 8 or the end of treatment. For the minority of subjects that recorded a shift, the pattern of shifts was largely similar across the treatment groups (Table 51).

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Table 51: Shift tables for urinary phosphate:creatinine ratio from baseline to Weeks 4 and 8: safety analysis set







Vehicle(n=95)


Urinary Phos-phate/Creatinine



LOW 2 9 0 0 6 0 2 2 0 0 0 0



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Mean urinary calcium values and changes from baseline are summarised in Table 86 and shifts in urinary calcium are summarised in Table 87. Likewise, urinary phosphate values and changes from baseline are summarised in Table 88 and shifts in urinary phosphate are summarised in Table 89 and urinary creatinine values and changes from baseline are summa-rised in Table 90 and shifts in urinary creatinine are summarised in Table 91.

12.5 VITAL SIGNS, PHYSICAL FINDINGS AND OTHER OBSERVATIONS RELATED TO SAFETY

Not applicable.

12.6 SAFETY CONCLUSIONS

The incidence of AEs was generally similar for the four treatment groups with 26.0% of subjects experiencing at least one AE in the DAIVOBET/DOVOBET gel group, 20.0% in the betamethasone gel group, 23.2% in the calcipotriol gel group and 23.2% in the gel vehicle group. Although statistical comparisons of the incidence of AEs in each treatment group showed a statistically significant difference between the betamethasone gel group (20.0%) and the DAIVOBET/DOVOBET gel group (26.0%, p=0.028) there were no statistically significant differences between DAIVOBET/DOVOBET gel and calcipotriol gel or gel vehicle. Most commonly, AEs were: infections or infestations, skin and subcutaneous tissue disorders, or affected the investigations system organ class. These events were all reported at similar incidences across the treatments groups. The majority of AEs were not considered treatment-related by the investigators. Overall ADRs were reported by 5.0% of subjects in the DAIVOBET/DOVOBET gel group, 3.1% in the betamethasone gel group, 5.3% in the calcipotriol gel group and 4.2% in the gel vehicle group. No statistically significant differences were detected between DAIVOBET/DOVOBET gel and betamethasone gel, calcipotriol gel and gel vehicle for the incidence of ADRs. The most common ADR reported was blood parathyroid hormone increased, which was reported for 1.5% of subjects in the DAIVOBET/DOVOBET gel group, 1.3% in the betamethasone gel group, 0% in the calcipotriol gel group and 1.1% in the gel vehicle group. Two centres accounted for the majority of blood parathyroid increased AEs (20/23 events). increased AE was reported Adverse events in the treatment area were reported for 2.7% of subjects in the DAIVOBET/DOVOBET gel group, 2.3% in the betamethasone gel group, 4.2% in the calcipotriol gel group and 4.2% in the gel vehicle group. The only AEs in

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the treatment area reported by more than a single case in any treatment group were pruritus, application site pain and paresthesia, which were reported at incidences of 0.4%, 0.4% and 0%, respectively, in the DAIVOBET/DOVOBET gel group. There were no deaths during the study. One SAE of hypertension was reported in the DAIVOBET/DOVOBET gel group (0.2%), which was not considered related to study treatment. In the betamethasone gel group, 8 SAEs were reported for 7 subjects (1.5%), all of which were considered unrelated to study treatment except for one case of nephrolithiasis. No SAEs were reported in the calcipotriol gel group and 1 subject (1.1%) in the gel vehicle group has an SAE (suicide attempt, unrelated to treatment). Although not necessarily the main reason for withdrawal, AEs led to the discontinuation of 6 subjects in the DAIVOBET/DOVOBET gel group and 5 each in the betamethasone gel and calcipotriol gel groups. An additional subject ( ) in the betamethasone gel group discontinued due to guttate psoriasis but recorded the reason for withdrawal as ‘other’. There were no clinically relevant mean changes in the laboratory parameters. The majority of subjects in all treatment groups had laboratory values within the normal reference range at baseline and did not record a shift at Weeks 4 and 8 or the end of treatment. For the minority of subjects that recorded a shift, the pattern of shifts was similar across the treatment groups.

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13 DISCUSSION AND OVERALL CONCLUSIONS

The primary objective of this study was to compare the efficacy of once daily treatment for up to 8 weeks of DAIVOBET/DOVOBET gel with betamethasone gel, calcipotriol gel and the gel vehicle alone in subjects with psoriasis vulgaris on the non-scalp regions of the body (trunk and/or limbs). The primary efficacy assessment was the proportion of subjects with ‘Controlled disease’ (defined as clear or almost clear for subjects with moderate disease at baseline and clear for subjects with mild disease at baseline) measured by the IGA at Weeks 4 and 8. Percentage change in PASI from baseline to Weeks 4 and 8 was also assessed as a secondary endpoint. Subjects included had a disease severity according to the IGA of mild or moderate on the body (trunk and/or limbs) at Day 0 (Visit 1) and a minimum PASI score for extent of 2 in at least one body region (i.e. an extent of at least 10% on the arms or trunk or legs). A total of 1423 subjects were recruited from 59 centres in the USA. Of these, 1152 subjects were randomised according to the 5:5:1:1 randomisation pattern and received treatment (482 in the DAIVOBET/DOVOBET gel group, 479 in the betamethasone gel group, 96 in the calcipotriol gel group and 95 in the gel vehicle group). Compliance with the treatment regimen was excellent with over 90% of subjects in the DAIVOBET/DOVOBET gel group, betamethasone gel group, and gel vehicle group and almost 90% in the calcipotriol gel group applying medication as instructed or missing 10% or less of applications. The analysis of the proportion of subjects who achieved ‘Controlled disease’ according to the IGA at week 8 (LOCF) showed that DAIVOBET/DOVOBET gel was superior to be-tamethasone gel, calcipotriol gel and the gel vehicle (p≤0.008). The proportion of subjects who achieved ‘Controlled disease’ was: 29.0% in the DAIVOBET/DOVOBET gel group compared with 21.5% in the betamethasone gel group, 14.6% in the calcipotriol gel group and 6.3% in the gel vehicle group. At Week 4 (LOCF) similar percentages of subjects had ‘Controlled disease’ in the DAIVOBET/DOVOBET gel group and in the betamethasone gel group, (13.3% and 12.5%, respectively, p=0.82). However, the response rate for DAIVOBET/DOVOBET gel was statistically significantly higher than for calcipotriol gel

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(5.2%, p=0.019) and the gel vehicle group (2.1%, p=0.001). As all three tests were not statistically significant at Week 4, a claim of superiority could not be made at this timepoint. For mean percentage change in PASI, DAIVOBET/DOVOBET gel was superior to be-tamethasone gel, calcipotrol gel and gel vehicle at both Week 4 (0≤0.038) and Week 8 (p<0.001). The mean percentage change in PASI from baseline to Week 4 (LOCF) was -46.4 in the DAIVOBET/DOVOBET gel group, compared with -42.7 in the betamethasone gel group, -32.2 in the calcipotriol gel group and -17.4 in the gel vehicle group. The corre-sponding numbers at Week 8 (LOCF) were: -55.8 in the DAIVOBET/DOVOBET gel group, compared with -48.6 in the betamethasone gel group, -43.6 in the calcipotriol gel group and -20.9 in the gel vehicle group. The analysis of the per protocol analysis set supported the results for the full analysis set at Week 8. The results from this pivotal phase 3 study were in agreement with the previous phase 2 study, MBL 0202 INT (23) and the previous phase 3 study, LEO 80185-G21 (24). In the phase 2 study, MBL 0202 INT, the proportion of subjects who achieved ‘Controlled disease’ at Weeks 4 and 8 respectively were 16.0% and 27.2% in the DAIVOBET/DOVOBET gel group, 9.6 % and 16.9 % in the betamethasone dipropionate in the gel vehicle group, 3.8 % and 11.4 % in the calcipotriol in the gel vehicle group and 2.5% and 0.0% in the gel vehicle group. The analysis of the proportion of subjects with ‘Controlled disease’ according to the IGA showed that DAIVOBET/DOVOBET gel was statistically significantly more effective than betamethasone dipropionate in the gel vehicle, calcipotriol in the gel vehicle and the gel vehicle at Week 8, and than calcipotriol in the gel vehicle and the gel vehicle at Week 4. In terms of the percentage change in PASI from baseline DAIVOBET/DOVOBET gel was statistically significantly more effective than betamethasone dipropionate in the gel vehicle, calcipotriol in the gel vehicle and the gel vehicle at Week 4 and than calcipotriol in the gel vehicle and the gel vehicle at Week 8. The percentage changes in PASI from baseline to Weeks 4 and 8 respectively were −48.1 and −55.3 in the DAIVOBET/DOVOBET gel group, −40.9 and −49.8in the betamethasone dipropionate in the gel vehicle group, −32.7 and −41.2 in the calcipotriol in the gel vehicle group and −16.9% and −11.9% in the gel vehicle group. Subjects in Study MBL 0202 INT had to have a disease severity of at least mild according to the IGA.

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Furthermore, Study LEO 80185-G21 in subjects with a disease severity of at least moderate according to the IGA and a minimum PASI for extent of 2 in at least one body region, showed that 39.9% of subjects achieved ‘Controlled disease’ at Week 8, in the DAIVOBET/DOVOBET gel group compared with 5.5% in the gel vehicle group. DAIVOBET/DOVOBET gel was statistically significantly more effective than the gel vehicle (OR 13.9; 95% CI 4.99 to 38.7; p<0.001). In Study LEO 80185-G21, DAIVOBET/DOVOBET gel was found to be statistically significantly more effective than the gel vehicle in terms of the proportion of subjects who achieved ‘Controlled disease’ according to the IGA at Week 4 (LOCF) and the percentage change in PASI from baseline to Weeks 4 and 8. In addition the percentages of subjects who achieved PASI 75, PASI 50 and ‘Con-trolled disease’ according to the patient’s global assessment of disease severity were greater at every visit in the DAIVOBET/DOVOBET gel group compared to the gel vehicle group. The incidence of AEs in the current study was low, as expected, and similar for the four treatment groups. The most common ADR: blood PTH increased, reported for 1.5% in the DAIVOBET/DOVOBET gel group, 1.3% in the betamethasone gel group, 0% in the cal-cipotriol gel group and 1.1% in the gel vehicle group. The next most common ADR was pruritus, which was amongst the most common ADRs in the MBL 0202 INT (23) study and the LEO 80185-G21 study (24). In previous studies blood PTH increased has not been observed most likely because the studies did not include laboratory assessment of this parameter. However, no between treatment differences in plasma PTH levels were detected in this study. Parathyroid hormone levels exhibit diurnal variation which is largely caused by endogenous circadian rhythm (36). Some studies showed that the intraindividual variation in PTH levels could be as much as 25% (37). Since the blood samples in the current study were not taken at a fixed time of the day, the ADRs of blood PTH increased reported in some of the subjects may be due to diurnal variation. Furthermore the samples for each subject were measured and reported at each visit rather than batched for assessment in the same assay. Thus inter-assay variation may also have confounded the clinical picture and contributed to the wide variation observed in the PTH levels reported. In the laboratory data for the overall study population there was no evidence to indicate that treatment with DAIVOBET/DOVOBET gel, betamethasone gel or calcipotriol gel had a different safety profile with respect to PTH than the gel vehicle. The mean values were similar among all the treatment groups at baseline and at Weeks 4 and 8 and the end of

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treatment. There was a small decrease from baseline in mean PTH during treatment and the pattern of shifts from normal at baseline to high values during treatment and high at baseline to normal values during treatment was similar among the groups. Thus the evidence to support an effect of DAIVOBET/DOVOBET gel on PTH is unclear and is not considered to represent a robust safety signal. It is also of interest to observe the proportion of subjects with increased PTH values at baseline. Approximately 20% of the subjects who had PTH values reported both at baseline and at least one other visit during the treatment period, had an increased PTH value at baseline. The reason for this apparent hyperparathyroidism is unknown. Primary hyperpara-thyroidism would seem unlikely since only a few subjects had increased calcium values. Indeed, decreased calcium values were a more frequent finding. Of the subjects who had both a baseline calcium value and at least one calcium value during the treatment period, approxi-mately 14% had a decreased calcium value at baseline which can indicate secondary hyper-parathyroidism. However, although secondary hyperparathyroidism can be caused by Vitamin D deficiency, there are several other possible causes of this condition. There were no mean changes in the other laboratory parameters that were considered clini-cally relevant. In conclusion, the efficacy of DAIVOBET/DOVOBET gel was superior to betamethasone gel, calcipotriol gel and the gel vehicle at Week 8. Additionally, DAIVOBET/DOVOBET gel was superior to betamethasone gel, calcipotriol gel and the gel vehicle at both Week 4 and Week 8 according to percentage change from baseline in PASI. No new safety concerns were raised for DAIVOBET/DOVOBET gel in the treatment of subjects with psoriasis vulgaris on the non-scalp regions of the body (trunk and/or limbs) for up to 8 weeks.

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14 TABLES, FIGURES AND GRAPHS REFERRED TO BUT NOT INCLUDED IN THE TEXT

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14.1 DEMOGRAPHIC DATA

Table 52: Reasons for withdrawal by last on-treatment visit for which data are recorded: randomised subjects


Last visit attended

Betamethasone gel(n=479)

Last visit attended


Last visit attended

Vehicle(n=95)

Last visit attended

Withdrawals 1 2 3 4 5 1 2 3 4 5 1 2 3 4 5 1 2 3 4 5 Unacceptable treat-ment efficacy

0 2 1 0 0 0 0 1 2 0 0 2 0 1 0 0 1 1 0 2

Unacceptable adverse event

1 0 1 1 0 0 0 1 0 2 1 0 1 2 0 0 0 0 0 0

Exclusion criteria emerging during study

0 2 1 1 0 0 0 2 0 0 0 0 0 0 0 0 0 0 0 0

Voluntary (and no other reason)

0 2 1 2 1 5 1 4 3 3 1 0 1 0 0 2 1 0 0 0

Lost to follow-up 5 3 4 3 0 9 5 11 2 3 1 1 1 1 0 3 0 3 2 1 Other reason(s)1,2,3,4 1 4 0 2 0 3 1 0 4 0 1 0 0 0 0 0 1 0 1 0 Total number of withdrawn subjects

7 13 8 9 1 17 7 19 11 8 4 3 3 4 0 5 3 4 3 3

02AUG11:10:26:00 LEO80185 G23 t52.doc

1) Other reasons: Investigator decision (subject ), Transportation problems (subjects and ), Clinically significant PTH levels at baseline (subject 2) and ), Work commitments (subjects and ), Pregnancy (subject ), Non-compliance (subjects , and ), 3) Personal reasons (subjects , and ), Schedule conflicts (subject ), Developed GUTTATE PSORIASIS (subject ), 4) Enrolled in error (subjects and )

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Table 53: Investigator’s assessment of clinical signs at baseline: randomised subjects

All subjects (n=1152)


Betamethasone gel



Location Clinical sign Assessment

Number of subjects

%

Number of subjects

%

Number of subjects

%

Number of subjects

%

Number of subjects

%

ARM Redness None 72 6.3 36 7.5 27 5.6 6 6.3 3 3.2 Mild 253 22.0 114 23.7 97 20.3 18 18.8 24 25.3 Moderate 685 59.5 264 54.8 296 61.8 65 67.7 60 63.2 Severe 137 11.9 65 13.5 57 11.9 7 7.3 8 8.4 Very severe 5 0.4 3 0.6 2 0.4 0 0.0 0 0.0 Total 1152 100.0 482 100.0 479 100.0 96 100.0 95 100.0 Thickness None 69 6.0 34 7.1 25 5.2 5 5.2 5 5.3 Mild 220 19.1 89 18.5 93 19.4 21 21.9 17 17.9 Moderate 712 61.8 296 61.4 299 62.4 60 62.5 57 60.0 Severe 141 12.2 60 12.4 58 12.1 8 8.3 15 15.8 Very severe 10 0.9 3 0.6 4 0.8 2 2.1 1 1.1 Total 1152 100.0 482 100.0 479 100.0 96 100.0 95 100.0 Scaliness None 73 6.3 36 7.5 28 5.8 5 5.2 4 4.2 Mild 237 20.6 97 20.1 95 19.8 18 18.8 27 28.4 Moderate 661 57.4 278 57.7 279 58.2 58 60.4 46 48.4 Severe 170 14.8 67 13.9 71 14.8 14 14.6 18 18.9 19AUG11:13:51:56 LEO80185 G23 t53.doc Continued...

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Table 53: Investigator’s assessment of clinical signs at baseline: randomised subjects, continued



Betamethasone gel




Number of subjects

%

Number of subjects

%

Number of subjects

%

Number of subjects

%

Number of subjects

%

ARM Scaliness Very severe 11 1.0 4 0.8 6 1.3 1 1.0 0 0.0 Total 1152 100.0 482 100.0 479 100.0 96 100.0 95 100.0 Extent No involvement 65 5.6 32 6.6 25 5.2 5 5.2 3 3.2 < 10% 366 31.8 146 30.3 156 32.6 30 31.3 34 35.8 10 - 29 % 635 55.1 276 57.3 253 52.8 54 56.3 52 54.7 30 - 49 % 70 6.1 23 4.8 34 7.1 7 7.3 6 6.3 50 - 69 % 12 1.0 3 0.6 9 1.9 0 0.0 0 0.0 70 - 89 % 4 0.3 2 0.4 2 0.4 0 0.0 0 0.0 Total 1152 100.0 482 100.0 479 100.0 96 100.0 95 100.0 TRUNK Redness None 373 32.4 157 32.6 159 33.2 25 26.0 32 33.7 Mild 200 17.4 85 17.6 87 18.2 15 15.6 13 13.7 Moderate 469 40.7 193 40.0 192 40.1 45 46.9 39 41.1 Severe 105 9.1 43 8.9 41 8.6 10 10.4 11 11.6 Very severe 5 0.4 4 0.8 0 0.0 1 1.0 0 0.0 Total 1152 100.0 482 100.0 479 100.0 96 100.0 95 100.0 Thickness None 379 32.9 160 33.2 160 33.4 26 27.1 33 34.7 19AUG11:13:51:56 LEO80185 G23 t53.doc Continued...

LEO 80185-G23 11-Oct-2011 of 349




Betamethasone gel




Number of subjects

%

Number of subjects

%

Number of subjects

%

Number of subjects

%

Number of subjects

%

TRUNK Thickness Mild 233 20.2 104 21.6 102 21.3 14 14.6 13 13.7 Moderate 472 41.0 193 40.0 189 39.5 48 50.0 42 44.2 Severe 64 5.6 22 4.6 27 5.6 8 8.3 7 7.4 Very severe 4 0.3 3 0.6 1 0.2 0 0.0 0 0.0 Total 1152 100.0 482 100.0 479 100.0 96 100.0 95 100.0 Scaliness None 381 33.1 160 33.2 164 34.2 25 26.0 32 33.7 Mild 265 23.0 116 24.1 112 23.4 17 17.7 20 21.1 Moderate 435 37.8 178 36.9 173 36.1 46 47.9 38 40.0 Severe 66 5.7 24 5.0 29 6.1 8 8.3 5 5.3 Very severe 5 0.4 4 0.8 1 0.2 0 0.0 0 0.0 Total 1152 100.0 482 100.0 479 100.0 96 100.0 95 100.0 Extent No involvement 368 31.9 154 32.0 158 33.0 24 25.0 32 33.7 < 10% 457 39.7 198 41.1 183 38.2 41 42.7 35 36.8 10 - 29 % 276 24.0 108 22.4 118 24.6 25 26.0 25 26.3 30 - 49 % 41 3.6 19 3.9 14 2.9 5 5.2 3 3.2 50 - 69 % 5 0.4 1 0.2 3 0.6 1 1.0 0 0.0 70 - 89 % 5 0.4 2 0.4 3 0.6 0 0.0 0 0.0 Total 1152 100.0 482 100.0 479 100.0 96 100.0 95 100.0 19AUG11:13:51:56 LEO80185 G23 t53.doc Continued...

LEO 80185-G23 11-Oct-2011 of 349




Betamethasone gel




Number of subjects

%

Number of subjects

%

Number of subjects

%

Number of subjects

%

Number of subjects

%

LEG Redness None 50 4.3 15 3.1 30 6.3 2 2.1 3 3.2 Mild 191 16.6 79 16.4 80 16.7 19 19.8 13 13.7 Moderate 688 59.7 294 61.0 278 58.0 55 57.3 61 64.2 Severe 211 18.3 89 18.5 86 18.0 19 19.8 17 17.9 Very severe 12 1.0 5 1.0 5 1.0 1 1.0 1 1.1 Total 1152 100.0 482 100.0 479 100.0 96 100.0 95 100.0 Thickness None 50 4.3 15 3.1 30 6.3 2 2.1 3 3.2 Mild 200 17.4 76 15.8 90 18.8 13 13.5 21 22.1 Moderate 740 64.2 328 68.0 289 60.3 68 70.8 55 57.9 Severe 154 13.4 61 12.7 64 13.4 13 13.5 16 16.8 Very severe 8 0.7 2 0.4 6 1.3 0 0.0 0 0.0 Total 1152 100.0 482 100.0 479 100.0 96 100.0 95 100.0 Scaliness None 50 4.3 15 3.1 31 6.5 2 2.1 2 2.1 Mild 217 18.8 89 18.5 89 18.6 15 15.6 24 25.3 Moderate 684 59.4 282 58.5 283 59.1 62 64.6 57 60.0 Severe 185 16.1 93 19.3 65 13.6 16 16.7 11 11.6 19AUG11:13:51:56 LEO80185 G23 t53.doc Continued...

LEO 80185-G23 11-Oct-2011 of 349




Betamethasone gel




Number of subjects

%

Number of subjects

%

Number of subjects

%

Number of subjects

%

Number of subjects

%

LEG Scaliness Very severe 16 1.4 3 0.6 11 2.3 1 1.0 1 1.1 Total 1152 100.0 482 100.0 479 100.0 96 100.0 95 100.0 Extent No involvement 41 3.6 10 2.1 27 5.6 2 2.1 2 2.1 < 10% 364 31.6 163 33.8 149 31.1 25 26.0 27 28.4 10 - 29 % 630 54.7 262 54.4 252 52.6 56 58.3 60 63.2 30 - 49 % 92 8.0 36 7.5 40 8.4 12 12.5 4 4.2 50 - 69 % 20 1.7 9 1.9 8 1.7 1 1.0 2 2.1 70 - 89 % 5 0.4 2 0.4 3 0.6 0 0.0 0 0.0 Total 1152 100.0 482 100.0 479 100.0 96 100.0 95 100.0 19AUG11:13:51:56 LEO80185 G23 t53.doc

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Table 54: Physical examination (weight, height, blood pressure): randomised subjects

Physical examination



Betamethasone gel



Height Mean 172.0 172.2 172.0 171.7 171.5 SD 10.1 10.0 10.1 10.6 10.1 Median 172.7 172.7 172.7 172.7 172.1 Minimum 137.2 137.2 149.9 150.5 139.7 Maximum 205.7 205.7 205.7 195.6 203.2 Number 1148 479 479 96 94 Weight Mean 91.6 91.8 91.2 94.2 90.6 SD 22.6 22.4 23.0 22.8 20.8 Median 89.2 88.5 89.3 91.2 88.3 Minimum 43.5 49.9 44.5 56.2 43.5 Maximum 226.8 198.7 226.8 165.0 158.8 Number 1147 479 478 96 94 Systolic Blood Pressure Mean 129.2 129.1 129.4 130.6 127.2 SD 15.4 15.2 15.6 16.2 14.6 Median 128.0 127.0 128.0 129.0 125.0 Minimum 92.0 98.0 92.0 102.0 95.0 Maximum 206.0 188.0 206.0 189.0 173.0 06JUL11:15:58:13 LEO80185 G23 t54.doc Continued...

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Table 54: Physical examination (weight, height, blood pressure): randomised subjects, continued

Physical examination



Betamethasone gel



Systolic Blood Pressure Number 1151 481 479 96 95 Diastolic Blood Pressure Mean 80.9 80.8 81.1 81.3 80.0 SD 9.4 9.7 9.2 9.4 9.4 Median 80.0 80.0 82.0 80.0 80.0 Minimum 50.0 50.0 50.0 60.0 56.0 Maximum 125.0 124.0 125.0 110.0 100.0 Number 1151 481 479 96 95 06JUL11:15:58:13 LEO80185 G23 t54.doc

LEO 80185-G23 11-Oct-2011 of 349

Table 55: Relevant medical history and concurrent diagnoses at baseline by MedDRA primary SOC: randomised subjects


Daivobet® gel

(n=482)

Betamethasone gel

(n=479)

Calcipotriol gel

(n=96)

Vehicle (n=95)

System Organ Classification1 No. Diag.

No. Subj.

%

No. Diag.

No. Subj.

%

No. Diag.

No. Subj.

%

No. Diag.

No. Subj.

%

No. Diag.

No. Subj.

%

Blood and lymphatic system disorders

13 13 1.1 4 4 0.8 7 7 1.5 2 2 2.1 0 0 0.0

Cardiac disorders 71 62 5.4 37 32 6.6 23 21 4.4 2 2 2.1 9 7 7.4 Congenital, familial and genetic disorders

11 11 1.0 6 6 1.2 5 5 1.0 0 0 0.0 0 0 0.0

Ear and labyrinth disorders 31 31 2.7 19 19 3.9 10 10 2.1 1 1 1.0 1 1 1.1 Endocrine disorders 85 82 7.1 36 35 7.3 37 35 7.3 9 9 9.4 3 3 3.2 Eye disorders 108 97 8.4 47 42 8.7 42 40 8.4 7 4 4.2 12 11 11.6 Gastrointestinal disorders 190 170 14.8 80 69 14.3 76 71 14.8 17 13 13.5 17 17 17.9 General disorders and administration site conditions

42 41 3.6 15 15 3.1 18 18 3.8 6 5 5.2 3 3 3.2

Hepatobiliary disorders 18 18 1.6 9 9 1.9 7 7 1.5 1 1 1.0 1 1 1.1 Immune system disorders 293 246 21.4 118 99 20.5 128 108 22.5 18 17 17.7 29 22 23.2 Infections and infestations 102 90 7.8 38 31 6.4 47 45 9.4 9 7 7.3 8 7 7.4 Injury, poisoning and procedural complications

57 51 4.4 24 21 4.4 23 20 4.2 7 7 7.3 3 3 3.2

Investigations 128 107 9.3 62 52 10.8 45 36 7.5 13 11 11.5 8 8 8.4 Metabolism and nutrition disorders

336 257 22.3 129 100 20.7 139 104 21.7 37 30 31.3 31 23 24.2

Musculoskeletal and connective tissue disorders

301 250 21.7 123 103 21.4 135 113 23.6 19 19 19.8 24 15 15.8


LEO 80185-G23 11-Oct-2011 of 349

Table 55: Relevant medical history and concurrent diagnoses at baseline by MedDRA primary SOC: randomised subjects, continued


Daivobet® gel

(n=482)

Betamethasone gel

(n=479)

Calcipotriol gel

(n=96)

Vehicle (n=95)


No. Subj.

%

No. Diag.

No. Subj.

%

No. Diag.

No. Subj.

%

No. Diag.

No. Subj.

%

No. Diag.

No. Subj.

%

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

73 61 5.3 34 27 5.6 32 28 5.8 5 4 4.2 2 2 2.1

Nervous system disorders 150 135 11.7 62 57 11.8 63 56 11.7 12 10 10.4 13 12 12.6 Pregnancy, puerperium and perinatal conditions

9 9 0.8 5 5 1.0 3 3 0.6 0 0 0.0 1 1 1.1

Psychiatric disorders 238 184 16.0 111 78 16.2 89 77 16.1 18 14 14.6 20 15 15.8 Renal and urinary disorders 29 28 2.4 15 14 2.9 10 10 2.1 2 2 2.1 2 2 2.1 Reproductive system and breast disorders

123 119 10.3 55 52 10.8 47 46 9.6 12 12 12.5 9 9 9.5

Respiratory, thoracic and mediastinal disorders

118 104 9.0 52 45 9.3 47 42 8.8 12 10 10.4 7 7 7.4

Skin and subcutaneous tissue disorders

140 124 10.8 58 51 10.6 56 50 10.4 15 12 12.5 11 11 11.6

Social circumstances 22 21 1.8 9 9 1.9 11 10 2.1 2 2 2.1 0 0 0.0 Surgical and medical procedures

896 512 44.4 387 219 45.4 355 208 43.4 77 42 43.8 77 43 45.3

Vascular disorders 262 257 22.3 110 110 22.8 111 107 22.3 19 19 19.8 22 21 22.1 Total number of diagnoses2

3846

1645

1566

322

313


LEO 80185-G23 11-Oct-2011 of 349

Table 55: Relevant medical history and concurrent diagnoses at baseline by MedDRA primary SOC: randomised subjects, continued


Daivobet® gel

(n=482)

Betamethasone gel

(n=479)

Calcipotriol gel

(n=96)

Vehicle (n=95)


No. Subj.

%

No. Diag.

No. Subj.

%

No. Diag.

No. Subj.

%

No. Diag.

No. Subj.

%

No. Diag.

No. Subj.

%

Total number of subjects

910

79.0

382

79.3

375

78.3

79

82.3

74

77.9

26AUG11:13:55:31 LEO80185 G23 t55.doc

1) Classification according to MedDRA version 6.1. 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.

LEO 80185-G23 11-Oct-2011 of 349

Table 56: Concomitant medication at baseline: randomised subjects





Vehicle (n=95)

ATC classificationindex level 11

No. Drugs

No. Subj %

No. Drugs

No. Subj %

No. Drugs

No. Subj %

No. Drugs

No. Subj %

No. Drugs

No. Subj %

ALIMENTARY TRACT AND METABOLISM

599 336 29.2 247 133 27.6 248 143 29.9 53 30 31.3 51 30 31.6

ANTIINFECTIVES FOR SYSTEMIC USE

15 11 1.0 2 2 0.4 10 8 1.7 0 0 0.0 3 1 1.1

ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS

5 5 0.4 1 1 0.2 4 4 0.8 0 0 0.0 0 0 0.0

BLOOD AND BLOOD FORMING ORGANS 175 140 12.2 81 63 13.1 63 51 10.6 14 13 13.5 17 13 13.7 CARDIOVASCULAR SYSTEM 740 369 32.0 327 163 33.8 288 148 30.9 59 30 31.3 66 28 29.5 DERMATOLOGICALS 34 30 2.6 15 12 2.5 17 16 3.3 1 1 1.0 1 1 1.1 GENITO URINARY SYSTEM AND SEX HORMONES

86 76 6.6 30 28 5.8 40 32 6.7 5 5 5.2 11 11 11.6

MUSCULO-SKELETAL SYSTEM 167 146 12.7 69 60 12.4 76 66 13.8 12 12 12.5 10 8 8.4 NERVOUS SYSTEM 400 243 21.1 184 104 21.6 155 101 21.1 33 20 20.8 28 18 18.9 RESPIRATORY SYSTEM 148 105 9.1 64 47 9.8 60 43 9.0 9 5 5.2 15 10 10.5 SENSORY ORGANS 14 12 1.0 3 3 0.6 8 6 1.3 1 1 1.0 2 2 2.1 SYSTEMIC HORMONAL PREP.,EXCL.SEX HORM.AND INSULIN

77 77 6.7 31 31 6.4 34 34 7.1 9 9 9.4 3 3 3.2

VARIOUS 49 30 2.6 20 12 2.5 24 14 2.9 2 1 1.0 3 3 3.2 Total number of drugs taken1 2509 1074 1027 198 210 28JUL11:16:15:59 LEO80185 G23 t56.doc Continued...

LEO 80185-G23 11-Oct-2011 of 349

Table 56: Concomitant medication at baseline: randomised subjects, continued





Vehicle (n=95)

ATC classificationindex level 11

No. Drugs

No. Subj %

No. Drugs

No. Subj %

No. Drugs

No. Subj %

No. Drugs

No. Subj %

No. Drugs

No. Subj %

Total number of subjects taking drugs

668 58.0 278 57.7 275 57.4 58 60.4 57 60.0

28JUL11:16:15:59 LEO80185 G23 t56.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.

LEO 80185-G23 11-Oct-2011 of 349

14.2 EFFICACY DATA

Table 57: Sensitivity analysis of Percentage of subjects with “Controlled disease” (IGA) at Week 4 – missing values set to “Controlled disease”: full analysis set

Daivobet® gel




Controlled Disease

Number of subjects

%

Number of subjects

%

Number of subjects

%

Number of subjects

%

Controlled 99 20.5 108 22.5 16 16.7 15 15.8 Non-controlled 383 79.5 371 77.5 80 83.3 80 84.2 Total 482 100.0 479 100.0 96 100.0 95 100.0 Statistical analysis Difference (%) -2.0 3.9 4.7 95% CI -7.2 to 3.2 -4.4 to 12.2 -3.4 to 12.9 Odds ratio1 0.9 1.3 1.5 95% CI 0.6 to 1.2 0.7 to 2.4 0.8 to 2.8 CMH test p-value2 0.44 0.39 0.21 Breslow-Day test p-value3

0.55 0.37 0.37

15JUL11:13:39:45 LEO80185 G23 t57.doc


LEO 80185-G23 11-Oct-2011 of 349

Table 58: Sensitivity analysis of Percentage of subjects with “Controlled disease” (IGA) at Week 4 – missing values set to “Non-controlled disease”: full analysis set

Daivobet® gel




Controlled Disease

Number of subjects

%

Number of subjects

%

Number of subjects

%

Number of subjects

%


0.64 0.46 0.97

15JUL11:13:39:56 LEO80185 G23 t58.doc


LEO 80185-G23 11-Oct-2011 of 349

Table 59: Sensitivity analysis of Percentage of subjects with “Controlled disease” (IGA) at Week 4 – missing values set to “Non-controlled disease” for LEO80185 and to “Controlled disease” for the other treatments: full analysis set

Daivobet® gel




Controlled Disease

Number of subjects

%

Number of subjects

%

Number of subjects

%

Number of subjects

%

Controlled 63 13.1 108 22.5 16 16.7 15 15.8 Non-controlled 419 86.9 371 77.5 80 83.3 80 84.2 Total 482 100.0 479 100.0 96 100.0 95 100.0 Statistical analysis Difference (%) -9.5 -3.6 -2.7 95% CI -14.3 to -4.7 -11.6 to 4.4 -10.6 to 5.2 Odds ratio1 0.5 0.8 0.8 95% CI 0.4 to 0.7 0.4 to 1.5 0.4 to 1.6 CMH test p-value2 < 0.001 0.48 0.59 Breslow-Day test p-value3

0.88 0.097 0.35

15JUL11:13:40:10 LEO80185 G23 t59.doc


LEO 80185-G23 11-Oct-2011 of 349

Table 60: Sensitivity analysis of Percentage of subjects with “Controlled disease” (IGA) at week 8 – missing values set to “Controlled disease”: full analysis set

Daivobet® gel




Controlled Disease

Number of subjects

%

Number of subjects

%

Number of subjects

%

Number of subjects

%

Controlled 176 36.5 161 33.6 28 29.2 24 25.3 Non-controlled 306 63.5 318 66.4 68 70.8 71 74.7 Total 482 100.0 479 100.0 96 100.0 95 100.0 Statistical analysis Difference (%) 2.9 7.3 11.3 95% CI -3.1 to 8.9 -2.7 to 17.4 1.5 to 21.0 Odds ratio1 1.1 1.5 1.8 95% CI 0.9 to 1.5 0.9 to 2.4 1.1 to 3.1 CMH test p-value2 0.34 0.14 0.024 Breslow-Day test p-value3

0.50 0.77 0.78

15JUL11:13:40:21 LEO80185 G23 t60.doc


LEO 80185-G23 11-Oct-2011 of 349

Table 61: Sensitivity analysis of Percentage of subjects with “Controlled disease” (IGA) at week 8 – missing values set to “Non-controlled disease”: full analysis set

Daivobet® gel




Controlled Disease

Number of subjects

%

Number of subjects

%

Number of subjects

%

Number of subjects

%


0.65 0.95 0.98

15JUL11:13:40:36 LEO80185 G23 t61.doc


LEO 80185-G23 11-Oct-2011 of 349

Table 62: Sensitivity analysis of Percentage of subjects with “Controlled disease” (IGA) at week 8 – missing values set to “Non-controlled disease” for LEO80185 and to “Controlled disease” for the other treatments: full analysis set

Daivobet® gel




Controlled Disease

Number of subjects

%

Number of subjects

%

Number of subjects

%

Number of subjects

%

Controlled 137 28.4 161 33.6 28 29.2 24 25.3 Non-controlled 345 71.6 318 66.4 68 70.8 71 74.7 Total 482 100.0 479 100.0 96 100.0 95 100.0 Statistical analysis Difference (%) -5.2 -0.7 3.2 95% CI -11.0 to 0.7 -10.7 to 9.2 -6.5 to 12.8 Odds ratio1 0.8 1.0 1.2 95% CI 0.6 to 1.0 0.6 to 1.6 0.7 to 2.1 CMH test p-value2 0.081 0.96 0.42 Breslow-Day test p-value3

0.42 0.68 0.79

15JUL11:13:39:31 LEO80185 G23 t62.doc


LEO 80185-G23 11-Oct-2011 of 349

Table 63: Percentage of subjects with “Controlled disease” (IGA) at Weeks 4 and 8 by centre: full analysis set

Daivobet® gel Betamethasone gel Calcipotriol gel Vehicle Week Site id Controlled disease

Number of subjects

%

Number of subjects

%

Number of subjects

%

Number of subjects

%

Week 4 Controlled 2 18.2 1 9.1 0 0.0 0 0.0 Non-controlled 9 81.8 10 90.9 5 100.0 2 100.0 Total 11 100.0 11 100.0 5 100.0 2 100.0 Controlled 2 20.0 4 33.3 1 100.0 1 20.0 Non-controlled 8 80.0 8 66.7 0 0.0 4 80.0 Total 10 100.0 12 100.0 1 100.0 5 100.0 Controlled 0 0.0 1 7.7 0 0.0 0 0.0 Non-controlled 12 100.0 12 92.3 1 100.0 3 100.0 Total 12 100.0 13 100.0 1 100.0 3 100.0 Controlled 1 10.0 0 0.0 0 0.0 0 0.0 Non-controlled 9 90.0 13 100.0 1 100.0 3 100.0 Total 10 100.0 13 100.0 1 100.0 3 100.0 Controlled 3 27.3 2 22.2 0 0.0 0 0.0 Non-controlled 8 72.7 7 77.8 3 100.0 1 100.0 15JUL11:13:37:29 LEO80185 G23 t63.doc Continued...

LEO 80185-G23 11-Oct-2011 of 349

Table 63: Percentage of subjects with “Controlled disease” (IGA) at Weeks 4 and 8 by centre: full analysis set, continued


Number of subjects

%

Number of subjects

%

Number of subjects

%

Number of subjects

%

Week 4 Total 11 100.0 9 100.0 3 100.0 1 100.0 Controlled 2 14.3 2 11.8 0 0.0 0 0.0 Non-controlled 12 85.7 15 88.2 5 100.0 3 100.0 Total 14 100.0 17 100.0 5 100.0 3 100.0 Controlled 2 15.4 1 11.1 0 0.0 0 0.0 Non-controlled 11 84.6 8 88.9 2 100.0 1 100.0 Total 13 100.0 9 100.0 2 100.0 1 100.0 Controlled 4 40.0 1 7.7 0 0.0 0 0.0 Non-controlled 6 60.0 12 92.3 3 100.0 4 100.0 Total 10 100.0 13 100.0 3 100.0 4 100.0 Controlled 2 20.0 1 6.3 0 0.0 0 0.0 Non-controlled 8 80.0 15 93.8 0 0.0 2 100.0 Total 10 100.0 16 100.0 0 0.0 2 100.0 Controlled 1 12.5 1 10.0 0 0.0 0 0.0 Non-controlled 7 87.5 9 90.0 7 100.0 2 100.0 Total 8 100.0 10 100.0 7 100.0 2 100.0 15JUL11:13:37:29 LEO80185 G23 t63.doc Continued...

LEO 80185-G23 11-Oct-2011 of 349



Number of subjects

%

Number of subjects

%

Number of subjects

%

Number of subjects

%

Week 4 Controlled 0 0.0 0 0.0 0 0.0 0 0.0 Non-controlled 14 100.0 12 100.0 0 0.0 3 100.0 Total 14 100.0 12 100.0 0 0.0 3 100.0 Controlled 3 11.5 3 12.0 0 0.0 0 0.0 Non-controlled 23 88.5 22 88.0 4 100.0 2 100.0 Total 26 100.0 25 100.0 4 100.0 2 100.0 Controlled 0 0.0 0 0.0 0 0.0 0 0.0 Non-controlled 12 100.0 13 100.0 1 100.0 0 0.0 Total 12 100.0 13 100.0 1 100.0 0 0.0 Controlled 0 0.0 1 8.3 0 0.0 0 0.0 Non-controlled 15 100.0 11 91.7 1 100.0 1 100.0 Total 15 100.0 12 100.0 1 100.0 1 100.0 Controlled 1 10.0 3 33.3 0 0.0 0 0.0 Non-controlled 9 90.0 6 66.7 2 100.0 4 100.0 Total 10 100.0 9 100.0 2 100.0 4 100.0 15JUL11:13:37:29 LEO80185 G23 t63.doc Continued...

LEO 80185-G23 11-Oct-2011 of 349



Number of subjects

%

Number of subjects

%

Number of subjects

%

Number of subjects

%


LEO 80185-G23 11-Oct-2011 of 349



Number of subjects

%

Number of subjects

%

Number of subjects

%

Number of subjects

%

Week 4 Controlled 2 15.4 0 0.0 1 33.3 0 0.0 Non-controlled 11 84.6 11 100.0 2 66.7 4 100.0 Total 13 100.0 11 100.0 3 100.0 4 100.0 Controlled 2 16.7 3 30.0 1 20.0 0 0.0 Non-controlled 10 83.3 7 70.0 4 80.0 1 100.0 Total 12 100.0 10 100.0 5 100.0 1 100.0 Controlled 2 11.1 1 8.3 0 0.0 0 0.0 Non-controlled 16 88.9 11 91.7 2 100.0 4 100.0 Total 18 100.0 12 100.0 2 100.0 4 100.0 Week 8 Controlled 2 18.2 2 18.2 0 0.0 0 0.0 Non-controlled 9 81.8 9 81.8 5 100.0 2 100.0 Total 11 100.0 11 100.0 5 100.0 2 100.0 Controlled 5 50.0 4 33.3 1 100.0 2 40.0 Non-controlled 5 50.0 8 66.7 0 0.0 3 60.0 15JUL11:13:37:29 LEO80185 G23 t63.doc Continued...

LEO 80185-G23 11-Oct-2011 of 349



Number of subjects

%

Number of subjects

%

Number of subjects

%

Number of subjects

%

Week 8 Total 10 100.0 12 100.0 1 100.0 5 100.0 Controlled 2 16.7 2 15.4 0 0.0 0 0.0 Non-controlled 10 83.3 11 84.6 1 100.0 3 100.0 Total 12 100.0 13 100.0 1 100.0 3 100.0 Controlled 3 30.0 1 7.7 0 0.0 0 0.0 Non-controlled 7 70.0 12 92.3 1 100.0 3 100.0 Total 10 100.0 13 100.0 1 100.0 3 100.0 Controlled 2 18.2 2 22.2 0 0.0 0 0.0 Non-controlled 9 81.8 7 77.8 3 100.0 1 100.0 Total 11 100.0 9 100.0 3 100.0 1 100.0 Controlled 4 28.6 4 23.5 1 20.0 0 0.0 Non-controlled 10 71.4 13 76.5 4 80.0 3 100.0 Total 14 100.0 17 100.0 5 100.0 3 100.0 Controlled 4 30.8 4 44.4 0 0.0 0 0.0 Non-controlled 9 69.2 5 55.6 2 100.0 1 100.0 Total 13 100.0 9 100.0 2 100.0 1 100.0 15JUL11:13:37:29 LEO80185 G23 t63.doc Continued...

LEO 80185-G23 11-Oct-2011 of 349



Number of subjects

%

Number of subjects

%

Number of subjects

%

Number of subjects

%


LEO 80185-G23 11-Oct-2011 of 349



Number of subjects

%

Number of subjects

%

Number of subjects

%

Number of subjects

%

Week 8 Controlled 3 16.7 2 16.7 0 0.0 0 0.0 Non-controlled 15 83.3 10 83.3 2 100.0 4 100.0 Total 18 100.0 12 100.0 2 100.0 4 100.0 15JUL11:13:37:29 LEO80185 G23 t63.doc

LEO 80185-G23 11-Oct-2011 of 349

Table 64: Centre specific odds ratio including 95% CI ranked from lowest to highest – DAIVOBET/DOVOBET vs each of the other treatments: full analysis set

Week1,2

Daivobet® gel vs

Betamethasone gel

OR (95 % CI)

Daivobet® gelvs

Calcipotriol gel

OR (95 % CI)

Daivobet® gel vs

Vehicle

OR (95 % CI) Week 4 0.0 ( to ) 0.0 ( to ) 0.0 ( to ) 0.0 ( to ) 0.0 ( to ) 0.2 (0.0 to 2.7) 0.3 (0.0 to 2.0) 0.5 (0.1 to 3.6) 0.5 (0.1 to 3.5) 0.5 (0.0 to 6.4) 0.8 (0.0 to 13.2) 0.8 (0.1 to 9.7) 1.0 (0.2 to 5.3) 1.0 (0.1 to 8.7) 1.1 (0.1 to 9.3) 1.3 (0.2 to 10.2) 1.3 (0.2 to 7.4) 1.3 (0.2 to 7.6) 1.3 (0.1 to 24.4) 0.0 ( to ) 1.3 (0.2 to 10.3) 0.0 ( to ) 1.4 (0.1 to 17.1) 0.4 (0.0 to 6.2) 1.5 (0.1 to 19.0) 0.5 (0.0 to 6.9) 1.5 (0.3 to 7.9) 0.8 (0.1 to 11.5) 1.6 (0.1 to 18.6) 0.3 (0.0 to 5.3) 1.7 (0.1 to 21.2) 1.0 (0.1 to 14.6) 2.2 (0.2 to 25.0) 2.2 (0.2 to 28.9) 2.7 (0.4 to 19.1) 3.8 (0.3 to 48.0) 8.0 (0.7 to 88.2) 15JUL11:15:50:19 LEO80185 G23 t64.doc Continued...

LEO 80185-G23 11-Oct-2011 of 349

Table 64: Centre specific odds ratio including 95% CI ranked from lowest to highest – DAIVOBET/DOVOBET vs each of the other treatments: full analysis set, continued

Week1,2

Daivobet® gel vs

Betamethasone gel

OR (95 % CI)

Daivobet® gelvs

Calcipotriol gel

OR (95 % CI)

Daivobet® gel vs

Vehicle

OR (95 % CI) Week 8 0.0 ( to ) 0.3 (0.0 to 2.0) 0.3 (0.0 to 2.4) 0.6 (0.1 to 3.2) 0.6 (0.1 to 2.7) 0.7 (0.1 to 3.8) 0.8 (0.1 to 7.0) 0.8 (0.2 to 2.6) 0.8 (0.1 to 5.0) 0.9 (0.2 to 4.1) 0.9 (0.2 to 4.6) 0.9 (0.1 to 6.5) 1.0 (0.1 to 8.7) 1.0 (0.1 to 7.1) 1.0 (0.1 to 7.1) 1.1 (0.1 to 9.3) 1.1 (0.2 to 7.0) 1.1 (0.2 to 6.4) 1.3 (0.3 to 6.5) 1.4 (0.2 to 10.0) 1.8 (0.1 to 23.2) 0.0 ( to ) 1.9 (0.3 to 11.8) 0.3 (0.0 to 4.4) 2.0 (0.4 to 11.2) 0.5 (0.0 to 7.1) 2.3 (0.4 to 13.6) 0.6 (0.0 to 9.2) 2.8 (0.2 to 30.5) 0.7 (0.0 to 10.3) 3.2 (0.3 to 34.6) 0.8 (0.1 to 9.9) 3.7 (0.5 to 26.2) 1.3 (0.1 to 20.1) 3.8 (0.3 to 48.0) 1.5 (0.1 to 18.4) 4.0 (0.5 to 32.0) 1.5 (0.2 to 12.5) 4.0 (0.4 to 42.4) 1.6 (0.1 to 19.1) 0.4 (0.0 to 8.1) 4.4 (0.4 to 47.6) 6.0 (0.5 to 75.3) 1.0 (0.1 to 20.0) 5.0 (0.5 to 53.0) 1.3 (0.1 to 14.9) 5.0 (0.5 to 49.4) 1.5 (0.2 to 13.2) 5.1 (0.4 to 59.5) 1.9 (0.2 to 23.4) 6.5 (0.6 to 76.2) 6.7 (1.0 to 44.3) 15JUL11:15:50:19 LEO80185 G23 t64.doc

1) The odds ratios are calculated for pooled centres 2) Missing entry: the odds ratio and/or confidence limits could not be calculated.

LEO 80185-G23 11-Oct-2011 of 349

Table 65: Percentage of subjects with “Controlled disease” (IGA) at Weeks 4 and 8 by sex: full analysis set

Daivobet® gel Betamethasone gel Calcipotriol gel Vehicle Week Sex Controlled disease

Number of subjects

%

Number of subjects

%

Number of subjects

%

Number of subjects

%

Week 4 Male Controlled 39 13.7 38 13.3 3 5.0 2 3.3 Non-controlled 245 86.3 248 86.7 57 95.0 58 96.7 Total 284 100.0 286 100.0 60 100.0 60 100.0 Female Controlled 25 12.6 22 11.4 2 5.6 0 0.0 Non-controlled 173 87.4 171 88.6 34 94.4 35 100.0 Total 198 100.0 193 100.0 36 100.0 35 100.0 Week 8 Male Controlled 83 29.2 62 21.7 8 13.3 4 6.7 Non-controlled 201 70.8 224 78.3 52 86.7 56 93.3 Total 284 100.0 286 100.0 60 100.0 60 100.0 Female Controlled 57 28.8 41 21.2 6 16.7 2 5.7 Non-controlled 141 71.2 152 78.8 30 83.3 33 94.3 Total 198 100.0 193 100.0 36 100.0 35 100.0 15JUL11:13:37:39 LEO80185 G23 t65.doc

LEO 80185-G23 11-Oct-2011 of 349

Table 66: Percentage of subjects with “Controlled disease” (IGA) at Weeks 4 and 8 by age group: full analysis set

Daivobet® gel Betamethasone gel Calcipotriol gel Vehicle Week Age group Controlled disease

Number of subjects

%

Number of subjects

%

Number of subjects

%

Number of subjects

%

Week 4 <=35 Controlled 10 12.5 14 15.4 2 12.5 0 0.0 Non-controlled 70 87.5 77 84.6 14 87.5 14 100.0 Total 80 100.0 91 100.0 16 100.0 14 100.0 36-50 Controlled 18 9.4 14 8.6 2 5.4 1 2.6 Non-controlled 173 90.6 148 91.4 35 94.6 38 97.4 Total 191 100.0 162 100.0 37 100.0 39 100.0 51-64 Controlled 19 12.4 22 13.3 1 3.2 1 3.3 Non-controlled 134 87.6 143 86.7 30 96.8 29 96.7 Total 153 100.0 165 100.0 31 100.0 30 100.0 >=65 Controlled 17 29.3 10 16.4 0 0.0 0 0.0 Non-controlled 41 70.7 51 83.6 12 100.0 12 100.0 Total 58 100.0 61 100.0 12 100.0 12 100.0 15JUL11:13:37:49 LEO80185 G23 t66.doc Continued...

LEO 80185-G23 11-Oct-2011 of 349

Table 66: Percentage of subjects with “Controlled disease” (IGA) at Weeks 4 and 8 by age group: full analysis set, continued

Daivobet® gel Betamethasone gel Calcipotriol gel Vehicle Week Age group Controlled disease

Number of subjects

%

Number of subjects

%

Number of subjects

%

Number of subjects

%

Week 8 <=35 Controlled 19 23.8 16 17.6 3 18.8 0 0.0 Non-controlled 61 76.3 75 82.4 13 81.3 14 100.0 Total 80 100.0 91 100.0 16 100.0 14 100.0 36-50 Controlled 45 23.6 32 19.8 5 13.5 2 5.1 Non-controlled 146 76.4 130 80.2 32 86.5 37 94.9 Total 191 100.0 162 100.0 37 100.0 39 100.0 51-64 Controlled 47 30.7 38 23.0 4 12.9 4 13.3 Non-controlled 106 69.3 127 77.0 27 87.1 26 86.7 Total 153 100.0 165 100.0 31 100.0 30 100.0 >=65 Controlled 29 50.0 17 27.9 2 16.7 0 0.0 Non-controlled 29 50.0 44 72.1 10 83.3 12 100.0 Total 58 100.0 61 100.0 12 100.0 12 100.0 15JUL11:13:37:49 LEO80185 G23 t66.doc

LEO 80185-G23 11-Oct-2011 of 349

Table 67: Percentage of subjects with “Controlled disease” (IGA) at Weeks 4 and 8 by ethnicity: full analysis set

Daivobet® gel Betamethasone gel Calcipotriol gel Vehicle Week Ethnicity Controlled disease

Number of subjects

%

Number of subjects

%

Number of subjects

%

Number of subjects

%

Week 4 Hispanic or Latino Controlled 5 7.2 6 9.4 2 10.0 0 0.0 Non-controlled 64 92.8 58 90.6 18 90.0 16 100.0 Total 69 100.0 64 100.0 20 100.0 16 100.0 Not Hispanic or Latino Controlled 59 14.3 54 13.0 3 3.9 2 2.5 Non-controlled 354 85.7 361 87.0 73 96.1 77 97.5 Total 413 100.0 415 100.0 76 100.0 79 100.0 Week 8 Hispanic or Latino Controlled 18 26.1 13 20.3 6 30.0 0 0.0 Non-controlled 51 73.9 51 79.7 14 70.0 16 100.0 Total 69 100.0 64 100.0 20 100.0 16 100.0 Not Hispanic or Latino Controlled 122 29.5 90 21.7 8 10.5 6 7.6 Non-controlled 291 70.5 325 78.3 68 89.5 73 92.4 Total 413 100.0 415 100.0 76 100.0 79 100.0 15JUL11:13:37:59 LEO80185 G23 t67.doc

LEO 80185-G23 11-Oct-2011 of 349

Table 68: Percentage of subjects with “Controlled disease” (IGA) at Weeks 4 and 8 by race: full analysis set

Daivobet® gel Betamethasone gel Calcipotriol gel Vehicle Week Race Controlled disease

Number of subjects

%

Number of subjects

%

Number of subjects

%

Number of subjects

%

Week 4 White Controlled 53 12.2 52 12.2 4 4.8 1 1.2 Non-controlled 382 87.8 373 87.8 79 95.2 83 98.8 Total 435 100.0 425 100.0 83 100.0 84 100.0 Black or African American Controlled 5 18.5 3 10.7 1 11.1 0 0.0 Non-controlled 22 81.5 25 89.3 8 88.9 7 100.0 Total 27 100.0 28 100.0 9 100.0 7 100.0 Asian Controlled 3 27.3 3 20.0 0 0.0 1 33.3 Non-controlled 8 72.7 12 80.0 1 100.0 2 66.7 Total 11 100.0 15 100.0 1 100.0 3 100.0 American Indian or Alaska Native Controlled 1 50.0 1 100.0 0 0.0 0 0.0 Non-controlled 1 50.0 0 0.0 1 100.0 0 0.0 Total 2 100.0 1 100.0 1 100.0 0 0.0 Native Hawaiian or Other Pacific Islander Controlled 1 50.0 0 0.0 0 0.0 0 0.0 Non-controlled 1 50.0 2 100.0 0 0.0 0 0.0 Total 2 100.0 2 100.0 0 0.0 0 0.0 15JUL11:13:38:09 LEO80185 G23 t68.doc Continued...

LEO 80185-G23 11-Oct-2011 of 349

Table 68: Percentage of subjects with “Controlled disease” (IGA) at Weeks 4 and 8 by race: full analysis set, continued


Number of subjects

%

Number of subjects

%

Number of subjects

%

Number of subjects

%

Week 4 Other Controlled 1 20.0 1 12.5 0 0.0 0 0.0 Non-controlled 4 80.0 7 87.5 2 100.0 1 100.0 Total 5 100.0 8 100.0 2 100.0 1 100.0 Week 8 White Controlled 124 28.5 92 21.6 12 14.5 5 6.0 Non-controlled 311 71.5 333 78.4 71 85.5 79 94.0 Total 435 100.0 425 100.0 83 100.0 84 100.0 Black or African American Controlled 8 29.6 7 25.0 1 11.1 0 0.0 Non-controlled 19 70.4 21 75.0 8 88.9 7 100.0 Total 27 100.0 28 100.0 9 100.0 7 100.0 Asian Controlled 5 45.5 2 13.3 0 0.0 1 33.3 Non-controlled 6 54.5 13 86.7 1 100.0 2 66.7 Total 11 100.0 15 100.0 1 100.0 3 100.0 American Indian or Alaska Native Controlled 1 50.0 0 0.0 1 100.0 0 0.0 Non-controlled 1 50.0 1 100.0 0 0.0 0 0.0 Total 2 100.0 1 100.0 1 100.0 0 0.0 15JUL11:13:38:09 LEO80185 G23 t68.doc Continued...

LEO 80185-G23 11-Oct-2011 of 349

Table 68: Percentage of subjects with “Controlled disease” (IGA) at Weeks 4 and 8 by race: full analysis set, continued


Number of subjects

%

Number of subjects

%

Number of subjects

%

Number of subjects

%

Week 8 Native Hawaiian or Other Pacific Islander Controlled 1 50.0 0 0.0 0 0.0 0 0.0 Non-controlled 1 50.0 2 100.0 0 0.0 0 0.0 Total 2 100.0 2 100.0 0 0.0 0 0.0 Other Controlled 1 20.0 2 25.0 0 0.0 0 0.0 Non-controlled 4 80.0 6 75.0 2 100.0 1 100.0 Total 5 100.0 8 100.0 2 100.0 1 100.0 15JUL11:13:38:09 LEO80185 G23 t68.doc

LEO 80185-G23 11-Oct-2011 of 349

Table 69: Percentage of subjects with “Controlled disease” (IGA) at Weeks 4 and 8 by baseline disease severity (IGA): full analysis set

Daivobet® gel Betamethasone gel Calcipotriol gel Vehicle Week Baseline IGA Controlled disease

Number of subjects

%

Number of subjects

%

Number of subjects

%

Number of subjects

%

Week 4 Mild Controlled 5 4.7 5 4.8 0 0.0 0 0.0 Non-controlled 102 95.3 100 95.2 20 100.0 21 100.0 Total 107 100.0 105 100.0 20 100.0 21 100.0 Moderate Controlled 59 15.7 55 14.7 5 6.6 2 2.7 Non-controlled 316 84.3 319 85.3 71 93.4 72 97.3 Total 375 100.0 374 100.0 76 100.0 74 100.0 Week 8 Mild Controlled 14 13.1 8 7.6 3 15.0 1 4.8 Non-controlled 93 86.9 97 92.4 17 85.0 20 95.2 Total 107 100.0 105 100.0 20 100.0 21 100.0 Moderate Controlled 126 33.6 95 25.4 11 14.5 5 6.8 Non-controlled 249 66.4 279 74.6 65 85.5 69 93.2 Total 375 100.0 374 100.0 76 100.0 74 100.0 15JUL11:13:38:19 LEO80185 G23 t69.doc

LEO 80185-G23 11-Oct-2011 of 349

Table 70: Percentage of subjects in each IGA-category at weeks 1, 2, 4, 6 and 8: full analysis set

Daivobet® gel




Week IGA

Number of subjects

%

Number of subjects

%

Number of subjects

%

Number of subjects

%

Week 1 Almost clear 20 4.3 17 3.7 2 2.2 1 1.1 Mild 185 40.1 179 39.3 26 28.0 26 29.2 Moderate 254 55.1 259 56.8 65 69.9 62 69.7 Severe 2 0.4 1 0.2 0 0.0 0 0.0 Total 461 100.0 456 100.0 93 100.0 89 100.0 Week 2 Clear 1 0.2 1 0.2 1 1.1 0 0.0 Almost clear 60 13.0 44 9.8 2 2.2 3 3.4 Mild 225 48.7 216 47.9 36 40.0 31 35.2 Moderate 176 38.1 188 41.7 50 55.6 54 61.4 Severe 0 0.0 2 0.4 1 1.1 0 0.0 Total 462 100.0 451 100.0 90 100.0 88 100.0 Week 4 Clear 7 1.6 9 2.1 0 0.0 0 0.0 Almost clear 93 20.9 88 20.4 9 10.6 5 6.1 Mild 222 49.8 188 43.6 36 42.4 30 36.6 Moderate 123 27.6 142 32.9 38 44.7 45 54.9 Severe 1 0.2 4 0.9 2 2.4 2 2.4 Total 446 100.0 431 100.0 85 100.0 82 100.0 15JUL11:13:38:29 LEO80185 G23 t70.doc Continued...

LEO 80185-G23 11-Oct-2011 of 349

Table 70: Percentage of subjects in each IGA-category at weeks 1, 2, 4, 6 and 8: full analysis set, continued

Daivobet® gel




Week IGA

Number of subjects

%

Number of subjects

%

Number of subjects

%

Number of subjects

%

Week 6 Clear 13 2.9 13 3.1 2 2.5 0 0.0 Almost clear 136 30.7 100 23.8 11 13.6 8 9.9 Mild 190 42.9 190 45.1 36 44.4 25 30.9 Moderate 103 23.3 114 27.1 31 38.3 43 53.1 Severe 0 0.0 4 1.0 1 1.2 5 6.2 Very severe 1 0.2 0 0.0 0 0.0 0 0.0 Total 443 100.0 421 100.0 81 100.0 81 100.0 Week 8 Clear 28 6.3 21 5.0 3 3.7 1 1.3 Almost clear 156 35.2 112 26.8 15 18.3 11 14.3 Mild 164 37.0 171 40.9 37 45.1 24 31.2 Moderate 95 21.4 112 26.8 26 31.7 38 49.4 Severe 0 0.0 2 0.5 1 1.2 3 3.9 Total 443 100.0 418 100.0 82 100.0 77 100.0 15JUL11:13:38:29 LEO80185 G23 t70.doc

LEO 80185-G23 11-Oct-2011 of 349

Table 71: Mean percentage change in PASI from baseline to Weeks 4 and 8 by centre: full analysis set Week Centre Percentage change in PASI

Daivobet® gel

(n=482)

Betamethasone gel

(n=479)

Calcipotriol gel

(n=96)

Vehicle (n=95)

Week 4 Mean -47.4 -50.4 -16.5 -26.1 SD 45.1 24.6 28.6 31.7 Median -62.5 -50.0 0.0 -26.1 Minimum -82.9 -84.8 -49.5 -48.5 Maximum 66.7 0.0 0.0 -3.7 Number 9 11 3 2 Mean -55.6 -49.7 -58.3 -52.5 SD 35.6 40.1 40.6 Median -67.2 -50.0 -58.3 -56.0 Minimum -100.0 -93.8 -58.3 -98.1 Maximum 0.0 20.0 -58.3 0.0 Number 10 11 1 4 Mean 12.2 -43.8 13.7 SD 38.0 26.9 93.8 Median 0.0 -47.3 13.7 Minimum -29.0 -74.1 -52.6 Maximum 73.2 14.3 80.0 Number 7 12 2 15JUL11:13:38:48 LEO80185 G23 t71.doc Continued...

LEO 80185-G23 11-Oct-2011 of 349

Table 71: Mean percentage change in PASI from baseline to Weeks 4 and 8 by centre: full analysis set, continued Week Centre Percentage change in PASI

Daivobet® gel

(n=482)

Betamethasone gel

(n=479)

Calcipotriol gel

(n=96)

Vehicle (n=95)

Week 4 Mean -51.6 -43.2 10.8 -24.9 SD 17.8 29.0 31.3 Median -50.6 -36.4 10.8 -14.8 Minimum -81.5 -90.0 10.8 -60.0 Maximum -24.6 0.0 10.8 0.0 Number 8 11 1 3 Mean -62.6 -37.0 -27.6 SD 19.0 25.0 25.2 Median -60.4 -32.1 -33.3 Minimum -87.5 -80.5 -49.5 Maximum -37.5 -5.1 0.0 Number 11 8 3 Mean -49.7 -47.8 -35.4 0.7 SD 28.9 23.4 34.4 31.1 Median -54.4 -44.4 -32.6 -2.6 Minimum -87.1 -85.7 -76.3 -28.6 Maximum -5.0 -8.4 0.0 33.3 Number 13 14 4 3 Mean -54.6 -53.1 -23.7 -20.0 15JUL11:13:38:48 LEO80185 G23 t71.doc Continued...

LEO 80185-G23 11-Oct-2011 of 349


Daivobet® gel

(n=482)

Betamethasone gel

(n=479)

Calcipotriol gel

(n=96)

Vehicle (n=95)

Week 4 SD 25.4 15.3 17.0 Median -53.7 -53.8 -23.7 -20.0 Minimum -91.1 -79.6 -35.7 -20.0 Maximum -9.4 -35.3 -11.7 -20.0 Number 13 9 2 1 Mean -62.5 -37.5 -36.4 -47.5 SD 22.4 33.1 5.0 2.8 Median -65.5 -38.1 -36.4 -48.1 Minimum -89.5 -78.0 -40.0 -50.0 Maximum -31.8 26.5 -32.9 -44.4 Number 10 11 2 3 Mean -60.9 -44.0 -45.0 SD 29.6 18.3 27.0 Median -75.0 -50.3 -45.0 Minimum -89.5 -70.2 -64.1 Maximum -11.4 -4.1 -25.9 Number 8 13 2 Mean -53.2 -70.3 -36.3 -29.0 SD 25.8 20.6 23.9 9.6 Median -64.9 -64.6 -36.2 -29.0 15JUL11:13:38:48 LEO80185 G23 t71.doc Continued...

LEO 80185-G23 11-Oct-2011 of 349


Daivobet® gel

(n=482)

Betamethasone gel

(n=479)

Calcipotriol gel

(n=96)

Vehicle (n=95)

Week 4 Minimum -83.3 -97.1 -66.7 -35.8 Maximum -10.0 -37.5 -9.5 -22.2 Number 8 7 6 2 Mean -42.6 -31.8 -26.3 SD 20.3 26.6 37.2 Median -41.3 -25.0 -26.3 Minimum -88.1 -93.3 -52.6 Maximum -13.6 0.0 0.0 Number 14 11 2 Mean -50.3 -53.9 -32.7 -3.6 SD 26.8 24.7 2.7 5.1 Median -53.2 -52.1 -32.7 -3.6 Minimum -100.0 -100.0 -35.4 -7.1 Maximum 14.3 -20.0 -30.0 0.0 Number 24 22 3 2 Mean -40.8 -24.2 -7.9 SD 34.7 29.4 Median -53.8 -22.9 -7.9 Minimum -91.7 -78.4 -7.9 Maximum 15.0 21.4 -7.9 15JUL11:13:38:48 LEO80185 G23 t71.doc Continued...

LEO 80185-G23 11-Oct-2011 of 349


Daivobet® gel

(n=482)

Betamethasone gel

(n=479)

Calcipotriol gel

(n=96)

Vehicle (n=95)

Week 4 Number 11 13 1 Mean -45.4 -29.0 -40.0 -50.0 SD 26.4 29.7 Median -56.7 -26.7 -40.0 -50.0 Minimum -88.9 -97.9 -40.0 -50.0 Maximum -4.4 9.8 -40.0 -50.0 Number 14 12 1 1 Mean -55.5 -67.1 -51.8 -10.2 SD 32.1 23.7 14.8 31.4 Median -71.7 -75.6 -51.8 -0.7 Minimum -85.7 -91.7 -62.2 -55.6 Maximum 9.3 -23.1 -41.3 16.4 Number 10 9 2 4 Mean -36.6 -32.6 -43.1 -66.5 SD 29.6 34.9 29.2 16.9 Median -36.1 -44.4 -50.0 -57.9 Minimum -76.5 -56.7 -68.2 -85.9 Maximum 36.4 44.4 -11.1 -55.6 Number 11 7 3 3 15JUL11:13:38:48 LEO80185 G23 t71.doc Continued...

LEO 80185-G23 11-Oct-2011 of 349


Daivobet® gel

(n=482)

Betamethasone gel

(n=479)

Calcipotriol gel

(n=96)

Vehicle (n=95)

Week 4 Mean -71.7 -60.8 SD 24.2 25.3 Median -80.8 -57.1 Minimum -94.1 -91.7 Maximum 0.0 -25.0 Number 13 9 Mean -66.1 -68.1 -54.7 -35.7 SD 21.8 21.5 21.9 16.7 Median -75.0 -70.9 -54.7 -34.5 Minimum -93.8 -100.0 -70.2 -57.1 Maximum -22.9 -29.4 -39.3 -16.7 Number 11 9 2 4 Mean -44.0 -33.5 -53.4 -44.8 SD 26.1 25.0 27.1 Median -45.0 -35.8 -53.4 -44.8 Minimum -89.7 -70.0 -53.4 -64.0 Maximum -6.5 0.0 -53.4 -25.6 Number 9 14 1 2 Mean -36.7 -32.7 -7.4 -14.5 15JUL11:13:38:48 LEO80185 G23 t71.doc Continued...

LEO 80185-G23 11-Oct-2011 of 349


Daivobet® gel

(n=482)

Betamethasone gel

(n=479)

Calcipotriol gel

(n=96)

Vehicle (n=95)

Week 4 SD 25.2 32.4 18.0 23.0 Median -30.9 -37.5 -9.5 -19.4 Minimum -82.9 -83.3 -25.0 -35.0 Maximum 8.2 50.0 14.3 28.6 Number 16 12 4 6 Mean -48.9 -45.6 -36.4 -25.0 SD 28.7 24.5 44.5 Median -52.4 -48.1 -60.5 -25.0 Minimum -100.0 -78.5 -63.6 -25.0 Maximum -10.0 4.3 14.9 -25.0 Number 11 12 3 1 Mean -38.0 -33.7 0.0 SD 30.8 30.3 Median -25.0 -23.8 0.0 Minimum -94.4 -87.9 0.0 Maximum 0.0 0.0 0.0 Number 9 13 1 Mean -41.9 -30.1 -12.1 SD 23.5 33.9 Median -48.8 -23.4 -12.1 15JUL11:13:38:48 LEO80185 G23 t71.doc Continued...

LEO 80185-G23 11-Oct-2011 of 349


Daivobet® gel

(n=482)

Betamethasone gel

(n=479)

Calcipotriol gel

(n=96)

Vehicle (n=95)

Week 4 Minimum -75.5 -100.0 -12.1 Maximum 0.0 0.0 -12.1 Number 14 7 1 Mean -46.4 -42.5 2.8 172.7 SD 24.7 33.4 7.9 Median -46.2 -40.0 2.8 172.7 Minimum -84.4 -89.2 -2.8 172.7 Maximum -12.2 13.8 8.3 172.7 Number 8 9 2 1 Mean -46.6 -41.4 -3.1 SD 37.2 30.8 20.3 Median -54.4 -31.3 -3.1 Minimum -100.0 -100.0 -17.5 Maximum 20.0 -12.5 11.3 Number 14 10 2 Mean -47.8 -71.6 -19.4 SD 21.4 22.7 3.9 Median -51.7 -70.4 -19.4 Minimum -68.0 -100.0 -22.2 Maximum 0.0 -27.3 -16.7 15JUL11:13:38:48 LEO80185 G23 t71.doc Continued...

LEO 80185-G23 11-Oct-2011 of 349


Daivobet® gel

(n=482)

Betamethasone gel

(n=479)

Calcipotriol gel

(n=96)

Vehicle (n=95)

Week 4 Number 11 11 2 Mean -44.1 -50.2 -12.0 6.5 SD 27.9 24.3 Median -47.3 -50.0 -12.0 6.5 Minimum -87.0 -93.3 -12.0 6.5 Maximum 4.2 -7.4 -12.0 6.5 Number 8 17 1 1 Mean -42.6 -50.1 -39.7 0.0 SD 28.5 26.7 18.3 Median -42.9 -55.2 -35.9 0.0 Minimum -88.0 -82.2 -65.2 0.0 Maximum 0.0 -9.1 -21.7 0.0 Number 15 7 4 1 Mean -53.1 -42.0 -30.4 -29.0 SD 26.2 35.0 44.9 32.9 Median -48.7 -50.0 -9.1 -14.8 Minimum -100.0 -91.7 -82.0 -66.7 Maximum -13.3 62.0 0.0 -5.6 Number 12 17 3 3 15JUL11:13:38:48 LEO80185 G23 t71.doc Continued...

LEO 80185-G23 11-Oct-2011 of 349


Daivobet® gel

(n=482)

Betamethasone gel

(n=479)

Calcipotriol gel

(n=96)

Vehicle (n=95)

Week 4 Mean -46.9 -49.2 -37.5 -16.6 SD 27.9 25.9 8.3 24.1 Median -46.4 -50.0 -33.3 -6.9 Minimum -91.7 -88.9 -50.0 -50.0 Maximum 0.0 0.0 -33.3 7.1 Number 18 17 4 5 Mean -43.9 -39.8 -32.1 -37.1 SD 33.7 27.3 1.8 12.4 Median -46.2 -36.6 -32.1 -34.6 Minimum -78.6 -87.5 -33.3 -50.5 Maximum 45.5 -7.7 -30.8 -26.1 Number 12 8 2 3 Mean -57.2 -67.4 -31.3 -58.7 SD 26.7 16.7 16.0 4.6 Median -60.9 -68.3 -31.3 -58.7 Minimum -88.6 -90.4 -42.6 -62.0 Maximum 1.0 -44.2 -20.0 -55.4 Number 13 7 2 2 Mean -32.3 -34.0 -29.1 -3.8 15JUL11:13:38:48 LEO80185 G23 t71.doc Continued...

LEO 80185-G23 11-Oct-2011 of 349


Daivobet® gel

(n=482)

Betamethasone gel

(n=479)

Calcipotriol gel

(n=96)

Vehicle (n=95)

Week 4 SD 20.3 21.9 23.0 5.4 Median -30.0 -30.1 -22.9 -3.8 Minimum -62.7 -65.4 -60.7 -7.7 Maximum 5.7 1.6 -10.0 0.0 Number 11 12 4 2 Mean -60.8 -59.7 -55.1 -37.8 SD 34.8 21.0 7.5 14.2 Median -76.3 -54.2 -51.6 -37.8 Minimum -91.7 -100.0 -63.6 -47.9 Maximum 5.6 -31.1 -50.0 -27.8 Number 8 11 3 2 Mean -62.1 -69.7 -58.8 -21.9 SD 25.6 13.1 10.2 6.5 Median -74.5 -72.7 -62.0 -18.2 Minimum -100.0 -89.8 -69.7 -29.4 Maximum -25.0 -50.0 -44.8 -18.2 Number 13 17 6 3 Mean -54.2 -31.6 -74.0 18.9 SD 27.6 17.2 23.3 50.6 Median -59.9 -39.5 -74.0 -1.7 15JUL11:13:38:48 LEO80185 G23 t71.doc Continued...

LEO 80185-G23 11-Oct-2011 of 349


Daivobet® gel

(n=482)

Betamethasone gel

(n=479)

Calcipotriol gel

(n=96)

Vehicle (n=95)

Week 4 Minimum -97.4 -51.5 -90.5 -13.9 Maximum -15.9 4.2 -57.5 92.9 Number 12 9 2 4 Mean -61.1 -45.9 -46.7 0.0 SD 28.6 38.4 40.6 Median -71.1 -31.5 -25.0 0.0 Minimum -96.8 -100.0 -93.8 0.0 Maximum 0.0 -4.8 -11.1 0.0 Number 12 10 5 1 Mean -34.2 -29.7 -29.5 22.6 SD 18.7 27.4 15.4 11.5 Median -36.3 -35.7 -29.5 18.6 Minimum -80.2 -69.0 -40.4 13.8 Maximum -8.0 40.0 -18.6 39.5 Number 15 12 2 4 Week 8 Mean -57.4 -57.1 -15.0 -58.1 SD 49.8 28.6 37.0 20.0 Median -62.1 -66.7 0.0 -58.1 15JUL11:13:38:48 LEO80185 G23 t71.doc Continued...

LEO 80185-G23 11-Oct-2011 of 349


Daivobet® gel

(n=482)

Betamethasone gel

(n=479)

Calcipotriol gel

(n=96)

Vehicle (n=95)

Week 8 Minimum -93.5 -92.0 -57.1 -72.2 Maximum 66.7 0.0 12.2 -43.9 Number 9 11 3 2 Mean -81.4 -49.9 -98.1 -64.9 SD 17.7 54.0 39.0 Median -83.3 -80.2 -98.1 -71.4 Minimum -100.0 -93.8 -98.1 -100.0 Maximum -50.0 63.6 -98.1 -16.7 Number 10 11 1 4 Mean -28.0 -52.7 46.6 SD 50.7 34.2 140.3 Median -27.1 -58.6 46.6 Minimum -94.7 -92.6 -52.6 Maximum 73.2 23.8 145.8 Number 10 11 2 Mean -57.2 -51.1 10.8 -17.6 SD 23.0 29.9 24.9 Median -55.0 -43.8 10.8 -17.6 Minimum -89.3 -96.7 10.8 -35.2 Maximum -24.6 -14.1 10.8 0.0 15JUL11:13:38:48 LEO80185 G23 t71.doc Continued...

LEO 80185-G23 11-Oct-2011 of 349


Daivobet® gel

(n=482)

Betamethasone gel

(n=479)

Calcipotriol gel

(n=96)

Vehicle (n=95)

Week 8 Number 8 10 1 2 Mean -68.6 -58.1 -40.4 SD 17.8 26.3 7.9 Median -68.1 -50.0 -36.7 Minimum -89.5 -92.9 -49.5 Maximum -39.3 -26.6 -35.1 Number 11 5 3 Mean -61.5 -61.2 -44.3 -28.6 SD 29.6 24.9 30.2 40.4 Median -67.6 -66.3 -40.5 -28.6 Minimum -100.0 -92.5 -78.1 -57.1 Maximum -5.0 -14.5 -18.2 0.0 Number 14 14 4 2 Mean -63.5 -63.2 -48.7 -13.3 SD 25.0 29.5 18.4 Median -65.6 -61.5 -48.7 -13.3 Minimum -100.0 -97.8 -61.7 -13.3 Maximum -13.5 -30.8 -35.7 -13.3 Number 13 9 2 1 15JUL11:13:38:48 LEO80185 G23 t71.doc Continued...

LEO 80185-G23 11-Oct-2011 of 349


Daivobet® gel

(n=482)

Betamethasone gel

(n=479)

Calcipotriol gel

(n=96)

Vehicle (n=95)

Week 8 Mean -58.8 -24.1 -51.8 -34.3 SD 31.3 49.7 13.7 16.5 Median -73.7 -46.8 -51.8 -29.2 Minimum -96.0 -75.5 -61.5 -52.8 Maximum 7.1 79.2 -42.1 -21.0 Number 10 10 2 3 Mean -66.7 -48.8 -50.2 SD 27.4 26.9 52.7 Median -64.8 -48.5 -50.2 Minimum -100.0 -85.5 -87.5 Maximum -26.9 12.8 -13.0 Number 9 12 2 Mean -65.0 -67.6 -31.5 -24.2 SD 25.3 21.7 34.0 67.9 Median -71.3 -62.5 -42.3 -24.2 Minimum -100.0 -96.2 -64.4 -72.2 Maximum -30.0 -38.2 11.6 23.9 Number 6 7 6 2 Mean -48.2 -32.8 -8.0 15JUL11:13:38:48 LEO80185 G23 t71.doc Continued...

LEO 80185-G23 11-Oct-2011 of 349


Daivobet® gel

(n=482)

Betamethasone gel

(n=479)

Calcipotriol gel

(n=96)

Vehicle (n=95)

Week 8 SD 24.9 35.0 100.3 Median -42.9 -27.5 -8.0 Minimum -92.1 -100.0 -78.9 Maximum -17.6 10.0 63.0 Number 14 10 2 Mean -57.9 -59.1 -30.3 15.2 SD 29.9 30.1 19.5 31.6 Median -70.7 -60.0 -24.0 15.2 Minimum -100.0 -100.0 -52.2 -7.1 Maximum 21.4 -11.1 -14.9 37.5 Number 24 21 3 2 Mean -41.5 -33.1 -0.9 SD 36.4 43.6 Median -39.1 -12.2 -0.9 Minimum -83.3 -95.0 -0.9 Maximum 20.0 17.1 -0.9 Number 12 13 1 Mean -57.1 -33.0 -75.6 -40.0 SD 30.5 26.5 Median -63.4 -30.0 -75.6 -40.0 15JUL11:13:38:48 LEO80185 G23 t71.doc Continued...

LEO 80185-G23 11-Oct-2011 of 349


Daivobet® gel

(n=482)

Betamethasone gel

(n=479)

Calcipotriol gel

(n=96)

Vehicle (n=95)

Week 8 Minimum -93.8 -97.9 -75.6 -40.0 Maximum -1.1 6.1 -75.6 -40.0 Number 14 12 1 1 Mean -67.9 -72.4 -50.2 -22.1 SD 22.6 20.3 12.7 36.4 Median -68.8 -75.4 -50.2 -2.2 Minimum -96.4 -100.0 -59.2 -64.2 Maximum -25.0 -45.0 -41.3 0.0 Number 8 9 2 3 Mean -67.1 -74.1 -85.2 -75.1 SD 27.6 6.8 13.3 21.7 Median -71.1 -76.8 -81.3 -64.8 Minimum -97.2 -80.4 -100.0 -100.0 Maximum 9.1 -64.3 -74.2 -60.5 Number 12 6 3 3 Mean -82.1 -65.7 -43.2 SD 24.1 25.4 Median -91.9 -63.3 -43.2 Minimum -100.0 -100.0 -43.2 Maximum -16.7 -29.7 -43.2 15JUL11:13:38:48 LEO80185 G23 t71.doc Continued...

LEO 80185-G23 11-Oct-2011 of 349


Daivobet® gel

(n=482)

Betamethasone gel

(n=479)

Calcipotriol gel

(n=96)

Vehicle (n=95)

Week 8 Number 13 9 1 Mean -71.9 -70.5 -41.7 -54.2 SD 25.1 29.5 18.6 60.4 Median -84.8 -76.1 -41.7 -76.9 Minimum -95.8 -100.0 -54.8 -100.0 Maximum -33.3 3.8 -28.6 14.3 Number 11 10 2 3 Mean -58.7 -41.1 -64.7 -67.3 SD 43.8 27.3 12.7 24.5 Median -79.3 -43.8 -64.7 -67.3 Minimum -94.8 -100.0 -73.6 -84.6 Maximum 37.5 0.0 -55.7 -50.0 Number 9 15 2 2 Mean -40.8 -40.3 -9.5 -15.8 SD 29.8 31.0 29.9 23.6 Median -42.6 -48.1 -16.7 -20.0 Minimum -82.9 -83.3 -33.3 -38.9 Maximum 7.3 7.6 28.6 28.6 Number 17 13 4 6 15JUL11:13:38:48 LEO80185 G23 t71.doc Continued...

LEO 80185-G23 11-Oct-2011 of 349


Daivobet® gel

(n=482)

Betamethasone gel

(n=479)

Calcipotriol gel

(n=96)

Vehicle (n=95)

Week 8 Mean -56.3 -44.2 -83.3 -12.5 SD 28.7 34.8 11.5 Median -57.1 -52.7 -81.6 -12.5 Minimum -100.0 -94.2 -95.5 -12.5 Maximum -11.5 9.9 -72.7 -12.5 Number 11 12 3 1 Mean -47.3 -38.6 0.0 SD 28.4 38.9 Median -45.8 -40.0 0.0 Minimum -100.0 -93.9 0.0 Maximum -14.3 50.0 0.0 Number 9 13 1 Mean -54.1 -40.4 -32.6 0.0 SD 29.6 40.8 Median -62.5 -19.1 -32.6 0.0 Minimum -91.4 -100.0 -32.6 0.0 Maximum 13.6 0.0 -32.6 0.0 Number 15 7 1 1 Mean -34.3 -43.7 -17.1 172.7 15JUL11:13:38:48 LEO80185 G23 t71.doc Continued...

LEO 80185-G23 11-Oct-2011 of 349


Daivobet® gel

(n=482)

Betamethasone gel

(n=479)

Calcipotriol gel

(n=96)

Vehicle (n=95)

Week 8 SD 48.8 58.1 35.9 Median -45.7 -59.7 -17.1 172.7 Minimum -86.7 -90.7 -42.5 172.7 Maximum 48.3 82.8 8.3 172.7 Number 8 8 2 1 Mean -71.2 -39.0 -11.8 SD 26.1 34.1 34.9 Median -75.0 -28.1 -11.8 Minimum -100.0 -100.0 -36.5 Maximum -13.2 0.0 12.9 Number 11 11 2 Mean -68.7 -81.8 -82.4 SD 22.8 14.3 1.3 Median -76.5 -81.3 -82.4 Minimum -92.0 -100.0 -83.3 Maximum -27.0 -59.4 -81.5 Number 9 11 2 Mean -60.9 -66.8 9.7 SD 30.1 26.5 Median -50.9 -76.1 9.7 15JUL11:13:38:48 LEO80185 G23 t71.doc Continued...

LEO 80185-G23 11-Oct-2011 of 349


Daivobet® gel

(n=482)

Betamethasone gel

(n=479)

Calcipotriol gel

(n=96)

Vehicle (n=95)

Week 8 Minimum -100.0 -100.0 9.7 Maximum -20.8 -11.7 9.7 Number 8 16 1 Mean -58.5 -58.7 -51.8 -20.3 SD 31.6 37.6 19.9 Median -65.2 -64.4 -55.6 -20.3 Minimum -100.0 -100.0 -71.4 -20.3 Maximum -8.3 -14.6 -24.4 -20.3 Number 14 7 4 1 Mean -63.1 -60.8 -76.5 -50.6 SD 29.6 35.0 20.9 28.3 Median -71.1 -78.8 -69.4 -35.2 Minimum -100.0 -100.0 -100.0 -83.3 Maximum 0.0 36.7 -60.0 -33.3 Number 12 16 3 3 Mean -53.4 -51.6 -41.7 -28.8 SD 27.5 34.7 39.7 38.5 Median -50.0 -50.0 -41.7 -19.5 Minimum -91.7 -94.4 -83.3 -83.3 Maximum -7.4 0.0 0.0 7.1 15JUL11:13:38:48 LEO80185 G23 t71.doc Continued...

LEO 80185-G23 11-Oct-2011 of 349


Daivobet® gel

(n=482)

Betamethasone gel

(n=479)

Calcipotriol gel

(n=96)

Vehicle (n=95)

Week 8 Number 17 17 4 4 Mean -46.2 -39.8 -29.3 -39.6 SD 33.4 44.7 2.1 11.9 Median -60.8 -45.5 -29.3 -41.3 Minimum -79.2 -87.5 -30.8 -50.5 Maximum 18.2 38.5 -27.8 -26.9 Number 12 7 2 3 Mean -71.9 -54.5 -38.3 -71.2 SD 26.5 40.1 40.7 Median -83.9 -69.9 -38.3 -71.2 Minimum -91.5 -85.0 -38.3 -100.0 Maximum -1.0 23.2 -38.3 -42.4 Number 12 6 1 2 Mean -65.9 -48.7 -61.6 -12.0 SD 28.0 35.2 26.5 0.7 Median -73.3 -33.3 -62.2 -12.0 Minimum -100.0 -92.3 -93.3 -12.5 Maximum -10.0 8.8 -28.6 -11.5 Number 11 12 4 2 15JUL11:13:38:48 LEO80185 G23 t71.doc Continued...

LEO 80185-G23 11-Oct-2011 of 349


Daivobet® gel

(n=482)

Betamethasone gel

(n=479)

Calcipotriol gel

(n=96)

Vehicle (n=95)

Week 8 Mean -85.4 -82.8 -77.5 -20.0 SD 32.5 22.0 14.3 91.1 Median -96.8 -91.3 -70.8 -20.0 Minimum -100.0 -100.0 -93.9 -84.4 Maximum -5.6 -30.8 -67.7 44.4 Number 8 11 3 2 Mean -72.0 -71.2 -70.5 -34.5 SD 17.4 15.6 8.3 56.7 Median -71.9 -75.0 -72.9 -64.7 Minimum -100.0 -92.7 -77.8 -69.7 Maximum -43.6 -38.8 -58.7 30.9 Number 14 15 4 3 Mean -55.3 -45.9 -66.5 11.2 SD 26.4 20.0 20.4 49.2 Median -50.8 -44.3 -66.5 0.3 Minimum -100.0 -90.3 -81.0 -34.5 Maximum -21.4 -16.7 -52.1 78.6 Number 12 10 2 4 Mean -74.6 -59.8 -62.9 13.3 15JUL11:13:38:48 LEO80185 G23 t71.doc Continued...

LEO 80185-G23 11-Oct-2011 of 349


Daivobet® gel

(n=482)

Betamethasone gel

(n=479)

Calcipotriol gel

(n=96)

Vehicle (n=95)

Week 8 SD 30.5 39.4 34.6 Median -85.4 -70.3 -60.3 13.3 Minimum -100.0 -100.0 -100.0 13.3 Maximum 0.0 0.0 -25.0 13.3 Number 12 9 5 1 Mean -26.3 -30.6 -34.6 -21.2 SD 48.5 37.7 41.3 Median -33.3 -37.3 -34.6 -31.0 Minimum -89.0 -90.9 -34.6 -56.7 Maximum 64.7 25.0 -34.6 24.1 Number 15 12 1 3 15JUL11:13:38:48 LEO80185 G23 t71.doc

LEO 80185-G23 11-Oct-2011 of 349

Table 72: Summary of mean absolute change in PASI from baseline to weeks 1, 2, 4, 6 and 8: full analysis set Visit Change from baseline




Vehicle (n=95)

Week 1 Mean -1.87 -1.69 -1.54 -1.04 SD 2.15 1.87 1.69 1.65 Median -1.50 -1.35 -1.20 -0.60 Minimum -11.4 -13.5 -8.6 -8.6 Maximum 7.2 4.2 2.8 1.8 Number 461 456 93 89 Week 2 Mean -3.12 -2.71 -2.40 -1.30 SD 2.62 2.30 2.80 2.26 Median -2.65 -2.40 -1.80 -0.90 Minimum -20.4 -13.5 -9.4 -9.9 Maximum 5.3 3.5 4.9 7.8 Number 462 451 90 88 Week 4 Mean -3.90 -3.52 -3.15 -1.41 SD 2.92 2.85 2.86 2.94 Median -3.60 -3.00 -2.60 -1.35 Minimum -20.8 -19.0 -13.0 -10.6 Maximum 6.0 7.2 2.3 9.6 Number 446 431 85 82 15JUL11:13:38:59 LEO80185 G23 t72.doc Continued...

LEO 80185-G23 11-Oct-2011 of 349

Table 72: Summary of mean absolute change in PASI from baseline to weeks 1, 2, 4, 6 and 8: full analysis set, continued Visit Change from baseline




Vehicle (n=95)

Week 6 Mean -4.48 -3.91 -3.93 -1.13 SD 3.31 3.15 3.17 3.96 Median -4.20 -3.60 -3.60 -1.40 Minimum -24.0 -19.0 -14.2 -10.8 Maximum 5.2 6.4 3.7 17.5 Number 443 421 81 81 Week 8 Mean -4.73 -4.13 -4.44 -1.77 SD 3.43 3.42 3.32 3.85 Median -4.40 -3.90 -4.25 -2.00 Minimum -24.2 -19.0 -14.2 -10.8 Maximum 6.0 5.2 1.6 17.5 Number 444 418 82 77 15JUL11:13:38:59 LEO80185 G23 t72.doc

LEO 80185-G23 11-Oct-2011 of 349

Table 73: Percentage of subjects with “Controlled disease” (Patient’s Global Assessment of disease severity) at weeks 1, 2, 4, 6 and 8: full analysis set

Daivobet® gel




Week Controlled disease patient assessment

Number of subjects

%

Number of subjects

%

Number of subjects

%

Number of subjects

%

Week 1 Controlled 67 14.5 66 14.5 7 7.5 9 10.1 Non-controlled 394 85.5 390 85.5 86 92.5 80 89.9 Total 461 100.0 456 100.0 93 100.0 89 100.0 Week 2 Controlled 113 24.5 100 22.2 5 5.6 12 13.6 Non-controlled 349 75.5 351 77.8 85 94.4 76 86.4 Total 462 100.0 451 100.0 90 100.0 88 100.0 Week 4 Controlled 158 35.4 148 34.3 16 18.6 13 15.9 Non-controlled 288 64.6 283 65.7 70 81.4 69 84.1 Total 446 100.0 431 100.0 86 100.0 82 100.0 Week 6 Controlled 190 42.9 155 36.8 16 19.8 13 16.0 Non-controlled 253 57.1 266 63.2 65 80.2 68 84.0 Total 443 100.0 421 100.0 81 100.0 81 100.0 Week 8 Controlled 212 47.6 173 41.4 28 34.1 16 20.8 Non-controlled 233 52.4 245 58.6 54 65.9 61 79.2 Total 445 100.0 418 100.0 82 100.0 77 100.0 15JUL11:13:38:39 LEO80185 G23 t73.doc

LEO 80185-G23 11-Oct-2011 of 349

Table 74: Percentage of subjects in each category of Patient’s Global Assessment of disease severity at weeks 1, 2, 4, 6 and 8: full analysis set

Daivobet® gel




Visit Patients global assessment

Number of subjects

%

Number of subjects

%

Number of subjects

%

Number of subjects

%

Week 1 Clear 5 1.1 1 0.2 1 1.1 0 0.0 Very mild 62 13.4 65 14.3 6 6.5 9 10.1 Mild 200 43.4 184 40.4 30 32.3 30 33.7 Moderate 176 38.2 187 41.0 48 51.6 45 50.6 Severe 18 3.9 19 4.2 8 8.6 5 5.6 Total 461 100.0 456 100.0 93 100.0 89 100.0 Week 2 Clear 8 1.7 7 1.6 0 0.0 1 1.1 Very mild 105 22.7 93 20.6 5 5.6 11 12.5 Mild 212 45.9 202 44.8 40 44.4 31 35.2 Moderate 128 27.7 133 29.5 38 42.2 40 45.5 Severe 9 1.9 16 3.5 7 7.8 5 5.7 Total 462 100.0 451 100.0 90 100.0 88 100.0 Week 4 Clear 17 3.8 17 3.9 0 0.0 0 0.0 Very mild 141 31.6 131 30.4 16 18.6 13 15.9 Mild 176 39.5 171 39.7 31 36.0 28 34.1 Moderate 106 23.8 102 23.7 35 40.7 35 42.7 Severe 6 1.3 10 2.3 4 4.7 6 7.3 Total 446 100.0 431 100.0 86 100.0 82 100.0 15JUL11:13:39:09 LEO80185 G23 t74.doc Continued...

LEO 80185-G23 11-Oct-2011 of 349

Table 74: Percentage of subjects in each category of Patient’s Global Assessment of disease severity at weeks 1, 2, 4, 6 and 8: full analysis set, continued

Daivobet® gel




Visit Patients global assessment

Number of subjects

%

Number of subjects

%

Number of subjects

%

Number of subjects

%

Week 6 Clear 19 4.3 22 5.2 3 3.7 3 3.7 Very mild 171 38.6 133 31.6 13 16.0 10 12.3 Mild 167 37.7 160 38.0 37 45.7 30 37.0 Moderate 80 18.1 99 23.5 25 30.9 29 35.8 Severe 6 1.4 7 1.7 3 3.7 9 11.1 Total 443 100.0 421 100.0 81 100.0 81 100.0 Week 8 Clear 32 7.2 36 8.6 3 3.7 3 3.9 Very mild 180 40.4 137 32.8 25 30.5 13 16.9 Mild 160 36.0 152 36.4 34 41.5 28 36.4 Moderate 66 14.8 82 19.6 18 22.0 28 36.4 Severe 7 1.6 11 2.6 2 2.4 5 6.5 Total 445 100.0 418 100.0 82 100.0 77 100.0 15JUL11:13:39:09 LEO80185 G23 t74.doc

LEO 80185-G23 11-Oct-2011 of 349

Table 75: Summary of change in plaque discomfort score from baseline to week 1, 2, 4, 6 and 8: full analysis set Visit Change in Plaque discomfort score

Daivobet® gel

(n=482)

Betamethasone gel

(n=479)

Calcipotriol gel

(n=96)

Vehicle (n=95)

Week 1 Mean -13.8 -13.9 -6.1 -5.8 SD 19.8 18.9 19.6 17.6 Median -10.0 -10.0 -5.0 -4.0 Minimum -90.0 -93.0 -69.0 -70.0 Maximum 60.0 55.0 67.5 32.5 Number 460 455 93 89 Week 2 Mean -20.5 -18.3 -10.9 -6.8 SD 22.3 20.0 19.0 19.4 Median -18.0 -16.0 -10.0 -4.0 Minimum -90.0 -90.0 -59.0 -80.0 Maximum 57.5 30.0 36.0 31.5 Number 463 449 91 87 Week 4 Mean -25.1 -21.9 -12.0 -8.5 SD 24.1 23.7 22.9 21.8 Median -20.0 -20.0 -8.5 -10.0 Minimum -100.0 -100.0 -70.0 -71.0 Maximum 53.5 65.0 40.0 41.0 Number 446 431 86 82 02AUG11:14:21:26 LEO80185 G23 t75.doc Continued...

LEO 80185-G23 11-Oct-2011 of 349

Table 75: Summary of change in plaque discomfort score from baseline to week 1, 2, 4, 6 and 8: full analysis set, continued Visit Change in Plaque discomfort score

Daivobet® gel

(n=482)

Betamethasone gel

(n=479)

Calcipotriol gel

(n=96)

Vehicle (n=95)

Week 6 Mean -26.7 -24.3 -15.3 -8.8 SD 25.5 25.5 24.6 22.0 Median -24.0 -22.0 -11.0 -5.0 Minimum -98.0 -93.0 -80.0 -61.0 Maximum 73.5 75.0 51.0 37.0 Number 444 421 81 81 Week 8 Mean -28.6 -25.8 -18.8 -9.3 SD 27.1 27.9 25.8 23.6 Median -25.0 -24.5 -18.0 -9.0 Minimum -100.0 -100.0 -80.0 -73.0 Maximum 53.0 80.0 45.5 51.0 Number 445 418 81 77 02AUG11:14:21:26 LEO80185 G23 t75.doc

LEO 80185-G23 11-Oct-2011 of 349

Table 76: Summary of DLQI score at baseline, week 2, 4 and 8: full analysis set Visit DLQI score




Vehicle (n=95)

Baseline Mean 10.3 9.8 11.6 10.2 SD 6.6 6.6 6.9 7.3 Median 10.0 8.0 11.0 9.0 Minimum 0.0 0.0 1.0 1.0 Maximum 30.0 30.0 30.0 30.0 Number 481 479 96 95 Week 2 Mean 5.3 5.6 7.8 8.2 SD 4.6 5.2 5.9 7.0 Median 4.0 4.0 7.0 6.0 Minimum 0.0 0.0 0.0 0.0 Maximum 25.0 28.0 30.0 29.0 Number 461 443 90 86 Week 4 Mean 4.3 4.8 6.6 8.0 SD 4.4 5.1 6.4 7.2 Median 3.0 3.0 5.0 5.5 Minimum 0.0 0.0 0.0 0.0 Maximum 25.0 30.0 30.0 29.0 Number 445 431 86 82 Week 8 Mean 3.7 4.3 5.9 7.0 02AUG11:15:26:31 LEO80185 G23 t76.doc Continued...

LEO 80185-G23 11-Oct-2011 of 349

Table 76: Summary of DLQI score at baseline, week 2, 4 and 8: full analysis set, continued Visit DLQI score




Vehicle (n=95)

Week 8 SD 4.5 4.8 6.0 6.8 Median 2.0 3.0 4.0 5.0 Minimum 0.0 0.0 0.0 0.0 Maximum 25.0 29.0 30.0 30.0 Number 443 418 80 77 02AUG11:15:26:31 LEO80185 G23 t76.doc

LEO 80185-G23 11-Oct-2011 of 349

14.3 SAFETY DATA

Table 77: AEs by MedDRA primary SOC and preferred term: safety analysis set

Daivobet® gel









Blood and lymphatic system disorders Thrombocytopenia 0 0.0 1 0.2 0 0.0 0 0.0 Cardiac disorders Angina pectoris 1 0.2 0 0.0 0 0.0 1 1.1 Ear and labyrinth disorders Cerumen impaction 0 0.0 0 0.0 0 0.0 1 1.1 Vertigo 0 0.0 0 0.0 0 0.0 1 1.1 Endocrine disorders Hypoparathyroidism 0 0.0 1 0.2 0 0.0 0 0.0 Thyroid disorder 0 0.0 1 0.2 0 0.0 0 0.0 Eye disorders Conjunctivitis 1 0.2 0 0.0 0 0.0 1 1.1 Erythema of eyelid 0 0.0 0 0.0 1 1.1 0 0.0 Gastrointestinal disorders Abdominal distension 1 0.2 0 0.0 0 0.0 0 0.0 Abdominal pain 0 0.0 1 0.2 0 0.0 0 0.0 Diarrhoea 2 0.4 1 0.2 1 1.1 1 1.1 Gastrooesophageal reflux disease

1 0.2 1 0.2 0 0.0 0 0.0

Haemorrhoids 1 0.2 0 0.0 0 0.0 0 0.0 22JUL11:16:20:47 LEO80185 G23 t77.doc Continued...

LEO 80185-G23 11-Oct-2011 of 349

Table 77: AEs by MedDRA primary SOC and preferred term: safety analysis set, continued

Daivobet® gel









Gastrointestinal disorders Nausea 1 0.2 2 0.4 1 1.1 0 0.0 Pancreatitis acute 0 0.0 1 0.2 0 0.0 0 0.0 Toothache 1 0.2 0 0.0 0 0.0 1 1.1 Vomiting 2 0.4 1 0.2 0 0.0 1 1.1 General disorders and administration siteconditions Application site pain 2 0.4 1 0.2 0 0.0 1 1.1 Cyst 1 0.2 0 0.0 0 0.0 0 0.0 Feeling of body temperature change

1 0.2 0 0.0 0 0.0 0 0.0

Pain 0 0.0 1 0.2 0 0.0 0 0.0 Pyrexia 0 0.0 0 0.0 0 0.0 1 1.1 Swelling 1 0.2 0 0.0 0 0.0 0 0.0 Hepatobiliary disorders Cholecystitis acute 0 0.0 1 0.2 0 0.0 0 0.0 Immune system disorders Allergy to plants 0 0.0 1 0.2 0 0.0 0 0.0 Drug hypersensitivity 1 0.2 0 0.0 0 0.0 0 0.0 Seasonal allergy 1 0.2 0 0.0 0 0.0 0 0.0 22JUL11:16:20:47 LEO80185 G23 t77.doc Continued...

LEO 80185-G23 11-Oct-2011 of 349


Daivobet® gel









Infections and infestations Abscess 1 0.2 0 0.0 0 0.0 0 0.0 Bronchitis 5 1.0 1 0.2 1 1.1 1 1.1 Candidiasis 0 0.0 0 0.0 1 1.1 1 1.1 Cellulitis 1 0.2 4 0.8 0 0.0 0 0.0 Conjunctivitis bacterial 0 0.0 1 0.2 0 0.0 0 0.0 Diverticulitis 1 0.2 1 0.2 0 0.0 0 0.0 Ear infection 2 0.4 0 0.0 0 0.0 0 0.0 Eye infection 0 0.0 0 0.0 0 0.0 1 1.1 Folliculitis 2 0.4 0 0.0 0 0.0 0 0.0 Furuncle 1 0.2 0 0.0 0 0.0 0 0.0 Gastroenteritis 1 0.2 0 0.0 0 0.0 0 0.0 Gastroenteritis viral 2 0.4 3 0.6 1 1.1 0 0.0 Influenza 5 1.0 4 0.8 1 1.1 1 1.1 Kidney infection 0 0.0 1 0.2 0 0.0 0 0.0 Labyrinthitis 1 0.2 0 0.0 0 0.0 0 0.0 Laryngitis 0 0.0 1 0.2 0 0.0 0 0.0 Lower respiratory tract infection

0 0.0 1 0.2 0 0.0 0 0.0

Nasopharyngitis 14 2.9 15 3.1 5 5.3 3 3.2 22JUL11:16:20:47 LEO80185 G23 t77.doc Continued...

LEO 80185-G23 11-Oct-2011 of 349


Daivobet® gel









Infections and infestations Otitis media acute 0 0.0 1 0.2 0 0.0 0 0.0 Pharyngitis 1 0.2 0 0.0 0 0.0 0 0.0 Pneumonia 2 0.4 0 0.0 0 0.0 0 0.0 Sinusitis 10 2.1 3 0.6 1 1.1 1 1.1 Skin infection 1 0.2 0 0.0 0 0.0 0 0.0 Streptococcal infection 0 0.0 1 0.2 0 0.0 0 0.0 Tinea pedis 1 0.2 0 0.0 0 0.0 0 0.0 Tooth abscess 2 0.4 1 0.2 0 0.0 0 0.0 Tooth infection 1 0.2 0 0.0 0 0.0 2 2.1 Upper respiratory tract infection

14 2.9 8 1.7 3 3.2 0 0.0

Urinary tract infection 2 0.4 3 0.6 0 0.0 0 0.0 Vulvovaginal mycotic infection

0 0.0 1 0.2 0 0.0 1 1.1

Injury, poisoning and proceduralcomplications Alcohol poisoning 0 0.0 1 0.2 0 0.0 0 0.0 Animal bite 0 0.0 1 0.2 0 0.0 1 1.1 Arthropod bite 1 0.2 2 0.4 0 0.0 0 0.0 Cartilage injury 0 0.0 0 0.0 1 1.1 0 0.0 22JUL11:16:20:47 LEO80185 G23 t77.doc Continued...

LEO 80185-G23 11-Oct-2011 of 349


Daivobet® gel









Injury, poisoning and proceduralcomplications Caustic injury 1 0.2 0 0.0 0 0.0 0 0.0 Contusion 1 0.2 2 0.4 0 0.0 0 0.0 Excoriation 1 0.2 1 0.2 0 0.0 0 0.0 Fall 0 0.0 1 0.2 0 0.0 0 0.0 Injury 0 0.0 2 0.4 0 0.0 0 0.0 Joint injury 1 0.2 0 0.0 0 0.0 0 0.0 Joint sprain 0 0.0 1 0.2 0 0.0 0 0.0 Muscle strain 1 0.2 1 0.2 0 0.0 0 0.0 Pocket erosion 0 0.0 1 0.2 0 0.0 0 0.0 Post procedural complication

0 0.0 1 0.2 0 0.0 0 0.0

Rib fracture 0 0.0 1 0.2 0 0.0 0 0.0 Skin laceration 0 0.0 1 0.2 0 0.0 0 0.0 Thermal burn 1 0.2 1 0.2 0 0.0 0 0.0 Wrist fracture 1 0.2 0 0.0 0 0.0 0 0.0 Investigations Angiogram 0 0.0 0 0.0 0 0.0 1 1.1 Biopsy bladder 0 0.0 1 0.2 0 0.0 0 0.0 Biopsy prostate 0 0.0 1 0.2 0 0.0 0 0.0 Blood glucose decreased 1 0.2 0 0.0 0 0.0 0 0.0 22JUL11:16:20:47 LEO80185 G23 t77.doc Continued...

LEO 80185-G23 11-Oct-2011 of 349


Daivobet® gel









Investigations Blood parathyroid hormone increased

13 2.7 9 1.9 0 0.0 1 1.1

Blood phosphorus decreased

1 0.2 0 0.0 0 0.0 0 0.0

Metabolism and nutrition disorders Diabetes mellitus 1 0.2 1 0.2 0 0.0 0 0.0 Hypercholesterolaemia 1 0.2 0 0.0 0 0.0 0 0.0 Hyperlipidaemia 0 0.0 1 0.2 0 0.0 0 0.0 Hypokalaemia 0 0.0 2 0.4 0 0.0 0 0.0 Type 2 diabetes mellitus 1 0.2 1 0.2 0 0.0 0 0.0 Musculoskeletal and connective tissuedisorders Arthralgia 0 0.0 1 0.2 0 0.0 2 2.1 Arthritis 1 0.2 0 0.0 0 0.0 0 0.0 Back pain 1 0.2 1 0.2 0 0.0 0 0.0 Bursitis 0 0.0 1 0.2 0 0.0 0 0.0 Joint swelling 0 0.0 0 0.0 1 1.1 0 0.0 Musculoskeletal pain 1 0.2 0 0.0 0 0.0 0 0.0 Myalgia 2 0.4 1 0.2 0 0.0 0 0.0 Psoriatic arthropathy 0 0.0 0 0.0 1 1.1 0 0.0 22JUL11:16:20:47 LEO80185 G23 t77.doc Continued...

LEO 80185-G23 11-Oct-2011 of 349


Daivobet® gel









Musculoskeletal and connective tissuedisorders Rheumatoid arthritis 1 0.2 0 0.0 0 0.0 0 0.0 Tendonitis 0 0.0 1 0.2 0 0.0 0 0.0 Neoplasms benign, malignant and unspecified(incl cysts and polyps) Squamous cell carcinoma 1 0.2 0 0.0 0 0.0 0 0.0 Nervous system disorders Amnesia 0 0.0 0 0.0 1 1.1 0 0.0 Dizziness 2 0.4 1 0.2 0 0.0 0 0.0 Headache 4 0.8 5 1.0 0 0.0 0 0.0 Hypoaesthesia 0 0.0 1 0.2 0 0.0 0 0.0 Neuralgia 1 0.2 0 0.0 0 0.0 0 0.0 Paraesthesia 0 0.0 2 0.4 0 0.0 0 0.0 Syncope 1 0.2 0 0.0 0 0.0 0 0.0 Tunnel vision 0 0.0 0 0.0 1 1.1 0 0.0 Psychiatric disorders Depression 0 0.0 0 0.0 0 0.0 1 1.1 Suicidal ideation 0 0.0 1 0.2 0 0.0 0 0.0 Suicide attempt 0 0.0 0 0.0 0 0.0 1 1.1 Renal and urinary disorders Haematuria 0 0.0 1 0.2 0 0.0 0 0.0 22JUL11:16:20:47 LEO80185 G23 t77.doc Continued...

LEO 80185-G23 11-Oct-2011 of 349


Daivobet® gel









Renal and urinary disorders Nephrolithiasis 0 0.0 1 0.2 0 0.0 0 0.0 Reproductive system and breast disorders Bartholin's cyst 0 0.0 2 0.4 0 0.0 0 0.0 Respiratory, thoracic and mediastinaldisorders Acute respiratory failure 0 0.0 1 0.2 0 0.0 0 0.0 Cough 4 0.8 3 0.6 1 1.1 0 0.0 Dyspnoea 1 0.2 0 0.0 0 0.0 0 0.0 Epistaxis 1 0.2 0 0.0 0 0.0 0 0.0 Nasal congestion 4 0.8 3 0.6 0 0.0 0 0.0 Oropharyngeal pain 1 0.2 0 0.0 1 1.1 2 2.1 Postnasal drip 1 0.2 0 0.0 0 0.0 0 0.0 Respiratory tract congestion

1 0.2 0 0.0 1 1.1 0 0.0

Rhinorrhoea 1 0.2 0 0.0 0 0.0 0 0.0 Sinus congestion 4 0.8 1 0.2 0 0.0 1 1.1 Skin and subcutaneous tissue disorders Acne 1 0.2 0 0.0 0 0.0 0 0.0 Acne cystic 1 0.2 0 0.0 0 0.0 0 0.0 Actinic keratosis 0 0.0 1 0.2 0 0.0 0 0.0 22JUL11:16:20:47 LEO80185 G23 t77.doc Continued...

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Daivobet® gel









Skin and subcutaneous tissue disorders Blister 0 0.0 1 0.2 0 0.0 0 0.0 Dermatitis 1 0.2 1 0.2 0 0.0 0 0.0 Dermatitis contact 1 0.2 1 0.2 1 1.1 0 0.0 Ecchymosis 0 0.0 1 0.2 0 0.0 0 0.0 Eczema asteatotic 1 0.2 0 0.0 0 0.0 0 0.0 Erythema 0 0.0 1 0.2 0 0.0 0 0.0 Guttate psoriasis 1 0.2 1 0.2 0 0.0 0 0.0 Ingrowing nail 1 0.2 0 0.0 0 0.0 0 0.0 Pruritus 3 0.6 1 0.2 1 1.1 2 2.1 Psoriasis 1 0.2 1 0.2 1 1.1 1 1.1 Rash 2 0.4 2 0.4 0 0.0 0 0.0 Rash papular 1 0.2 0 0.0 0 0.0 1 1.1 Scab 1 0.2 0 0.0 0 0.0 0 0.0 Skin discolouration 1 0.2 0 0.0 0 0.0 0 0.0 Skin fissures 0 0.0 1 0.2 0 0.0 0 0.0 Skin irritation 0 0.0 1 0.2 1 1.1 0 0.0 Surgical and medical procedures Abortion induced 1 0.2 1 0.2 0 0.0 0 0.0 Prostatectomy 1 0.2 0 0.0 0 0.0 0 0.0 Stent placement 0 0.0 1 0.2 0 0.0 0 0.0 22JUL11:16:20:47 LEO80185 G23 t77.doc Continued...

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Surgical and medical procedures Surgery 0 0.0 0 0.0 0 0.0 1 1.1 Transurethral prostatectomy

0 0.0 1 0.2 0 0.0 0 0.0

Vascular disorders Flushing 1 0.2 0 0.0 0 0.0 0 0.0 Hypertension 3 0.6 3 0.6 0 0.0 0 0.0 Thrombophlebitis superficial

0 0.0 1 0.2 0 0.0 0 0.0

Total number of adverse events2

169 144 28 35


125 26.0 96 20.0 22 23.2 22 23.2

22JUL11:16:20:47 LEO80185 G23 t77.doc


LEO 80185-G23 11-Oct-2011 of 349

Table 78: Causal relationship of AEs by MedDRA primary SOC and preferred term: safety analysis set

Daivobet® gel




System Organ Class Preferred Term1 NR3 Poss3 Prob3 NR3 Poss3 Prob3 NR3 Poss3 Prob3 NR3 Poss3 Prob3 Blood and lymphatic system disorders Thrombocytopenia 0 0 0 1 0 0 0 0 0 0 0 0 Cardiac disorders Angina pectoris 1 0 0 0 0 0 0 0 0 1 0 0 Ear and labyrinth disorders Cerumen impaction 0 0 0 0 0 0 0 0 0 1 0 0 Vertigo 0 0 0 0 0 0 0 0 0 0 1 0 Endocrine disorders Hypoparathyroidism 0 0 0 1 0 0 0 0 0 0 0 0 Thyroid disorder 0 0 0 1 0 0 0 0 0 0 0 0 Eye disorders Conjunctivitis 1 0 0 0 0 0 0 0 0 1 0 0 Erythema of eyelid 0 0 0 0 0 0 1 0 0 0 0 0 Gastrointestinal disorders Abdominal distension 1 0 0 0 0 0 0 0 0 0 0 0 Abdominal pain 0 0 0 1 0 0 0 0 0 0 0 0 Diarrhoea 2 0 0 1 0 0 1 0 0 1 0 0 Gastrooesophageal reflux disease

1 0 0 1 0 0 0 0 0 0 0 0

Haemorrhoids 1 0 0 0 0 0 0 0 0 0 0 0 13SEP11:16:33:57 LEO80185 G23 t78.doc Continued...

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Table 78: Causal relationship of AEs by MedDRA primary SOC and preferred term: safety analysis set continued

Daivobet® gel




System Organ Class Preferred Term1 NR3 Poss3 Prob3 NR3 Poss3 Prob3 NR3 Poss3 Prob3 NR3 Poss3 Prob3 Gastrointestinal disorders Nausea 1 0 0 1 1 0 1 0 0 0 0 0 Pancreatitis acute 0 0 0 1 0 0 0 0 0 0 0 0 Toothache 1 0 0 0 0 0 0 0 0 1 0 0 Vomiting 2 0 0 1 0 0 0 0 0 1 0 0 General disorders and administration siteconditions Application site pain 0 0 2 0 0 1 0 0 0 0 0 1 Cyst 1 0 0 0 0 0 0 0 0 0 0 0 Feeling of body temperature change

0 1 0 0 0 0 0 0 0 0 0 0

Pain 0 0 0 1 0 0 0 0 0 0 0 0 Pyrexia 0 0 0 0 0 0 0 0 0 1 0 0 Swelling 1 0 0 0 0 0 0 0 0 0 0 0 Hepatobiliary disorders Cholecystitis acute 0 0 0 1 0 0 0 0 0 0 0 0 Immune system disorders Allergy to plants 0 0 0 1 0 0 0 0 0 0 0 0 Drug hypersensitivity 1 0 0 0 0 0 0 0 0 0 0 0 Seasonal allergy 1 0 0 0 0 0 0 0 0 0 0 0 13SEP11:16:33:57 LEO80185 G23 t78.doc Continued...

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System Organ Class Preferred Term1 NR3 Poss3 Prob3 NR3 Poss3 Prob3 NR3 Poss3 Prob3 NR3 Poss3 Prob3 Infections and infestations Abscess 1 0 0 0 0 0 0 0 0 0 0 0 Bronchitis 5 0 0 0 0 1 1 0 0 1 0 0 Candidiasis 0 0 0 0 0 0 0 1 0 1 0 0 Cellulitis 0 1 0 3 1 0 0 0 0 0 0 0 Conjunctivitis bacterial 0 0 0 1 0 0 0 0 0 0 0 0 Diverticulitis 1 0 0 1 0 0 0 0 0 0 0 0 Ear infection 2 0 0 0 0 0 0 0 0 0 0 0 Eye infection 0 0 0 0 0 0 0 0 0 1 0 0 Folliculitis 1 1 0 0 0 0 0 0 0 0 0 0 Furuncle 1 0 0 0 0 0 0 0 0 0 0 0 Gastroenteritis 1 0 0 0 0 0 0 0 0 0 0 0 Gastroenteritis viral 2 0 0 3 0 0 1 0 0 0 0 0 Influenza 5 0 0 4 0 0 1 0 0 1 0 0 Kidney infection 0 0 0 1 0 0 0 0 0 0 0 0 Labyrinthitis 1 0 0 0 0 0 0 0 0 0 0 0 Laryngitis 0 0 0 1 0 0 0 0 0 0 0 0 Lower respiratory tract infection

0 0 0 1 0 0 0 0 0 0 0 0

Nasopharyngitis 14 0 0 15 0 0 5 0 0 3 0 0 13SEP11:16:33:57 LEO80185 G23 t78.doc Continued...

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System Organ Class Preferred Term1 NR3 Poss3 Prob3 NR3 Poss3 Prob3 NR3 Poss3 Prob3 NR3 Poss3 Prob3 Infections and infestations Otitis media acute 0 0 0 1 0 0 0 0 0 0 0 0 Pharyngitis 1 0 0 0 0 0 0 0 0 0 0 0 Pneumonia 2 0 0 0 0 0 0 0 0 0 0 0 Sinusitis 9 1 0 3 0 0 1 0 0 1 0 0 Skin infection 1 0 0 0 0 0 0 0 0 0 0 0 Streptococcal infection 0 0 0 1 0 0 0 0 0 0 0 0 Tinea pedis 1 0 0 0 0 0 0 0 0 0 0 0 Tooth abscess 2 0 0 1 0 0 0 0 0 0 0 0 Tooth infection 1 0 0 0 0 0 0 0 0 2 0 0 Upper respiratory tract infection

14 0 0 8 0 0 3 0 0 0 0 0

Urinary tract infection 2 0 0 3 0 0 0 0 0 0 0 0 Vulvovaginal mycotic infection

0 0 0 1 0 0 0 0 0 1 0 0

Injury, poisoning and proceduralcomplications Alcohol poisoning 0 0 0 1 0 0 0 0 0 0 0 0 Animal bite 0 0 0 1 0 0 0 0 0 1 0 0 Arthropod bite 1 0 0 2 0 0 0 0 0 0 0 0 13SEP11:16:33:57 LEO80185 G23 t78.doc Continued...

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System Organ Class Preferred Term1 NR3 Poss3 Prob3 NR3 Poss3 Prob3 NR3 Poss3 Prob3 NR3 Poss3 Prob3 Injury, poisoning and proceduralcomplications Cartilage injury 0 0 0 0 0 0 1 0 0 0 0 0 Caustic injury 1 0 0 0 0 0 0 0 0 0 0 0 Contusion 1 0 0 2 0 0 0 0 0 0 0 0 Excoriation 1 0 0 1 0 0 0 0 0 0 0 0 Fall 0 0 0 1 0 0 0 0 0 0 0 0 Injury 0 0 0 2 0 0 0 0 0 0 0 0 Joint injury 1 0 0 0 0 0 0 0 0 0 0 0 Joint sprain 0 0 0 1 0 0 0 0 0 0 0 0 Muscle strain 1 0 0 1 0 0 0 0 0 0 0 0 Pocket erosion 0 0 0 1 0 0 0 0 0 0 0 0 Post procedural complication 0 0 0 1 0 0 0 0 0 0 0 0 Rib fracture 0 0 0 1 0 0 0 0 0 0 0 0 Skin laceration 0 0 0 1 0 0 0 0 0 0 0 0 Thermal burn 1 0 0 1 0 0 0 0 0 0 0 0 Wrist fracture 1 0 0 0 0 0 0 0 0 0 0 0 Investigations Angiogram 0 0 0 0 0 0 0 0 0 1 0 0 Biopsy bladder 0 0 0 1 0 0 0 0 0 0 0 0 Biopsy prostate 0 0 0 1 0 0 0 0 0 0 0 0 Blood glucose decreased 1 0 0 0 0 0 0 0 0 0 0 0 13SEP11:16:33:57 LEO80185 G23 t78.doc Continued...

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System Organ Class Preferred Term1 NR3 Poss3 Prob3 NR3 Poss3 Prob3 NR3 Poss3 Prob3 NR3 Poss3 Prob3 Investigations Blood parathyroid hormone increased

6 6 1 3 6 0 0 0 0 0 1 0

Blood phosphorus decreased 0 1 0 0 0 0 0 0 0 0 0 0 Metabolism and nutrition disorders Diabetes mellitus 1 0 0 1 0 0 0 0 0 0 0 0 Hypercholesterolaemia 1 0 0 0 0 0 0 0 0 0 0 0 Hyperlipidaemia 0 0 0 1 0 0 0 0 0 0 0 0 Hypokalaemia 0 0 0 2 0 0 0 0 0 0 0 0 Type 2 diabetes mellitus 1 0 0 1 0 0 0 0 0 0 0 0 Musculoskeletal and connective tissuedisorders Arthralgia 0 0 0 1 0 0 0 0 0 2 0 0 Arthritis 1 0 0 0 0 0 0 0 0 0 0 0 Back pain 1 0 0 1 0 0 0 0 0 0 0 0 Bursitis 0 0 0 1 0 0 0 0 0 0 0 0 Joint swelling 0 0 0 0 0 0 1 0 0 0 0 0 Musculoskeletal pain 1 0 0 0 0 0 0 0 0 0 0 0 Myalgia 2 0 0 1 0 0 0 0 0 0 0 0 Psoriatic arthropathy 0 0 0 0 0 0 1 0 0 0 0 0 Rheumatoid arthritis 1 0 0 0 0 0 0 0 0 0 0 0 13SEP11:16:33:57 LEO80185 G23 t78.doc Continued...

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System Organ Class Preferred Term1 NR3 Poss3 Prob3 NR3 Poss3 Prob3 NR3 Poss3 Prob3 NR3 Poss3 Prob3 Musculoskeletal and connective tissuedisorders Tendonitis 0 0 0 1 0 0 0 0 0 0 0 0 Neoplasms benign, malignant and unspecified(incl cysts and polyps) Squamous cell carcinoma 1 0 0 0 0 0 0 0 0 0 0 0 Nervous system disorders Amnesia 0 0 0 0 0 0 1 0 0 0 0 0 Dizziness 0 2 0 1 0 0 0 0 0 0 0 0 Headache 4 0 0 4 1 0 0 0 0 0 0 0 Hypoaesthesia 0 0 0 1 0 0 0 0 0 0 0 0 Neuralgia 1 0 0 0 0 0 0 0 0 0 0 0 Paraesthesia 0 0 0 1 1 0 0 0 0 0 0 0 Syncope 1 0 0 0 0 0 0 0 0 0 0 0 Tunnel vision 0 0 0 0 0 0 1 0 0 0 0 0 Psychiatric disorders Depression 0 0 0 0 0 0 0 0 0 1 0 0 Suicidal ideation 0 0 0 1 0 0 0 0 0 0 0 0 Suicide attempt 0 0 0 0 0 0 0 0 0 1 0 0 Renal and urinary disorders Haematuria 0 0 0 1 0 0 0 0 0 0 0 0 Nephrolithiasis 0 0 0 0 1 0 0 0 0 0 0 0 13SEP11:16:33:57 LEO80185 G23 t78.doc Continued...

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Daivobet® gel




System Organ Class Preferred Term1 NR3 Poss3 Prob3 NR3 Poss3 Prob3 NR3 Poss3 Prob3 NR3 Poss3 Prob3 Reproductive system and breast disorders Bartholin's cyst 0 0 0 2 0 0 0 0 0 0 0 0 Respiratory, thoracic and mediastinaldisorders Acute respiratory failure 0 0 0 1 0 0 0 0 0 0 0 0 Cough 4 0 0 3 0 0 1 0 0 0 0 0 Dyspnoea 1 0 0 0 0 0 0 0 0 0 0 0 Epistaxis 1 0 0 0 0 0 0 0 0 0 0 0 Nasal congestion 4 0 0 3 0 0 0 0 0 0 0 0 Oropharyngeal pain 1 0 0 0 0 0 1 0 0 2 0 0 Postnasal drip 1 0 0 0 0 0 0 0 0 0 0 0 Respiratory tract congestion 1 0 0 0 0 0 1 0 0 0 0 0 Rhinorrhoea 1 0 0 0 0 0 0 0 0 0 0 0 Sinus congestion 4 0 0 1 0 0 0 0 0 1 0 0 Skin and subcutaneous tissue disorders Acne 1 0 0 0 0 0 0 0 0 0 0 0 Acne cystic 1 0 0 0 0 0 0 0 0 0 0 0 Actinic keratosis 0 0 0 1 0 0 0 0 0 0 0 0 Blister 0 0 0 1 0 0 0 0 0 0 0 0 Dermatitis 0 1 0 1 0 0 0 0 0 0 0 0 13SEP11:16:33:57 LEO80185 G23 t78.doc Continued...

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Daivobet® gel




System Organ Class Preferred Term1 NR3 Poss3 Prob3 NR3 Poss3 Prob3 NR3 Poss3 Prob3 NR3 Poss3 Prob3 Skin and subcutaneous tissue disorders Dermatitis contact 0 1 0 1 0 0 0 0 1 0 0 0 Ecchymosis 0 0 0 1 0 0 0 0 0 0 0 0 Eczema asteatotic 1 0 0 0 0 0 0 0 0 0 0 0 Erythema 0 0 0 1 0 0 0 0 0 0 0 0 Guttate psoriasis 0 1 0 1 0 0 0 0 0 0 0 0 Ingrowing nail 1 0 0 0 0 0 0 0 0 0 0 0 Pruritus 0 2 1 1 0 0 0 0 1 0 1 1 Psoriasis 0 1 0 1 0 0 0 1 0 1 0 0 Rash 1 0 1 2 0 0 0 0 0 0 0 0 Rash papular 0 1 0 0 0 0 0 0 0 0 1 0 Scab 1 0 0 0 0 0 0 0 0 0 0 0 Skin discolouration 1 0 0 0 0 0 0 0 0 0 0 0 Skin fissures 0 0 0 0 1 0 0 0 0 0 0 0 Skin irritation 0 0 0 0 1 0 0 1 0 0 0 0 Surgical and medical procedures Abortion induced 1 0 0 1 0 0 0 0 0 0 0 0 Prostatectomy 1 0 0 0 0 0 0 0 0 0 0 0 Stent placement 0 0 0 1 0 0 0 0 0 0 0 0 Surgery 0 0 0 0 0 0 0 0 0 1 0 0 Transurethral prostatectomy 0 0 0 1 0 0 0 0 0 0 0 0 13SEP11:16:33:57 LEO80185 G23 t78.doc Continued...

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System Organ Class Preferred Term1 NR3 Poss3 Prob3 NR3 Poss3 Prob3 NR3 Poss3 Prob3 NR3 Poss3 Prob3 Vascular disorders Flushing 0 1 0 0 0 0 0 0 0 0 0 0 Hypertension 3 0 0 3 0 0 0 0 0 0 0 0 Thrombophlebitis superficial 0 0 0 1 0 0 0 0 0 0 0 0 Total number of adverse events4,2

143 21 5 129 13 2 23 3 2 29 4 2

13SEP11:16:33:57 LEO80185 G23 t78.doc

1) Classification according to MedDRA version 13.0 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 3) NR=Not Related, Poss=Possibly Related, Prob=Probably Related 4) Two subjects received wrong trial medication during the study, subject from visit 4 and subject at visit 6.

LEO 80185-G23 11-Oct-2011 of 349

Table 79: Intensity of AEs by MedDRA primary SOC and preferred term: safety analysis set

Daivobet® gel




System Organ Class Preferred Term1 Mild Moderate Severe Mild Moderate Severe Mild Moderate Severe Mild Moderate Severe Blood and lymphatic system disorders Thrombocytopenia 0 0 0 0 1 0 0 0 0 0 0 0 Cardiac disorders Angina pectoris 1 0 0 0 0 0 0 0 0 0 1 0 Ear and labyrinth disorders Cerumen impaction 0 0 0 0 0 0 0 0 0 1 0 0 Vertigo 0 0 0 0 0 0 0 0 0 1 0 0 Endocrine disorders Hypoparathyroidism 0 0 0 1 0 0 0 0 0 0 0 0 Thyroid disorder 0 0 0 1 0 0 0 0 0 0 0 0 Eye disorders Conjunctivitis 1 0 0 0 0 0 0 0 0 0 1 0 Erythema of eyelid 0 0 0 0 0 0 0 1 0 0 0 0 Gastrointestinal disorders Abdominal distension 0 1 0 0 0 0 0 0 0 0 0 0 Abdominal pain 0 0 0 1 0 0 0 0 0 0 0 0 Diarrhoea 1 0 1 0 1 0 1 0 0 0 1 0 Gastrooesophageal reflux disease

1 0 0 1 0 0 0 0 0 0 0 0

Haemorrhoids 0 1 0 0 0 0 0 0 0 0 0 0 16AUG11:13:42:58 LEO80185 G23 t79.doc Continued...

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Table 79: Intensity of AEs by MedDRA primary SOC and preferred term: safety analysis set, continued

Daivobet® gel




System Organ Class Preferred Term1 Mild Moderate Severe Mild Moderate Severe Mild Moderate Severe Mild Moderate Severe Gastrointestinal disorders Nausea 1 0 0 2 0 0 1 0 0 0 0 0 Pancreatitis acute 0 0 0 0 1 0 0 0 0 0 0 0 Toothache 1 0 0 0 0 0 0 0 0 1 0 0 Vomiting 1 0 1 1 0 0 0 0 0 0 1 0 General disorders and administration siteconditions Application site pain 1 1 0 0 1 0 0 0 0 0 1 0 Cyst 1 0 0 0 0 0 0 0 0 0 0 0 Feeling of body temperature change

1 0 0 0 0 0 0 0 0 0 0 0

Pain 0 0 0 0 1 0 0 0 0 0 0 0 Pyrexia 0 0 0 0 0 0 0 0 0 0 1 0 Swelling 0 1 0 0 0 0 0 0 0 0 0 0 Hepatobiliary disorders Cholecystitis acute 0 0 0 0 1 0 0 0 0 0 0 0 Immune system disorders Allergy to plants 0 0 0 0 1 0 0 0 0 0 0 0 Drug hypersensitivity 1 0 0 0 0 0 0 0 0 0 0 0 Seasonal allergy 1 0 0 0 0 0 0 0 0 0 0 0 16AUG11:13:42:58 LEO80185 G23 t79.doc Continued...

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System Organ Class Preferred Term1 Mild Moderate Severe Mild Moderate Severe Mild Moderate Severe Mild Moderate Severe Infections and infestations Abscess 0 1 0 0 0 0 0 0 0 0 0 0 Bronchitis 1 3 1 1 0 0 0 1 0 1 0 0 Candidiasis 0 0 0 0 0 0 0 1 0 0 1 0 Cellulitis 0 1 0 1 3 0 0 0 0 0 0 0 Conjunctivitis bacterial

0 0 0 0 1 0 0 0 0 0 0 0

Diverticulitis 1 0 0 1 0 0 0 0 0 0 0 0 Ear infection 1 0 1 0 0 0 0 0 0 0 0 0 Eye infection 0 0 0 0 0 0 0 0 0 0 0 1 Folliculitis 2 0 0 0 0 0 0 0 0 0 0 0 Furuncle 0 1 0 0 0 0 0 0 0 0 0 0 Gastroenteritis 0 1 0 0 0 0 0 0 0 0 0 0 Gastroenteritis viral 2 0 0 2 1 0 1 0 0 0 0 0 Influenza 2 3 0 3 1 0 1 0 0 0 1 0 Kidney infection 0 0 0 0 0 1 0 0 0 0 0 0 Labyrinthitis 1 0 0 0 0 0 0 0 0 0 0 0 Laryngitis 0 0 0 0 1 0 0 0 0 0 0 0 Lower respiratory tract infection

0 0 0 0 1 0 0 0 0 0 0 0


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Daivobet® gel




System Organ Class Preferred Term1 Mild Moderate Severe Mild Moderate Severe Mild Moderate Severe Mild Moderate Severe Infections and infestations Nasopharyngitis 13 0 1 14 1 0 5 0 0 1 2 0 Otitis media acute 0 0 0 1 0 0 0 0 0 0 0 0 Pharyngitis 1 0 0 0 0 0 0 0 0 0 0 0 Pneumonia 1 0 1 0 0 0 0 0 0 0 0 0 Sinusitis 8 2 0 3 0 0 1 0 0 0 0 1 Skin infection 1 0 0 0 0 0 0 0 0 0 0 0 Streptococcal infection 0 0 0 1 0 0 0 0 0 0 0 0 Tinea pedis 0 1 0 0 0 0 0 0 0 0 0 0 Tooth abscess 1 1 0 1 0 0 0 0 0 0 0 0 Tooth infection 1 0 0 0 0 0 0 0 0 1 1 0 Upper respiratory tract infection

10 4 0 7 1 0 1 2 0 0 0 0

Urinary tract infection 2 0 0 2 1 0 0 0 0 0 0 0 Vulvovaginal mycotic infection

0 0 0 0 1 0 0 0 0 1 0 0

Injury, poisoning and proceduralcomplications Alcohol poisoning 0 0 0 0 1 0 0 0 0 0 0 0 Animal bite 0 0 0 0 1 0 0 0 0 0 0 1 16AUG11:13:42:58 LEO80185 G23 t79.doc Continued...

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System Organ Class Preferred Term1 Mild Moderate Severe Mild Moderate Severe Mild Moderate Severe Mild Moderate Severe Injury, poisoning and proceduralcomplications Arthropod bite 1 0 0 2 0 0 0 0 0 0 0 0 Cartilage injury 0 0 0 0 0 0 1 0 0 0 0 0 Caustic injury 1 0 0 0 0 0 0 0 0 0 0 0 Contusion 1 0 0 2 0 0 0 0 0 0 0 0 Excoriation 1 0 0 1 0 0 0 0 0 0 0 0 Fall 0 0 0 0 1 0 0 0 0 0 0 0 Injury 0 0 0 1 1 0 0 0 0 0 0 0 Joint injury 0 1 0 0 0 0 0 0 0 0 0 0 Joint sprain 0 0 0 0 1 0 0 0 0 0 0 0 Muscle strain 0 0 1 0 1 0 0 0 0 0 0 0 Pocket erosion 0 0 0 1 0 0 0 0 0 0 0 0 Post procedural complication

0 0 0 0 1 0 0 0 0 0 0 0

Rib fracture 0 0 0 0 0 1 0 0 0 0 0 0 Skin laceration 0 0 0 0 1 0 0 0 0 0 0 0 Thermal burn 1 0 0 1 0 0 0 0 0 0 0 0 Wrist fracture 0 0 1 0 0 0 0 0 0 0 0 0 Investigations Angiogram 0 0 0 0 0 0 0 0 0 1 0 0 Biopsy bladder 0 0 0 0 1 0 0 0 0 0 0 0 16AUG11:13:42:58 LEO80185 G23 t79.doc Continued...

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System Organ Class Preferred Term1 Mild Moderate Severe Mild Moderate Severe Mild Moderate Severe Mild Moderate Severe Investigations Biopsy prostate 0 0 0 0 1 0 0 0 0 0 0 0 Blood glucose decreased 1 0 0 0 0 0 0 0 0 0 0 0 Blood parathyroid hormone increased

11 2 0 8 1 0 0 0 0 1 0 0

Blood phosphorus decreased

1 0 0 0 0 0 0 0 0 0 0 0

Metabolism and nutrition disorders Diabetes mellitus 1 0 0 0 1 0 0 0 0 0 0 0 Hypercholesterolaemia 0 1 0 0 0 0 0 0 0 0 0 0 Hyperlipidaemia 0 0 0 0 1 0 0 0 0 0 0 0 Hypokalaemia 0 0 0 2 0 0 0 0 0 0 0 0 Type 2 diabetes mellitus

1 0 0 0 1 0 0 0 0 0 0 0

Musculoskeletal and connective tissuedisorders Arthralgia 0 0 0 0 0 1 0 0 0 1 1 0 Arthritis 0 1 0 0 0 0 0 0 0 0 0 0 Back pain 1 0 0 0 1 0 0 0 0 0 0 0 Bursitis 0 0 0 0 1 0 0 0 0 0 0 0 Joint swelling 0 0 0 0 0 0 0 1 0 0 0 0 16AUG11:13:42:58 LEO80185 G23 t79.doc Continued...

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System Organ Class Preferred Term1 Mild Moderate Severe Mild Moderate Severe Mild Moderate Severe Mild Moderate Severe Musculoskeletal and connective tissuedisorders Musculoskeletal pain 0 0 1 0 0 0 0 0 0 0 0 0 Myalgia 2 0 0 0 1 0 0 0 0 0 0 0 Psoriatic arthropathy 0 0 0 0 0 0 1 0 0 0 0 0 Rheumatoid arthritis 1 0 0 0 0 0 0 0 0 0 0 0 Tendonitis 0 0 0 0 0 1 0 0 0 0 0 0 Neoplasms benign, malignant and unspecified(incl cysts and polyps) Squamous cell carcinoma 0 1 0 0 0 0 0 0 0 0 0 0 Nervous system disorders Amnesia 0 0 0 0 0 0 1 0 0 0 0 0 Dizziness 2 0 0 0 1 0 0 0 0 0 0 0 Headache 3 1 0 4 1 0 0 0 0 0 0 0 Hypoaesthesia 0 0 0 1 0 0 0 0 0 0 0 0 Neuralgia 0 1 0 0 0 0 0 0 0 0 0 0 Paraesthesia 0 0 0 2 0 0 0 0 0 0 0 0 Syncope 0 1 0 0 0 0 0 0 0 0 0 0 Tunnel vision 0 0 0 0 0 0 1 0 0 0 0 0 Psychiatric disorders Depression 0 0 0 0 0 0 0 0 0 0 1 0 Suicidal ideation 0 0 0 0 1 0 0 0 0 0 0 0 16AUG11:13:42:58 LEO80185 G23 t79.doc Continued...

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System Organ Class Preferred Term1 Mild Moderate Severe Mild Moderate Severe Mild Moderate Severe Mild Moderate Severe Psychiatric disorders Suicide attempt 0 0 0 0 0 0 0 0 0 0 1 0 Renal and urinary disorders Haematuria 0 0 0 0 1 0 0 0 0 0 0 0 Nephrolithiasis 0 0 0 0 0 1 0 0 0 0 0 0 Reproductive system and breast disorders Bartholin's cyst 0 0 0 1 0 1 0 0 0 0 0 0 Respiratory, thoracic and mediastinaldisorders Acute respiratory failure

0 0 0 0 0 1 0 0 0 0 0 0

Cough 3 1 0 1 2 0 1 0 0 0 0 0 Dyspnoea 0 1 0 0 0 0 0 0 0 0 0 0 Epistaxis 0 0 1 0 0 0 0 0 0 0 0 0 Nasal congestion 2 2 0 3 0 0 0 0 0 0 0 0 Oropharyngeal pain 1 0 0 0 0 0 1 0 0 2 0 0 Postnasal drip 1 0 0 0 0 0 0 0 0 0 0 0 Respiratory tract congestion

1 0 0 0 0 0 1 0 0 0 0 0

Rhinorrhoea 1 0 0 0 0 0 0 0 0 0 0 0 Sinus congestion 4 0 0 1 0 0 0 0 0 1 0 0 16AUG11:13:42:58 LEO80185 G23 t79.doc Continued...

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Daivobet® gel




System Organ Class Preferred Term1 Mild Moderate Severe Mild Moderate Severe Mild Moderate Severe Mild Moderate Severe Skin and subcutaneous tissue disorders Acne 1 0 0 0 0 0 0 0 0 0 0 0 Acne cystic 1 0 0 0 0 0 0 0 0 0 0 0 Actinic keratosis 0 0 0 1 0 0 0 0 0 0 0 0 Blister 0 0 0 1 0 0 0 0 0 0 0 0 Dermatitis 0 0 1 1 0 0 0 0 0 0 0 0 Dermatitis contact 1 0 0 1 0 0 0 0 1 0 0 0 Ecchymosis 0 0 0 1 0 0 0 0 0 0 0 0 Eczema asteatotic 1 0 0 0 0 0 0 0 0 0 0 0 Erythema 0 0 0 1 0 0 0 0 0 0 0 0 Guttate psoriasis 0 1 0 0 1 0 0 0 0 0 0 0 Ingrowing nail 1 0 0 0 0 0 0 0 0 0 0 0 Pruritus 1 2 0 1 0 0 1 0 0 2 0 0 Psoriasis 0 1 0 1 0 0 0 1 0 0 1 0 Rash 2 0 0 2 0 0 0 0 0 0 0 0 Rash papular 1 0 0 0 0 0 0 0 0 1 0 0 Scab 1 0 0 0 0 0 0 0 0 0 0 0 Skin discolouration 1 0 0 0 0 0 0 0 0 0 0 0 Skin fissures 0 0 0 0 1 0 0 0 0 0 0 0 Skin irritation 0 0 0 1 0 0 1 0 0 0 0 0 16AUG11:13:42:58 LEO80185 G23 t79.doc Continued...

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Daivobet® gel




System Organ Class Preferred Term1 Mild Moderate Severe Mild Moderate Severe Mild Moderate Severe Mild Moderate Severe Surgical and medical procedures Abortion induced 0 0 1 0 1 0 0 0 0 0 0 0 Prostatectomy 0 1 0 0 0 0 0 0 0 0 0 0 Stent placement 0 0 0 0 0 1 0 0 0 0 0 0 Surgery 0 0 0 0 0 0 0 0 0 1 0 0 Transurethral prostatectomy

0 0 0 0 1 0 0 0 0 0 0 0

Vascular disorders Flushing 1 0 0 0 0 0 0 0 0 0 0 0 Hypertension 2 0 1 1 2 0 0 0 0 0 0 0 Thrombophlebitis superficial

0 0 0 0 1 0 0 0 0 0 0 0

Total number of adverse events3,2

116 40 13 87 49 8 20 7 1 17 15 3

16AUG11:13:42:58 LEO80185 G23 t79.doc

1) Classification according to MedDRA version 13.0 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 3) Two subjects received wrong trial medication during the study, subject from visit 4 and subject at visit 6.

LEO 80185-G23 11-Oct-2011 of 349

Table 80: Intensity of ADRs by MedDRA primary SOC and preferred term: safety analysis set

Daivobet® gel




System Organ Class Preferred Term1 Mild Moderate Severe Mild Moderate Severe Mild Moderate Severe Mild Moderate Severe Ear and labyrinth disorders Vertigo 0 0 0 0 0 0 0 0 0 1 0 0 Gastrointestinal disorders Nausea 0 0 0 1 0 0 0 0 0 0 0 0 General disorders and administration siteconditions Application site pain 1 1 0 0 1 0 0 0 0 0 1 0 Feeling of body temperature change

1 0 0 0 0 0 0 0 0 0 0 0

Infections and infestations Bronchitis 0 0 0 1 0 0 0 0 0 0 0 0 Candidiasis 0 0 0 0 0 0 0 1 0 0 0 0 Cellulitis 0 1 0 0 1 0 0 0 0 0 0 0 Folliculitis 1 0 0 0 0 0 0 0 0 0 0 0 Sinusitis 1 0 0 0 0 0 0 0 0 0 0 0 Investigations Blood parathyroid hormone increased

7 0 0 6 0 0 0 0 0 1 0 0


LEO 80185-G23 11-Oct-2011 of 349

Table 80: Intensity of ADRs by MedDRA primary SOC and preferred term: safety analysis set, continued

Daivobet® gel




System Organ Class Preferred Term1 Mild Moderate Severe Mild Moderate Severe Mild Moderate Severe Mild Moderate Severe Investigations Blood phosphorus decreased

1 0 0 0 0 0 0 0 0 0 0 0

Nervous system disorders Dizziness 2 0 0 0 0 0 0 0 0 0 0 0 Headache 0 0 0 1 0 0 0 0 0 0 0 0 Paraesthesia 0 0 0 1 0 0 0 0 0 0 0 0 Renal and urinary disorders Nephrolithiasis 0 0 0 0 0 1 0 0 0 0 0 0 Skin and subcutaneous tissue disorders Dermatitis 0 0 1 0 0 0 0 0 0 0 0 0 Dermatitis contact 1 0 0 0 0 0 0 0 1 0 0 0 Guttate psoriasis 0 1 0 0 0 0 0 0 0 0 0 0 Pruritus 1 2 0 0 0 0 1 0 0 2 0 0 Psoriasis 0 1 0 0 0 0 0 1 0 0 0 0 Rash 1 0 0 0 0 0 0 0 0 0 0 0 Rash papular 1 0 0 0 0 0 0 0 0 1 0 0 Skin fissures 0 0 0 0 1 0 0 0 0 0 0 0 Skin irritation 0 0 0 1 0 0 1 0 0 0 0 0 16AUG11:13:43:18 LEO80185 G23 t80.doc Continued...

LEO 80185-G23 11-Oct-2011 of 349

Table 80: Intensity of ADRs by MedDRA primary SOC and preferred term: safety analysis set, continued

Daivobet® gel




System Organ Class Preferred Term1 Mild Moderate Severe Mild Moderate Severe Mild Moderate Severe Mild Moderate Severe Vascular disorders Flushing 1 0 0 0 0 0 0 0 0 0 0 0 Total number of adverse events3,2

19 6 1 11 3 1 2 2 1 5 1 0

16AUG11:13:43:18 LEO80185 G23 t80.doc

1) Classification according to MedDRA version 13.0 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. 3) Two subjects received wrong trial medication during the study, subject from visit 4 and subject at visit 6.

LEO 80185-G23 11-Oct-2011 of 349

Table 81: Intensity of AEs in treatment area by MedDRA primary SOC and preferred term: safety analysis set

Daivobet® gel




System Organ Class Preferred Term1 Mild Moderate Severe Mild Moderate Severe Mild Moderate Severe Mild Moderate Severe General disorders and administration siteconditions Application site pain 1 1 0 0 1 0 0 0 0 0 1 0 Cyst 1 0 0 0 0 0 0 0 0 0 0 0 Infections and infestations Candidiasis 0 0 0 0 0 0 0 1 0 0 0 0 Cellulitis 0 1 0 0 1 0 0 0 0 0 0 0 Otitis media acute 0 0 0 1 0 0 0 0 0 0 0 0 Injury, poisoning and proceduralcomplications Arthropod bite 1 0 0 0 0 0 0 0 0 0 0 0 Contusion 0 0 0 1 0 0 0 0 0 0 0 0 Excoriation 1 0 0 1 0 0 0 0 0 0 0 0 Wrist fracture 0 0 1 0 0 0 0 0 0 0 0 0 Nervous system disorders Hypoaesthesia 0 0 0 1 0 0 0 0 0 0 0 0 Paraesthesia 0 0 0 2 0 0 0 0 0 0 0 0 Skin and subcutaneous tissue disorders Dermatitis contact 1 0 0 0 0 0 0 0 1 0 0 0 Erythema 0 0 0 1 0 0 0 0 0 0 0 0 16AUG11:13:43:33 LEO80185 G23 t81.doc Continued...

LEO 80185-G23 11-Oct-2011 of 349

Table 81: Intensity of AEs in treatment area by MedDRA primary SOC and preferred term: safety analysis set, continued

Daivobet® gel




System Organ Class Preferred Term1 Mild Moderate Severe Mild Moderate Severe Mild Moderate Severe Mild Moderate Severe Skin and subcutaneous tissue disorders Guttate psoriasis 0 1 0 0 1 0 0 0 0 0 0 0 Pruritus 0 2 0 0 0 0 1 0 0 2 0 0 Psoriasis 0 1 0 1 0 0 0 1 0 0 1 0 Rash 0 0 0 1 0 0 0 0 0 0 0 0 Rash papular 1 0 0 0 0 0 0 0 0 0 0 0 Skin fissures 0 0 0 0 1 0 0 0 0 0 0 0 Total number of adverse events3,2

6 6 1 9 4 0 1 2 1 2 2 0

16AUG11:13:43:33 LEO80185 G23 t81.doc

1) Classification according to MedDRA version 13.0 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 3) Two subjects received wrong trial medication during the study, subject from visit 4 and subject at visit 6.

LEO 80185-G23 11-Oct-2011 of 349

Table 82: Summary of serum calcium and change from baseline at baseline and Weeks 4 and 8: safety analysis set

Serum calcium (mmol/L)

Daivobet® gel

(n=482)

Betamethasone gel

(n=479)

Calcipotriol gel

(n=96)

Vehicle (n=95)

Summary1 Baseline Mean 2.333 2.319 2.338 2.316 SD 0.107 0.106 0.106 0.108 Median 2.330 2.330 2.350 2.330 Minimum 2.03 1.83 2.08 1.98 Maximum 2.70 2.70 2.65 2.75 Number 474 465 93 91 Week 4 Mean 2.307 2.303 2.316 2.293 SD 0.105 0.101 0.109 0.113 Median 2.300 2.300 2.330 2.280 Minimum 1.98 2.00 2.05 2.05 Maximum 2.70 2.70 2.58 2.63 Number 436 416 85 79 Week 8 Mean 2.312 2.302 2.318 2.301 SD 0.098 0.101 0.116 0.095 Median 2.300 2.300 2.300 2.280 Minimum 2.08 2.00 2.10 2.13 Maximum 2.68 2.63 2.70 2.63 Number 435 403 82 74 End of Treatment Mean 2.311 2.302 2.321 2.297 SD 0.097 0.102 0.117 0.102 Median 2.300 2.300 2.300 2.280 Minimum 2.08 2.00 2.10 2.05 Maximum 2.68 2.63 2.70 2.63 Number 460 434 91 83 Change from Baseline Week 4 Mean -0.027 -0.015 -0.025 -0.020 SD 0.107 0.104 0.088 0.117 Median -0.030 -0.020 -0.025 -0.010 Minimum -0.45 -0.30 -0.25 -0.30 23SEP11:12:02:12 LEO80185 G23 t82.doc Continued...

LEO 80185-G23 11-Oct-2011 of 349

Table 82: Summary of serum calcium and change from baseline at baseline and Weeks 4 and 8: safety analysis set , continued

Serum calcium (mmol/L)

Daivobet® gel

(n=482)

Betamethasone gel

(n=479)

Calcipotriol gel

(n=96)

Vehicle (n=95)

Change from Baseline Week 4 Maximum 0.28 0.47 0.18 0.28 Number 433 410 82 76 Week 8 Mean -0.022 -0.019 -0.022 -0.009 SD 0.104 0.101 0.102 0.097 Median -0.020 -0.020 -0.030 -0.020 Minimum -0.33 -0.40 -0.28 -0.22 Maximum 0.38 0.30 0.25 0.25 Number 432 397 79 71 End of Treatment Mean -0.022 -0.017 -0.016 -0.017 SD 0.102 0.101 0.102 0.106 Median -0.020 -0.020 -0.010 -0.020 Minimum -0.33 -0.40 -0.28 -0.25 Maximum 0.38 0.30 0.25 0.25 Number 457 427 88 80 23SEP11:12:02:12 LEO80185 G23 t82.doc


LEO 80185-G23 11-Oct-2011 of 349

Table 83: Shift tables for serum calcium from baseline to Weeks 4 and 8: safety analysis set







Vehicle(n=95)


Serum Calcium



LOW 2 9 0 4 8 0 1 2 0 1 2 0



LEO 80185-G23 11-Oct-2011 of 349

Table 84: Summary of serum albumin and change from baseline at baseline and Weeks 4 and 8: safety analysis set

Serum albumin (g/L)

Daivobet® gel

(n=482)

Betamethasone gel

(n=479)

Calcipotriol gel

(n=96)

Vehicle (n=95)

Summary1 Baseline Mean 44.6 44.5 44.7 44.0 SD 2.5 2.8 2.7 2.8 Median 45.0 45.0 45.0 44.0 Minimum 35 35 34 36 Maximum 52 54 50 52 Number 474 465 93 91 Week 4 Mean 44.3 44.3 44.2 43.4 SD 2.5 2.6 3.0 2.6 Median 44.0 44.0 45.0 43.0 Minimum 36 35 31 38 Maximum 52 51 52 49 Number 436 416 85 79 Week 8 Mean 44.3 44.3 44.1 43.8 SD 2.6 2.6 2.8 2.5 Median 44.0 44.0 44.0 44.0 Minimum 34 36 32 39 Maximum 53 52 50 50 Number 435 403 82 74 End of Treatment Mean 44.3 44.3 44.3 43.7 SD 2.5 2.7 2.8 2.6 Median 44.0 44.0 44.0 44.0 Minimum 34 36 32 38 Maximum 53 52 50 50 Number 460 434 91 83 Change from Baseline Week 4 Mean -0.4 -0.2 -0.5 -0.4 SD 2.1 1.9 1.9 2.0 Median 0.0 0.0 -0.5 -1.0 Minimum -9 -8 -6 -4 23SEP11:12:02:39 LEO80185 G23 t84.doc Continued...

LEO 80185-G23 11-Oct-2011 of 349

Table 84: Summary of serum albumin and change from baseline at baseline and Weeks 4 and 8: safety analysis set, continued

Serum albumin (g/L)

Daivobet® gel

(n=482)

Betamethasone gel

(n=479)

Calcipotriol gel

(n=96)

Vehicle (n=95)

Change from Baseline Week 4 Maximum 6 5 3 5 Number 433 410 82 76 Week 8 Mean -0.3 -0.2 -0.4 -0.2 SD 2.1 2.1 2.1 2.2 Median 0.0 0.0 -1.0 0.0 Minimum -9 -6 -4 -4 Maximum 8 6 7 8 Number 432 397 79 71 End of Treatment Mean -0.3 -0.2 -0.4 -0.2 SD 2.1 2.1 2.0 2.5 Median 0.0 0.0 -1.0 -0.5 Minimum -9 -6 -4 -5 Maximum 8 6 7 8 Number 457 427 88 80 23SEP11:12:02:39 LEO80185 G23 t84.doc


LEO 80185-G23 11-Oct-2011 of 349

Table 85: Shift tables for serum albumin from baseline to Weeks 4 and 8: safety analysis set



Betametha-sone gel (n=479)

End of Period

category1



Vehicle (n=95)

End of Period

category1

Serum Albumin Baseline category1,2 Low Normal High Normal Low Normal Normal

Week 4 LOW 0 0 0 0 1 0 0 NORMAL 0 433 0 409 0 81 76 HIGH 0 0 0 1 0 0 0 Week 8 LOW 0 0 0 0 1 0 0 NORMAL 1 430 1 396 0 78 71 HIGH 0 0 0 1 0 0 0 End of Treatment LOW 0 0 0 0 1 0 0 NORMAL 1 455 1 426 0 87 80 HIGH 0 0 0 1 0 0 0 23SEP11:12:02:49 LEO80185 G23 t85.doc


LEO 80185-G23 11-Oct-2011 of 349

Table 86: Summary of urinary calcium and change from baseline at baseline and Weeks 4 and 8: safety analysis set

Urinary calcium (mmol/L)

Daivobet® gel

(n=482)

Betamethasone gel

(n=479)

Calcipotriol gel

(n=96)

Vehicle (n=95)

Summary1 Baseline Mean 3.18 3.29 2.83 2.46 SD 2.48 2.71 1.90 2.00 Median 2.60 2.60 2.50 1.90 Minimum 0.4 0.5 0.5 0.5 Maximum 13.6 19.8 8.7 12.6 Number 468 468 95 91 Week 4 Mean 2.96 2.85 2.95 2.59 SD 2.21 2.27 2.25 1.95 Median 2.40 2.30 2.40 2.30 Minimum 0.5 0.5 0.3 0.5 Maximum 12.2 15.5 10.7 8.7 Number 427 415 83 78 Week 8 Mean 3.09 3.14 3.21 2.50 SD 2.38 2.45 2.32 2.17 Median 2.70 2.60 2.60 2.00 Minimum 0.3 0.2 0.5 0.1 Maximum 18.0 13.2 9.2 14.7 Number 434 405 81 74 End of Treatment Mean 3.07 3.08 3.26 2.57 SD 2.37 2.41 2.33 2.10 Median 2.60 2.50 2.60 2.20 Minimum 0.3 0.2 0.5 0.1 Maximum 18.0 13.2 9.2 14.7 Number 458 434 91 83 Change from Baseline Week 4 Mean -0.26 -0.35 0.19 0.24 SD 2.48 2.48 2.41 2.07 Median -0.10 -0.30 -0.05 0.20 Minimum -11.3 -12.2 -5.3 -8.6 23SEP11:12:02:59 LEO80185 G23 t86.doc Continued...

LEO 80185-G23 11-Oct-2011 of 349

Table 86: Summary of urinary calcium and change from baseline at baseline and Weeks 4 and 8: safety analysis set, continued

Urinary calcium (mmol/L)

Daivobet® gel

(n=482)

Betamethasone gel

(n=479)

Calcipotriol gel

(n=96)

Vehicle (n=95)

Change from Baseline Week 4 Maximum 8.7 10.0 9.4 5.9 Number 418 410 82 75 Week 8 Mean -0.10 -0.16 0.44 0.08 SD 2.46 2.47 2.20 2.36 Median 0.00 -0.10 0.10 0.00 Minimum -9.3 -10.1 -5.7 -8.8 Maximum 11.9 6.8 6.0 11.5 Number 427 400 80 72 End of Treatment Mean -0.11 -0.14 0.38 0.15 SD 2.50 2.41 2.24 2.31 Median 0.00 -0.10 0.10 0.00 Minimum -11.3 -10.1 -5.7 -8.8 Maximum 11.9 6.8 6.0 11.5 Number 448 429 90 80 23SEP11:12:02:59 LEO80185 G23 t86.doc


LEO 80185-G23 11-Oct-2011 of 349

Table 87: Shift tables for urinary calcium from baseline to Weeks 4 and 8: safety analysis set


End of Period

category1


End of Period

category1


End of Period

category1

Vehicle (n=95)

End of Period

category1 Urinary Calcium Baseline category1,2 Normal Normal Normal Normal Week 4 NORMAL 418 410 82 75 Week 8 NORMAL 427 400 80 72 End of Treatment NORMAL 448 429 90 80 23SEP11:12:03:09 LEO80185 G23 t87.doc


LEO 80185-G23 11-Oct-2011 of 349

Table 88: Summary of urinary phosphate and change from baseline at baseline and Weeks 4 and 8: safety analysis set

Urinary phosphate (mmol/L)

Daivobet® gel

(n=482)

Betamethasone gel

(n=479)

Calcipotriol gel

(n=96)

Vehicle (n=95)

Summary1 Baseline Mean 17.61 18.19 18.47 15.44 SD 12.14 12.99 11.75 10.80 Median 15.90 15.75 16.20 14.50 Minimum 0.1 0.6 0.5 0.5 Maximum 73.3 113.4 64.4 52.2 Number 468 468 95 91 Week 4 Mean 18.89 18.08 20.41 16.82 SD 13.14 12.19 13.13 11.01 Median 16.60 16.10 19.30 14.80 Minimum 0.2 0.1 2.0 1.2 Maximum 88.0 62.0 82.6 50.5 Number 427 415 83 78 Week 8 Mean 19.02 19.56 21.90 18.53 SD 12.69 13.40 12.19 13.12 Median 16.50 17.50 21.10 16.75 Minimum 0.4 0.3 0.2 0.4 Maximum 80.8 90.1 60.6 55.7 Number 434 405 81 74 End of Treatment Mean 19.08 19.43 21.49 17.99 SD 13.01 13.25 11.89 12.62 Median 16.50 17.50 20.70 16.00 Minimum 0.4 0.3 0.2 0.4 Maximum 80.8 90.1 60.6 55.7 Number 458 434 91 83 Change from Baseline Week 4 Mean 1.12 0.41 2.27 0.84 SD 14.66 13.23 14.12 11.86 Median 0.75 0.90 1.40 1.20 Minimum -50.8 -51.4 -47.2 -25.5 23SEP11:12:03:29 LEO80185 G23 t88.doc Continued...

LEO 80185-G23 11-Oct-2011 of 349

Table 88: Summary of urinary phosphate and change from baseline at baseline and Weeks 4 and 8: safety analysis set, continued

Urinary phosphate (mmol/L)

Daivobet® gel

(n=482)

Betamethasone gel

(n=479)

Calcipotriol gel

(n=96)

Vehicle (n=95)

Change from Baseline Week 4 Maximum 57.8 56.0 60.1 33.4 Number 418 410 82 75 Week 8 Mean 1.26 1.86 3.55 2.56 SD 13.88 15.94 13.04 13.28 Median 1.40 1.60 2.90 1.75 Minimum -56.8 -99.6 -51.1 -42.1 Maximum 49.9 68.1 30.4 35.0 Number 427 400 80 72 End of Treatment Mean 1.39 1.76 3.06 2.62 SD 13.91 15.64 12.81 12.93 Median 1.45 1.60 2.75 2.05 Minimum -56.8 -99.6 -51.1 -42.1 Maximum 49.9 68.1 30.4 35.0 Number 448 429 90 80 23SEP11:12:03:29 LEO80185 G23 t88.doc


LEO 80185-G23 11-Oct-2011 of 349

Table 89: Shift tables for urinary phosphate from baseline to Weeks 4 and 8: safety analysis set


End of Period

category1


End of Period

category1


End of Period

category1

Vehicle (n=95)

End of Period

category1 Urinary Phosphate Baseline category1,2 Normal Normal Normal Normal Week 4 NORMAL 418 410 82 75 Week 8 NORMAL 427 400 80 72 End of Treatment NORMAL 448 429 90 80 23SEP11:12:03:19 LEO80185 G23 t89.doc


LEO 80185-G23 11-Oct-2011 of 349

Table 90: Summary of urinary creatinine and change from baseline at baseline and Weeks 4 and 8: safety analysis set

Urinary creatinine (mmol/L)

Daivobet® gel

(n=482)

Betamethasone gel

(n=479)

Calcipotriol gel

(n=96)

Vehicle (n=95)

Summary1 Baseline Mean 10.50 10.84 10.91 9.56 SD 6.15 7.15 6.15 5.70 Median 9.90 9.60 10.10 9.20 Minimum 1.0 0.8 0.6 0.4 Maximum 33.7 43.6 28.6 31.4 Number 468 468 95 91 Week 4 Mean 10.78 10.30 12.23 9.96 SD 6.43 6.69 6.59 5.93 Median 9.80 9.30 10.80 9.55 Minimum 0.6 0.2 1.3 0.9 Maximum 38.9 37.8 34.1 28.1 Number 427 415 83 78 Week 8 Mean 11.08 10.39 11.57 9.68 SD 6.75 5.99 6.26 5.69 Median 10.00 9.10 10.70 8.95 Minimum 1.0 0.8 0.9 0.9 Maximum 39.2 32.3 29.8 26.3 Number 434 405 81 74 End of Treatment Mean 11.20 10.47 11.63 9.58 SD 6.84 6.07 6.08 5.47 Median 10.00 9.20 10.80 8.80 Minimum 0.6 0.8 0.9 0.9 Maximum 39.2 32.3 29.8 26.3 Number 458 434 91 83 Change from Baseline Week 4 Mean 0.40 -0.32 1.41 0.70 SD 6.16 7.29 6.76 6.72 Median -0.10 -0.20 0.95 1.40 Minimum -18.8 -33.2 -19.0 -22.6 23SEP11:12:03:39 LEO80185 G23 t90.doc Continued...

LEO 80185-G23 11-Oct-2011 of 349

Table 90: Summary of urinary creatinine and change from baseline at baseline and Weeks 4 and 8: safety analysis set, continued

Urinary creatinine (mmol/L)

Daivobet® gel

(n=482)

Betamethasone gel

(n=479)

Calcipotriol gel

(n=96)

Vehicle (n=95)

Change from Baseline Week 4 Maximum 20.1 31.8 16.8 13.5 Number 418 410 82 75 Week 8 Mean 0.62 -0.17 0.85 0.23 SD 6.98 7.14 6.62 6.46 Median 0.30 0.50 0.45 0.20 Minimum -21.4 -30.7 -18.4 -18.2 Maximum 33.3 19.0 15.4 15.2 Number 427 400 80 72 End of Treatment Mean 0.73 -0.10 0.74 0.45 SD 7.00 7.16 6.60 6.27 Median 0.30 0.50 0.15 0.45 Minimum -21.4 -30.7 -18.4 -18.2 Maximum 33.3 19.0 15.4 15.2 Number 448 429 90 80 23SEP11:12:03:39 LEO80185 G23 t90.doc


LEO 80185-G23 11-Oct-2011 of 349

Table 91: Shift tables for urinary creatinine from baseline to Weeks 4 and 8: safety analysis set


End of Period

category1


End of Period

category1


End of Period

category1

Vehicle (n=95)

End of Period

category1 Urinary Creatinine Baseline category1,2 Normal Normal Normal Normal Week 4 NORMAL 418 410 82 75 Week 8 NORMAL 427 400 80 72 End of Treatment NORMAL 448 429 90 80 23SEP11:12:03:49 LEO80185 G23 t91.doc


LEO 80185-G23 11-Oct-2011 of 349

15 REFERENCES

1. Gottlieb AB. Psoriasis. Dis Manag Clin Outcomes 1998; 1(6): 195-202. 2. Lowes MA, Bowcock AM, Krueger JG. Pathogenesis and therapy of psoriasis. Nature

2007; 445: 866-73. 3. Gottlieb AB, Miller B, Lowe N, Shapiro W, Hudson C, Bright R at al. Subcutaneously

Administered Efalizumab (Anti-CD11a) Improves Signs and Symptoms of Moderate to Severe Plaque Psoriasis. J Cutan Med Surg 2003; 198-207.

4. Callen JP, Krueger GG, Lebwohl M, McBurney EI; Mease P, Menter A et al. AAD consensus statement on psoriasis therapies. J Am Acad Dermatol 2003; 49(5): 897-9.

5. Berth-Jones J, Chu AC, Dodd WA, Ganpule M, Griffiths WA, Haydey RP et al. A multicentre, parallel-group comparison of calcipotriol ointment and short-contact dithranol therapy in chronic plaque psoriasis. Br J Dermatol 1992; 127(3): 266-71.

6. Tham SN, Lun KC, Cheong WK. A Comparative study of calcipotriol ointment and tar in chronic plaque psoriasis. Br J Dermatol 1994; 131(5): 673-7.

7. Cunliffe WJ, Berth-Jones J, Claudy A, Fairiss G, Goldin D, Gratton D et al. Comparative study of calcipotriol (MC 903) ointment and betamethasone 17-valerate ointment in pa-tients with psoriasis vulgaris. J Am Acad Dermatol 1992; 26(5 Pt 1): 736-43.

8. Kragballe K, Gjertsen BT, De Hoop D, Karlsmark T, van de Kerkhof PC, Larko O et al. Double-blind, right/left comparison of calcipotriol and betamethasone valerate in treat-ment of psoriasis vulgaris. Lancet 1991; 337(8735): 193-6.

9. Ellis J, Griffiths W, Klaber M. Long-term treatment of chronic plaque psoriasis with calcipotriol ointment in patients unresponsive to short contact dithranol. Eur J Clin Res 1995; 7:247-57.

10. Kragballe K, Fogh K, Sogaard H. Long-term efficacy and tolerability of topical cal-cipotriol in psoriasis. Results of an open study. Acta Derm Venereol 1991; 71(6): 475-8.

11. Poyner T, Hughes JW, Dass JW, Adnitt PI. Long-term treatment of chronic plaque psoriasis with calcipotriol. J Dermatol Treat 1993; 4(4): 173-7.

12. Ramsay CA, Berth-Jones J, Brundin G, Cunliffe WJ, Dubertret L, van de Kerkhof PC et al. Long-term use of topical calcipotriol in chronic plaque psoriasis. Dermatology 1994; 189(3): 260-4.

13. Bourke JF, Berth-Jones J, Iqbal SJ, Hutchinson PE. High-dose topical calcipotriol in the treatment of extensive psoriasis vulgaris. Br J Dermatol 1993; 129(1): 74-6.

LEO 80185-G23 11-Oct-2011 of 349

14. Chuang T, Samson C. Clinical efficacy and safety of augmented betamethasone dipropi-onate ointment and difloresone diacetate ointment for psoriasis, a multicentre, random-ised, double-blind study. J Dermatol Treat 1991; 2:63-6.

15. Roberts DT. Comparison of fluticasone propionate ointment, 0.005%, and bethamethasone-17,21-dipropionate ointment, 0.05%, in the treatment of psoriasis. Cutis 1996; 57(2 Suppl): 27-31.

16. Shupack JL, Jondreau L, Kenny C, Stiller MJ. Diflorasone diacetate ointment 0.05% versus betamethasone dipropionate ointment 0.05% in moderate-severe plaque-type pso-riasis. Dermatology 1993; 186(2): 129-32.

17. 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 ingredi-ents and the vehicle in the treatment of scalp psoriasis. J Am Acad Dermatol 2008; 59 (3); 455-63.

18. 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 random-ised, double-blind, controlled trial. Br J Dermatol 2009; 160; 170-76.

19. Luger T, Cambazard F, Larsen FG, Bourcier M, Gupta G, Clonier F et al. A study of the safety and efficacy of calcipotriol and betamethasone dipropionate scalp formulation in the long-term management of scalp psoriasis. Dermatology 2008; 217: 321-28.

20. Tyring S, Mendoza N, Appell M, Bibby A, Foster R, Hamilton T et al. A calcipotriene/ betamethasone dipropionate two-compound scalp formulation in the treatment of scalp psoriasis in Hispanic/Latino and Black/African American patients: results of the random-ized, 8 week, double-blind phase of a clinical trial. Int J Dermatology 2010, 49, 1328–1333.

21. 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.

22. Buckley C, Hoffmann V, Shapiro J, Saari S, Cambazard F, Milsgaard M. Calcipotriol plus betamethasone dipropionate scalp formulation is effective and well tolerated in the treatment of scalp psoriasis (a phase II study). Dermatology 2008; 217. 107-13.

23. Fleming C, Ganslandt C, Guenther L, Johannesson A, Buckley C, Simon J C, Stegmann H, Tingleff Lotte V. Calcipotriol 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: 465-71.

LEO 80185-G23 11-Oct-2011 of 349

24. Efficacy and safety of calcipotriol plus bethamethasone dipropionate gel compared with tacalcitol ointment and the gel vehicle alone in patients with psoriasis vulgaris. LEO Study Number LEO 80185-G21. Report dated 16-JUN-2009.

25. Patient preference for topical psoriasis formulations. Abstract for EADV; Abstract 2: 08-FEB-2010.

26. 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 mono-therapy with betamethasone dipropionate or calcipotriol in psoriasis vulgaris. Acta Derm Venereol 2002; 82(2): 131-5.

27. 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.

28. 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.

29. 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.

30. Code of Federal Regulations (CFR) Title 21 Part 300.50 available at: www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm

31. CPMP, 17 April 1996: Note for Guidance on Fixed Combination Medicinal Products 32. FDA, May 1998: Guidance for Industry. Providing Clinical Evidence of Effectiveness for

Human Drug and Biological Products available at: www.fda.gov/cder/guidance/index.htm 33. Kragballe K, Noerrelund KL, Lui JP, Ortonne JP, Wosel G, Uurasmaa T et al. Efficacy of

once-daily treatment regimens with calcipotriol/ betamethasone dipropionate ointment and calcipotriol ointment in psoriasis vulgaris. Br J Dermatol 2004; 150(6): 1167-73.

34. CHMP, 18 November 2004: Guideline on Clinical Investigation of Medicinal Products Indicated for the Treatment of Psoriasis.

35. Hochberg Y. A sharper Bonferroni procedure for multiple tests of significance. Bio-metrika 1988; 75: 800-2.

36. El-Hajj Fuleihan G, Klerman EB, Brown EN, Choe Y, Brown EM, Czeisler CA, The parathyroid hormone circadian rhythm is truly endogenous - a general clinical research center study. J Clin Endocrinol Metab. 1997; 82: 281-6.

LEO 80185-G23 11-Oct-2011 of 349

37. Ankrah-Tetteh T, Wijeratne S, Swaminathan R Intraindividual variation in serum thyroid hormones, parathyroid hormone and insulin-like growth factor-1. Ann Clin Biochem. 2008; 45: 167-9.

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16 LIST OF APPENDICES

App. No.

Appendix Date of appendix Enclosed/N.A.

16.1 STUDY INFORMATION

16.1.1 Protocol and protocol amendments 12-May-2011 Enclosed 16.1.2 Sample case report form (unique pages only) 12-May-2011 Enclosed 16.1.3 List of IECs or IRBs (plus the name of the commit-

tee Chair if required by the regulatory authority) - Representative written information for subject and sample consent forms

12-May-2011 Enclosed

16.1.4

List and description of investigators and other important participants in the trial, including brief (1 page) CVs or equivalent summaries of training and experience relevant to the performance of the clinical trial


16.1.5 Signatures of principal or coordinating investiga-tor(s) or sponsor’s responsible medical officer, depending on the regulatory authority's requirement


16.1.6 Listing of subjects receiving test drug(s)/investigational product(s) from specific batches, where more than one batch was used

05-Oct-2011 Enclosed

16.1.7 Randomisation scheme and codes (subject identifi-cation and treatment assigned)

19-Sep-2011 Enclosed

16.1.8 Audit certificates 03-Oct-2011 Enclosed 16.1.9 Documentation of statistical methods 05-Oct-2011 Enclosed 16.1.10 Documentation of inter-laboratory standardisation

methods and quality assurance procedures if used N.A.

16.1.11 Publications based on the trial N.A. 16.1.12 Important publications referenced in the report N.A.

16.2 SUBJECT DATA LISTINGS

16.2.1 Discontinued subjects 19-Sep-2011 Enclosed 16.2.2 Protocol deviations 19-Sep-2011 Enclosed

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16.2.3 Subjects excluded from the efficacy analysis 19-Sep-2011 Enclosed 16.2.4 Demographic data 19-Sep-2011 Enclosed 16.2.5 Compliance and/or drug concentration data (if

available) 19-Sep-2011 Enclosed

16.2.6 Individual efficacy response data 19-Sep-2011 Enclosed 16.2.7 Adverse event listings (each subject) 11-Oct-2011 Enclosed 16.2.8 Listing of individual laboratory measurements by

subject, when required by regulatory authorities 10-Oct-2011 Enclosed

16.3 CASE REPORT FORMS

16.3.1 CRFs for deaths, other serious adverse events and withdrawals for AE

Available on request

16.3.2 Other CRFs submitted Available on request

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