Main Clinical Study Report

Transcription

1 Main Clinical Study Report The pharmacokinetics of LEO (calcipotriol hydrate plus betamethasone dipropionate) in Japanese subjects with extensive psoriasis vulgaris A study investigating the pharmacokinetic profile of LEO (calcipotriol hydrate 52.2 mcg/g [equivalent to 50 mcg/g calcipotriol] plus betamethasone dipropionate mg/g [equivalent to 0.5 mg/g betamethasone]) applied once daily in subjects with extensive psoriasis vulgaris on the body (trunk and/or limbs) A national, multi-centre, prospective, non-controlled, open, single-group, 4-week clinical study in subjects with extensive psoriasis vulgaris LEO Pharmaceutical Products Ltd. A/S MCB 0904 (LEO Pharma A/S) 23-Apr-2013 Clinical Development

2 MCB Apr-2013 Page 2 of REPORT STATEMENTS APPROVAL STATEMENT On behalf of LEO Pharma A/S (hereafter referred to as LEO), only the Head of Medical Department and the Head of Biostatistics and Data Management, LEO Head Quarters (HQ) are authorised to approve the main Clinical Study Report. All LEO approvers will be identified on a signature page automatically generated as the last page of the pdf-file of the final main Clinical Study Report, when the last LEO approval is obtained. The time and date of their e-signatures are likewise presented on the approval page. The following persons have approved this main Clinical Study Report (including appendices) by use of electronic signatures: Head of Biostatistics and Data Management, LEO HQ Head of Medical Department APPROVAL STATEMENT, INVESTIGATORS The Japanese Medical Expert approves the main Clinical Study Report (including appendices) by manually signing the Clinical Study Report Approval Form, which is a separate document adjoined to this report. The following person has approved this main Clinical Study Report (including appendices):, MD Japanese Medical Expert

3 MCB Apr-2013 Page 3 of 218 COMPLIANCE WITH GOOD CLINICAL PRACTICE (GCP) This Clinical Study Report is designed to comply with the standards issued by the International Conference on Harmonisation (ICH) (E3 Structure and Content of Clinical Study Reports; E6 GCP; E9 Statistical Principles for Clinical Trials and M4 Common Technical Document) and the Ministry of Health and Welfare (MHW) Ordinance on GCP (MHW Ordinance No. 28 dated 27-Mar-1997, J-GCP). TRADEMARKS DAIVOBET/DOVOBET/TACLONEX and DAIVONEX/DOVONEX are trademarks owned by LEO (or its subsidiaries). DISCLOSURE OF CLINICAL TRIAL RESULTS Results from this clinical trial will be posted on which is a publicly accessible database. 2 SYNOPSIS The synopsis of this Clinical Study Report exists as a separately approved document.

4 MCB Apr-2013 Page 4 of TABLE OF CONTENTS 1 REPORT STATEMENTS SYNOPSIS TABLE OF CONTENTS... 4 LIST OF IN-TEXT TABLES... 8 LIST OF IN-TEXT FIGURES LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ETHICS INDEPENDENT ETHICS COMMITTEE OR INSTITUTIONAL REVIEW BOARD ETHICAL CONDUCT OF THE TRIAL SUBJECT INFORMATION AND INFORMED CONSENT INVESTIGATORS AND TRIAL ADMINISTRATIVE STRUCTURE INTRODUCTION PSORIASIS VULGARIS INVESTIGATIONAL PRODUCT DESCRIPTION TRIAL RATIONALE TRIAL OBJECTIVES PRIMARY OBJECTIVE SECONDARY OBJECTIVES INVESTIGATIONAL PLAN OVERALL TRIAL DESIGN AND PLAN - DESCRIPTION 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 Randomisation code list Subject identification list Selection of Doses in the Trial... 36

5 MCB Apr-2013 Page 5 of Selection and Timing of Dose for Each Subject Blinding Prior and Concomitant Therapy Treatment Compliance PHARMACOKINETICS, EFFICACY AND SAFETY VARIABLES Pharmacokinetics, Efficacy and Safety Measurements Assessed and Flow Chart Flow chart Subject eligibility Clinical assessment Laboratory assessments Adverse events Serious adverse events Appropriateness of Measurements Primary Pharmacokinetic Variable(s) Drug Concentration Measurements DATA QUALITY ASSURANCE STATISTICAL METHODS PLANNED IN THE PROTOCOL AND DETERMINATION OF SAMPLE SIZE Statistical and Analytical Plans Subject qualification for analysis Baseline characteristics Analysis of pharmacokinetics and efficacy Analysis of safety General principles Determination of Sample Size CHANGES IN THE CONDUCT OF THE TRIAL OR PLANNED ANALYSES TRIAL POPULATION DISPOSITION OF SUBJECTS PROTOCOL DEVIATIONS PHARMACOKINETICS AND EFFICACY EVALUATION DATA SETS ANALYSED DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS MEASUREMENT OF TREATMENT COMPLIANCE PHARMACOKINETICS AND EFFICACY RESULTS AND TABULATION OF INDIVIDUAL SUBJECT DATA Analysis of Pharmacokinetics and Efficacy... 67

6 MCB Apr-2013 Page 6 of Pharmacokinetics (Primary endpoint) Efficacy (Secondary endpoints) 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-Drug and Drug-Disease Interactions By-Subject Displays Pharmacokinetics and Efficacy Conclusions SAFETY EVALUATION EXTENT OF EXPOSURE ADVERSE EVENTS Brief Summary of Adverse Events Display of Adverse Events 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 Adverse Events and Other Significant Adverse Events Analysis and Discussion of Deaths, other Serious Adverse Events and Other Significant Adverse Events CLINICAL LABORATORY EVALUATION Listing of Individual Laboratory Measurements by Subject (16.2.8)... 87

7 MCB Apr-2013 Page 7 of Evaluation of Each Laboratory Parameter VITAL SIGNS, PHYSICAL FINDINGS AND OTHER OBSERVATIONS RELATED TO SAFETY SAFETY CONCLUSIONS DISCUSSION AND OVERALL CONCLUSIONS TABLES, FIGURES AND GRAPHS REFERRED TO BUT NOT INCLUDED IN THE TEXT DEMOGRAPHIC DATA PHARMACOKINETICS AND EFFICACY DATA SAFETY DATA REFERENCES LIST OF APPENDICES

8 MCB Apr-2013 Page 8 of 218 LIST OF IN-TEXT TABLES Table 1: Identity of IP Table 2: PK parameters Table 3: Study period by centre: enrolled subjects Table 4: Reasons for withdrawal by last visit attended: enrolled subjects Table 5: Subject demographics: safety analysis set Table 6: Percentage change in m-pasi from baseline to Visit 4 (LOCF): PK analysis set Table 7: Subjects with 'clear' or 'almost clear' disease by investigator's global assessment at Visit 4 (LOCF): PK analysis set Table 8: Average amount of study medication used per week: safety analysis set Table 9: AEs by MedDRA primary SOC: safety analysis set Table 10: AEs by MedDRA primary SOC and preferred term: safety analysis set Table 11: Change in haemoglobin from baseline Visit 1 to Visit 2 and Visit 3 (LOCF): safety analysis set Table 12: Change in haematocrit from baseline Visit 1 to Visit 2 and Visit 3 (LOCF): safety analysis set Table 13: Change in platelets from baseline Visit 1 to Visit 2 and Visit 3 (LOCF): safety analysis set Table 14: Change in RBC count from baseline Visit 1 to Visit 2 and Visit 3 (LOCF): safety analysis set Table 15: Change in WBC count from baseline to Week 4 (LOCF): safety analysis set Table 16: Change in serum calcium from baseline Visit 1 to Visit 2 and Visit 3 (LOCF): safety analysis set Table 17: Change in albumin-corrected serum calcium from baseline Visit 1 to Visit 2 and Visit 3 (LOCF): safety analysis set Table 18: Change in serum phosphate from baseline Visit 1 to Visit 2 and Visit 3 (LOCF): safety analysis set Table 19: Change in serum BUN from baseline Visit 1 to Visit 2 and Visit 3 (LOCF): safety analysis set Table 20: Change in serum creatinine from baseline Visit 1 to Visit 2 and Visit 3 (LOCF): safety analysis set Table 21: Change in serum total bilirubin from baseline Visit 1 to Visit 2 and Visit 3 (LOCF): safety analysis set Table 22: Change in serum total protein from baseline Visit 1 to Visit 2 and Visit 3 (LOCF): safety analysis set... 99

9 MCB Apr-2013 Page 9 of 218 Table 23: Change in serum albumin from baseline Visit 1 to Visit 2 and Visit 3 (LOCF): safety analysis set Table 24: Change in SGOT (AST) from baseline Visit 1 to Visit 2 and Visit 3 (LOCF): safety analysis set Table 25: Change in SGPT (ALT) from baseline Visit 1 to Visit 2 and Visit 3 (LOCF): safety analysis set Table 26: Change in serum GGT from baseline Visit 1 to Visit 2 and Visit 3 (LOCF): safety analysis set Table 27: Change in serum LDH from baseline Visit 1 to Visit 2 and Visit 3 (LOCF): safety analysis set Table 28: Change in serum alkaline phosphatase from baseline Visit 1 to Visit 2 and Visit 3 (LOCF): safety analysis set Table 29: Time interval from Visit 1 to each study visit: PK analysis set Table 30: Age, height and weight Table 31: Duration of psoriasis, percentage of BSA involvement and m-pasi at baseline Table 32: Concurrent diagnoses at baseline by MedDRA primary SOC Table 33: Concomitant medication at baseline Table 34: Compliance with treatment instructions: PK analysis set Table 35: Listing and summary statistics of plasma betamethasone dipropionate concentrations (pg/ml) by nominal time and study visit following topical application of LEO in Japanese subjects with extensive psoriasis vulgaris (PK population) 132 Table 36: Listing and summary statistics of plasma betamethasone 17-propionate concentrations (pg/ml) by nominal time and study visit following topical application of LEO in Japanese subjects with extensive psoriasis vulgaris (PK population) 133 Table 37: Listing and summary statistics of plasma calcipotriol concentrations (pg/ml) by nominal time and study visit following topical application of LEO in Japanese subjects with extensive psoriasis vulgaris (PK population) Table 38: Listing and summary statistics of plasma MC1080 concentrations (pg/ml) by nominal time and study visit following topical application of LEO in Japanese subjects with extensive psoriasis vulgaris (PK population) Table 39: Listing and summary statistics of plasma betamethasone dipropionate PK parameters (PK population) following topical application of LEO in Japanese subjects with extensive psoriasis vulgaris by study visit Table 40: Listing and summary statistics of plasma betamethasone 17-propionate PK parameters (PK population) following topical application of LEO in Japanese subjects with extensive psoriasis vulgaris by study visit

10 MCB Apr-2013 Page 10 of 218 Table 41: Listing and summary statistics of plasma calcipotriol PK parameters (PK population) following topical application of LEO in Japanese subjects with extensive psoriasis vulgaris by study visit Table 42: Listing and summary statistics of plasma MC1080 PK parameters (PK population) following topical application of LEO in Japanese subjects with extensive psoriasis vulgaris by study visit Table 43: Investigator's global assessment of disease severity by visit: PK analysis set Table 44: LEO Pharma A/S, Study MCB 0904 summary of plasma betamethasone dipropionate, betamethasone 17 propionate, calcipotriol and MC1080 concentrations following once-daily topical application of LEO in Japanese subjects with extensive psoriasis vulgaris Table 45: Amount of study medication used: safety analysis set Table 46: Relationship of AEs to study medication by MedDRA primary SOC and preferred term: safety analysis set Table 47: ADRs by MedDRA primary SOC and preferred term: safety analysis set Table 48: Intensity of ADRs by MedDRA primary SOC and preferred term: safety analysis set Table 49: Lesional/perilesional AEs by MedDRA primary SOC and preferred term: safety analysis set

11 MCB Apr-2013 Page 11 of 218 LIST OF IN-TEXT FIGURES Figure 1: Schedule/chart of trial procedures Figure 2: Number of subjects at each visit: enrolled subjects Figure 3: Subject analysis sets: enrolled subjects Figure 4: Semi-log and linear plots of mean (+ 1 SD) plasma concentration versus time for betamethasone 17-propionate following topical application of LEO to Japanese patients with psoriasis vulgaris - Visit Figure 5: Semi-log and linear plots of mean (+ 1 SD) plasma concentration versus time for betamethasone 17-propionate following topical application of LEO to Japanese patients with psoriasis vulgaris - Visit Figure 6: Semi-log and linear plots of mean (+ 1 SD) plasma concentration versus time for betamethasone 17-propionate following topical application of LEO to Japanese patients with psoriasis vulgaris - Visit Figure 7: Mean percentage change in m-pasi from baseline to each visit and to Visit 4 (Day 28 - LOCF): PK analysis set Figure 8: Composite plot of plasma betamethasone 17-propionate concentration-time profiles by subject Visit Figure 9: Composite plot of plasma betamethasone 17-propionate concentration-time profiles by subject Visit Figure 10: Composite plot of plasma betamethasone 17-propionate concentration-time profiles by subject Visit Figure 11: Semilog and linear composite plots of individual plasma analyte concentration-time profiles for Subject by study visit Figure 12: Semilog and linear composite plots of individual plasma analyte concentration-time profiles for Subject by study visit Figure 13: Semilog and linear composite plots of individual plasma analyte concentration-time profiles for Subject by study visit Figure 14: Semilog and linear composite plots of individual plasma analyte concentration-time profiles for Subject by study visit Figure 15: Semilog and linear composite plots of individual plasma analyte concentration-time profiles for Subject by study visit Figure 16: Semilog and linear composite plots of individual plasma analyte concentration-time profiles for Subject by study visit Figure 17: Semilog and linear composite plots of individual plasma analyte concentration-time profiles for Subject by study visit

12 MCB Apr-2013 Page 12 of 218 Figure 18: Semilog and linear composite plots of individual plasma analyte concentration-time profiles for Subject by study visit Figure 19: Semilog and linear composite plots of individual plasma analyte concentration-time profiles for Subject by study visit Figure 20: Semilog and linear composite plots of individual plasma analyte concentration-time profiles for Subject by study visit Figure 21: Semilog and linear composite plots of individual plasma analyte concentration-time profiles for Subject by study visit Figure 22: Semilog and linear composite plots of individual plasma analyte concentration-time profiles for Subject by study visit Figure 23: Semilog and linear composite plots of individual plasma analyte concentration-time profiles for Subject by study visit

13 MCB Apr-2013 Page 13 of LIST OF ABBREVIATIONS AND DEFINITION OF TERMS LIST OF ABBREVIATIONS ACE Angiotensin Conversion Enzyme ADR Adverse Drug Reaction AE Adverse Event ALT Alanine Aminotransferase AST Aspartate Aminotransferase AUC 0-t Area under the Plasma Concentration-Time Curve from Time 0 to t Hours AUC extr Area under the Plasma Concentration-Time Curve Accounted for by the Extrapolation between Time of the Last Quantifiable Concentration and Infinity Expressed as a Percentage AUC inf Area under the Plasma Concentration-Time Curve from Time 0 to Infinity AUC last Area under the Plasma Concentration-Time Curve from Time 0 to the Last Observed Measurable Concentration AUMC Area under the First Moment Curve Including the Area Extrapolated from the Last Quantifiable Time Point to Time Infinity BLQ Below the Quantifiable Limit BSA Body Surface Area BUN Blood Urea Nitrogen CI Confidence Interval C last Last Observed Quantifiable Plasma Concentration in the Plasma Concentration Versus Time Profile C max Maximum Observed Plasma Concentration C min Minimum Plasma Concentration CRF Case Report Form CRO Contract Research Organisation C ss Area under the Plasma Concentration-Time Curve at Steady-State during a Dose Interval/Tau CTS Clinical Trial Supply CV% Percent Coefficient of Variation DK Denmark EMA European Medicines Agency EU European Union FDA Food and Drug Administration

14 MCB Apr-2013 Page 14 of 218 GCP GGT GPV HQ ICCC ICH ICTM IGA IL IP IRB λ z LC-MS/MS LDH LLOQ LOCF MedDRA MHW m-pasi MRT NA PASI PK PUVA QC RBC SAE SD SGOT SGPT SOC SOP t 1/2 t lag t last t max Good Clinical Practice Gamma-Glutamyl Transpeptidase Global Pharmacovigilance Head Quarters In Country Clinical Trial Caretaker International Conference on Harmonisation International Clinical Trial Manager Investigator s Global Assessment Interleukin Investigational Product Institutional Review Board Apparent Terminal Elimination Rate Constant in Plasma Liquid Chromatography with Tandem Mass Spectrometry Lactate Dehydrogenase Lower Limit of Quantitation Last Observation Carried Forward Medical Dictionary for Regulatory Activities Ministry of Health and Welfare Modified Psoriasis Area and Severity Index Mean Residence Time Not Applicable Psoriasis Area and Severity Index Pharmacokinetic, Pharmacokinetics Psoralen plus Ultraviolet Radiation A Quality Control Red Blood Cell Serious Adverse Event Standard Deviation Serum Glutamic Oxaloacetic Transaminase Serum Glutamic Pyruvic Transaminase System Organ Class Standard Operating Procedure Apparent Terminal Elimination Half-Life in Plasma Time from Dosing to the First Quantifiable Concentration Time of the Last Quantifiable Concentration Time to Reach Maximum Observed Plasma Concentration

15 MCB Apr-2013 Page 15 of 218 UK US UVA UVB WBC WHO United Kingdom United States Ultraviolet Radiation A Ultraviolet Radiation B White Blood Cell World Health Organisation DEFINITION OF TERMS Terms defined by ICH Guidelines are not mentioned here. Assessment A (cluster of) characteristic(s) measured and/or recorded for a subject. Clinical Trial Agreement A contract between on the one hand LEO and/or a contract research organisation (CRO) and on the other hand an investigator and/or the institution specifying the conditions for the cooperation in the clinical trial and the investigator s and/or the institution s responsibilities. Concomitant Medication Any medication used by a subject during a clinical trial apart from the trial medication. Enrolled Subject A subject for whom informed consent has been obtained. Fraud Fabrication of data, selective and undisclosed rejection of undesired results, substitution with fictitious data, deliberately incorrect use of statistical methods for the purposes of reaching other conclusions than those warranted by the data, misinterpretation of results and conclusions, plagiarism of results or entire articles from other researchers, misrepresentation of other researchers results, unwarranted authorship and misleading application for positions or funds. In Country Clinical Trial Caretaker (ICCC) According to Japanese Law, the ICCC represents the Sponsor in Japan in requesting the trial and in taking necessary measures to prevent the development or expansion of risk to health and hygiene from the investigational products (IPs). The ICCC performs the procedures related to requesting the trial.

16 MCB Apr-2013 Page 16 of 218 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 standard operating procedure (SOPs). Investigator Staff Signature Form A form used: 1. for the investigator to delegate trial-related tasks/duties 2. for trial site staff to sign and date to accept delegation 3. for trial site staff to document signatures and initials 4. for the investigator to authorise tasks/duties delegated. Investigator Trial File The collection of trial documents required by LEO GCP SOPs, ICH Guidelines and/or regulatory requirements to be on file at the trial site. LEO LEO (no suffix): Refers to the corporate organisation of LEO. Monitor A person appointed to carry out monitoring of a clinical trial. National Clinical Trial Manager The person appointed by LEO to be the national representative responsible for all aspects of a clinical trial within a country as outlined in Clinical Development SOPs. 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 (CI) is stated, or for which tabulation serves as important supportive evidence of efficacy/safety.

17 MCB Apr-2013 Page 17 of 218 Subject Identification List A summary list kept by the investigator in the Investigator Trial File that records the names of all subjects enrolled and the date of enrolment in the trial at that trial site, with the subject s corresponding case report form (CRF) number, to allow the investigator/institution to reveal the identity of any subject, if required. Subject Screening Log A document kept by the investigator which identifies patients/subjects who entered pre-trial screening. 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 IP.

18 MCB Apr-2013 Page 18 of ETHICS 5.1 INDEPENDENT ETHICS COMMITTEE OR INSTITUTIONAL REVIEW BOARD The clinical study protocol was approved by/received favourable opinion from the relevant Institutional Review Boards (IRBs). The appropriate regulatory authority was notified of/approved the clinical trial, as required. A list of all IRBs consulted is given in Appendix ETHICAL CONDUCT OF THE TRIAL The clinical trial was conducted to conform to the principles of the Declaration of Helsinki as adopted by the 18 th World Medical Assembly, 1964 and subsequent amendments. The clinical trial was conducted in accordance with the principles of GCP. Subjects were asked to consent that data could be recorded, collected, processed and transferred to European Union (EU) and non-eu countries in accordance with any national legislation implementing the EU Data Protection Directive (95/46/EC). All information containing personal data was to be handled in accordance with the general terms of the authorisation granted by the Danish Data Protection Agency to LEO (as appended to the Clinical Study Protocol) in accordance with the EU Data protection Directive (95/46/EC) as well as any national data protection legislation. 5.3 SUBJECT INFORMATION AND INFORMED CONSENT All subjects received written and verbal information concerning the clinical trial. This information emphasised that participation in the trial was voluntary and that the subject could withdraw from the trial at any time and for any reason. All subjects were given an opportunity to ask questions and were given sufficient time to consider all relevant issues before consenting.

19 MCB Apr-2013 Page 19 of 218 The subject's signed and dated informed consent to participate in the clinical trial was obtained prior to any trial-related activities being carried out. A representative subject information sheet and informed consent form is provided in Appendix

20 MCB Apr-2013 Page 20 of INVESTIGATORS AND TRIAL ADMINISTRATIVE STRUCTURE LEO was the sponsor of the clinical trial and participating LEO affiliates were authorised by the sponsor to act on behalf of the sponsor in the country where the clinical trial was conducted. The CRO was authorised by the sponsor to act on behalf of the sponsor as the ICCC in Japan. Role Medical Expert (Japan): Name, title, affiliation, MD, Director, Department of Dermatology, Tokyo Teishin Hospital, Head of Medical Department:, MD, Head of Medical Department, LEO, Industriparken 55, DK-2750 Ballerup, Denmark (DK), Head of Biostatistics, LEO HQ:, MSc, Head of Biostatistics and Data Management, LEO, Industriparken 55, DK-2750 Ballerup, DK, Trial Statisticians:, Clinical Biometrics Manager, Clinical Biometrics, LEO Pharma, Longwick Road, Princes Risborough, Buckinghamshire, HP27 9RR, United Kingdom (UK),, Senior Biostatistician, ICTM:, Clinical Operations, LEO, Industriparken 55, DK-2750 Ballerup, DK,

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23 MCB Apr-2013 Page 23 of 218 A list of investigators and other persons whose participation materially affected the conduct of the trial is included in Appendix

24 MCB Apr-2013 Page 24 of INTRODUCTION This clinical trial was conducted as part of the clinical development programme to obtain approval of LEO ointment (a combination of calcipotriol hydrate plus betamethasone dipropionate) in Japan. The study is intended to be submitted as part of a Japanese New Drug Application (JNDA). 7.1 PSORIASIS VULGARIS Psoriasis vulgaris is one of the most common chronic skin diseases, with a prevalence generally estimated at between 1 to 3% of the world s population (1, 2). The prevalence of the disease in Japan could be lower (3). It is characterised by sharply marginated areas of affected skin which appear thickened, red and scaly. The scalp, elbows, knees, lower back, hands, feet and nails are commonly affected sites. About 80% of affected subjects complain of pruritus (4). Psoriasis is a significant problem in everyday life for the affected subjects, and has a significant impact on their health-related quality of life, an impact that increases with increasing skin involvement (5). Psoriasis is a dermatological disease which is characterised by an immune inflammatory reaction, proliferation of epidermal keratinocytes and a disorder of differentiation. The psoriatic appearance of the skin is a consequence of an increased rate of epidermal proliferation with impaired differentiation of keratinocytes resulting in a thickened, undulating epidermis covered by a thickened, parakeratotic stratum corneum (6, 7). Activated T- cells (TH17 and TH1) as well as dendritic cells play an important role in the immune and inflammatory reactions in psoriasis. Cytokines (interleukin [IL]-23 and IL-12) produced by dendritic cells are involved in T-cell proliferation and differentiation. IL-22 and IL-17 produced by activated Th17 cause epidermal keratinocyte growth as well as abnormal keratinisation. Therefore, the target of psoriasis treatment is epidermal keratinocytes and immune cells, as well as cytokines produced by these cells. The investigational drug in this study (LEO 90105) contains two medicinal agents with different mechanisms of action: a vitamin D analogue and a corticosteroid. The vitamin D analogue (calcipotriol) is mainly targeted at the epidermal keratinocytes. On the other hand the corticosteroid (betamethasone dipropionate) targets immune cells (8). Treatment of psoriasis

25 MCB Apr-2013 Page 25 of 218 Psoriasis vulgaris is a chronic disease for which there is currently no cure. Treatment is targeted at reducing the signs of redness, thickness and scaliness, and associated symptoms such as pruritus. Psoriasis treatments can be divided into three main types: topical treatments, phototherapy and systemic treatments. Each has its own advantages and disadvantages, and several treatment options, for example monotherapy and combination therapy, can be considered in medical practice (9, 10, 11). Topical treatment is well recognised as the firstline medication. Phototherapy (photochemotherapy [psoralen plus ultraviolet radiation A {PUVA}] and ultraviolet radiation B [UVB]) and systemic treatments (such as methotrexate [which is out of insurance reimbursement in Japan], retinoids and ciclosporin) are generally used in extensive, therapy-resistant and socially disabling disease and in the serious forms of erythrodermic and pustular psoriasis (3, 12). Among the newest therapies approved in Japan are the biological agents, which reduce the effect of T-cells, either by a direct effect on the T- cells or by inhibition of their secreted cytokines. Currently three such biological products (adalimumab, infliximab and ustekinemab) have been approved in Japan for the treatment of moderate to severe psoriasis. For the first-line therapy of psoriasis, topical corticosteroids and vitamin D analogues (such as calcipotriol, tacalcitol and maxacalcitol) are effective and the two most commonly used therapies for psoriasis vulgaris. Vitamin D analogues do not act as quickly, and have to be applied for more than 6 weeks in order that similar efficacy to corticosteroids can be obtained (13). Guidelines of Care for the Management and Treatment of Psoriasis with Topical Therapies in the United States (US) (14) refers to the efficacy of the combination therapy of topical corticosteroids and vitamin D analogues. It is very common in Japan to apply both topical corticosteroids and vitamin D analogues on the same area simultaneously, to make the best clinical use of each drug. The efficacy of the combination therapy of topical corticosteroids and vitamin D analogues in patients with psoriasis vulgaris has been reported in a number of clinical studies performed both in Japan and overseas (15, 16, 17, 18, 19, 20, 21). In addition to the simultaneous application by patients of topical drugs, combined topical drugs prepared by physicians or pharmacists are often provided to patients in medical practice. Ozawa presented the residual ratio of active vitamin D and corticosteroid after the mixing of various types of topical corticosteroids and vitamin D analogues, and indicated that some inappropriate combinations causing degradation of each of the drugs were observed (22). The compatibility of topical vitamin D analogues with topical corticosteroids was also investigated in overseas studies, and the results showed calcipotriol had been degraded substantially when it

26 MCB Apr-2013 Page 26 of 218 was mixed with some corticosteroids. This indicates that mixing of vitamin D analogues and corticosteroids without regard for this incompatibility should be avoided (23). In addition, as regards to combined drugs prepared by physicians or pharmacists, there are concerns about potential risk of contamination in preparation and the lack of established standard regimes. Moreover, the issue that has increasingly attracted attention recently is that topical treatment becomes a source of stress for psoriasis patients due to the time taken to apply it. The stress caused by topical treatment is an important factor contributing not only to the decrease of the patients quality of life, but also to the reduction of drug compliance and therefore to the clinical effectiveness. To reduce the patient s burden of topical treatment and realise a significant improvement over the currently available treatment, it is essential to decrease time and frequency required to apply the treatments. For these purposes, it is intended to provide a stable and pre-fixed product of an appropriately combined topical corticosteroid and vitamin D analogue (24, 25, 26). 7.2 INVESTIGATIONAL PRODUCT DESCRIPTION LEO ointment LEO ointment contains both calcipotriol hydrate 52.2 mcg/g (equivalent to 50 mcg/g of calcipotriol) and mg/g of the corticosteroid betamethasone dipropionate (equivalent to 0.5 mg/g of betamethasone). It was first launched in DK in 2001 for the topical treatment of psoriasis vulgaris. Since then it has been approved for use in more than 60 countries, including most European countries, the US, China, Korea and Taiwan under the trade names DAIVOBET/DOVOBET/TACLONEX. From approval in 2001 to 31-May-2010, approximately 20 million treatment courses were prescribed. It is being developed for the Japanese market under the code LEO The clinical trial programme has enrolled more than 6,000 subjects, of whom approximately 2,500 have been treated with LEO in controlled phase 3 trials (27, 28, 29, 30, 31, 32, 33, 34, 35, 36). The trials showed that up to 4 weeks treatment with LEO ointment is more effective for psoriasis vulgaris with a more rapid onset of action than either active constituent (calcipotriol or betamethasone dipropionate) used alone in the same vehicle or in an already-marketed formulation. Treatment with LEO ointment was well tolerated as evidenced by a similar proportion of patients reporting adverse events (AEs) with LEO ointment and with betamethasone dipropionate, whereas more patients reported AEs with calcipotriol applied alone.

27 MCB Apr-2013 Page 27 of 218 Based on data from clinical trials and post-marketing use, the common undesirable effects are pruritus, skin rashes and burning sensation of skin. Uncommon undesirable effects are skin pain and irritation, dermatitis, erythema, exacerbation of psoriasis, folliculitis and application site pigmentation changes. Pustular psoriasis is a rare undesirable effect. Only three serious adverse events (SAEs) reported in the total clinical trial programme were judged to be possibly related to LEO Two long-term studies have been conducted to investigate once daily treatment, used when required, for up to 52 weeks. The studies showed that the incidence of possibly steroid-related events (identified by blinded adjudication) during treatment with LEO ointment for up to 52 weeks was low and not significantly different from the incidence reported for Dovonex ointment used for up to 48 weeks. Although most of the subjects in the clinical trial programme were of Caucasian race, studies have also been performed in subjects of Black/African American (33), Hispanic (33) and Chinese (36) race/ethnicity, with similar results for efficacy and safety as seen in Caucasian subjects. Two phase 1 studies have been performed with LEO ointment in Japan. The first of these investigated the skin irritation, phototoxicity and safety of LEO ointment and its components by both 48-hour closed patch tests and photo patch tests (37). Twenty healthy Japanese male subjects were enrolled, and all were treated with LEO ointment and its components. No skin irritation or phototoxicity was observed with LEO ointment in any subject. There were no unexpected or significant safety issues. The second study investigated the safety of LEO ointment compared with its vehicle after multiple administrations (38). Twelve healthy Japanese male subjects were randomised double-blind to receive either LEO ointment (nine subjects) or its vehicle (three subjects). Treatment was applied topically to the intact skin on the back, at a dose of approximately 6.5 g, twice daily for 5 days. All subjects completed the study. No skin reactions were observed in any subjects, and there were no unexpected or significant safety issues. 7.3 TRIAL RATIONALE In order to make a relevant assessment of the systemic absorption and the pharmacokinetic (PK) profile of LEO 90105, study drug had to be applied to a sufficiently large area to be close to or to achieve maximum use. The required extent of psoriasis vulgaris in this study was below 30%, which was considered to be a sufficiently large area to be treated. Psoriasis

28 MCB Apr-2013 Page 28 of 218 vulgaris with an extent of >30% is usually considered not amenable to topical treatment. The degree of skin barrier damage affects the systemic absorption, which was the reason to include subjects with at least moderate disease severity according to the investigator s global assessment (IGA) and a modified psoriasis area and severity index (m-pasi) score of 12 and exclude subjects with mild disease severity. In the overseas phase 3 study (MCB 0003 INT), only a low number (1%) of subjects were rated to have absence of disease at Week 2 compared to 9.3% at Week 4. It was therefore expected that the vast majority of subjects in this study would require application of significant amounts of ointment at least for the first 2 weeks of the study. In a previous study LEO was applied to extensive psoriasis on the body together with calcipotriol plus betamethasone dipropionate gel to extensive scalp psoriasis (MBL 0404 FR). After 4 weeks of treatment neither calcipotriol nor betamethasone dipropionate could be measured in serum, and their main metabolites were measurable in a few of the samples at low concentrations, indicating that there was no accumulation of the drugs at this time point. In summary the likelihood of systemic absorption is therefore expected to be greater early in the treatment course, when the extent of disease is greatest and the skin barrier is more severely damaged. The study was planned to include a small number of subjects (10-12 subjects) to be able to rule out significant absorption that might have an impact on safety in Japanese psoriasis patients. The number of subjects was in line with the number of subjects included in similar PK studies of topical products conducted in Japan.

29 MCB Apr-2013 Page 29 of TRIAL OBJECTIVES 8.1 PRIMARY OBJECTIVE To assess the PK profile of the components of LEO and any metabolites in the blood in Japanese subjects with extensive psoriasis vulgaris on the body (trunk and/or limbs). 8.2 SECONDARY OBJECTIVES To evaluate the safety and efficacy of LEO applied once daily in Japanese subjects with extensive psoriasis vulgaris on the body (trunk and/or limbs).

30 MCB Apr-2013 Page 30 of INVESTIGATIONAL PLAN The entire Clinical Study Protocol is presented in Appendix and the unique pages of the CRF are presented in Appendix OVERALL TRIAL DESIGN AND PLAN - DESCRIPTION Overall design This was a national, multi-centre, prospective, non-controlled, open-label, single-group, 4- week clinical study of topical LEO in male and female adult subjects with extensive psoriasis vulgaris. At least 10 subjects were to be treated with the study medication for 4 weeks. Individual phases Washout/screening phase Prior to treatment at Visit 1 (Day 1), a washout period was completed if the subject was treated or had recently been treated with anti-psoriatic treatments or other relevant medication, as defined by the exclusion criteria. The washout period could last up to a maximum of 4 weeks. Subjects had to give written informed consent either at or before the washout/screening visit. Subjects providing informed consent were considered to be enrolled in the study, and a CRF was to be completed for all such subjects. If a washout period was not required, the minimum period between the washout/screening visit and Visit 1 was three working days; this was to allow time for the site to receive the laboratory results from the samples taken at the washout/screening visit. Treatment phase The treatment phase lasted for up to 4 weeks. The study consisted of four (4) clinic visits on Days 1, 7 (±1), 14 (±2) and 28 (± 2) (Visits 1 to 4). If subjects were outside the visit window, the (sub)investigator was to record the reason in the patient s medical record, but LEO/CRO did not need to be notified. Subjects received once daily topical treatment with calcipotriol hydrate (52.2 mcg/g) plus betamethasone dipropionate (0.643 mg/g) ointment (LEO 90105) on all lesions on the trunk and/or limbs (excluding psoriasis on the genitals and skin folds) for 4 weeks. Subjects were supplied with an amount of medication at Visits 1, 2 and 3 such that the maximum usage of

31 MCB Apr-2013 Page 31 of 218 LEO could be 90 g per week. At the study visit days, application was performed in the clinic by designated site staff. The amount of ointment applied was determined by weighing the tubes before and after use. The subject was not to apply the study medication within approximately 24 hours prior to Day 7; Visit 2 and Day 14; Visit 3 (i.e. no application since the previous morning). Blood samples for PK analysis were taken on Days 1, 7 (±1) and 14 (±2) (Visits 1, 2 and 3) prior to application of treatment and 1, 2, 3, 5 and 7 hours after application had finished (± 10 min at each time point). Same time of blood collection was to apply for every visit for the same patient. 9.2 DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF CONTROL GROUPS LEO ointment is a combination of both calcipotriol and betamethasone dipropionate in the same concentrations as in Dovonex and Rinderon -DP ointment, respectively. The objective of this trial was to assess the PK profile of the components of LEO and any metabolites in the blood in Japanese subjects with extensive psoriasis vulgaris on the body (trunk and/or limbs). The duration of treatment was 4 weeks, as this duration of treatment with LEO ointment has been shown to be safe and effective in the clinical trial programme, and is the approved duration of treatment in Europe and the US. In order to make a relevant assessment of systemic absorption and obtain PK data, study drug had to be applied to a sufficiently large area. The most extensive area of exposure was during the first 2 weeks when treatment was started. The trial rationale (i.e. the trial design, trial population, administration method and duration of treatment) is detailed in Section SELECTION OF TRIAL POPULATION Following receipt of verbal and written information about the clinical trial, the subject was to provide signed and dated informed consent before any trial related activity was carried out, including activities relating to washout periods.

32 MCB Apr-2013 Page 32 of 218 Any implementation of national requirements/law for the subject s participation in the clinical trial was ensured and was described in submission documentation to authorities/irbs, as applicable Inclusion Criteria 1. Japanese subjects having understood and signed a written informed consent form prior to any study related procedures being carried out (including activities related to the wash out period) years of age or above. 3. Either sex. 4. Clinical diagnosis of psoriasis vulgaris amenable to topical treatment involving arms and/or trunk and/or legs. 5. Psoriasis vulgaris on the trunk/limbs (excluding psoriasis on the genitals/skin folds) of not more than 30% body surface area (BSA). 6. An IGA of disease severity on area(s) to be treated of moderate, severe or very severe and a m-pasi score of Females of childbearing potential had to have a negative result for a urine pregnancy test at Day 1 (Visit 1) and had to agree to use an adequate method of birth control, as judged by the (sub)investigator, during the study. The contraceptive method was to have started an adequate amount of time before the pregnancy test, which was dependent on the particular method used and as judged by the (sub)investigator, and had to continue for at least 1 week after the last application of study medication. A female was defined as not of childbearing potential if she was postmenopausal (12 months with no menses without an alternative medical cause) or surgically sterile (tubal ligation/section, hysterectomy or bilateral ovariectomy) Exclusion Criteria 1. Systemic use of biological treatments with a potential effect on psoriasis vulgaris within the following time periods prior to Visit 1: - etanercept, adalimumab, infliximab 3 months. - ustekinumab 4 months. - other products within 3 months/5 half-lives (whichever was longer). 2. Systemic treatments with all therapies other than biological treatments with a potential effect on psoriasis vulgaris (e.g. corticosteroids, vitamin D analogues, retinoids, immu-

33 MCB Apr-2013 Page 33 of 218 nosuppressants such as ciclosporin and methotrexate) within 4 weeks prior to Visit 1 (use of inhaled and nasal corticosteroids, and of systemic antihistamines was allowed). 3. Topical treatment of scalp psoriasis with vitamin D analogues (e.g. calcipotriol, tacalcitol, maxacalcitol), or very potent World Health Organisation (WHO) group IV corticosteroids within 2 weeks prior to Visit PUVA therapy, UVB therapy or ultraviolet radiation A (UVA) therapy within 4 weeks prior to Visit Topical treatment of psoriasis on the face, genitals or skin folds with vitamin D analogues (e.g. calcipotriol, tacalcitol, maxacalcitol), or potent or very potent WHO group III or IV corticosteroids within 2 weeks prior to Visit Topical treatment of psoriasis on area(s) to be treated with study medication within the 2-week period prior to Visit 1 (use of emollients was allowed during this 2-week period, but not during the study). 7. Planned initiation of, or changes in, concomitant medication that might affect psoriasis vulgaris (e.g. beta-blockers, antimalaria drugs, lithium and angiotensin conversion enzyme [ACE] inhibitors) during the study. 8. Topical treatment of conditions other than psoriasis with vitamin D analogues (e.g. calcipotriol, tacalcitol, maxacalcitol), or potent or very potent WHO group III or IV corticosteroids within 2 weeks prior to Visit Current diagnosis of erythrodermic, exfoliative, guttate or pustular psoriasis. 10. Clinical signs or symptoms of Cushing s disease or Addison s disease 11. Patients with any of the following disorders (a) or symptoms (b) present on the area(s) to be treated with study medication: (a) viral (e.g. herpes or varicella) lesions of the skin, fungal or bacterial skin infections, parasitic infections, skin manifestations in relation to syphilis or tuberculosis, rosacea, acne vulgaris, atrophic skin, striae atrophicae, ichthyosis, acne rosacea, ulcers, burns, frostbite, wounds, or (b) fragility of skin veins. 12. Other inflammatory skin diseases (e.g. seborrhoeic dermatitis, contact dermatitis and cutaneous mycosis) that might confound the evaluation of psoriasis vulgaris. 13. Planned excessive exposure of treated areas(s) to either natural or artificial sunlight (including tanning booths, sun lamps, etc.) during the study. 14. Known or suspected disorders of calcium metabolism associated with hypercalcaemia (subjects with results for albumin-corrected serum calcium above the reference range from the sample taken at the washout/screening visit). 15. Severe renal insufficiency, severe hepatic disorders or severe heart disease. 16. Known or suspected hypersensitivity to components of the IPs. 17. Current participation in any other interventional clinical study.

34 MCB Apr-2013 Page 34 of Subjects who had received treatment with any non-marketed drug substance (i.e. an agent which had not yet been made available for clinical use following registration) within the 4-week period prior to Visit 1 or longer, if the class of substance required a longer washout as defined above (e.g. biological treatments). 19. Females who were pregnant, wishing to become pregnant during the study, or were breastfeeding. 20. Patients suspected of being unable to comply with the study protocol, e.g. due to alcoholism, drug dependence or psychotic state. 21. Previous enrolment in this study. 22. Hospitalised patients Removal of Subjects from Therapy or Assessment Subjects could withdraw for any of the following reasons: 1. Medical reasons: the investigator was free to withdraw the subject at any time for medical reasons. 2. Unacceptable treatment efficacy: the investigator was free to withdraw the subject at any time for medical reasons. 3. Unacceptable AEs: any AEs that the investigator or the subject considered unacceptable. 4. Exclusion criteria: any exclusion criteria which emerged/became apparent during the subject s participation in the clinical trial. 5. Voluntary withdrawal: subjects were free to withdraw from the clinical trial at any time and for any reason. 6. Other reasons: other reasons than stated above which required the subject to (be) withdraw(n) was to be specified. Subjects had to be withdrawn if they were found to have become pregnant. Subjects who were discovered, after enrolment, not to have fulfilled all inclusion criteria or to have fallen under any of the exclusion criteria at the time of enrolment, were to be withdrawn from treatment unless the investigator, based on clinical and ethical evaluation, found withdrawal inappropriate. Such deviation(s) from the Clinical Study Protocol had to be reported to LEO (and the IRB, as appropriate) and recorded in the Clinical Study Report. The reason for withdrawal was to be recorded in the CRF.