Main Clinical Stud dy Report LEO in the Treatment of Psoriasis Vulgaris

Transcription

1 Main Clinical Study Report LEO 9 in the Treatment of Psoriasis Vulgaris A phase study comparing treatment with LEO 9 with betamethasone in LEO 9 vehicle and calcipotriol in LEO 9 vehicle in with psoriasis vulgaris A multi-centre, prospective, randomised, double-blind, -arm, parallel group, -week study in with psoriasis vulgaris LEO Pharmaceutical Products Ltd. A/S (LEO Pharma A/S) Clinical Development and Safety LEO Apr-

2 LEO Apr- Page of 89 Report Statement APPROVAL STAT TEMENT The following persons have approved this Clinical Study Report on behalf of LEO Pharma A/S using electronic signatures: Biostatistics and Dataa Management Medical Department APPROVAL STAT TEMENT, INVESTIGATORS The International Co-ordinating Investigator approves the main Clinical Study Report by manually signing the International Co-ordinating Investigator Clinical Study Report Approval Form, which is a separate document adjoined to this report. The following person has approved this main Clinical Study Report: International Co-ordinating Investigator

3 LEO Apr- Page of 89 COMPLIANCE WITH GOOD CLINICAL PRACTICE This Clinical Study Report is designed to comply with the standards issued by the Interna- Reports; E Good Clinical Practice; E9 Statistical Principles for Clinical Trials and M Common Technical Document). DISCLOSURE OF CLINICAL TRIAL RESULTSS Results from this clinical trial will be posted under the identifier NCT98 on tional Conference on Harmonisation (ICH) (E Structure and Content of Clinical Study gov which is a publicly accessiblee database. Synopsis The synopsis of this Clinical Study Report exists as a separately approved document. Synopsis

4 LEO Apr- Page of 89 Table of Contents Report Statement... Synopsis... Table of Contents... List of Tables... 8 List of Figures... List of Abbreviations and Definition of Terms... Ethics Independent Ethics Committee (IEC) or Institutional Review Board (IRB) Ethical Conduct of the Trial Subject Information and Informed Consent... 7 Investigators and Trial Administrative Structure Introduction Psoriasis vulgaris Investigational Product Trial Rationale... 8 Trial Objectives Primary Objective Secondary Objectives... 9 Investigational Plan Overall Trial Design and Plan Description Individual Phases Discussion of Trial Design, Including the Choice of Control Groups Selection of Trial Population Inclusion Criteria Exclusion Criteria Removal of Subjects from Therapy or Assessment Treatments Treatments Administered Identity of Investigational Product(s) Method of Assigning Subjects to Treatment Groups... 7

5 LEO Apr- Page of Selection of Doses in the Trial Selection and Timing of Dose for each Subject Blinding Prior and Concomitant Therapy Treatment Compliance Efficacy and Safety Variables Efficacy and Safety Measurements Assessed and Flow Chart Subject Eligibility Efficacy assessments Safety Assessments Appropriateness of Measurements Primary Efficacy Variable(s) Secondary and Furtherr Response Criteria Drug Concentration Measurements Data Quality Assurance Statistical Methods Planned in the Protocol and Determination of Sample Size Statistical and Analytical Plans Reasons for Leaving the Study Baselinee Characteristics Analysiss of Efficacy Analysiss of Safety Evaluation of Other Observations General Principles Determination of Sample Size Changes in the Conduct of the Trial or Planned Analyses... 7 Trial Population Disposition of Subjects Protocol Deviations... 7 Efficacy Evaluation Data Sets Analysed Full analysis set Safety Analysis Set Per Protocol Analysis Set Trial analysis sets by treatment Demographic and other Baseline Characteristics... 78

6 LEO Apr- Page of 89.. Demographic data Disease-related and other baseline data Concurrent diagnosis and use of concomitant medication Conclusionn on study Measurement of Treatment Compliance Efficacy Results and Tabulation of Individual Subject Dataa Analysis of Efficacy Psoriasis on Trunk and Limbs Primary Endpoint Controlled disease according to the IGA of the trunk and limbs at week Secondary Endpoint Controlled disease according to the IGA on the trunk and limbs at week m-pasi of the trunk and limbs Analysis of Efficacy - Scalp Psoriasis Controlled disease according to the IGA of the scalp m-pasi of the scalp..... Analysis of Efficacy- Overall assessment of psoriasis of the trunk, limbs and scalp 7... Controlled disease according to the IGA of the trunk and limbs and scalp m-pasi of the trunk, limbs and scalp Patient reported outcomes Patients assessment of disease severity Subject s assessment of itch Health related quality of life..... Statistical/Analytical Issues Adjustments for Covariates Handling of Dropouts or Missing Data Interim Analyses and Data Monitoring Multi-Site Clinical Trials Multiple Comparison/Multiplicity Use of an Efficacy Subset of Subjects Active-Control Studies Intended to Show Equivalence Examination of Subgroups Tabulation of Individual Response Data Drug Dose, Drug Concentration, and Relationships to Response Drug-Drugg and Drug-Disease Interactions By-Subject Displays Efficacy Conclusions Safety Evaluation...

7 LEO Apr- Page 7 of 89. Extent of Exposure.... Adverse events (AEs)..... Brief Summary of Adverse Events..... Display of Adverse Events Adverse events by system organ class and preferred term Adverse events by severity Adverse drug reactions Analysis of Adverse Events..... Listing of Adverse Events by Subject.... Deaths, Other Serious Adverse Events and Other Significant Adverse Events..... Listing of Deaths, Other Serious Adverse Events and Other Significant Adverse Events Deaths Other Serious Adverse Events Other Significant Adverse Events..... Narratives of Deaths, Other Serious Adversee Events and Other Significant Adverse Events Narratives of serious adverse events Narratives of adverse events leading to discontinuation..... Analysis and Discussion of Deaths, Other Serious Adverse Events and Other Significant Adverse Events.... Clinical Laboratory Evaluation..... Listing of Individual Laboratory Measurements by Subject (..8)..... Evaluation of Each Laboratory Parameter Laboratory Values Over Time Individual Subject Changes Individual Clinically Significant Abnormalities Vital Signs, Physical Findings and Other Observations Related to Safety Vital signs Local safety and tolerability.... Safety Conclusions... Discussion and Overall Conclusions.... Discussion.... Overall conclusions... Tables, Figures and Graphs Referred to But Not Included In The Text.... Trial population...

8 LEO Apr- Page 8 of 89. Demographic Data Measurement of treatment compliance Efficacy Dataa Efficacy data for the trunk and limbs Efficacy data for the scalp Overall assessment of the trunk, limbs and scalp Subject s assessments Safety Data Adverse events Vital signs, physical findings and other observations... 9 References... 8 List of Appendices List of Tables Table : Identity of LEO 9... Table : Identity of BDP in LEO 9 vehicle... Table : Identity of calcipotriol in LEO 9 vehicle Table : Schedule of trial procedures... Table : Fitzpatrick Skin Type... Table : Investigator s Global Assessment of Diseasee Severity -point Scale... Table 7: Severity score for redness, thickness and scaliness... 7 Table 8: Patient s Global Assessment of Disease Severity -point Scale... 8 Table 9: Serum biochemistry and urinalysis... Table : Reason for withdrawal: randomised... 7 Table : Protocol deviations: randomisedd... 7 Table : Age: randomised Table : Sex: randomised... 8 Table Race: randomised... 8 Table : Ethnicity: randomised Table : Skin type: randomised... 8 Table 7: Duration of psoriasis vulgaris: randomisedd... 8 Table 8: Investigators global assessment (IGA) of disease severity at baseline: randomised... 8 Table 9: m-pasi at baseline: randomisedd... 8 Table : BSA involvement of psoriasis vulgaris affecting the trunk and limbs at baseline: randomised... 8 Table : Extent of scalp psoriasis at baseline: randomised... 8 Table : BSA involvement of psoriasis vulgaris affecting the trunk, limbs and scalp at baseline: randomised... 87

9 LEO Apr- Page 9 of 89 Table : Other locations of psoriasis vulgaris: randomised Table : Previous psoriasis treatments: randomised Table : Compliance with treatment instructions for the trunk and limbs over the total trial period: randomised... 9 Table : Compliance with treatment instructions for the scalp over the total trial period: randomised... 9 Table 7: Analysis of 'Controlled disease' (IGA of the trunk and limbs) at Week (LOCF): full analysis set... 9 Table 8: Analysis of 'Controlled disease' (IGA of the trunk and limbs) at Week (LOCF): per protocol analysis set... 9 Table 9: Analysis of 'Controlled disease' (IGA of the trunk and limbs) at Week (LOCF): full analysis set... 9 Table : 'Controlled disease' (IGA of the trunk and limbs) at each visit: full analysis set Table : Analysis of m-pasi of the trunk and limbs at Week (LOCF): full analysis set Table : Analysis of m-pasi of the trunk and limbs at Week (LOCF): full analysis set Table : Analysis of PASI 7 of the trunk and limbs at Week (LOCF): full analysis set.. Table : Analysis of PASI of the trunk and limbs at Week (LOCF): full analysis set.. Table : Analysis of 'Controlled disease' (IGA of the scalp) at Week (LOCF): full analysis set Table : Analysis of 'Controlled disease' (IGA of the scalp) at Week (LOCF): full analysis set Table 7: Analysis of m-pasi of the scalp at Week (LOCF): full analysis set... Table 8: Analysis of m-pasi of the scalp at Week (LOCF): full analysis set... Table 9: Analysis of PASI 7 of the scalp at Week (LOCF): full analysiss set... Table : Analysis of PASI of the scalp at Week (LOCF): full analysiss set... 7 Table : Analysis of 'Controlled disease' (IGA of the trunk, limbs and scalp) at Week (LOCF): full analysis set... 8 Table : Analysis of 'Controlled disease' (IGA of the trunk, limbs and scalp) at Week (LOCF): full analysis set... 9 Table : Analysis of m-pasi of the trunk, limbs and scalp at Week (LOCF): full analysis set Table : Analysis of m-pasi of the trunk, limbs and scalp at Week (LOCF): full analysis set Table : Analysis of PASI 7 of the trunk, limbs and scalp at Week (LOCF): full analysis set Table : Analysis of PASI of the trunk, limbs and scalp at Week (LOCF): full analysis set Table 7: Analysis of 'Controlled disease' (Patient s Global Assessment) at Week (LOCF): full analysis set... Table 8: Analysis of change in itching (Visual Analogue Scale) from baseline to each visit: full analysis set... Table 9: Analysis of change in DLQI from baseline to each visit: full analysis set... Table : Duration and extent of exposuree to treatment: safety analysis set... Table : Average weekly amount of study medication used between visits: safety analysis set...

10 LEO Apr- Page of 89 Table : Overall summary of adverse events: safety analysis set... Table : Adverse events by MedDRA primary system organ class and preferred term: safety analysis set... 7 Table : Adverse drug reactions by MedDRA primary system organ class and preferred term: safety analysis set... Table : Intensity of adverse drug reactions by MedDRA primary system organ class and preferred term: safety analysis set... Table : Adverse events leading to withdrawal of from the trial.... Table 7: Change in albumin corrected serum calcium from baseline to Week (LOCF): safety analysis set... Table 8: Change in urinary calcium:creatinine ratio from baseline to Week (LOCF): safety analysis set... 7 Table 9: Albumin corrected serum calcium categorised as low, normal or high at Week (LOCF) shown against baseline category: safety analysis set... 8 Table : Urinary calcium:creatinine ratio categorised as low, normal or high at Week (LOCF) shown against baseline category: safety analysis set... 9 Table : Study period by centre: enrolled Table : Subject enrolment and randomisation by centre: enrolled and randomised... Table : Reasons for withdrawal by last on-treatment visit for which data are recorded: randomised... 7 Table : Age by centre: randomised... 8 Table : Sex by centre: randomised Table : Race by centre: randomised Table 7: Ethnicity by centre: randomisedd... 8 Table 8: Physical examination (weight, height and BMI): randomised... Table 9: -hydroxy vitamin D categorised as low, normal or high: randomised. Table 7: IGA of disease severity of the trunk and limbs at baseline by centre: randomised... Table 7: Concomitant medication at baseline: randomised... Table 7: Concurrent diagnoses at baseline by MedDRA primary system organ class: randomised... 7 Table 7: Compliance with treatment instructions for the trunk and limbs by visit: randomised... 9 Table 7: Compliance with treatment instructions for the scalp by visit: randomised... 7 Table 7: 'Controlled disease' (IGA of the trunk and limbs) at Week (LOCF) by centre: full analysis set... 7 Table 7: 'Controlled disease' (IGA of the trunk and limbs) at Week (LOCF) by baseline IGA of the trunk and limbs: full analysis set... 7 Table 77: Investigator's globall assessment of the trunk and limbs at each visit: full analysis set... 7 Table 78: m-pasi of the trunk and limbs at each visit: full analysis set Table 79: Percentage change in m-pasi of the trunk and limbs from baseline to each visit: full analysis set... 79

11 LEO Apr- Page of 89 Table 8: PASI 7 of the trunk and limbs at each visit: full analysis set... 8 Table 8:.PASI of the trunk and limbs at each visit: full analysis set... 8 Table 8: 'Controlled disease' (IGA of the scalp) at each visit: full analysis set... 8 Table 8: Investigator's globall assessment of the scalp at each visit: full analysis set... 8 Table 8: m-pasi of the scalp at each visit: full analysis set... 8 Table 8: Percentage change in m-pasi of the scalp from baseline to each visit: full analysis set Table 8: PASI 7 of the scalp at each visit: full analysis set Table 87: PASI of the scalp at each visit: full analysis set Table 88: Investigator's globall assessment of the trunk, limbs and scalp at each visit: full analysis set Table 89: m-pasi of the trunk, limbs and scalp at each visit: full analysis set... 9 Table 9: Percentage change in m-pasi of the trunk, limbs and scalp from baseline to each visit: full analysis set... 9 Table 9: PASI 7 of the trunk, limbs and scalp at each visit: full analysis set... 9 Table 9: PASI of the trunk, limbs and scalp at each visit: full analysis set... 9 Table 9: Patient's global assessment of disease severity at each visit: full analysis set... 9 Table 9: amount of study medication used between visits: safety analysis set Table 9: Adverse events by MedDRA primary system organ class: safety analysis set Table 9: Intensity of adverse events by MedDRA primary system organ class and preferred term: safety analysis set Table 97: Relationship of adverse events to study medication by MedDRA primary system organ class and preferred term: safety analysis set... Table 98: Subjects with albumin-corrected serum calcium or calcium:creatinine ratio outside the reference range.... Table 99: Change in vital signs (blood pressure, heart rate) from baseline to Week : safety analysis set... 9 Table : Investigator s assessment of application site reaction of erythema at each visit by centre: safety analysis set Table : Investigator s assessment of application site reaction of dryness at each visit by centre: safety analysis set Table : Investigator s assessment of application site reaction of erosion at each visit by centre: safety analysis set Table : Investigator s assessment of application site reaction of oedema at each visit by centre: safety analysis set Table : Subject s self reporting of application site reaction of burning at each visit by centre: safety analysis set Table : Subject's self reporting of application site reaction of pain at each visit by centre: safety analysis set... 7 Table : BSA involvement of psoriasis vulgaris affecting the trunk, limbs and scalp at each visit: safety analysis set... 8

12 LEO Apr- Page of 89 List of Figures Figure : Trial design for LEO Figure : Visit attendance by treatment: randomised... 7 Figure : Trial analysis sets by treatment: randomised Figure : Percentage of with Controlled disease (IGA of the trunk and limbs) at each visit: full analysis set Figure : Percentage of with Controlled disease (IGA of the scalp) at each visit: full analysis set... Figure : Baseline BSA involvement of psoriasis vulgaris affecting the trunk, limbs and scalp versus average weekly amount of study medication used: safety analysis set... Figure 7: Subject recruitment over time...

13 LEO Apr- Page of 89 List of Abbreviations and Definition of Terms LIST OF ABBREVIATIONS ADR AE BDP BSA ecrf CRO CMO CSP DLQI DME EMA EoT EU FDA FU GCP GPV HPA HQ ICH ICTM IEC IGA IND IRB MedDRA LCRA LOCF PASI m-pasi PUVA SAE Adverse Drug Reaction Adverse Event Betamethasone Body Surface Area Electronic Case Report Form Contract Research Organisation Contract Manufacturing Organisation Clinical Study Protocol Dermatology Life Quality Index Dimethyl Ether European Medicines Agency End of Text European Union Food and Drug Administration Follow-up Good Clinical Practice Global Pharmacovigilance Hypothalamic-pituitary-adrenal Head Quarter International Conference on Harmonisation International Clinical Trial Manager Independent Ethics Committee Investigator s Global Assessment of disease severity Investigational New Drug Institutional Review Board Medical Dictionary for Regulatory Activities Lead Clinical Research Associate Last Observation Carried Forward Psoriasis Area and Severity Index Modified Psoriasis Area and Severity Index Psoralen plus ultraviolet light A Serious Adverse Event

14 LEO Apr- Page of 89 SAPU SOC SOP SUSAR UVB VAS Statistical Analysis Plan Update System Organ Class Standard Operating Procedure Suspected, Unexpected Serious Adverse Reactions Ultraviolet light B Visual Analogue Scale DEFINITION OF TERMS Terms defined by ICH Guidelines are not mentioned here. Assessment A (cluster of) characteristic(s) measured and/or recorded for a subject. Concomitant Medication Any medication taken by a subject during a clinical trial apart from the trial medication. 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, misinterpret tation of results and conclu- of other sions, plagiarism of results or entire articles from other researchers, misrepresentation 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 and Safety (formerly Interna- tional 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.

15 LEO Apr- Page of 89 Investigator Staff Signature Form A form used:. for the investigator to delegate trial-related tasks/duties. for trial site staff to sign and date to accept delegation. for trial site staff to document signatures and initials. 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 organisationn of LEO Pharma. Monitor A person appointed by LEO to carry out monitoring of a clinical trial. Lead Clinical Research Associate (LCRA) The person appointed by LEO to be the national sponsor representative responsible for all aspects of a clinical trial within a country as outlined in Clinicall Development and Safety (formerly International Clinical Development) SOPs. Subject Identification List A summary list kept by the investigator in the Investigator Trial File that records the names of all enrolled and the date of enrolment in the trial at thatt trial site, with the subject s corresponding CRF Book Number, to allow the investigator/institution to reveal the identity of any subject, if required. 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. 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).

16 LEO Apr- Page of 89 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 Screening Log A document kept by the investigator which identifies patients/ who entered pre-trial screening. Subject Screening Log is synonymous with Patient Screening Log.

17 LEO Apr- Page 7 of 89 Ethics. 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(ies) was notified of/approved the clinical trial, as required. A list of all IRBs consulted is given in Appendix.... Ethical Conduct of the Trial The clinical trial was conducted to conform to the principles of the Declaration of Helsinki as adoptedd by the 8 th World Medical Assembly, 9, and subsequent amendments. The clinical trial was conducted in accordance with the principles of GCP. The study was conducted in accordance with applicable national regulatory requirements and under a US Investigational New Drug (IND). 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 (9//EC) as well as any national data protection legislation.. Subject Information and Informed Consent Subjects were asked to consent that data could be recorded, collected, processed and trans- the EU Data Protection Directive (9//EC). ferred to EU and non-eu countries in accordance with any national legislation implementing All received written and verbal information concerning the clinical trial. This information emphasised that participation in the trial was voluntary and that the subject could withdraw from the trial at any time and for any reason. All were given an opportunity to ask questions and were given sufficient time to consider all relevant issues before consent- ing.

18 LEO Apr- Page 8 of 89 The subject's signed and datedd 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... All investigators signed an Investigator Agreement before the clinical trial was initiated to confirm the above.

19 LEO Apr- Page 9 of89 Investigators and Trial Administrative Structure LEO Pharma A/S was the sponsor of the clinical u ial and participating LEO affiliates were authorised by the sponsor to act on behalf of the sponsor in the counu ies where the clinical u ial was conducted. Role Name, title, affiliation Intemational Co-ordinating.-MD,- Deprutment of Dennatology, The Investigator: Mmmt Sinai School of Medicine, New York, TeL: Fax:--, Head ofmedical Deprut---MD,. I Medical Deprut ment, LEO ment: PhrumaA/S, Indusu iparken, DK-7 Ballemp, Denmark, TeL: Head of Biostatistics: --MSc,.l Biostatistics and Data Management, LEO PhrumaA/S, Indusu ipru ken, DK-7 Ballemp,,Fax:-- . Trial Statistician: ----LEO Phruma, Longwick Road, Princes Risborough, Buckinghamshire, HP7 9RR, United Kingdom, Tel.: II Intemational Clinical Trial - -ICTM, t, LEO Manager (ICTM): PhrumaA/S, Indusu iparken, 7 Ballemp, Denmark, TeL: Lead CRA (LCRA): -~-----LEO Phruma Inc., Commerce Valley Drive East Suite, Thomhill, ON, LT 7W8, Canada, Tel.: ' Mobile:

20 LEO Apr- Page of 89 Sponsor 's Medical Expert: --n, MD, PhD,--Medical Department, LEO PhannaA/S, Industriparken, 7 Ballemp, Denmark, Tel.: Central Laboraty: --,--ACM Global Centml LaboratOiy, Elmgrove Park, Rochester, NY, USA, Tel: II The CRO was responsible for centi allaboratoiy analyses. Conu act Research Organi-, ' TKL Research sation (CRO): Inc., W. Passaic Su eet, Rochelle Park, NJ 7, USA, Tel: ext- Ill The CRO was responsible for project management, clinical conduct, data management, interactive web response system (IWRS) for randomisation, and monitoring. Clinical u ial supply: The CMO was responsible for the seconda!y packaging, labelling and disu ibution ofu ial medication, and also the receipt, accmmtability, reconciliation and destruction of retumed u ial medication. Medical Director Global Ill -~ Section I PV Science, Global Phrumacovigilance: Phrumacovigilance, LEO PharmaA/S, Indusu iparken, DK- 7 Ballemp, Denmru k, Tel.: II RepiAuthor(s): - -ICTM, Clinical Project Management, LEO PhrumaA/S, Indusu iparken, DK-7 Ballemp, Denmark, Tel.:

21 LEO Apr- Page of LEO Phruma, Longwick Road, Princes Risborough, Buckinghamshire, HP7 9RR, United Kingdom, Tel.: - --n, MD, PhD,--Medical Deprutment, LEO PhrumaA/S, Industripru ken, DK-7 Ballemp, Denmark, TeL: PhD,--Medical Deprui ment, LEO PhrumaA/S, Industriparken, DK-7 Ballemp, Denmark, TeL: A list of investigators, including CmTiculum Vitae and other persons whose prui icipation materially affected the conduct of the trial is included in Appendix...

22 LEO Apr- Page of 89 7 Introduction The trial was performed as a phase trial evaluating the efficacy and safety of LEO 9, a fixed combination product containing calcipotriol plus betamethasone (BDP) in an aerosol formulation, in with psoriasis vulgaris. 7. Psoriasis vulgaris Psoriasis is a multisystem disease with predominantly skin and joint manifestations affecting approximately to of the population (-). The major manifestation of psoriasis is chronic inflammation of the skin, characterised by sharply demarcated, scaling, and erythematous plaques that may be painful and often severely pruritic. The psoriatic appearance of the skin is produced by an increased rate of epidermal proliferation with impaired differentiation of keratinocytes resulting in a thickened, undulating epidermis covered by a thickened, parakera- of both epidermis and dermis with immunologically active cells (, totic stratum corneum. Dermal capillaries become tortuous and dilated and there is infiltration ). The most common clinical type of psoriasis, affecting 8 to 9 of patients, is psoriasis vulgaris (plaque-type psoriasis) (). Although psoriasis may occur at any site, the scalp, elbows, legs, knees, arms and trunk are commonly affected sites. The nails are involved in about of patients with psoriasis and in about psoriatic arthritis arises, usually many years after the initial cutaneous manifestation (). Psoriasis is associated with multiple medical as well as psychiatric comorbidities such as the metabolic syndrome, cardiovascular disease (7-9) and depression ncluding suicidal ideation (-). Studies have revealed that patients with psoriasis are emotionally and physicallyy impaired by their disease to an extent comparable to patients with heart disease, diabetes or cancer (-). Psoriasis is therefore a significant problem for affected in everydayy life, and has a significant impact on their health-related quality of life. Psoriasis is a chronic disease that waxes and wanes during a patient s lifetime, with few spontaneous remissions (). 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, and improving patient quality of life (). Treatments are selected based on disease severity, patient preference and response. Topical therapy is the regimen of choice for s with less extensive disease who comprise two thirds of all psoriasis in order to reduce the risk of systemic toxicity (). A number of topical therapies are available for psoriasis vulgaris, including corticosteroids, vitamin D analogues, retinoids and coal tar.

23 LEO Apr- Page of 89 Among these, vitamin D analogues and topical corticosteroids are the two with the greatest proven efficacy in randomisedd clinical trials, particularly when used in combination (). However, application of topical therapies can be cumbersome, messy and time-consuming, which can have a negative impact on adherence to the prescribed treatmentt regimen and ultimately result in poor control of the disease (7). Thus there is an ongoing need for development of topical psoriasis treatments that are, in addition to being highly efficacious, also convenient and easy to use. 7. Investigational Product LEO 9 is an aerosol formulation of calcipotriol mcg/g and betamethasone. mg/g (as ) currently under development for the topical treatment of psoriasis vulgaris. The formulation is manufactured by dissolving DAIVOBET/DOVOBET/TACLONEX ointmen in a mixture of the propellants dimethyl ether (DME) and butane, in a pressurized container with a continuous valve. The pressurized drug product is a homogeneous, white, opalescent liquid. At discharge, a quick-breaking foam is formed. LEO 9 has been developed with the purpose of providing additional choices to users and prescribers of the currently approved product DAIVOBET/DOVOBET/TACLONEX ointment, which contains the same active ingredients in the same concentration. The aerosol, foam formulation is expected to be easier and less time consuming to apply, and to have favourable cosmetic properties which might improve patient adherence as compared to an ointmen formulation. 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 monotherapy. The assumption that the same constituents (calcipotriol plus BDP) combined in an aerosol delivery system would also be effective in the treatment of psoriasis vulgaris was supported by the results of an exploratory clinical study (modified psoriasiss plaque test), in whichh LEO 9 showed better anti-psoriatic effect than DAIVOBET/DOVOBET/TACLONEX ointment and betamethasone in LEO 9 vehicle. Further informationn regarding the properties, mechanism of action, and safety and tolerability data of the investigational product can be found in the Clinical Study Protocol (CSP), Appendix...

24 LEO Apr- Page of Trial Rationale The present trial was designedd to investigate the comparative efficacy of LEO 9 to each of its active constituents (calcipotriol and BDP) in the same vehicle in with psoriasis vulgaris on the trunk, limbs and scalp. The aim was to establish that both calcipotriol and BDP in the new formulation make a contribution to the therapeutic effect of LEO 9, in accordance with the US FDA regulation regarding the development of fixed-combination prescription drugs for use in humans ( CFR.). The primary focus of this trial was on the psoriasis of the trunk and/or limbs. The rationale for including with psoriasis involving the scalp was to also explore the efficacy of LEO 9 in scalp psoriasis. For this reason, assessments of efficacy were done separately for each body area. The results from this trial will form a basis for the design of phase trials with respect to sample size and power calculation. This trial was one of two concurrent, multicentre, randomised phase trials investigating the safety and efficacy of LEO 9 in subject with psoriasis vulgaris. The objective of the other phase trial (LEO 9-) was to compare LEO 9 to the vehicle and to DAIVOBET/ DOVOBET/TACLONEX ointment.

25 LEO Apr- Page of 89 8 Trial Objectives 8. Primary Objective The primary objective was to compare the efficacy of treatment with LEO 9 with BDP in LEO 9 vehiclee and calcipotriol in LEO 9 vehicle for up to weeks in with psoriasis vulgaris on the trunk and limbs. 8. Secondary Objectives Secondary objectives were: To compare the safety of treatment with LEO 9 with BDP in LEO 9 vehicle and calcipotriol in LEO 9 vehicle for up to weeks in s with psoriasis vulgaris. To compare the efficacy of treatment with LEO 9 with BDP in LEO 9 vehi- cle and calcipotriol in LEO 9 vehicle for up to weeks in with psoriasis vulgaris on the scalp. To compare the efficacy of treatment with LEO 9 with BDP in LEO 9 vehi- cle and calcipotriol in LEO 9 vehicle at week separately for each of the three areas: trunk and limbs; scalp; and trunk and limbs and scalp in with psoriasis vulgaris. To compare the efficacy of treatment with LEO 9 with BDP in LEO 9 vehi- cle and calcipotriol in LEO 9 vehicle for up to weeks in with psoriasis vulgaris on the trunk, limbs and scalp.

26 LEO Apr- Page of 89 9 Investigational Plan The entire Clinical Study Protocol and any amendments are presented in Appendix.. and the unique pages of the case report form (CRF) are presented in Appendix Overall Trial Design and Plan Description This was a phase trial comparing the efficacy and safety of LEO 9 with its active constituents, BDP in LEO 9 vehicle and calcipotriol in LEO 9 vehicle, in with psoriasis vulgaris. It was designed as a multi-centre, prospective, randomised, double- and/or limbs and scalp. It was planned to include approximately. blind, -arm, parallel group, -week trial in with psoriasis vulgaris on the trunks Subjects with at least mild disease severity according to the IGA were enrolled. Eligible s were randomised, using a central Interactivee Web Response System (IWRS), to receive up to weeks treatment once daily with either: LEO 9 BDP in LEO 9 vehicle in LEO 9 vehicle Randomisation to treatment groups was in the ratio ::. The randomisation of was stratified according to baselinee disease severity (mild:at least moderate) as determinedd by the IGA of the trunk and limbs. The overall trial design is shown in Figure.

27 LEO Apr- Page 7 of 89 Figure : Trial design for LEO 9-7 Infmmed consent Randomisation t ~ ~ ~ ~ Washout Treatment phase Follow-up Week - Visit sv Treatm ent LEO 9 aet osol foam (calcipotriol mcg/g plus betamethasone. mg/g as ) FU I I Betamethasone in the LEO 9 vehicle (betamethasone. mg/g as ) J I Calcipotliol in the LEO 9 vehicle (calcipotriol meg/g) 9-Ll Individual Phases The u ial consisted of a washout/screening period for withdrawal of pre-u ial medication, a - week u eatment period (Visits -) and, if required, a -week safety follow-up period. Washout/Screening phase Prior to attending any u ial procedm e, a signed infonned consent had to be obtained from the subject. Prior to randomisation, the subject entered a washout phase (if required) where anti-psoriatic u eatlnent and other relevant medicationfti eatinents were discontinued as defined by the exclusion criteria (see Section 9..). The wash-out/screening phase could last for up to weeks, depending on which disallowed u eatments the subject received. However, if no washout was needed the subject could enter Visit directly.

28 LEO Apr- Page 8 of 89 Treatment phase The treatment phase lasted for up to weeks. There were visits: Visit (week, baseline), Visit (week ), Visit (week ) and Visit (week ). Visits to were to be performed within ± days of the scheduled time relative to Visit ; if the visit was performed outside of the visit window, the (sub)investigator recorded the reason in the subject s medical record. Subjects were assessed at all treatment visits, i.e., at baseline and after,, and weeks of treatment. Efficacy assessments included the IGA and the modified Psoriasis Area Severity Index (m-pasi). For the IGA, the investigator assessed the psoriasis vulgaris on the trunk and limbs, and the scalp separately. In addition, an overall IGA including trunk, limbs and scalp was assessed. The investigator also assessed the extent and severity of the three clinical signs (redness, thickness, and scaliness) on each of the body areas scalp, arms, trunk and legs. These assessments were used to calculate the m-pasi on the trunk and limbs, the scalp and the trunk, limbs and scalp. Subject s assessments included global assessment of disease severity and assessments of itching and quality of life. Follow-up phase The treatment phase was followed by a follow-up (FU) phase if there was an on-goingg adverse event at the last on treatment visit, which was classified as possible or probably related to the study medication or not assessable in relation to the trial medication. This phase lasted for ± days relative to the last on-treatment visit and was concluded by a follow-up visit/contact. The follow-up visit/contact could have been conducted earlierr if final outcome of the event has been determined. The follow-up visit/contact was made either as a telephone call or as a regular visit, according to the investigator s discretion. The investigational product was to be applied once daily to all psoriasis lesions. Subjects classified as clear according to the IGA on the trunk and limbs and/or scalp at any of Visits or were allowed to stop the treatment on the cleared area at the (sub)investigator s discre- the (sub)investigator. All had their last visit at Visit even if their psoriasis cleared tion. If their psoriasis reappeared the subject was to reinitiate the treatment without consulting before. 9. Discussion of Trial Design, Including the Choice of Control Groups Design The objective of this trial was to compare the efficacy of LEO 9 with each of its active constituents (calcipotriol and BDP) formulated in the LEO 9 vehicle in the treatment of psoriasis vulgaris. The trial design (randomised, double-blind, multicentre study with a

29 LEO Apr- Page 9 of 89 parallel-grouintendedd to minimise any potential bias that could compromise the conduct of the trial. design) is the established standard for comparison of safety and efficacy and is Subjects The inclusion/exclusion criteria were designed to select a population that is representative for the target population; i.e., of all disease severities ( mild to severe according to the IGA) amenable to topical therapy. The rationale for including with psoriasis involv- scalp ing the scalp was to explore the efficacy of the aerosol formulation for the treatment of psoriasis. Assessment of scalp psoriasis was done separately from the psoriasis on the trunk and limbs, which was the primary focus of this trial. Duration and dosing regimen The treatment duration of weeks was considered appropriate to obtain sufficient dataa on the efficacy and safety of the evaluated investigational product. Treatment duration of weeks has been shown to be safe and effective in previous studies of DAIVOBET/DOVOBET/TAC- LONEX ointment (8-). A once daily treatment regimen has been chosen as this is consid- ered 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 enhancee subject compliance. Endpoints The IGA was chosen as the primary efficacy assessment. The IGA is a static skin scoring system, consisting of a five point scale from clear to severe. The primary endpoint was s with controlled disease according to the IGA of trunk and limbs. Controlled disease is defined as clear or almost clear for with at least moderate disease at baseline, and clear for with mild disease at baseline. The percentage of who achieve controlled disease is regarded as the best evidence of efficacy (). Comparison of the percentage of with controlled disease between the treatment arms reflects the difference in the effect of the treatments. In orderr to facilitate standardisation of assessments and to minimise inter-rater variability, the IGA scale includes a detailed description of the morphological characteristics for each severity category, thus assisting the investigator in evaluation. The Psoriasis Area and Severity Index (PASI), used as a secondary response criterion, is a well established assessment that has been used in all previous studies of psoriasis conducted by LEO. The PASI was included to enable comparison of results across several studiess and also to assess the development of response to treatment over time. This trial used a modified

30 LEO Apr- Page of 89 PASI (m-pasi), calculated as described in Section 9... To support the clinical decision- Therefore, evaluation of quality of life was included in this study by means of the Dermatol- ogy Life Quality Index (DLQI) which is a validated dermatology specific questionnaire which making when treating psoriasis patients, it is important to consider quality of life issues. measures specific factors influencing the quality of life for patients with skin disease. Becausee of the potential effect of the vitamin D analogue containing investigational products on calcium metabolism and homeostasis, safety analysis of parameters of calcium metabolism was made following sampling of venous blood and urine collected at Day and Day 8 (or the last on-treatment visit as applicable). Local safety was evaluated by scoring of application site skin reactions. Concomitant treatments During the course of the trial, were not allowed to use any concomitant treatments that have a possible effect on the psoriasis on the trunk, limbs or scalp. This included various systemic treatments (e.g. systemic corticosteroids, retinoids, methotrexate, ciclosporin and other immunosuppressants and biologicall therapies). Topical treatments which could have had a systemic effect on the psoriasis lesions on trunk, limbs or scalp if used to treat psoriasis or other skin conditions (e.g. eczema) in other locations were also not allowed (i.e. vitamin D analogues and class - corticosteroids on the face and skin folds). Treatment options for psoriasis or other dermatological disorders on the face and skin folds were therefore limited to the immunomodulators such as tacrolimus or pimecrolimus or class & 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 trial and to allow use of the trial medication up to the maximum recommended level. A stable concomitant treatment regimen (no start or change of dosage during the study) with drugs that have a potential effect on psoriasis (e.g., beta blockers, anti-malarials, 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 trial medication. Prior to randomisation, a washout period was to be completed if the patientt was treated, or had recently been treated with anti-psoriatic treatments or other relevant medication that could influence the outcome of the trial.

31 LEO Apr- Page of Selection of Trial Population 9.. Inclusionn Criteria For inclusion in the trial patients had to fulfil all of the following criteria: The inclusion/exclusion criteria were designed to select s with psoriasis involving both body and scalp, with at least mild diseasee severity according to the IGA, amenable to topical therapy with up to 9 g of study medication per week. A total of ( per treatment group) were to be enrolled in the trial.. Signed and dated informed consent obtained prior to any trial related activities (includ- ing washout period).. Age 8 years or above. Either sex. Any race or ethnicity. All skin types. Attending a hospital outpatient clinic or the private practice of a board certified derma- tologist. 7. A clinical diagnosis of psoriasis vulgaris of at least months duration involving the trunk and/or limbs and the scalp amenable to treatment with a maximum of 9 g of study medication per week. 8. Psoriasis vulgaris on the trunk and/or limbs (excluding psoriasis on the genitals and skin folds) nvolving at least of the Body Surface Area (BSA). 9. Psoriasis vulgaris on the scalp involving at least of the total scalp area.. A total psoriatic involvement on trunk, limbs and scalp not exceeding BSA.. An Investigator s Global Assessment of disease severity (IGA) of at least mild on the trunk and/or limbs at Day (Visit ).. An Investigator s Global Assessment of disease severity (IGA) of at least mild on the scalp at Day (Visit ).. An m-pasi score of at least on the trunk and/or limbs at Day (Visit ).. Females of childbearing potential must have a negative pregnancy test at Day (Visit ).. Females of childbearing potential must agree to use a highly effective method of birth control during the study. A highly effective method of birth control is defined as one which results in a low failure rate (less than per year) such as implants, injectables, combined oral contraceptives, some intra-uterine devices, sexual abstinence or vasec- tomised partner. The must have used the contraceptive method continuously

32 LEO Apr- Page of 89 for at least month prior to the pregnancy test, and must continue using the contracep- female tive method for at least week after the last application of study medication. A is defined as not of child-bearing potential if she is postmenopausal ( months with no menses without an alternative medical cause), or surgically sterile (tubal liga- with the re- quirements of the study. tion/section, hysterectomy or bilateral ovariectomy).. Able to communicate with the investigator and understand and comply 9.. Exclusion Criteria Any of the following was regarded as a criterion for exclusion from the study:. Systemic treatment with biologicall therapies, whether marketed or not, with a possible effect on psoriasis vulgaris within the following time periods prior to randomisation: etanercept within weeks prior to randomisation adalimumab, alefacept, infliximab within 8 weeks prior to randomisation ustekinumab within weeks prior to randomisation other products weeks/ half-lives (whichever is longer). Systemic treatment with all other therapies with a possible effect on psoriasis vulgaris ( e.g., corticosteroids, retinoids, methotrexate, ciclosporin and other immunosuppres- sants) within weeks prior to randomisation.. Subjects who have received treatment with any non-marketed drug substance (i.e. a drug which has not yet been made available for clinical use following registration) within the -week period prior to randomisation or longer, if the class of substance re- quired a longer treatment free period as defined in exclusion criterion for biological treatments.. PUVA therapy within weeks prior to randomisation.. UVB therapy within weeks priorr to randomisation.. Topical anti-psoriatiweeks prior to randomisation. 7. Topical anti-psoriatic treatment on the scalp (except for emollients and non-medicated shampoos) within weeks prior to randomisation. 8. Topical treatment on the face and skin folds with class - corticosteroids or vitamin D analogues within weeks prior to randomisation. 9. Planned excessive exposure of area(s) to be treated with study medication to either natural or artificial sunlight (including tanning booths, sun lamps, etc.) during the treatment on the trunk and limbs (except for emollients) within study.

33 LEO Apr- Page of 89. Planned initiation of, or changes to, concomitant medication that could affect psoriasis vulgaris (e.g. beta blockers, antimalarial drugs, lithium, ACE inhibitors) during the study.. Current diagnosis of guttate, erythrodermic, exfoliative or pustular psoriasis.. Subjects with any of the following conditions present on the treatment area: viral (e.g. herpes or varicella) lesions of the skin, fungal and bacterial skin infections, parasitic in- atro- phic skin, striae atrophicae, fragility of skin veins, icthyosis, ulcers and wounds.. Other inflammatory skin disorders (e.g. seborrhoeic dermatitis or contact dermatitis) on fections, skin manifestations in relation to syphilis or tuberculosis, acne vulgaris, the treatment area that may confound the evaluation of psoriasis vulgaris.. Known or suspected disorders of calcium metabolism associated with hypercalcaemia.. Known or suspected severe renal insufficiency or severe hepatic disorders.. Known or suspected hypersensitivity to component(s) of the investigational products. 7. Current participation in any other interventional clinical study. 8. Previously randomised in this study. 9. Females who are pregnant, wishing to becomee pregnant during the study, or are breast- feeding. 9.. Removal of Subjects from Therapy or Assessment Subjects could have been withdrawn for any of the following reasons:. Unacceptable treatment efficacy: the investigator was free to withdraw the subject at any time for medical reasons.. Unacceptable adverse events: any adverse event that the investigator or the subject considered unacceptable.. Exclusion criteria: any exclusion criteria which emerged/ /became apparent during the subject s participation in the clinical trial.. Voluntary withdrawal: was free to withdraw from the clinical trial at any time and for any reason.. Other reasons: other reasons than stated above which required the subject to (be) with- draw(n) were to be specified. Subjects who weree discovered, after enrolment/randomisation, not to have fulfilled alll in- investigator, based on clinical and ethical evaluation, found withdrawal inappropriate. The /exclusion criteria at time of enrolment, were to be withdrawn from treatment unless the final efficacy assessment (at the correct scheduled time) should, however, have been at- tempted to be completed for all. Such deviation(s) from the (Consolidated) Clinical

34 LEO Apr- Page of 89 Study Protocol had to be reported to LEO Pharma A/ /S (and IEC/IRB, as appropriate) and recordedd in the Clinical Study Report. Subjects who withdrew from treatment for any other reasons should likewise, as a minimum, have been asked to complete the final efficacy assessment (at the correct scheduled time). Reason( (s) for withdrawal weree recorded in the ecrf. Subjects withdrawn were not substituted. 9. Treatments 9.. Treatments Administered Subjects were randomised to receive one of the following treatments: LEO 9 BDP in LEO 9 vehicle (referred to as BDP) in LEO 9 vehicle (referred to as calcipotriol) At Day (Visit ) were given a treatment instruction sheet and verbal instruction about how to apply trial medication. The first application of the trial medication was made under the supervision and instruction of the trial staff. The trial medication was to be applied to psoriasis affected areas on the trunk, limbs and scalp once daily for up to weeks. Subjects were instructed not to apply the trial medication on psoriasis on the face, genitals or skin folds. Skin folds included the axillae, the inguinal folds, the intergluteal folds, and the inframammary folds. There was no specific requirement with regard to the time of day for application. Subjects classified as clear on the trunk and limbs and/or scalp at any of Visits or were allowed to stop the treatment on the cleared area at the (sub)investigator s discretion. Subjects were not allowed to discontinue treatment themselves between visits, but were only allowed to stop using the treatment on the advice of the (sub)investigator at a scheduled visit. If their psoriasis reappeared the subject was asked to reinitiate the treatment without consulting the (sub)investigator. 9.. Identity of Investigational Product(s) LEO 9 and its active constituents (calcipotriol and BDP) in the LEO 9 vehicle were provided as cans containing g of aerosol formulation. Details of the investigational products are given in Table, Table and Table.

35 LEO Apr- Page of89 Table : Identity of LEO 9 m ~mea product (Brand) name (if investigational product: (as hydrate) mcg/g plus be-. mg/g (as ) name of bulk medication name of IMP in primruy. Pw~.n.a. name of secondruy... i"j and labelling: 's name of secondruy packaging labelling: number(s)/expny date(s):

36 LEO Apr- Page of89 Table : Identity of BDP in LEO 9 vehicle m~mea product (Brand) name (if investigational product: in LEO 9 vehicle. mg/g (as )....,..,++ " white soft, Pru affm, liquid, PPG- stea... u.-..., all-rae-alpha-tocopherol, Diinethyl ether, name of bulk medication name of IMP in primruy. Pw~.n.a. name of secondruy... i"j and labelling: 's name of secondruy packaging labelling: number(s)/expny date(s):

37 LEO Apr- Page 7 of89 Table : Identity of calcipotriol in LEO 9 vehicle m ~mea product (Brand) name (if investigational product: in LEO 9 vehicle (as hydrate) mcg/g name of bulk medication name of IMP in primruy. Pw~.n.a. name of secondruy... i"j and labelling: 's name of secondruy packaging labelling: number(s)/expny date(s): For details on labelling, storage and accountability of the investigational product, see Sections..,.. and..8 ofthe CSP (Appendix..). 9- Method of Assigning Subjects to Treatment Groups Subjects who were fmmd to comply with all the protocol's inclusion and exclusion criteria were randomised to receive one of the three trial treatments. Treatment was assigned via a central IWRS in accordance with a pre-platmed, computer generated randomisation schedule in a : : ratio. A subject was assigned the next (ascending) randomisation code number available. Two sepru ate randomisation code lists were used, one for with mild disease and one for with at least moderate disease according to the IGA for trunk and liinbs at baseline.

38 LEO Apr- Page 8 of Selection of Dosess in the Trial Once-daily regimen and the treatment duration of weeks weree selected based on previous experience with DAIVOBET/ DOVOBET/TACLONEX ointment. Likewise, the maximum weekly dose of LEO 9 was selected based on the approved maximum dose for DAIVOBET/DOVOBET/TACLONEX ointment, which is g. However, for practical purposes - g was the only available pack-size the maximumm weekly dose was set to 9 g ( cans) per week. 9.. Selection and Timing of Dose for each Subject Described in Section Blinding 9..7 Prior and Concomitant Therapy This study was a double-blind trial. The packaging and labelling of the investigational products contained no evidence of their identity. It was not considered possible to differentiate between the investigational products solely by sensory evaluation. No effects of the investiga- allocations. Consequently, it was expected that the and the (sub)investigators would tional products were expected which would reveal the identity of the individual treatment remain unaware of the individual treatment assignment during the conduct of the clinical trial. Emergency un-blinding of individual subject treatment was possible by contacting the IWR system to obtain information regarding an individual subject's treatment assignment. An emergency un-blinding request could be made by the (sub)investigators, other health care professional, or authorised LEO Pharma A/S personnel. Treatment codes were not broken for the planned analyses of data until all decisions on the evaluability of the data from each individual subject had been made and documented. Prior to the Study Treatment Phase The washout phase was up to weeks (8 days). Subjects who had been treated with medica- tions requiring more than weeks washout were not eligible for the trial. However, a subject would be eligible if s/he has had a treatment free period prior to entering the trial (i.e. having signed Informed Consent), e.g. if a subject had been off infliximab weeks prior to entering the trial, the subject might stilll have been eligible for the trial after weeks washout.

39 LEO Apr- Page 9 of 89 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 usteki- (e.g. corticosteroids, retinoids, methotrexate, ciclosporin and other immunosuppressants) ( weeks). numab (see exclusion criterion ).* Systemic treatments with all other therapies with a potential effect on psoriasis vulgaris PUVA therapy ( weeks) UVB therapy ( weeks) Topical anti-psoriatic treatment on the trunk and limbs ( weeks)** Topical anti-psoriatic treatment on the scalp ( weeks)*** Topical treatment with class -**** corticosteroids and vitamin D analogues on the face and skin folds ( weeks) Use of medicated shampoos (containing Coal Tar, Sulfur, Salicylic Acid or Zinc Pyrithi- one) on the scalp ( weeks) Use of non-marketed drug substancess (see exclusion criterion ) *) Note: duration of the washout phase should not exceed 8 days **) Note: use of emollients was allowed on treatment areas during this -week period ***) Note: use of emollients and non-medicated shampoos was allowed on treatment areas during this -week period ****) Please see Appendix II II of the study protocol (Appendix..) for Potency Classifi- cation of Topical Corticosteroids During the Study Treatmentt Phase Concomitant medication for conditions other than psoriasis vulgaris (with no potential effect on psoriasis vulgaris) could be continued throughoutt the trial without any change in dosage whenever possible. Use of concomitant medication was recorded in the subject s medical record and the ecrf (treatment/drug name, dose, indication and dates of start and stop). 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, antimalarial drugs, lithium and ACE inhibitors. Use of non-marketed/other investigational products was not permitted during the trial.

40 LEO Apr- Page of 89 Use of hair conditioners and chemical treatments of the hair (e.g. relaxers, perms and colourings) was not permitted. Inhaled steroids, bath oils and moisturising soaps were allowed during the study. Except for some topical treatments on the face, skin folds and scalp (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 trial: Face and skin folds All topical medications were allowed except class to corticosteroidss and vitamin D analogues. Unlimited use of emollients was allowed. Scalp Non-medicatedd shampoos were allowed Treatment Compliance At all on-treatmentt visits, the subject was asked if she/he has used the medication as pre- scribed. If this was not the case, the degree and nature of non-compliance was specified. Subjects classified as clear on either the trunk and limbs, and/or scalp at any of Visits or were allowed to stop the treatment on the cleared area(s) at the (sub)investigator s discretion. They remained in the trial and attended all visits up to and including week (Visit ). Although classified as clear, the subject still had study medication dispensed at each visit and were instructed to restart treatment if required, based on their own judgement. More than one discontinuation/restart cycle was allowed. The were not allowed to discontinue treatment themselves between visits, but were only allowed to stop using the treatment on the advice of the (sub)investigator at a scheduled visit. Subjects who for other reasonss than above wished to discontinue treatmentt on either trunk and limbs or scalp weree allowed to do that after consultation with the (sub)investigator. They continued in the trial attending all visits up to and including week (Visit ). Information on discontinuation of treatment on trunk and limbs or scalp was to be recordedd in the ecrf.

41 LEO Apr- Page of 89 At the end of trial, the investigational products returned to the CMO were reconciled with the Individual Drug Accountability Forms. All returned cans were weighed by the CMO to determine the amount of the investigational product used. Following packaging, and prior to supply of the investigational product, cans were weighed and the average used as a basis to calculate the amount of trial medication used per treatment phase visit interval for each subject. 9. Efficacy and Safety Variables 9.. Efficacy and Safety Measurements Assessed and Flow Chart Methods used to measure response variables are described in Sections 9... (efficacy) and 9... (safety). The definitions of outcome variables are given in Sections 9.. and 9... Details of the timing of the procedures (i. e. the activities to be conducted at each visit) are contained in the trial plan below (Table ) ).

42 LEO Apr- Page of 89 Table : Schedule of trial procedures Visit Week Visit window/day Informed consent Subject demographics In-/exclusion criteria Pregnancy test ) Relevant medical history Concurrent diagnoses Concomitant medication Vital Signs ) Physical examination n ) Randomisation Adverse Event(s) Laboratory biochemistry, urinalysis ) Laboratory -hydroxy vitamin D Investigator s assessment of BSA involvement on trunk and limbs Investigator s assessment of BSA involvement on trunk, limbs and scalp Investigator s globall assessment of disease severity (IGA) on trunk and limbs Investigator s globall assessment of disease severity (IGA) on the scalp Investigator s globall assessment of disease severity (IGA) on the trunk, limbs and scalp Investigator s assessment of extent and severity of clinical signs (m-pasi) Local safety and tolerability Patient s global assessment of Screening - to Up to -8 X X X X X X X ) ) ) FU 7), if required weeks after last visit 7± Day ± Day 8± Day +± Day X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X

43 LEO Apr- Page of 89 Visit Screening Week - to Visit window/day Up to -8 disease severity Subject s assessment of itching by use of VAS Subject s assessments of quality of life by use of DLQI Dispensing of trial medication Compliance check Return of trial medication End of trial Form ) ) ) ) ) ) ) 7) ) ) ) FU 7), if required weeks after last visit 7± Day ± Day 8± Day +± Day X X X X X X X X X X X X X X X X X X For women of childbearing potential a urine pregnancy test had to be performed at visit. Vital signs included blood pressure and heart rate. Physical examination was to as minimum include height and weight Biochemistry and urinalysis included serum calcium, serum albumin, urine calcium and urine creatinine. For prematurely withdrawn from treatment all trial procedures scheduled for Visit had to be completed. If no washout was needed the subject could enter Visit directly. Subjects entering Visit without washout needed to have all trial procedures done applicable for screening visit. The treatment phase was followed by a FU phase if there was an on-going adverse event at the last on treatment visit, which was classified as possible or probably related to the study medication or not assessable in relation to the study medication 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 schedule above. Demographic dataa Demographic data comprised of date of birth, sex, ethnic origin and race. The s were asked to self-report their ethnicity (Hispanic or Latino, not Hispanic or Latino) and race (American Indian or Alaska Native, Asian, Black or African American, Native Hawaiian or Other Pacific Islander, White, Other).

44 LEO Apr- Page of 89 Skin type In addition, the skin type of the was recorded according to the classification in Table : Table : Fitzpatrick Skin Type Skin Type Skin Colour (unexposed skin) History (to first to minutes of sun exposure after a winter season of no sun exposure) I II III IV V VI White White White White Brown Black Always burns easily; never tans Always burns easily; tans minimally Burns moderately; tans gradually (light brown) Burns minimally; always tans well (moderate brown) Rarely burns; tans profusely (dark brown) Never burns; deeply pigmented Duration of psoriasis The duration of psoriasis vulgaris was to be recorded, to the nearest whole year. Medical history/concurrent diagnoses/concomitant medication Relevant medical history, all concurrent diagnoses and all concomitant medication were recorded, including previous use of biologics available in the US, immunosuppressant, corticosteroids, retinoids, Vitamin D analogues, calcineurin inhibitors and coal tar. Approxi- were mate date and route of administration were to be recorded. Other locations for psoriasis recorded, i.e. skin folds, face, nails and genitals. Vital Signs Heart rate and blood pressure were measured after the subject had been resting in a supine position for five minutes. Physical Examination A routine medical examinationn was made which as minimum included weight and height. Any findings that prevented eligibility for the trial or were documented as concurrent diagnoses, as appropriate.

45 LEO Apr- Page of Efficacy assessments 9... Investigator s assessments Definition of the body areas to be assessed The treatment areas which were to be assessed were the trunk, limbs and scalp. The trunk and limbs included the arms (including hands), trunk (including neck) and the legs (including buttocks and feet). The scalp was defined by the hair line - or the hair line prior to onset of balding. If in doubt of the anterior hair line prior to onset of balding, this was to be defined by a distance above the eyebrows equal to half the distance between the eyebrows and the chin. The face, skin folds 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 assessmentss for a subject were to be made by the same (sub)investigator. Investigator s global assessment of disease severity (IGA) At all treatment phase visits ( to ) the (sub)investigator made three separate global assess- ments of the disease severity of the psoriasis - one for the trunk and limbs, one for the scalp and one for the trunk, limbs and scalp - using the -point scale shown in Table. These assessments represented the average lesion severity on the trunk and limbs, the scalp and the trunk, limbs and scalp, respectively. The assessmentss were based on the condition of the disease at the time of evaluation and not in relation to the condition at a previous visit.

46 LEO Apr- Page of 89 Table : Investigator s Global Assessment of Disease Severity -point Scale Clear Plaque thickening = no elevation or thickening of normal skin Scaling = no evidence of scaling Erythema = none (no residual red coloration but post-inflammatory hyperpigmentation may be present) Almost clear Moderate Severee Plaque thickening = none or possible thickening but difficult to ascertain whether theree is a slight elevation above normal skin levell Scaling = none or residual surface dryness and scaling Erythema = light pink coloration Plaque thickening = slight but definite elevation Scaling = fine scales partially or mostly covering lesions Erythema = light red coloration Plaque thickening = moderate elevation with rounded or sloped edges Scaling = most lesions at least partially covered Erythema = definite red coloration Plaque thickening = marked or very marked elevation typically with hard or sharp edges Scaling = non-tenacious or thick tenacious scale, covering most or alll of the lesions Erythema = very bright red coloration; extremee red coloration; deep red coloration Note: At Day (Visit ) the disease severity must have been graded as at least mild on the trunk and/or limbs and the scalp in order to meet the inclusion criteria. Subjects classified as having at least moderate disease at baseline who achieved clear or almost clear disease severity were considered to have controlled disease. Subjects classified at baseline as having mild disease must have achieved clear to be considered to have controlled disease. Investigator s assessment of the extent and severity of clinical signs (redness, thickness, scaliness). At all treatment phase visits (Visits to ) the (sub)investigator made assessments of the extent and severity of clinical signs of the subject s psoriasis using a m-pasi scoring system (excluding face), in terms of three clinical signs: redness, thickness and scaliness.

47 LEO Apr- Page 7 of 89 The extent of psoriatic involvement was recorded for each of the four areas: scalp, arms, trunk and legs using the following scale: = no involvement = < = - 9 = - 9 = - 9 = 7-89 = 9 - The severity of the psoriatic lesions in each of the four areas was recorded for each of the signs of redness, thickness and scaliness. For each clinical sign, a single score, reflecting the averagee severity of all psoriatic lesions on given body region, was determined according to the scale in Table 7. Table 7: Severity score for redness, thickness and scaliness Redness = = none (no erythema) mild (faint erythema, pink to very light red) = moderate (definitee light red erythema) = severe (dark red erythema) = very severe (very dark red erythema) Thickness = = none (no plaque elevation) mild (slight, barely perceptible elevation) = moderate (definitee elevation but not thick) = severe (definite elevation, thick plaque with sharp edge) = very severe (very thick plaque with sharp edge) Scaliness = none (no scaling) = mild (sparse, fine-scale lesions, only partially covered) = (coarserr scales, most of lesions covered) moderate = severe (entire lesion covered with coarse scales) = very severe (very thick coarse scales, possibly fissured) Investigator s assessment of the body surface areaa involvement of psoriasis vulgaris At all treatment phase visits (Visits to ) the (sub)investigator assessed the extent of the subject s psoriatic involvement on the trunk, limbs and scalp. In addition, the extent of the psoriatic involvement on the trunk and limbs was assessed separately at Visit. The total psoriatic involvement on the trunk, limbs and scalp (excluding skin folds and genitals) were recorded as a percentage of the total body surface area (BSA), estimating that

48 LEO Apr- Page 8 of 89 the surface of the subject s full, flat palm (including the five digits) correlates to approxi- on the mately of the total BSA. The purpose of this was to obtain an estimate of the area trunk, limbs and scalp to be treated with study medication Subject Assessments The subject s assessments had to be made prior to the investigator s assessments. Patient s global assessment of disease severity This assessment was made at all treatment phase visits ( to ), based on the conditionn of the disease at the time of the evaluation and not in relation to the condition at a previous visit, using the scale shown in Table 8. 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. Table 8: Patient s Global Assessment of Disease Severity -point Scale Assessment Severity of symptoms Clear No psoriasiss symptomss at all Very mild Very slight psoriasis symptoms, does not interfere with daily life Slight psoriasis symptoms, interferes with daily life only occasionally Moderate Definite psoriasis symptoms, interferes with daily life frequently Severe Intense psoriasis symptoms, interferes or restricts daily life very frequently Subjects classifying themselves as being to have controlled disease. clear or having veryy mild disease were considered Subject s assessment of itching by use of a Visual Analogue Scale This assessment was made by the subject at all treatment phase visits (Visits to ). The visual analogue scale (VAS) was used to assess itch using a horizontal line. The line repre- sented the range of itch severity, from (no itch at all) at one end to (worst itch you can imagine) at the other. The subject was asked to put a single vertical line across the horizontal line at the spot he/she felt best reflected the severity of itch during the past hours. Subject s assessment of quality of life by use of Dermatology Life Quality Index ( DLQI) The subject s assessments of quality of life were performed at all treatmentt phase visits (Visit -) by means of the Dermatology Life Quality Index (DLQI) which is a validated dermatol- at the ogy specific questionnaire. The questionnaire was to be completed by the subject while investigator site.

49 LEO Apr- Page 9 of Safety Assessments 9... Local Safety and Tolerability Local safety and tolerability comprised of signs assessed by the (sub)investigator and symptoms reported by the subject. At Visits - the (sub)investigator assessed application site reactions for the following signs: Erythema, dryness, erosion and oedema. For each sign a skin reaction score was recorded by use of a -point scale: =absent, =mild (slight, barely perceptible), =moderate (distinct presence), =severe (marked, intense). At Visits - the subject reported application site reactions for the following symptoms: Burning and pain. The (sub)investigator explained the scores/categories of the scale to the subject and the subject was to tell the (sub)investigator which scores/category to mark. For each symptom a skin reaction score was recorded by use of a -point scale: =absent, =mild (slight, barely perceptible), = =moderate ( distinct presence), =severe (marked, intense) Laboratory analysis Samples for analysis of the parameters listed below were taken as scheduled in the flowchart (Table ) or on withdrawal from or early completion of the treatment phase of the clinical trial. A urine pregnancy test was performed at the trial site at Day (Visit ), prior to ran- domisation, in female s of child-bearing potential. The test kits weree 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 (Visit /Baseline) and at Day 8 (Visit ). If at the last on treatment visit the albumin corrected serum calcium was above the referencee range or if any other laboratory 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 instructions necessary for the collections and transport of the samples. Parameters analysed in blood and urine samples are given in Table 9.

50 LEO Apr- Page of 89 Table 9: Serum biochemistry and urinalysis Serum Biochemistry Urinalysis (spot urine sample) Calcium Albumin Visit and Visit and Calcium Creatinine -hydroxy vitamin D Visit a Albumin-corrected serum calcium was calculated in mmol/l using the formula: serum calcium (total) in mmol/l + (. [-serum albumin in g/l]) b Calcium:creatinine ratio was calculated. Visit and Visit and Review of laboratory resultss If any of the laboratory resultss 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. Clinically significant laboratory values were to be regarded as an AE Adverse Events An adverse event ( AE) is defined as: Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An adverse event (AE) can therefore be any unfavourable and unintended sign(including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medici- Practice, E nal(investigational) product. (ICH Harmonized Tripartite Guideline for Good Clinical (R)). A serious adverse event (SAE) is any untoward medical occurrence that: results in death is life-threatening requires inpatient hospitalisation or prolongationn of existing hospitalisation results in persistent or significant disability/incapacity or is a congenital anomaly/birth defect or other medically important conditions* )

51 LEO Apr- Page of 89 * ) 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 broncho- spasm, blood dyscrasias, and convulsions. Global Pharmacovigilance was responsible for the assessment of headquarter expectedness according to LEO procedures. The relevant referencee document for this clinical trial was Investigator s Brochure (LEO 9), edition and subsequent updates as agreed between the Head of International Clinical Development and the Medical Director, Global Pharma- covigilance, LEO Pharma A/S. At all visits, the subject was asked a non-leadinspecific symptoms were asked for. question by the investigator: How have you felt since I saw you last? No If there were no AEs to record, no furtherr 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 recordedd these changes. 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 adversee event page of the CRF and described in the following manner: The nature of the event was described in precise, English medical terminology (i.e., not necessarily the exact words used by the subject). Whenever possible, a specific diagnosis was to be stated (e.g., allergic contact dermatitis). For cutaneous adverse events the location had to be part of the adverse event description and may be described as either scalp or non-scalp. Additionally, the location was describedd using the following terminology: lesional/perilesional ( cm from the border of lesion(s) treated with investigational product) or distant (> cm from the lesion border)

52 LEO Apr- Page of 89 The intensity of the event was described in terms of mild, moderate or severe according to the investigator s clinical judgement. : The adverse event does not interfere in a significant manner with the subject s normal functioning level and requires no medical intervention. Moderate: The adverse event interferes with the subject s normal functioning level and may or may not require medical intervention. Severe: The adverse event produces significant impairment of the subject s functioning or requires medical intervention. The duration of the event was reported as the start date and stop date of the event. The causal relation of the event to the use of the investigational product was described in terms of probable, possible, not related or not assessable according to the following: Probably related: Follows a reasonable temporal sequence from administrationn of the investigational product Could not be reasonably explained by the subject s clinical state, environmental or toxic factors or other therapies administeredd to the subject Follows a known pattern of response to the investigational product Disappears or decreases on cessation or reduction in dose of the investigational product Reappears or worsens upon re-challenge. Possibly related: Follows a reasonable temporal sequence from administrationn of the investigational product Could also be reasonably explained by the subject s clinical state, environmental or toxic factors or other therapies administeredd 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 Is better explained by other factor like the subject s clinical state, environmental or toxic factors or other therapies administeredd to the subject Does not follow a known pattern of response to the investigational product.

53 LEO Apr- Page of 89 Not assessable: The adverse event cannot be judged otherwise because the information is insufficient or contradictory. All attempts to obtain more information have been in vain during the course of the trial. The outcome of the event was classified and handledd as follows: Recovered/resolved: Recovering/resolving: Not recovered/not resolved: Recovered with sequelae: Fatal: Unknown: The event has stopped. The stop date of the event was to be recorded. The subject is clearly recovering from an event. The event is, however, not yet completely resolved. Follow- has been up on the event was required until final outcome established. Event is still ongoing. Follow-up on the event was required until final outcome has been established. 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. The subject has died as a consequence of the event. Date of death was recorded as stop date for the adversee event. 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 until last follow-up visit or until final outcome was determined, whichever came first. Likewise, non-serious adversee events occurring after completion of the trial but prior to last follow-up visit were collected and followed up by investigator until last follow-up visit or until final outcome was determined, whichever came first.

54 LEO Apr- Page of Other Events to be Reported Pregnancy Pregnancy, which occurred during the clinical trial, was to be reported to LEO Pharmaa A/S within hours of first knowledge using the Pregnancy Follow-up Form supplied by LEO Pharmaa A/S. 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 adverse event 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 Serious Adverse Events Reporting of Serious Adverse Events Any Serious Adverse Event (SAE), related or unrelated to the investigational product or any trial procedure after signature of the Informed Consent Form was to be reported to TKL Research and LEO on the (paper) Serious Adverse Event Form Clinical Trial within hours. Note: Planned hospitalisation or planned prolonged of hospitalisation do not fulfil the criteria for being an SAE. The elective nature of the event must be clearly documentedd in the subject s medical record. SAEs were to be reported on the adverse event form of the CRF book. Additionally reports were to be made using the paper Serious Adverse Event 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 comprehensive narrative description of the course of the event. The completed Serious Adverse Event Form Clinical Trial was to be faxed or scanned and ed to both LEO and TKL Research as specified in the CSP (Appendix..).

55 LEO Apr- Page of 89 All other relevant reports of diagnostic procedures, hospital records, autopsy reports etc. were to be included, as applicable or upon request from TKL Research or LEO Pharma Global Pharmacovigilance. The IRB(s)/IEC(s), regulatory authorities and concerned investigators weree to be notified of SAEs according to current regulation and local requirements. All Suspected, Unexpected Serious Adverse Reactions (SUSARs) are subject to expedited reporting to regulatory authorities. Global Pharmacovigilance 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 might continue beyond the end of the clinical trial. SAEs occurring after completion of the trial were not to be routinely sought or collected beyond the last follow-up visit. However, if reported, such casess were to be regarded for expedited reporting purposes as though they were trial case reports. Therefore, a causality assessment and determination of expectedness were needed for a decision on whether or not expedited reporting was required. 9.. Appropriateness of Measurements The efficacy measures used in this trial (IGA, PASI) are standard in clinical trials of psoriasis. The -point scale used for the IGA was developed in consultation with the FDA. The DLQI is a validated dermatology specific questionnaire whichh measures specific factors influencing the quality of life for patients with skin disease. A visual analogue scale ( VAS) is a commonly used method to quantify pruritus. All safety measures used in this trial are also standard. 9.. Primary Efficacy Variable( (s) The primary response criterion was with controlled disease ( clear or almost clear for with at least moderate disease at baseline, clear for with mild disease at baseline) according to the IGA on the trunk and limbs at week. 9.. Secondary and Further Response Criteria Secondary response criterion was with controlled disease according to the IGA on the trunk and limbs at week.

56 LEO Apr- Page of 89 Further response criteria included:. Subjects with controlled disease according to the IGA at week on: a. Scalp b. Trunk and limbs and scalp. Subjects with controlled disease according to the IGA at week on: a. Scalp b. Trunk and limbs and scalp Note: Response criteria involving m-pasi were analysed separately for the three areas: Trunk and limb, Scalp, Trunk and limbs and scalp. m-pasi at week. m-pasi at week. Subjects with PASI (at least reduction in m-pasi from baseline) at week. Subjects with PASI 7 (at least 7 reduction in m-pasi from baseline) at week 7. Subjects with controlled disease ( clear or very mild ) according to the patients global assessment of disease severity at week 8. The change in itch as assessed by the Visual Analogue Scale from baseline to each subsequent visit 9. The change in DLQI from baselinee to each subsequent visit m-pasi was calculated using the formula given below based on the investigator s assessment of the extent and severity of the disease locally (trunk, arms, legs, scalp). The following formula was used to calculate the m-pasi: Arms.. (R + T + S)E = X Trunk. (R + T + S)E = Y Legs. (R + T + S)E = Z Scalp. (R + T + S)E = W where: R = score for redness; extent Trunk and limbs: The sum of X + Y + Z gives the m-pasi, which can range from to.8. Scalp: W is the m-pasi, whichh can range from to.. T = score for thickness; S = score for scaliness; E = score for

57 LEO Apr- Page 7 of 89 Trunk, limbs and scalp: The sum of X + Y + Z + W gives the total m-pasi, which can range from to 8.. The evaluation of safety was based on the following parameters: Any reported adverse event. Any reported adverse drug reaction. Change in albumin corrected serum calcium from baseline to week Change in urine calcium:creatinine ratio from baseline to week Reason for withdrawal from the study Investigator's assessment of the BSA involvement of psoriasis vulgaris Change in vital signs (blood pressure, heart rate) from baseline to week Local safety and tolerability parameters 9.. Drug Concentration Measurements Not applicable. 9. 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- to ments and Good Clinical Practice. Quality control is applied to each stage of data handling 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, one site audit was conducted. No critical findings were identified. The audit site audit certificate is provided in Appendix..8. 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 ecrfs. 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,

58 LEO Apr- Page 8 of 89 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 ecrf designed by LEO. A uniquely numbered CRF was used for each subject enrolled. Data recordedd in the ecrf were accessible to site staff throughh a secure internet connection immediately after entry of data had taken place. The ecrfs 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, weree to electronically sign all sections of ecrfs used. This signature information (incl. 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 ecrf, 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 authorised 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 ecrf 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, would be in an electronicc format. This systematic validation was made to ensure that a clean and consistent database was provided prior to the statistical analysis being performed. 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 (9//EC). LEO HQ is considered data responsible for all international clinical trials sponsored by LEO.

59 LEO Apr- Page 9 of Statistical Methods Planned in the Protocol and Determination of Sample Size 9.7. Statistical and Analytical Plans The statistical analysis was planned in the clinical study protocol and further detailed in the Statistical Analysiss Plan Update (SAPU) dated 7-Nov- (Appendix..9). All enrolled, defined as having signed an informed consent form and with a CRF number assigned, were accounted for. Alll randomised were included in the full analysiss set and analysed for efficacy. A per protocol analysis set was defined by excluding 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 trial and/or who did not fulfil the disease inclusion criteria (i.e., inclusion criteria 7, 8, 9,,,, see Section 9..). Furtherr exclusion of or subject data were decided upon after the blind review of the data, reviewing alll remaining in- and exclusion criteria, but focusing on concomitant medication that may affect the investigated psoriasis lesions. Other criteria considered were poor compliance and violations of visit-window ws. A safety analysis set was defined by excluding from the full analysis set who received no treatment with trial medication and/or for whom data on the presence or con- analysiss sets were documentedd in the Statistical Analysis Plan Update before breaking the firmed absence of adverse events were not available. The decisions regarding inclusion/exclusion of and/or subject dataa from the trial randomisation code Reasons for Leaving the Study The reasons for leaving the study were presented for all randomised and by treatment group. The reasonss for leaving the study were also presented by last visit attended and by treatment group Baseline Characteristics Descriptive statistics of demographics, disease-related and other baseline characteristics were presented for all randomised and by treatment group. Presentationss of age, sex,

60 LEO Apr- Page of 89 ethnicity, race and baseline IGA of the trunk and limbs by treatment were also given by pooled centre as described in the SAPU. Categorical data were summarised by presenting the number and percentage of in each category and treatment group. Continuous data were summarised using the mean, standardd deviation (SD), median, minimum and maximum values Analysis of Efficacy The statistical analysis of efficacy was based on the defined response criteria. For IGA, m-pasi and patient s global assessment of disease severity, the analyses were performed using the last observation carried forward (LOCF) values. The analyses of patient s assessment of itching by use of a visual analogue scale and Dermatology Life Quality Index (DLQI) are exploratory and were performed on the observed values Primary Response Criterion The primary response criterion was analysed for the full analysis set and for the per protocol analysiss set. The analysis using the full analysis set was regarded as primary while the per protocol analysis acted as supportive. The proportion of with Controlled disease at week was compared between treatments using the Cochran-Mantel-Haenszel the odds ratio (odds of Controlled disease for LEO 9 relative to that for each of the other treatments [, BDP]), corresponding 9 confidence interval and a p-value were calculated. The efficacy of the LEO 9 (calcipo- triol plus BDP) group was not based on detecting a significant treatment effect for any one of test adjusting for pooled centre. For each of the treatment comparisons, the two comparisons considered rather the two comparisons must show a statistically significant effect at the level in favour of the combination treatment. Therefore no adjustment of significance levels to account for multiple testing was deemed necessary. The number and percentage of who achieved Controlled disease according to the IGA of the trunk and limbs at week were tabulated for each treatment group and also presented for each pooled centre and also for each baseline disease severity category by treatment group Secondary and Furtherr Response Criteria The secondary and further efficacy response criteria were analysed for the full analysiss set.

61 LEO Apr- Page of 89 Investigator s global assessment of disease severity of the trunk and limbs The number and percentage of in each of the five categories ( Clear to Severe ) were tabulated at each visit for each treatment group. Additionally, the number and percentage of with\without Controlled disease were tabulated at each visit for each treatment group as described in the SAPU. The analysis of the proportion of s with Controlled disease at week was the same as for the primary response criterion. Investigator s global assessment of disease severity of the scalp The number and percentage of in each of the five categories ( Clear to Severe ) were tabulated at each visit for each treatment group. Additionally, the number and percentage of with\without Controlled disease were tabulated at each visit for each treatment group as described in the SAPU. The analysis of the proportion of with Controlled disease at week and the analysiss of the proportion of with Controlled disease at week was the same as for the primary response criterion. Investigator s global assessment of disease severity of the trunk and limbs and the scalp The number and percentage of in each of the five categories ( Clear to Severe ) were tabulated at each visit for each treatment group. The number and percentage of who achieved Controlled disease according to the IGA of the trunk and limbs and the scalp at week were tabulated for each treatment. The analysiss of the proportion of with Controlled disease at week was the same as for the primary response criterion. The number and percentage of who achieved Controlled disease according to the IGA of the trunk and limbs and the scalp at week were tabulated for each treatment. The analysiss of the proportion of with Controlled disease at week was the same as for the primary response criterion. Investigator s assessment of modified PASI The following weree performed for each of the three areas trunk and limbs, scalp, and trunk, limbs and scalp.

62 LEO Apr- Page of 89 The m-pasi at each visit, and the percentage change in m-pasi from baseline to each visit were summarised as mean, SD, median, minimum and maximumm values for each treatment group. For m-pasi at week and week respectively, the treatment groups were compared using ANCOVA including pooled centre, treatment and baseline m-pasi in the model. The global F-test from the ANCOVA was not considered but for each of the treatment comparisons, the adjustedd differencee (LEO 9 - and LEO 9 BDP), its 9 confidence interval and a p-value were calculated from the analysis of covariance model. For who achieved at least or who received at least 7 reduction in m- PASI from baselinee (PASI or PASI 7) the number and percentage were tabulated at each visit for each treatment group. The proportion of with PASI at week and the proportion of with PASI 7 at week were analysed in the same way as the primary response criterion. Patient s global assessment of disease severity The number and percentage of in each of the five categories ( Clear to severe ) were tabulated at each visit for each treatment group. The number and percentage of who achieved Controlled disease according to the patient s global assessment of disease severity at week were tabulated for each treatment. The proportion of with Controlled disease was analysed in the same way as the primary response criterion. Patient s assessment of itching by use of visual analogue scale The change in itch as assessed by the visual analogue scale from baseline to each visit was summarised as mean, SD, median, minimum and maximum values for each treatment group. For the change in itch as assessed by the visual analogue scale from baseline to week, week, and week, respectively, the treatmentt groups were compared in the same way as the modified PASI, where baseline visual analogue score was included in the model rather than baselinee m-pasi. Dermatology Life Quality Index (DLQI) The change in the DLQI from baseline to each visit was summarised as mean, SD, median, minimum and maximum values for each treatment group.

63 LEO Apr- Page of 89 For the change in the DLQI from baselinee to week, week, and week, the treatment groups were compared in the same way as the modified PASI, where baseline DLQI score was included in the model rather than baseline m-pasi Analysis of Safety The analysis of safety was based on the safety analysis set 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 Primary System Organ Class and Preferred Terms. All AEs recorded during the course of the trial were included in the individual subject data listings. An event was considered emergent with the study treatment if it started after the first application of the trial medication or if it started before this and worsened in intensity after. The tabulations described below only included the AEs that were emergent with trial treat- ment. The number of experiencing each type of AE (according to the Preferred Term within Primary System Organ class) was tabulated by treatment group regardless of the number of times each adversee event was reported by each subject. The intensity for each type of AE (according to the Preferred Term) was tabulated by treat- ment group. Wheree there weree several recordings of intensity for a given type of AE (accord- ing to the Preferred Term), intensity was taken as the most severe recording for that AE. The causal relationship to trial medication for each type of AE (according to the Preferred Term) was tabulated by treatment group. Where there are several recordings of causal relationship to trial medication for a given type of AE (according to the Preferred Term), causal relationship was taken as the most related recording from the last report of that AE, since that was when the investigator was in possession of most informationn and so best able to judge causal relationship. Adversee drug reactions (ADRs) were defined as AEs for which the investigator had not described the causal relationship to trial medication as not related. The number of who experienced each type of ADR (according to the Preferred Term) was tabulated regard-

64 LEO Apr- Page of 89 less of the number of times each ADR was reported by each subject. The percentage of s with ADRs was compared between treatment groups by a chi-square test. An overall summary of adverse events table presenting the number of events and the number and percentage of with events for each of the following: Adverse events Severe adverse events Adverse drug reactions Serious adversee events Adverse events leading to withdrawal A table presenting the intensity of adversee drug reactions by MedDRA primary SOC and preferred term was produced for each treatment group. A common adversee event was defined as an event that occurred in at least of in any treatment group. The following tables of common adverse events were to be produced: Common adverse events by MedDRA primary SOC and preferred term Intensity of common adverse events by MedDRA primary SOC and preferred term Relationship of common adverse events to study medication by MedDRA primary SOC and preferred term However, the tables of common adverse events weree not produced as there were few events to report Laboratory Safety Examinations Serious adverse events and adverse events leading to discontinuation were presented sepa- rately, and a narrative for each was given. In the SAPU, the following additional presentations of adverse event data were described. The change in albumin corrected serum calcium and the change in urinary calcium:creatinine ratio from baselinee to week were summarised as mean, SD, median, minimum and maxi- mum values for each treatment group. The albumin corrected serum calcium and the urinary calcium:creatinine ratio were classified as low, normal or high, depending on whether the values were below, within or above the

65 LEO Apr- Page of 89 reference range, respectively. Shift tables were produced showing the categories at baseline against those at week. The Vitamin D level was classified as low, normal or high, depending on whether the value was below, within or above the reference range, respectively, at Visit Vital Signs Evaluation of Other Observations The change in vital signs (blood pressure, heart rate) from baseline to week were summa- rised as mean, SD, median, minimum and maximumm values for each treatment group. The weight of study medication used was calculated by subtracting the weight of the used dispensed cans from the mean weight of a set of full cans and multiplying by a correction factor. to subtract the propellant gasses. The weight of study medication used was summarised by treatment group for each visit interval and for the total treatment period using the mean, SD, median, minimum and maximum values for the safety analysis set. The average weekly amount of study medication used was calculated for each subject as the amount of medication used for a particular visit interval, dividedd by the duration (days) of the visit interval and then multiplied by 7. The average weekly amount of study medication used was summarised in the same way as weight of study medication used as described in the SAPU. The duration of exposure to treatment was calculated as the number of days from visit to the date of last application of study medication. If that date was missing, the date of the last treatment visit was used. If the only attendedd visit, then the duration was set at one day. The duration of exposure (weeks) was summarised using the mean, SD, median, minimum and maximum values. The extent of exposure was summarised as subject-treatment-weeks as described in the SAPU. Compliance with treatment instructions was summarised for each treatment group for all randomised, separately for usage on the trunk and/or limbs and for usage on the scalp. The percentage of missed applications for each visit interval (Visit to Visit, Visit to Visit and Visit to Visit ) were calculated as follows: the number of applications of

66 LEO Apr- Page of 89 study medication missed for a particular visit interval was divided by the total number of days for the visit interval and multiplied by to give a percentage. The percentage of missed applications for the total treatment period was calculated as follows: the total number of applications of study medication missed between Visit and the last on-treatment visit was divided by the total number of days between Visit and the last on-treatment visit and multiplied by to give a percentage. The percentage of missed applications was allocated to one of the following categories:, > to, > to, > to, > to, >. The BSA involvement on the trunk, limbs and scalp was summarised by treatment group at each visit using the mean, SD, median, minimum and maximumm values for the safety analysis set. The six assessments of local safety and tolerability were to be summarised for each treatment group as categorical data at Visits - for the safety analysis set. Due to the inconsistency of reporting local safety and tolerability (seee Section 9. 8) these assessments were summarised by centre for each treatment group as described in the SAPU General Principles All significance tests were two-sided, using a significance level, and all confidence intervals were presented with 9 degreee of confidence. If a centre randomised fewer than 8, it was to be pooled with the next smallest centre to form a pooled centre of 8 or more randomised. To facilitate aggregation of results from this trial and the concurrent phase trial comparing LEO 9 to calcipotriol/ BDP ointment (LEO 9-), it was decided to pool centres common to both trials based on geographical location, rather than on the number of randomisedd in a particular trial. Details of centre pooling was documented in the SAPU before breaking the randomisa- tion code. An observed cases approach was used for tabulations of data by visit (i.e. nvolving only those who attended each specificc visit). For IGA, m-pasi and patient s global assessment of disease severity data an additional week visit and an additional week visit weree tabulated using the last observation carried forward (LOCF) approach. The week (LOCF) value for a particular efficacy measure was defined as

67 LEO Apr- Page 7 of 89 the last value recorded for thatt efficacy measure. The week (LOCF) value for a particular efficacy measure was defined as the value recorded at baseline for that efficacy measure. For laboratory safety data and vital signs data the week (LOCF) value was defined as the last value recordedd for the parameter after baseline. 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 may have been refined, before breaking the randomisa- tion 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 dataa actually obtained and the SAPU was finalised beforee breaking the randomisation code Determination of Sample Size A total of were to be randomised in a : :: ratio to the three treatment groups, i.e. in each group. It was calculated thatt a sample size of in each group would give each comparison of the LEO 9 with its active components 8 power to detect a difference between of having controlled disease according to the IGA for the trunk and limbs in the LEO 9 group and of having controlled disease in the active comparison groups. This uses a two group likelihood ratio chi-square test with a. significance level. Each centre was to recruit a minimum of 9. Withdrawn were not replaced. No centre was allowed to recruit more than (approximately of the total sample size). The sample size calculation was carried out using the Proc Power in SAS, version Changes in the Conduct of the Trial or Planned Analyses There were no protocol amendments but there was one important change to the protocol planned analyses of local safety and tolerability due to the inconsistency in reporting of local safety and tolerability data across centres (described below). This change was made prior to breaking the blind and was documented in the SAPU (Appendix..9).

68 LEO Apr- Page 8 of 89 During the trial, the sponsor observed through medical monitoring of the clinical database some trends (large inter-site variability) within data collected for the Local Safety and Tolerability which indicated the possibility that guidance on how to conduct this assessment might have not optimally communicated to all study sites. This assessment was described in the Clinical study protocol only briefly, and further detailed guidance was given in the Guide to Clinical Assessments (Appendix..). On -Jul-, the sponsor sent a letter to all investigators to highlight the importance of conducting this assessment as described in the Guide to Clinicall Assessments. For local safety and tolerability assessments conducted until this time, data discrepancies were issued in the ecrfs asking the investigators to clarify how the assessments had been conducted. Issued data discrepancies were answered by the investigators, confirming inconsistency in how the assessments had been performed and reported acrosss centres. According to the Guide, the investigator was to assess the perilesional area (but not the lesions itself) for erythema, dryness, oedema and erosion. Furthermore, the subject was to assess the lesional/perilesional area for burning and pain. Any score of mild to severe for any sign/symptom was to be reported as an AE marked as lesional/perilesional. From investigators responses to discrep- and erosion in the lesional area. Furthermore, scores of mild to severe for the signs/symptoms were not consistently reported as ances it was evident that some investigators reported also erythema, dryness, oedema AEs. Due to these inconsistencies, local safety and tolerability assessments weree only summarised by centre and treatment group and no overall summary by treatment group was made.

69 LEO Apr- Page 9 of 89 Trial Population. Disposition of Subjects A total of from 8 centres in the USA were enrolled into the trial (i.e., informed consent form signed and CRF number assigned). The first subject entered the trial/was enrolled on 7-May- [EoT] Table ). Figure 7: (EoT) summarises subject recruitment over time. Of the enrolled, did not meet inclusion and/or met exclusion criteria and were and the last completed the trial (last visit) on -Oct- (End-of-Text not randomised. An additional 8 were not randomised for other reasons. Thus, were randomised; to LEO 9, to BDP and to calcipotriol (EoT Table ). Of these, 8 (9) completed the study (Table ). Withdrawal rates were similar across the three treatment groups ( to 7.9) ). The most common reason for with- drawal was lost to follow up. Two () in the LEO 9 group and () s in the calcipotriol group withdreww due to unacceptable adverse events. The reasons for withdrawal are summarised by last on-treatmen nt visit for which data were recordedd in EoT Table.

70 LEO Apr- Page 7 of 89 Table : Reason for withdrawal: randomised All randomised Betamethasone LBO 9 {n=) {n=l) {n=l) {n=l) Reason for Number o f Discontinuation Withdrawals Unacceptabl e.... adverse event Voluntary {and.... no other eason) Lost to f ollow-.... up Other reason (s).7... number of withdrawn Completers ) Other reasons were: Subject i s non compliant: Vi sit has been rescheduled and subject no showed every t i me. ; Subject II was inadvertentl y scheduled earl y for visi t. ) A compl eter i s defined a s a subject who does not have a reason for wi thdrawal stated. See Appendix.. for individual subject data on discontinued subject (Listing ) and Appendix.. actual study period (Listing ). A subject index is available in Appendix.. 7 (Listing ) as well as individual data on the randomisation and treatment number (Listing ). Figme summarises visit attendance. As stated in the footnotes, there were who attended all visits and also had a reason for withdrawal stated. Subject.JI in the LEO 9 group (other reason) was inadvertently scheduled for visit early and had visit assessments done only 8 days after visits, after having been on u eatment for only days. Subject-in the calcipou iol group withdrew due to anae on day.

71 LEO Apr- Page 7 of 89 Figure : Visit attendance by treatment: r andomised LEO 9 Primary reason fot withdrawal Visit (day ) Visit (day 7) Visit (day ) Visit (day 8) Unacceptable adverse event Lost to follow up Other reason(s) ) One subject attended all fom visits and also had a reason for withdrawal recorded: other reasons.

72 LEO Apr- Page 7 of 89 Betamethasone Primary reason for withdrawal Visit (day ) not attending Visit (day 7) Lost to follow-up Voluntary Lost to follow-up Visit (day ) Visit (day 8) Voluntaty Lost to follow up

73 LEO Apr- Page 7 of 89 Primary reason for withdrawal Visit (day ) Lost to follow-up not attending Visit (day 7) Visit (day ) Unacceptable adverse event Voluntary Lost to follow-up Lost to follow up Visit (day 8). One subject attended all four visits and also had a reason for withdrawal recorded: unacceptable adverse event. - Protocol Deviations All important protocol deviations (i.e., those that could significantly impact the completeness, accuracy, and/or reliability of the study data or that may significantly affect a subject's rights, safety, or well-being) are reported in accordance with ICH guideline. The number of with important protocol deviations in each n eatment group are summarised in Table. All individual with protocol deviations are listed in Appendix...

74 LEO Apr- Page 7 of89 Table : Pr otocol deviations: r andomised All randomised Betamethasone LBO 9 {n=) {n=l) {n=l) {n=l) Protocol Deviations Disallowed.... concomitant medication Enro llment of a.... subject who did not satisfy a ll I nclusion/ Ex - elusion c r iteria Informed consent i mproperl y administered PEB,,, LE9 7 tpdev. doc There were with impiant protocol deviations. In cases, started treatment with disallowed medication during the study or did not have an adequate washout of mediation prior to the baseline visit. In one case, a subject was randomised despite not fulfilling inclusion criterion number due to use of condom/spennicide, which has higher than the required per year failure rate. Finally, there were 7 cases where a subject either signed the wrong (obsolete) version of the infmed consent fonn (ICF) or signed the ICF for a similar study with LEO 9 nm at the same centre (LEO 9-; comparative trial with calcipotriol/bdp ointment), the Investigator did not sign the ICF, or a physician not listed as (sub )-investigator for this study signed the ICF. When these mistakes were discovered infmed consent was documented using the conect fm I the investigator signed the ICF. All deviations related to infmed consent were repied to the IRB. In addition to the described in Table there was one additional subject (CRF - randomised and treated with LEO 9) with important protocol deviation related to infmed consent. After this subject was no longer in the trial it was discovered that the infmed consent fm was never signed by the investigator. As it could not be asceiained that the infmed consent process was conducted conectly, data for this subject were excluded from all analyses.

75 LEO Apr- Page 7 of 89 None of the deviations summarised in Table weree consideredd of sufficient importance to justify exclusion of from the full and safety analysis set. For information regarding the criteria for exclusion of from the per protocol analysis set, see Section..

76 LEO Apr- Page 7 of89 Efficacy Evaluation L Data Sets Analysed LL Full analysis set All randomised were included in the full analysis set. LL Safety Analysis Set The safety analysis set consisted of those who received any treatment with u ial medication and for whom the presence or confnmed absence of adverse events is available. For three (CRF- -and -the date of last application of study medication was recorded as ' unknown'. For one additional subject (CRF -the date of last application was recorded as being the same as the date of randomisation. All fom of these were lost to follow up after visit and no dispensed medication was retumed. Therefore it was assumed that these did not apply any study medication and they were excluded from the safety analysis set. Therefore the safety analysis set consists of 98. LL Per Protocol Analysis Set The per protocol analysis set was defined by excluding from the full analysis set who: Provided no efficacy data following stat of u eatment Took the wrong u ial medication (due to enor in u eatment assignment) throughout the u eatment phase of the u ial Applied no u ial medication Did not fulfil the disease inclusion criteria (i.e. inclusion criteria 7, 8, 9,,, ). Subjects violating visit (Day 8) visit window of plus/minus days Subjects withdrawing prior to visit Subjects that missed more than of applications of trial medication on the hunk/limbs A total of were excluded from the per protocol analysis set. The per protocol analysis set comprised. For details on exclusion from the per protocol analysis set on individual subject level, see SAPU in Appendix..9.

77 LEO Apr- Page 77 of 89.. Trial analysis sets by treatment The analysis sets and the number of included in each analysis set are summarised by treatment in Figure. See Appendix.. Listing for individual data on excluded from the analysis sets and Listing for analysis sets. Figure : Trial analysis sets by treatment: randomised LEO 9 Randomised Full analysis set Safety analysis set violated visit window Per protocol analysis set 79 withdrew prior to visit disallowed treatment 7 missed more than applications. Note had more than one reason for exclusion.

78 LEO Apr- Page 78 of 89 Betamethasone Randomised Full analysis set Safety analysis set 99 did not apply any study medication Per protocol analysis set 8 no post baseline efficacy data violated visit window withdrew prior to visit disallowed treatment missed more than applications Randomised Full analysis 99 did not apply any study medication no post baseline efficacy data Per protocol analysis set 8 violate visit window withdrew prior to visit disallowed treatment missed more than applications. Note had more than one reason for exclusion.. Demographic and other Baseline Characteristics Demographic and baseline characteristics, concurrent diagnosess and concomitant drug treatment are presented for all the randomised.

79 LEO Apr- Page 79 of 89.. Demographic dataa Demographic data (age, sex, race, ethnicity and skin type) are summarised in Table to Table. A comparison of demographic data by centre is provided in Section., EoT Table (age), Table (sex), Table (race) and Table 7 (ethnicity). Of the s allocated to treatment, 7 (.) were male and (.7) were female. Their mean age was 9 years (median.; range: to 8 years). Most (88.7) were White and self-reported Not Hispanic or Latino ethnicity (78.). Black or African American accounted for of randomised and Asian accounted for of randomised. American Indian or Alaska native ac- counted for only.. and native Hawaiian or other Pacific Islander for of randomised. Most recorded skin type III (over of randomised ) and skin types II and IV (approximately of randomised each). The distributions of age, race, ethnicity and skin type were similar among the groups. Table : Age: randomised Age (years) All randomised (n=) LEO 9 (n=) Betamethasone (n=) (n=) Mean SD Median Minimumm Maximumm Number JAN::: LEO9 7 tage.doc

80 LEO Apr- Page 8 of 89 Table : Sex: randomised All randomised (n=) LEO 9 (n=) Betamethasone (n=) (n=) Sex Male Female JAN::: LEO9 7 tsex.doc Table Race: randomised All Randomised Subjects (n=) LEO 9 (n=) Betamethasone (n=) (n=) Race White Black or African American Asian American Indian or Alaska Native Native Hawaiian or Other Pacificc Islander Other JAN:::9 LEO9 7 trace.doc

81 LEO Apr- Page 8 of 89 Table : Ethnicity: randomised All Randomised Subjects (n=) LEO 9 (n=) Betamethasone (n=) (n=) Ethnicity Hispanic or Latino Not Hispanic or Latino JAN::: LEO9 7 tethn.doc

82 LEO Apr- Page 8 of 89 Table : Skin type: randomised All Randomised Subjects (n=) LEO 9 (n=) Betamethasone (n=) (n=) Skin Type TYPE I = White: Always burns easily; never tans TYPE III = White: Always burns easily; tans minimally TYPE II II = White: Burns moderately; tans gradually (light brown) TYPE IV = White: Burns minimally; always tans well (moderate brown) TYPE V = Brown: Rarely burns; tans profusely (dark brown) TYPE VI = Black: Never burns; deeply pigmented MAR::8: LEO9 7 tskin.doc.. Disease-related and other baseline data The key disease-related baseline characteristics are summarised in Table 7 to Table. A comparison of some of these data by centre is provided in Section. (EoT Table 7) ). The height, weight and BMI are summarised for all randomised in EoT Table 8. A table summarising levels of -hydroxy vitamin D at baseline is also given in Section. (EoT Table 9). All included in the study had a diagnosis of psoriasis; the mean duration of psoriasis was. years (range: to ) (Table 7) ). According to the Investigator s Global Assessment

83 LEO Apr- Page 8 of 89 of Disease Severity, the majority of, 7., were assessed as having moderate disease on the trunk and limbs; mild disease on the trunk and limbs accounted for. and severe for. of (Table 8). The corresponding figures for the scalp weree similar, with majority of (.) having moderate disease, 9.9 having mild and.9 severe disease. The distribution of the IGA scores at baseline was similar among the three treatment groups. m-pasi at baselinee is shown in Table 9. The mean scores at baseline weree 7. for the trunk and limbs,.87 for the scalp and 8.7 for the trunk, limbs and scalp together. The distribution of the m-pasi scores at baseline was similar across the three treatment groups. Table 7: Duration of psoriasis vulgaris: randomised Duration of Psoria- sis Vulgaris (years) All Randomised Subjects (n=) LEO 9 (n=) Betamethasone (n=) (n=) Mean SD Median Minimumm Maximumm Number JAN::: LEO9 7 tdur.doc

84 LEO Apr- Page 8 of 89 Table 8: Investigators global assessment (IGA) of disease severity at baseline: random- ised All randomised (n=) LEO 9 (n=) Betamethasone (n=) (n=) Body Area IGA Trunk and Limbs Moderate Severee Scalp Moderate Severee Trunk, Limbs and Scalp Moderate Severee JAN::: LEO9 7 tigabase. doc

85 LEO Apr- Page 8 of 89 Table 9: m-pasi at baseline: randomised Body Area m-pasi All randomised (n=) LEO 9 (n=) Betamethasone (n=) (n=) Trunk and Limbs Mean SD Median Minimum Maximum Number Scalp Mean SD Median Minimum Maximum Number Trunk, Limbs and Scalp Mean SD Median Minimum Maximum Number JAN::: LEO9 7 tpas.doc Extent of psoriasis at study entry is summarized separately for the trunk and limbs (Table ), the scalp (Table ) and the body plus scalp together (Table ). Subjects participating in this trial had psoriasis of the trunk and limbs affecting between to 8 of the BSA (mean 7., median.). The range of BSA involvement was the same across the treatment groups and the three treatment groups weree consideredd comparable with respect to extent of psoriasis on the trunk and limbs at baseline. With respect to the scalp, most (.) had lesions affecting between and 9 of the scalp. The distribution of extent of scalp psoriasis at baseline was similar across the three treatment groups. The overall BSA involvement (body and scalp) was also similar, on average around (range to ) ).

86 LEO Apr- Page 8 of 89 Table : BSA involvement of psoriasiss vulgaris affecting the trunk and limbs at baseline: randomised BSA () All randomised (n=) LEO 9 (n=) Betamethasone (n=) (n=) Mean SD Median Minimumm Maximumm Number JAN:::9 LEO9 7 tbsatl.doc Table : Extent of scalp psoriasis at baseline: randomised All randomised (n=) LEO 9 (n=) Betamethasone (n=) (n=) Extent () JAN::: LEO9 7 texts.doc

87 LEO Apr- Page 87 of 89 Table : BSA involvement of psoriasiss vulgaris affecting the trunk, limbs and scalp at baseline: randomised Body Surface Area of Trunk/Limbs and Scalp All randomised (n=) LEO 9 (n=) Betamethasone (n=) (n=) Mean SD Median Minimumm Maximumm Number JAN::: LEO9 7 tbsatls.doc As indicated in Table, about to of participants had psoriatic lesions also on other parts of the body, such as the skin folds, face, nails or genitals. The majority of participants (8) had previously received treatment for their psoriasis, most commonly with topical corticosteroids and topical vitamin D analogues, used as monotherapy or in combination, see Table. The measurements of -hydroxy vitamin D levels at baseline revealed that approximately 9 of had levels below the normal reference range of 7.-. nmol/l (EoT Table 9).

88 LEO Apr- Page 88 of 89 Table : Other locations of psoriasis vulgaris: randomised All randomised (n=) LEO 9 (n=) Betamethasone (n=) (n=) Location of psoriasis Psoriasis vulgaris of the skin folds Yes No Psoriasis vulgaris of the face Yes No Psoriasis vulgaris of the nails Yes No Psoriasis vulgaris of the genitals Yes No FEB::: LEO9 7 tcurloc.doc

89 LEO Apr- Page 89 of 89 Table : Previous psoriasis treatments: randomised All randomised (n=) LEO 9 (n=) Betamethasone (n=) (n=) Previous Treatment Biologics Coal Tar Medicated shampoos Photo therapy Systemic treatment (excl. biologics) Topical calcineurin inhibitors Topical corticoste - roids Topical vitamin D analogues, plain and combinations with corticoster - oids Other FEB::: LEO9 7 tprevtt.doc See Appendix.. for individual subject demographic, disease-related and other baseline data. See Appendix.. for individual subject dataa on IGA and the investigator s assess- history recorded at baseline. The most common relevant medical history and concurrent diagnoses were vascular disorders and surgical and medical procedures, followed by metabo- lism and nutrition disorders. The distribution of concurrent diagnoses at baseline was ment of extent and severity of clinical signs... Concurrent diagnosis and use of concomitantt medication EoT Table 7 summarises the concurrent diagnoses which includes the relevant medical considered similar across the three treatment groups.

90 LEO Apr- Page 9 of 89 EoT Table 7 summarises concomitant medication use at baseline. The most common concomitant medications at baseline weree for disorders of the cardiovascular system, the alimentary tract and metabolism, and the nervous system. The use of concomitant medication at baseline was similar across the treatment groups. A full list of all past and current medical history and concomitant medication use is given in Appendix..... Conclusion on study Demographic and other subject characteristics were in line with the intentions of the study protocol. The randomised population consisted of with mostly moderate psoriasis vulgaris (IGA) on the trunk and/or limbs and scalp, involving on average about of BSA (psoriasis on the trunk and limbs on average 7. of BSA), with a mean m-pasi of the trunk and limbs of 7.. The majority were White, were men, and mean age was 9 years. The treatment groups were well-balanced with regard to demographi ic and baseline clinicall characteristics.. Measurement of Treatment Compliance At all on-treatmentt visits, the subject was asked if she/he has used the medication as pre- scribed. Compliance with treatment instructions for the prescribed study medication is shown in Table for the treatment of the trunk and limbs and in Table for the scalp. Compliance data were available for all but. The self-reported compliance with using the treatments as prescribed was high; about 9 of in each group reported that they either applied the treatment on the trunk and limbs as instructed and were fully compliant, or missed at most of applications. Slightly less, approximately 8 to 8 of s across the treatment groups reported that they applied the treatment on the scalp as instructed and weree fully compliant, or missed at most of applications. Compliance with treatment instructions is presented by visit in EoT Table 7 for the trunk and in EoT Table 7 for the scalp. In general the number of who were fully compliant with treatment instructions, or missed at most of applications, was similar throughout the study. See Appendix.. for individual subject data on drug accountability and compliance.

91 LEO Apr- Page 9 of 89 Table : Compliance with treatment instructionss for the trunk and limbs over the total trial period: randomised LEO 9 (n=) Betamethaso one (n=) (n=) Percentage of Missed Applications No missed applica- tions <= applications missed > to <= applica- tions missed > to <= applica- tions missed > to <= applica- tions missed > to <= applica- tions missed > applications missed JAN::: LEO9 7 tcomptl.doc ) Yes recorded at all post randomisation visits attended.

92 LEO Apr- Page 9 of 89 Table : Compliance with treatment instructionss for the scalp over the total trial period: randomised s LEO 9 (n=) Betamethaso one (n=) (n=) Percentage of Missed Applications No missed applica- tions <= applications missed > to <= applica- tions missed > to <= applica- tions missed > to <= applica- tions missed > to <= applica- tions missed > applications missed Unknownn JAN:::9 LEO9 7 tcomps.doc ) Yes recorded at all post randomisation visits attended.. Efficacy Results and Tabulation of Individual Subject Data Efficacy results are summarised in subsections, the first presenting the results of investiga- the tor s assessments of the trunk and limbs (including the primary and secondary endpoints), second presenting the results for the scalp and the third the results of an overall assessment of psoriasis vulgaris ncluding both body and scalp. The fourth subsection presents the results of patient s assessments of disease severity, itch and quality of life assessment... Analysis of Efficacy Psoriasis on Trunk and Limbs.... Primary Endpoint Controlled disease according to the IGA of the trunk and limbs at week The percentage of with controlled disease (clear or almost clear for s with at least moderate disease at baseline, clear for with mild disease at baseline) at week (LOCF) and the results of comparison between treatment groups are shown in Table 7 for the full analysis set and in Table 8 for the per protocol analysis set.

93 LEO Apr- Page 9 of 89 For the full analysis set, the proportion of who achieved controlled disease on the trunk and limbs according to the IGA at week (LOCF) was. in the LEO 9 group compared to.7 in the BDP group and.9 in the calcipotriol group. LEO 9 was statistically significantly more effective than BDP in the aerosol foam vehicle (OR.8; 9 CI. to.; p= =.7) and calcipotrioll in the aerosol foam vehicle (OR.; 9 CI. to 8.7; p<.). The results from the per-protocol analysiss set were similar, with.8 of in the LEO 9 group achieving controlled disease compared to.7 of in the BDP group and. of in the calcipotriol group. Compared to the results for the full analysiss set, the proportion of achieving controlled disease was slightly higher in all treatment groups (.8 higher in the LEO 9,. in the BDP and. in the cal- cipotriol group). The comparison of LEO 9 to calcipotriol was highly significant (OR.8; 9 CI.7 to 8.9; p<.), however the comparison to BDP was not statistically significant (OR.7; 9 CI.89 to.; p=.). Results for the primary endpoint are presented by centre in EoT Table 7. The Breslow-Day test to investigate the consistency of the response across centres was not statistically signifi- calcipotriol) whichh means thatt no treatment by centree interactions were found indicating a cant at the level (p=.7 for comparison LEO 9 versus BDP and p=. versus consistent responsee among centres. EoT Table 7 shows results for the primary endpoint for each baseline IGA category. For s with baseline IGA scores of mild and moderate (. and 7. of randomised, respectively), LEO 9 showed a higher response rate than BDP and calcipotriol. For enrolled with a baseline IGA score of severe, the response rates were higher in the BDP group.

94 LEO Apr- Page 9 of 89 Table 7: Analysiss of 'Controlled disease' (IGA of the trunk and limbs) at Week (LOCF): full analysis set LEO 9 (n=) Betamethasonee (n=) (n=) Controlled Diseasee Controlled Non-controlled Statistical analysis Odds ratio 9 CI CMH test p-value.8. to..7.. to 8.7 <. JAN::: LEO9 7 tigafas. doc ) Odds of having controlled diseasee in LEO 9 group treatment given in column heading. ) Treatment comparison by Cochran-Mantel-Haenszel test pooled centre. relative to adjusted for

95 LEO Apr- Page 9 of 89 Table 8: Analysiss of 'Controlled disease' (IGA of the trunk and limbs) at Week (LOCF): per protocol analysis set LEO 9 ( n=79) Betamethasonee (n=8) (n=8) Controlled Diseasee Controlled Non-controlled Statistical analysis Odds ratio 9 CI CMH test p-value.7.89 to to 8.9 <. JAN::: LEO9 7 tigapp.doc ) Odds of having controlled diseasee in LEO 9 group treatment given in column heading. ) Treatment comparison by Cochran-Mantel-Haenszel test pooled centre. relative to adjusted for.... Secondary Endpoint Controlled disease according to the IGA on the trunk and limbs at week The percentage of with controlled disease (IGA) on the trunk and limbs at week (LOCF) are shown in Table 9. The proportion of who achieved controlled disease at week (LOCF) was low across all treatment groups, ranging from () in the calcipotriol group to () in the LEO 9 group. Both of the treatment compari- sons were not statistically significant.

96 LEO Apr- Page 9 of 89 Table 9: Analysiss of 'Controlled disease' (IGA of the trunk and limbs) at Week (LOCF): full analysis set LEO 9 (n=) Betamethasonee (n=) (n=) Controlled Diseasee Controlled Non-controlled Statistical analysis Odds ratio 9 CI CMH test p-value.. to to JAN::: LEO9 7 tigatl.doc ) Odds of having controlled diseasee in LEO 9 group treatment given in column heading. ) Treatment comparison by Cochran-Mantel-Haenszel test pooled centre. relative to adjusted for The percentage of with controlled disease according to the IGA of the trunk and limbs at weeks, and is shown in Figure and Table. In each treatment group, the proportion of with controlled disease increased as the study progressed. The figure shows that over the second week of treatment, the percentage of with controlled disease increased more rapidly for LEO 9 group than for BDP and calcipotriol groups, and remained higher throughout the treatment period. The percentage of in each IGA category at weeks, and is summarised for the full analysis set in EoT Table 77.

97 LEO Apr- Page 97 of 89 Table : 'Controlled disease' (IGA of the trunk and limbs) at each visit: full analysis set Betamethasone LBO 9 d ipropionat e Cacipot rio (n=loo) (n= ) (n= ) Control led Disease subj ects subject s subject s Week Cont roll ed... Non- contro l led To t a l Week Cont roll ed... Non- contro l led To t a l Week Cont roll ed... 9 Non- contro l led To t a l OJAN ' ' ' LE9 7 tiaatl.doc Figure : Percentage of with 'Controlled disease' (IGA of the trunk and limbs) at each visit: full analysis set

98 LEO Apr- Page 98 of m-pasi of the trunk and limbs Further response criteria for psoriasis of the trunk and limbs included m-pasi at weeks and, with PASI at week and with PASI 7 at week. Mean m-pasi scores at week (LOCF) and week (LOCF) are presented in Table and Table, respectively, together with the results of the statistical comparison of treatment groups. Mean m-pasi of the trunk and limbs at each visit is summarised in Table 78 (absolute values) and Table 79 (percentage change from baseline). The m-pasi scoress at week (LOCF) indicated improvements from baseline in all three treatment groups (Table ). The mean m-pasi at week (LOCF) was.7 in the LEO 9 group compared with.7 in the BDP group and.9 in the calcipotriol group. LEO 9 was statistically significantly more effective than BDP (mean difference -.9; 9 CI: -.8 to -.9; p<.) and calcipotriol (mean difference -.; 9 CI: -. to -.; p<.). A reduction in mean m-pasi score was seen in all treatment groups already at week (Table ). The mean m-pasi at week (LOCF) was.8 in the LEO 9 group compared with.9 in the BDP group and. in the calcipotriol group. The comparison of LEO 9 to calcipotriol was statistically significant (mean difference -.8; 9 CI -. to -.; p=.) but not the comparison to BDP (mean difference -.; 9 CI -.9 to.9; p=.) ).

99 LEO Apr- Page 99 of 89 Table : Analysiss of m-pasi of the trunk and limbs at Week (LOCF): full analysis set m-pasi LEO 9 (n=) Betamethasone (n=) (n=) Mean SD Median Minimumm Maximumm Number Statistical analysis Difference 9 CI P-value to -.9 < to -. <. JAN::: LEO9 7 tpastl.doc ) LEO 9 minus treatment group in column heading. ) Adjusted for the effect of pooled centre and baselinee m-pasi by analysis of covariance. Table : Analysiss of m-pasi of the trunk and limbs at Week (LOCF): full analysis set m-pasi LEO 9 (n=) Betamethasone (n=) (n=) Mean SD Median Minimumm Maximumm Number Statistical analysis Difference 9 CI P-value to to -.. JAN::: LEO9 7 tpastl.doc ) LEO 9 minus treatment group in column heading. ) Adjusted for the effect of pooled centre and baselinee m-pasi by analysis of covariance. The percentage of with at least a 7 reduction in the baseline m-pasi of the trunk and limbs at week is summarised in Table. The summary of PASI 7 of the trunk and limbs at each visit is given in EoT Table 8. The corresponding numbers for PASI of the trunk and limbs are given in Table and EoT Table 8.

100 LEO Apr- Page of 89 The percentage of that achieved at least a 7 improvement from their baseline m- PASI at week (LOCF) was higher in the LEO 9 group (9.) than in the comparator groups (.7 and 7.8 for BDP and calcipotriol, respectively). LEO 9 was statisti- cally significantly more effective than calcipotriol (OR.; 9 CI. to 8.7; p<.), however the comparison to BDP was not statistically significant (OR.7; 9 CI.97 to.9.; p=.9). It is evident from EoT Table 8 thatt response rates were consistently higher with LEO 9 than with the other two treatments. Likewise, the percentage of that achieved at least a improvement from their baselinee m-pasi at week (LOCF) was higher in the LEO 9 group (8.) than in the BDP (9.) and calcipotriol groups (.). LEO 9 was statistically significantly more effective than BDP (OR.8; 9 CI.9 to.; p=.) and calcipotriol (OR.; 9 CI.9 to 9.88; p< <.). Table : Analysiss of PASI 7 of the trunk and limbs at Week (LOCF): full analysis set Reduction of PASI of Trunk and Limbs LEO 9 (n=) Betamethasonee (n=) (n=) <7 PASI reduction >=7 PASI reduction Statistical analysis Odds ratio 9 CI CMH test p-value.7.97 to to 8.7 <. JAN:::9 LEO9 7 tpast7. doc ) Odds of having PASI 7 in LEO 9 group relative to treatmentt given in column heading. ) Treatment comparison by Cochran-Mantel-Haenszel test adjusted for pooled centre.

101 LEO Apr- Page of 89 Table : Analysiss of PASI of the trunk and limbs at Week (LOCF): full analysis set Reduction of PASI of Trunk and Limbs LEO 9 (n=) Betamethasonee (n=) (n=) < PASI reduction >= PASI reduction Statistical analysis Odds ratio 9 CI CMH test p-value.8.9 to....9 to 9.88 <. JAN::: LEO9 7 tpast. doc ) Odds of having PASI in LEO 9 group relative to treatmentt given in column heading. ) Treatment comparison by Cochran-Mantel-Haenszel test adjusted for pooled centre... Analysis of Efficacy - Scalp Psoriasis.... Controlled disease according to the IGA of the scalp The percentage of with controlled disease according to the IGA of the scalp at week (LOCF) is shown in Table and at week (LOCF) in Table. After weeks of treatment, the proportion of who achieved controlled disease on the scalp was. in the LEO 9 group compared to 7. in the BDP group and. in the calcipotriol group. LEO 9 was statistically significantly more effective than calcipotriol (OR. 9, 9 CI.9 to.; p=.) but not BDP (OR.; 9 CI.7 to.; p= =.). At week, the proportion of with controlled disease on the scalp was greater in the LEO 9 group (.) than in the BDP and calcipotriol groups (.9 and 7.9 respectively). LEO 9 was statistically significantly more effective than both BDP (OR

102 LEO Apr- Page of 89.8, 9 CI.8 to.; p=.) and calcipotrioll (OR., 9 CI.9 to.9, p<.). Figure depicts the response rate across time for all three treatment groups. It appears from the curves that the treatment effect between LEO 9 and BPD is greaterr at week than at week, and that there is virtually no difference at week. The magnitude of treatmentt effect between LEO 9 and calcipotriol appears similar at all threee time points. The percentage of with controlled disease (IGA) at weeks, and is shown in EoT Table 8. The number and percentage of in each IGA category is provided in EoT Table 8. Table : Analysiss of 'Controlled disease' (IGA of the scalp) at Week (LOCF): full analysis set LEO 9 (n=) Betamethasonee (n=) (n=) Controlled Diseasee Controlled Non-controlled Statistical analysis Odds ratio 9 CI CMH test p-value..7 to to.. JAN::: LEO9 7 tigas.doc ) Odds of having controlled diseasee in LEO 9 group treatment given in column heading. ) Treatment comparison by Cochran-Mantel-Haenszel test pooled centre. relative to adjusted for

103 LEO Apr- Page of89 Table : Analysis of 'Controlled disease' (IGA of the scalp) at Week (LOCF): full analysis set LBO 9 (n=) Betamethasone (n=l) (n=) C"ontrolled Disease rontrol led Non- controlled 'l'otal Statistical analysis Odds ratio 9 CI rmh test p-value.8. 8 to to. 9 <. OJAN : : : Lro9l OO 7 t i gal s. doc ) Odds of having control led disease in LEO 9 group rel ative to treatment g i ven i n col umn head ing. ) Treatment compari son by Cochran-Mantel- Haenszel test adjusted for pooled centre. Figure : Percentage of with 'Controlled disease' (IGA of the scalp) at each visit: full analysis set

104 LEO Apr- Page of m-pasi of the scalp Mean m-pasi scores for the scalp at week (LOCF) and week (LOCF) are presented in Table 7 and Table 8, respectively, together with the results of the statistical comparison of treatment groups. Mean m-pasi of the scalp at each visit is summarised in EoT Table 8 (absolute values) and EoT Table 8 (percentage change from baseline). The m-pasi scoress for the scalp at week indicated improvements from baseline in all three treatment groups. At week (LOCF), LEO 9 was statistically significantly more effective than calcipotriol (mean difference -.; 9 CI: -.9 to -.; p<.) with regard to m-pasi of the scalp but the result for comparison to BDP did not reach the nominal significance level (mean difference -.8; 9 CI: -.7 to.; p=.8). Likewise, at week, LEO 9 was statistically significantly more effective than cal- cipotriol (mean difference -.9; 9 CI: -.8 to -.; p=.7) but the comparison to BDP was not statistically significant (mean difference -.; 9 CI: -. to. ; p=.8) ). Table 7: Analysiss of m-pasi of the scalp at Week (LOCF): full analysis set m-pasi LEO 9 (n=) Betamethasone (n=) (n=) Mean SD Median Minimumm Maximumm Number Statistical analysis Difference 9 CI P-value to to -. <. JAN::: LEO9 7 tpass.doc ) LEO 9 minus treatment group in column heading. ) Adjusted for the effect of pooled centre and baselinee m-pasi by analysis of covariance.

105 LEO Apr- Page of 89 Table 8: Analysiss of m-pasi of the scalp at Week (LOCF): full analysis set m-pasi LEO 9 (n=) Betamethasone (n=) (n=) Mean SD Median Minimumm Maximumm Number Statistical analysis Difference 9 CI P-value to to -..7 JAN::7: LEO9 7 tpass.doc ) LEO 9 minus treatment group in column heading. ) Adjusted for the effect of pooled centre and baselinee m-pasi by analysis of covariance. The percentage of with a 7 reduction in the baselinee m-pasi of the scalp at week (LOCF) is summarised in Table 9. The summary of PASI 7 of the scalp at each visit is given in Table 8. The corresponding numbers for PASI of scalp are given in Table and EoT Table 87. The percentage of that achieved at least a 7 improvement from their baseline m- PASI of the scalp at week was higher in the LEO 9 group (7.) than in the BDP (.) and the calcipotriol groups (.). LEO 9 was statistically significantly more effective than calcipotriol (p=.) but the comparison to BDP was not statistically signifi- cant (p= =.). Also the PASI response rate was higher in the LEO 9 group (89.) than in the BDP (79.) and the calcipotriol groups (.). Again, LEO 9 was statistically significantly more effective than calcipotriol (p<.) but the comparison to BDP was not statistically significant (p=.8).

106 LEO Apr- Page of 89 Table 9: Analysiss of PASI 7 of the scalp at Week (LOCF): full analysis set LEO 9 (n=) Betamethasonee (n=) (n=) Reduction of PASI of Scalp <7 PASI reduction >=7 PASI reduction Statistical analysis Odds ratio 9 CI CMH test p-value..78 to...8. to.8. JAN::7: LEO9 7 tpass7. doc ) Odds of having PASI 7 in LEO 9 group relative to treatmentt given in column heading. ) Treatment comparison by Cochran-Mantel-Haenszel test adjusted for pooled centre.

107 LEO Apr- Page 7 of 89 Table : Analysiss of PASI of the scalp at Week (LOCF): full analysis set LEO 9 (n=) Betamethasonee (n=) (n=) Reduction of PASI of Scalp < PASI reduction >= PASI reduction Statistical analysis Odds ratio 9 CI CMH test p-value.9.9 to to. 9 <. JAN::: LEO9 7 tpass. doc ) Odds of having PASI in LEO 9 group relative to treatmentt given in column heading. ) Treatment comparison by Cochran-Mantel-Haenszel test adjusted for pooled centre... Analysis of Efficacy- Overall assessment of psoriasis of the trunk, limbs and scalp.... Controlled disease according to the IGA of the trunk and limbs and scalp The statistical analysis of controlled disease according to the IGA of the trunk, limbs and scalp is shown for week (LOCF) in Table, and for week (LOCF) in Table. After weeks of treatment, the proportion of who achieved controlled disease on the trunk and limbs and scalp was. in the LEO 9 group compared to.7 in the BDP group and..9 in the calcipotriol group. LEO 9 was statistically significantly more effective than calcipotriol (OR.; 9 CI. to 8.; p<.) but not BDP (OR.7; 9 CI.9 to., p=.).

108 LEO Apr- Page 8 of 89 At week, the proportion of who achieved controlled disease on the trunk and limbs and scalp was overall low (8 in the LEO 9 group, in the BDP group and in the calcipotriol group), and none of the treatment comparisons were statistically significant. Table : Analysiss of 'Controlled disease' (IGA of the trunk, limbs and scalp) at Week (LOCF): full analysis set LEO 9 (n=) Betamethasonee (n=) (n=) Controlled Diseasee Controlled Non-controlled Statistical analysis Odds ratio 9 CI CMH test p-value.7.9 to.... to 8. <. JAN::7:9 LEO9 7 tigatls. doc ) Odds of having controlled diseasee in LEO 9 group treatment given in column heading. ) Treatment comparison by Cochran-Mantel-Haenszel test pooled centre. relative to adjusted for

109 LEO Apr- Page 9 of 89 Table : Analysiss of 'Controlled disease' (IGA of the trunk, limbs and scalp) at Week (LOCF): full analysis set LEO 9 (n=) Betamethasonee (n=) (n=) Controlled Diseasee Controlled Non-controlled Statistical analysis Odds ratio 9 CI CMH test p-value.79. to....8 to. 8.8 JAN::: LEO9 7 tigatls. doc ) Odds of having controlled diseasee in LEO 9 group treatment given in column heading. ) Treatment comparison by Cochran-Mantel-Haenszel test pooled centre. relative to adjusted for.... m-pasi of the trunk, limbs and scalp Mean m-pasi scores for the trunk, limbs and scalp at week (LOCF) and week (LOCF) are presented in Table and Table, respectively, together with the results of the statistical comparison of treatment groups. Mean m-pasi of the trunk, limbs and scalp at each visit is summarised in EoT Table 89 (absolute values) and EoT Table 9 (percentage change from baseline). The m-pasi scoress for the trunk, limbs and scalp at week indicated improvements from baselinee in all threee treatment groups. At week, LEO 9 achieved a statistically signifi- cantly lower m-pasi score than the two comparators (mean difference -.8; 9 CI -.9 to -.; p<. and mean difference -.; 9 CI -.88 to -.; p<. for the comparison with BDP and calcipotriol respectively). At week, LEO 9 achieved a statistically significantly lower m-pasi score than calcipotriol (mean difference -.9; 9 CI -. to -.7; p=..) but the comparison to BDP was not statistically significant (mean difference -.9; 9 CI -. to.8; p= =.9).

110 LEO Apr- Page of 89 Table : Analysiss of m-pasi of the trunk, limbs and scalp at Week (LOCF): full analysis set m-pasi LEO 9 (n=) Betamethasone (n=) (n=) Mean SD Median Minimumm Maximumm Number Statistical analysis Difference 9 CI P-value to -. < to -. <. JAN::7: LEO9 7 tpastls. doc ) LEO 9 minus treatment group in column heading. ) Adjusted for the effect of pooled centre and baselinee m-pasi by analysis of covariance. Table : Analysiss of m-pasi of the trunk, limbs and scalp at Week (LOCF): full analysis set m-pasi LEO 9 (n=) Betamethasone (n=) (n=) Mean SD Median Minimumm Maximumm Number Statistical analysis Difference 9 CI P-value to to -.7. JAN::: LEO9 7 tpastls. doc ) LEO 9 minus treatment group in column heading. ) Adjusted for the effect of pooled centre and baselinee m-pasi by analysis of covariance.

111 LEO Apr- Page of 89 The percentage of with a 7 reduction in the baselinee m-pasi of the trunk, limbs and scalp at week (LOCF) is summarised in Table. The summary of PASI 7 of the trunk, limbs and scalp at each visit is given in EoT Table 9. The corresponding numbers for PASI of the trunk, limbs and scalp are given in Table and EoT Table 9. The percentage of that achieved at least a 7 improvement from their baseline PASI of the trunk, limbs and scalp at week (LOCF) was higher in the LEO 9 group (.) than in the BDP (.7) and the calcipotriol groups (.8). LEO 9 was superior to both calcipotriol (OR.9; 9 CI. to.7; p= =<.) and BDP (OR.88; 9 CI. to.; p=.) with regard to PASI 7 of the trunk, limbs and scalp at week. As for PASI 7, also the PASI response rate for the trunk and limbs and scalp at week (LOCF) was higher in the LEO 9 (8.) than in the BDP (9.) and calcipotriol groups (.). The comparisons of LEO 9 to BDP and calcipotriol were both highly significant (OR.; 9 CI.77 to.9; p<. and OR.; 9 CI. to.7; p<. for the comparison with BDP and calcipotriol respectively). Table : Analysiss of PASI 7 of the trunk, limbs and scalp at Week (LOCF): full analysis set Reduction of PASI of Trunk/Limbs and Scalp LEO 9 (n=) Betamethasonee (n=) (n=) <7 PASI reduction >=7 PASI reduction Statistical analysis Odds ratio 9 CI CMH test p-value.88. to...9. to. 7 <. JAN::: LEO9 7 tptls7. doc ) Odds of having PASI 7 in LEO 9 group relative to treatmentt given in column heading. ) Treatment comparison by Cochran-Mantel-Haenszel test adjusted for pooled centre.

112 LEO Apr- Page of 89 Table : Analysiss of PASI of the trunk, limbs and scalp at Week (LOCF): full analysis set Reduction of PASI of Trunk/Limbs and Scalp LEO 9 (n=) Betamethasonee (n=) (n=) < PASI reduction >= PASI reduction Statistical analysis Odds ratio 9 CI CMH test p-value..77 to.9 <... to. 7 <. JAN::: LEO9 7 tptls. doc ) Odds of having PASI in LEO 9 group relative to treatmentt given in column heading. ) Treatment comparison by Cochran-Mantel-Haenszel test adjusted for pooled centre... Patient reported outcomes The patient reported outcomes in this trial included patient global assessment of psoriasis, assessment of itch and assessment of health related quality of life by the use of DLQI. All three were collected at baseline and weeks, and..... Patients assessment of disease severity The percentage of with controlled disease according to Patient s global assessment of disease severity at week (LOCF) is given in Table 7. The definition of controlled disease was clear or very mild disease. The percentage of in each category at weeks,, and is summarised for the full analysis set in EoT Table 9. Results for Patient s global assessment of disease severity were in line with results of investigators assessments. At week, statistically significantly greater proportion,. of s who received LEO 9 assessed their disease as controlled, as compared with

113 LEO Apr- Page of 89. in the BDP group (OR., 9 CI. to.97; p=.) and 9.7 in the cal- cipotriol group (OR.7, 9 CI. to.9; p<.). Table 7: Analysiss of 'Controlled disease' (Patient s Global Assessment) at Week (LOCF): full analysis set LEO 9 (n=) Betamethasonee (n=) (n=) Controlled Diseasee Controlled Non-controlled Statistical analysis Odds ratio 9 CI CMH test p-value.. to to.9 <. 8FEB::: LEO9 7 tpga.doc ) Odds of having controlled diseasee in LEO 9 group treatment given in column heading. ) Treatment comparison by Cochran-Mantel-Haenszel test pooled centre. relative to adjusted for.... Subject s assessment of itch The change in itching as assessed by the Visual Analogue Scale from baseline to each subsequent visit is summarised in Table 8. Using a VAS score ranging from to, the intensity of itch was assessed at all treatment visits. At baseline, mean scores weree largely similar across all the groups. At week, the intensity of pruritus at week was reducedd by. (from 7 at baseline) following LEO 9 treatment, whereas the mean pruritus score dropped by.8 following BDP and by. after calcipotriol treatment. Only the comparison to calcipotriol was statistically significant (mean difference -.8; 9 CI -. to -9.; p<.). Statistically significantly greater improvement in s receiving LEO 9 versus calcipotriol was observed as early as week. For comparison with BDP, a slight numerical difference in favour of BDP was seen at weeks, and, but the comparisons were not statistically significant at any time point.

114 LEO Apr- Page of 89 Table 8: Analysiss of change in itching (Visual Analogue Scale) from baseline to each visit: full analysis set Visit Change in itching LEO 9 (n=) Betamethasone (n=) (n=) Baseline Mean SD Median Minimum Maximum Number Week Mean SD Median Minimum Maximum Number Difference 9 CI P-value to to -..7 Week Mean SD Median Minimum Maximum Number Difference 9 CI P-value to to -8. <. JAN::: LEO9 7 titch.doc Continued...

115 LEO Apr- Page of 89 Table 8: Analysiss of change in itching (Visual Analogue Scale) from baseline to each visit: full analysis set (Continued ) Visit Change in itching LEO 9 (n=) Betamethasone (n=) (n=) Week Mean SD Median Minimum Maximum Number Difference 9 CI P-value to to -9. <. JAN::: LEO9 7 titch.doc ) LEO 9 minus treatment group in column heading. ) Adjusted for the effect of pooled centre and baselinee itching score by analysis of covariance..... Health related quality of life A DLQI total score is the sum of the equal-weighted items and ranges from to, with higher scores indicating poorer quality of life. The DLQI score at baseline and weeks, and (as a change from baseline) are summarized in Table 9. At week, LEO 9 produced statistically significantly greater improvement from baseline than calcipotriol (mean difference -.; 9 CI -.8 to.; p<.), however, there was no statistically significant difference in the total DLQI scores between LEO 9 and BDP. Significant improvements over calcipotriol in the total DLQI score were observed in the LEO 9 group as early as week and persisted through the study period. There was no evidence of a difference between LEO 9 and BDP at any time point.

116 LEO Apr- Page of 89 Table 9: Analysiss of change in DLQI from baseline to each visit: full analysis set Visit Change in DLQI LEO 9 (n=) Betamethasone (n=) (n=) Baseline Mean SD Median Minimum Maximum Number Week Mean SD Median Minimum Maximum Number Difference 9 CI P-value. -. to to -. <. Week Mean SD Median Minimum Maximum Number Difference 9 CI P-value.8 -. to to -.7 <. JAN::: LEO9 7 tdlqi.doc Continued...

117 LEO Apr- Page 7 of 89 Table 9: Analysiss of change in DLQI from baseline to each visit: full analysis set (Continued ) Visit Change in DLQI LEO 9 (n=) Betamethasone (n=) (n=) Week Mean SD Median Minimum Maximum Number Difference 9 CI P-value to to -. <. JAN::: LEO9 7 tdlqi.doc ) LEO 9 minus treatment group in column heading. ) Adjusted for the effect of pooled centre and baselinee DLQI score by analysis of covariance... Statistical/Analytical Issuess The analyses were conducted according to the protocol and the Section 9.7. and further changes as described in Section Adjustments for Covariates In ANCOVA models of m-pasi at Week (LOCF) and of m-pasi at Week (LOCF), baselinee m-pasi was added to the model as a baseline adjustment for covariate. Similarly for the ANCOVA models of the change in itch from baseline to Week, from baseline to Week, and from baseline to Week and for the ANCOVA models of the change in DLQI from baselinee to Week, from baseline to Week, and from baseline to Week, the baseline itch score and the baseline DLQI, respectively, was addedd to the model as a baseline adjustment for covariate..... Handling of Dropouts or Missing Data SAPU as summarised in For IGA, m-pasi and patient s global assessment of disease severity, the statistical analysis was carried out using LOCF. This means that, for example, an IGA-value missing at Week

118 LEO Apr- Page 8 of 89 was imputed by the last non-missing IGA value priorr to Week. The same approach was used for analyses of response criteria at Week. For laboratory safety data and vital signs data the tabulations of Week data were presented using LOCF, defined as the last value recorded for a parameter after baseline..... Interim Analyses and Data Monitoring No interim analysiss was planned nor performed..... Multi-Site Clinical Trials In the protocol, it was stated that if a centre randomised fewer than 8 it would be pooled with the next smallest centre to form a pooled centre of 8 or more randomisedd. To facilitate aggregation of results from the LEO 9-7 and LEO 9- trials, it was decided to pool centres common to both trials based on geographical location as described in the SAPU..... Multiple Comparison/Multiplicity The LEO 9 treatment group was compared with calcipotriol and with BDP, i.e. there were two treatmentt comparisons considered. For the primary response criterion, the efficacy of LEO 9 was not based on detecting a significant treatment effect for any one of the two comparisons considered rather the two comparisons had to show a statistically significant effect at the level in favour of LEO 9. Therefore no adjustment of significance levels to account for multiple testing was deemed necessary. There was only one secondary response criterion therefore multiplicity was not a concern for the same reasons as described for the primary response criterion. The analyses of the further response criteria were exploratory and results are presented with 9 confidence intervals for display purposes only..... Use of an Efficacy Subset of Subjects Not applicable Active-Control Studies Intended to Show Equivalence Not applicable.

119 LEO Apr- Page 9 of Examination of Subgroups No subgroup analyses were planned nor performed, but summaries are available by centre and IGA of the trunk and limbs at baseline for the primary response criterion... Tabulation of Individual Response Data Not applicable...7 Drug Dose, Drug Concentration, and Relationships to Responsee Not applicable...8 Drug-Drug and Drug-Disease Interactions Not applicable..9 By-Subject Displays Not applicable. Individual subject data are presented in listings in Appendices..7 and.. to Efficacy Conclusions Efficacy in psoriasis on the trunk and limbs The proportion of controlled disease on the trunk and limbs at week (LOCF) (primary endpoint) was. in the LEO 9 group,.7 in the BDP group and.9 in the calcipotriol group. LEO 9 aerosol foam was superior to both BDP in the aerosol foam vehicle (OR.8; 9 CI:. to.; p=.7) and calcipotriol in the aerosol foam vehicle (OR.; 9 CI:. to 8.7; p<.). The results of the per protocol sensitiv- ity analysis supported the results of analysis using the full analysis set. The proportion of controlled disease on the trunk and limbs at week (secondary endpoint) was overall low; in the LEO 9 group, in the BDP and in the calcipotriol group, and none of the comparisons were statistically significant. The results for m-pasi of the trunk and limbs at week supported the results for the primary endpoint. The mean m-pasi at week was statistically significantly lower in the LEO 9 group compared to BDP (p<.) and compared to calcipotriol (p<.). The percentagee of s with PASI 7 at week and with PASI at week was

120 LEO Apr- Page of 89 higher in the LEO 9 group compared to BDP and calcipotriol (9.,.7, 7.8 respectively for PASI 7 and 8., 9.,. respectively for PASI ). With regard to m-pasi at week, LEO 9 was statistically significantly more effec- (p=.). tive than calcipotriol (p=.) but the comparison to BDP was not statistically significant Efficacy in scalp psoriasis At week, the proportion of who achieved controlled disease (IGA) on the scalp was. in the LEO 9 group, 7. in the BDP group and. in the calcipotriol group. LEO 9 was superior to calcipotriol (OR.9, 9 CI.9 to.; p=.) but the comparison to BDP was not statistically significant (OR.; 9 CI.7 to.; p=.). Results for m-pasi at week were in line with the results for the IGA. LEO 9 was statistically significantly more effective than calcipotriol (p< <.) with regard to m-pasi at week but the comparison to BDP was not statistically significant (p=.8). The pro- portion of with PASI 7 at week and with PASI at week was higher in the LEO 9 group compared to BDP and calcipotriol (7.,. and. for PASI 7 and 89., 79. and. for PASI, respectively). At week, the proportion of controlled disease (IGA) on the scalp was. in the LEO 9 group,.9 in the betamethasone group and 7.9 in the calcipotrioll group. LEO 9 was superior to both BDP (OR.8; 9 CI.8 to.; p=.) and cal-, cipotriol (OR.; 9 CI.9 to.9; p<.). With regard to m-pasi at week LEO 9 was statistically significantly more effective than calcipotriol (p=.7) but the comparison to BDP was not statistically significant (p=.8). Overalll assessment of psoriasis on the trunk, limbs and scalp Results for the overall assessment of psoriasis on the trunk, limbs and scalp (IGA) generally mirrored the results for the trunk and limbs. At week, the proportion of with controlled disease on the trunk and limbs and scalp was. in the LEO 9 group compared to.7 in the BDP group and.9 in the calcipotriol group. LEO 9 was statistically significantly more effective than calcipotriol (OR., 9 CI. to 8.; p<.) but not BDP (OR.7; 9 CI. 9 to., p=.).

121 LEO Apr- Page of 89 LEO 9 was statistically significantly more effective than BDP and calcipotriol with regard to m-pasi score at week (both p<.) ). The proportion of with PASI 7 at week and with PASI at week was higher in the LEO 9 group compared to BDP and calcipotriol (.,.7 and.8 for PASI 7 and 8., 9. and. for PASI ). At week, the proportion of with controlled disease on the trunk and limbs and scalp was overall low (8 in the LEO 9 group, in the BDP group and in the calcipotriol group), and none of the comparisons were statistically significant. With regard to m-pasi at week, LEO 9 was statistically significantly more effective than calcipotriol (p=.) but the comparison to BDP was not statistically significant (p= =.9). Patient reported outcomes The proportion of controlled disease according to Patients global assessment of disease severity at week (LOCF) was. in the LEO 9 group,. in the BDP group and 9.7 in the calcipotriol group. LEO 9 aerosol foam was more effective than BDP (OR.; 9 CI:. to.97; p=.) and calcipotriol (OR. 7; 9 CI:. to.9; p<.). LEO 9 was statistically significantly more effective in relieving itching than cal- cipotriol at all post baseline visits, and had similar efficacy to BDP. LEO 9 was statistically significantly more effective in improving health related quality of life as assessed using the DLQI than calcipotriol at all post baseline visits (p<. at each visit), and had similar efficacy to BDP.

122 LEO Apr- Page of 89 Safety Evaluation The evaluation of safety was based on the safety analysis set.. Extent of Exposure The duration and extent of exposure to treatment are summarised in Table for the safety analysiss set. The average amount of study medication used per week during the study is shown in Table. The total amount of study medication used by each subject per week versus body area treated (in terms of BSA at baseline) is illustrated in Figure. The mean duration of treatment and the overall extent of exposure were similar for all treatment groups. The mean amount of study medication used per week over the total treatment period was slightly lower in the LEO 9 group (.9 g) compared with the BDP and calcipotriol groups (.8 g and. g, respectively). As can be seen from Figure there appears to be no clear pattern in the relationship between individual BSA at baseline and the averagee weekly amount of medication used. Table : Duration and extent of exposure to treatment: safety analysiss set Duration and extent of treatment exposure (weeks) LEO 9 (n=) Betamethasone ( n=99) Mean SD Median Minimumm Maximumm Number Extent of exposure to treat- ment(subject-treatment-weeks) 8 9 FEB::8: LEO9 7 textdur.doc

123 LEO Apr- Page of 89 Table : Averagee weekly amount of study medication used between visits: safety analysis set Study medication used (g per week) LEO 9 (n=) Betamethaso one dipropionat te Visit to Visit ( Mean SD Median Minimum Maximum Number week) Visit to Visit ( Mean SD Median Minimum Maximum Number week) Visit to Visit ( Mean SD Median Minimum Maximum Number weeks) Visit to End of Treatment (total treatment period) Mean SD Median Minimum Maximum Number JAN::: LEO9 7 tavgmed.doc ) Calculated by subtracting the weight of the used cans from the mean normal weight of full cans multiplied by a correction factor to subtract propellant gases. ) Only s who returned dispensed cans provide data. The total amount of study medication used between visits can be found in EoT Table 9. BSA involvement of psoriasis vulgaris affecting the trunk, limbs and scalp at each visit is shown for safety analysis set in EoT Table. For individual subject data on trial medication used see Appendix... Listing.

124 LEO Apr- Page of 89 Figure : Baseline BSA involvement of psoriasis vulgaris affecting the trunk, limbs and scalp versus average weekly amount of study medication used: safety analysis set LEO 9 9 :Q' QJ QJ QJ.... ::J "'. I.....::-.. -"... QJ.. QJ. s. I Q). I. en ~. I QJ I.. ~.. I ~ BSA of trunk, limbs and scalp at baseline Betamethaso"'e 9. 9C :Q'. :Q'. QJ 8. QJ 8C... t I ~. 7.. ~ 7C.. ~.. ~... QJ.. QJ C... "' "'. ::J... ::J...::-. >- C " J C. Q) l. Q) QJ. QJ I.. s. ] s C... QJ..... QJ. en. en I I. C ~. i.. ~ :.:... QJ QJ l... I C.. ~... I ~. c 'I BSA of trunk, limbs and scalp at baseline BSA of trunk, limbs and scalp at!baseline

125 LEO Apr- Page of 89. Adverse events (AEs) This section gives an overview of all treatment emergent AEs (i.e., those that started after the first application of the trial medication, or started before this and worsened in intensity after). It summarises the overall frequency of AEs by treatment group. The summary is done on the preferred term level, which means that multiple occurrences of AEs on a particular preferred term level in the same subject count as one occurrence. For a given preferred term, severity is taken as the worst severity experienced and relationship is taken from the last available assessment... Brief Summary of Adversee Events An overall summary of the AEs in this study is presented in Table. The overall incidence of AEs was low and similar in the three treatment groups, with (.) in the LEO 9 group, (.) in the BDP group and (.) in the calcipotriol group. Adversee drug reactions (AEs for which the causal relationship to the drug cannot be ruled out) were reported for (.) in the LEO 9, 7 (7.) in the BDP group and (.) in the calcipotriol group. One subject in the LEO 9 group experienced a severe and serious AE (hypersensitivity) that led to withdrawal from the trial. AEs led to withdrawal of one additional subject in the LEO 9 group, and in the calcipotriol group. Table : Overall summary of adverse events: safety analysis set LEO 9 (n= =) Betamethasone dipropi- onate Adversee event category Number of adverse events Number of Number of adverse events Number of Number of adverse events Number of All adverse events Severee adverse events Adverse drug reactions Serious adverse events Events leading to Withdrawal FEB::: LEO9 7 taesum.doc

126 LEO Apr- Page of 89.. Display of Adverse Events.... Adverse events by system organ class and preferred term All adverse events are presented by MedDRA system organ class (SOC) and preferred term in Table, and by MedDRA system organ class only in EoT Table 9. There were few AEs overall, and no notable differences between treatments. No AE (preferred term) was reported by more than one subject in the LEO 9 group. AEs were most commonly reported in the General disorders and administrationn site conditions SOC and Infections and infestations SOC. The AEs reported by more than one subject across all treatment groups were medication residue (verbatim text: greasy/ /oily hair) ( ; in the BDP group and in the cal- cipotriol group), application site pain ( ; one in each treatment group), hypersensitiv- ity ( ; one in LEO 9 and one in the calcipotriol group), nasopharyngitis ( ; one in the BDP group and one in the calcipotriol group), contusion ( ; one in the LEO 9 group and one in the BDP group), vitamin D decreased ( ; one in the LEO 9 group and one in the BDP group) and bronchitis ( ; both in the BDP group). Medication site residue (verbatim text: greasy/oily hair) was reported only in the comparator groups. However, it should be noted thatt not all complaints about greasy hair were reported as AEs. Additional comments on greasy hair/medicat tion difficult to removee from the hair were made in the comment-field in the CRF (Appendix.., Listing.).

127 LEO Apr- Page 7 of 89 Table : Adversee events by MedDRA primary system organ class and preferred term: safety analysis set System Organ Class Preferred Term LEO 9 (n= ) Betamethasone Ear and labyrinth disorders Ear pain Eye disorders Vision blurred.. Gastrointestinal disorderss Buccal mucosal roughening Diarrhoea Nauseaa... General disorders and administration site conditions Application site erosion Application site erythema Application site oedema Application site pain Fatigue Medication residue Immune system disorders Hypersensitivity. Infections and infestations Bronchitis Herpes zoster Nasopharyngitis Pharyngitis streptococcal Staphylococcal infection Tinea infection Injury, poisoning and procedural complications Contusion Sunburn Investigations Urine calcium/creatinine ratio increased Vitamin D decreased.... Neoplasms benign, malignant and unspecified (incl cysts and polyps) Melanocytic naevus. Nervous system disorders Headache Sciatica MAR::7:7 LEO9 7 taept.doc Continued...

128 LEO Apr- Page 8 of 89 Table : Adversee events by MedDRA primary system organ class and preferred term: safety analysis set (Continued ) System Organ Class Preferred Term LEO 9 (n= ) Betamethasone Psychiatric disorders Anxiety. Renal and urinary disorders Nephrolithiasis. Reproductive system and breast disorders Breast mass Menstruation irregular.. Respiratory, thoracic and mediastinal disorders Dry throat Sinus congestionn.. Skin and subcutaneous tissue disorders Alopecia Alopecia effluvium Dermatitis contact Pruritus Vascular disorders Hypertension number of adverse events 9 number of... MAR::7:7 LEO9 7 taept.doc ) Classification according to MedDRA version.. ) 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..... Adverse events by severity All AEs were to be assessed for intensity (mild, moderate, severe). The summary of AEs by MedDRA primary SOC and preferred term with information on maximum intensity is given in EoT Table 9. Of the 7 AEs reported in the trial, the majority (7 events) were of mild intensity. There was only one case of a severe AE in the trial; this was hypersensitivity reported as an SAE in a

129 LEO Apr- Page 9 of 89 subject receiving LEO 9. This event is describedd in more detail in Section.... All other AEs reported in the LEO 9 group were of mild intensity..... Adverse drug reactions All AEs were to be assessed for causal relationship to the investigational product, as judged by the investigator. Adverse drug reactions (defined as AEs for which the investigator had not described the causal relationship to trial medication as not related ) are presented by Med- DRA primary system organ class and preferred term in Table. Information on their maximum intensity is provided in Table. The overall incidence of ADRs was. in the LEO 9 group, 7. in the BDP and. in the calcipotriol group. In the LEO 9 group, no individual ADR was reported by more than one subject. The ADRs reported in the LEO 9 group weree application site pain, hypersensitivity, alopecia and buccal mucosal roughening g. Application site pain was reported also by one subject in each comparator group and hypersensitivity by one subject in the calcipotriol group.

130 LEO Apr- Page of 89 LEO 9 (n= ) Betamethasone Table : Adversee drug reactions by MedDRA primary system organ class and pre- ferred term: safety analysis set System Organ Class Preferred Term Gastrointestinal disorderss Buccal mucosal roughening Diarrhoea General disorders and administration site conditions Application site erosion Application site erythema Application site oedema Application site pain Medication residue Immune system disorders Hypersensitivity... Infections and infestations Staphylococcal infection Tinea infection Investigations Urine calcium/creatinine ratio increased... Skin and subcutaneous tissue disorders Alopecia Alopecia effluvium Dermatitis contact Pruritus number of drug reactions 8 number of Statistical analysis Odds ratio 9 CI p-value.. to to.. MAR::9: LEO9 7 tadr.doc ) Classification according to MedDRA version.. ) 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. ) Odds of experiencing an ADR in LEO 9 group relative to treatment given in column heading. ) Treatment comparison by Chi-squared test.

131 LEO Apr- Page of 89 Table : Intensity of adverse drug reactions by MedDRA primary system organ class and preferred term: safety analysis set System Organ Class Preferred Term LEO 9 (n=) Mode rate Severe Betamethasone dipropionat te Mode rate Severe Mode rate Severe Gastrointestinal Buccal mucosal roughening Diarrhoea disorderss General disorders and administration site conditions Application site erosion Application site erythema Application site oedema Application site pain Medication residue Immune system disorders Hypersensitivity Infections and Staphylococcal infection Tinea infection Investigations Urine infestations calcium/creatinii - ne ratio increased Skin and subcutaneous tissue disorders Alopecia Alopecia effluvium Dermatitis contact Pruritus number of adverse events 7 MAR::: LEO9 7 tadrint.doc ) Classification according to MedDRA version.. ) 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.

132 LEO Apr- Page of 89.. Analysis of Adverse Events Statistical comparison of the incidence of ADRs in each treatment group showed no differ- Events.. Listing of Deaths, Other Serious Adverse Events and Other Signifi- cant Adverse Events.... Deaths No AEs with fatal outcome were reported in this study..... Other Serious Adverse Events There was one report of an SAE in this study; a case of hypersensitivity in a subject in the ence between LEO 9 and the two other treatment groups... Listing of Adversee Events by Subject All AE data are listed in Appendix..7.. Deaths, Other Serious Adverse Events and Other Significant Adverse LEO 9 group. This event is described in Section Other Significant Adverse Events In total in the LEO 9 group (subject with SAE described above included) and in the calcipotriol group were withdrawn from the trial as a result of an AE. The key information regarding the AEs leading to withdrawal is listed in Table below. The narratives of these events are given in Section... There were no other significant adverse events identified in this study.

133 LEO Apr- Page of89 Table : Adverse events leading to withdrawal of from the trial Unique subject Sex/ Age/ I nvestigat or term/ St art day, Centre identifier Rac e Preferred term duration SAE, Severity Relat ionship Outcome _ ALLERGI _. GREASY _ I LEO 9 _ MENSTRUAL ~al c ipotriol - Menstruation C REACTI ON/, l asted Yes, SEVERE POSSIBLY RECOVERED/RESOLVED Hypersensiti vity f or days RELATED S POTTI NG FOR DAYS/ 7, l asted No, MILD NOT RELATED RECOVERED/RESOLVED irregul ar f or days HAI R/, l asted No, MILD PROBABLY RECOVERED/RESOLVED Medicati on residue f or 8 days RELATED RRITANT DERMATITIS/, l asted No, MODERATE PROBABLY RECOVERED/RESOLVED Dermati tis contact for days RELATED 9MAR::9: LE 9 7 t a.edi sc.doc ) Classi fication according to MedORA version..

134 LEO Apr- Page of 89 - Narratives of Deaths, Other Serious Adverse Events and Other Significant Adverse Events Narratives of serious adverse events CRF number: -- SAE: Hypersensitivity Treatment: LEO 9 Alii II II was emolled into the study and started treatment with LEO 9 on ~--The subject had no relevant medical histy aprui from psoriasis since. and was not receiving any concomitant medication at en:iy to the study. On Ill-the subject experienced mi icaria and took aspirin mg. The following moming, on ~-- the subject woke up with swollen lips and eyelids llattended the emergency room (ER) and was u eated for an allergic reaction due to mild shiness of breath, mild u ouble swallowing, and slight swelling of tongue with inu avenous methylprednisolone mg, diphenhydramine mg, ranitidine mg and famotidine mg. The subject was dischru ged fi:om the ER within hours of being u iaged. The subj ect received last study u eatment onl-. and discontinued the study due to this event. The AE was resolved onl-- The investigator considered the event to be of severe intensity and possibly related to the study medication. The event was assessed as possibly related by LEO Phanna. Narratives of adverse events leading to discontinuation CRF number: -- Treatment: LEO 9 AE leading to discontinuation: Menstruation irregular Alii II-was emolled into the study and struied u eatment with LEO 9 on I-ll-The subject had no relevant medical histy and was not receiving any concomiant medication at en:iy to the study. Onl-. (day 7 ofu eatment), the subject experienced mens:iual spotting. The event was considered to be of mild intensity and resolved the day after, onijiii- The subject applied last study u eatment onijiii. and discontinued the study due to this event. The investigator considered the event to be not related to the study medication. CRF number: -- Treatment: Calcipou iol AE leading to discontinuation: Dermatitis contact Alii II-was emolled into the study and struied u eatment with calcipou iol on ~-- The subject had no relevant medical histy and was not receiving any concomitant medication at en:iy to the study. Onl-. (day ofu ea:inent), the subject

135 LEO Apr- Page of89 experienced initant dermatitis. The event was considered to be of moderate intensity, probably related to study medication and lasted for days. The subject applied last study treatment on and discontinued the study due to this event. On ( days after withdrawal), the subject experienced Generalized allergic eruption of moderate intensity which lasted for days. The investigator considered the event to be probably related to the study medication. CRF number: -- Treatment: AE leading to discontinuation: Medication residue Alii II-was enrolled into the study and started treatment with calcipotriol on ~-- The subject had no relevant medical history and was not receiving any concomitant medication at entry to the study. Onl-. (day of tr eatment), the subject experienced greasy hair. The event was considered to be of mild intensity and probably related to tr eatment by the investigator. At the next visit to the clinics, a week later, on II the event was reporied resolved. The subject applied last study tr eatment on II and discontinued the study due to this event. Analysis and Discussion of Deaths, Other Serious Adverse Events and Other Significant Adverse Events There were no deaths during the study. One SAE of hypersensitivity was reported in the LEO 9 group, which was considered possibly related to study tr eatment and led to discontinuation oftr eatment with investigational product. Hypersensitivity reactions to calcipotr iol and calcipotr iol/bdp combination products have been described previously. In addition to the case of SAE, AEs led to the discontinuation of one additional subject in the LEO 9 group and in the calcipotr iol group. Overall, these events do not indicate any new safety concems. - Clinical Laboratory Evaluation -- Listing of Individual Laboratory Measurements by Subject (--8) For individual subject data on laboratory parameters see Appendix..8.