Main Clinical Study Report. Safety and efficacy of TACLONEX ointment in adolescent patients (aged 12 to 17 years) with psoriasis vulgaris

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1 Main Clinical Study Report Safety and efficacy of TACLONEX ointment in adolescent patients (aged 12 to 17 years) with psoriasis vulgaris A Phase 2 study evaluating the safety and efficacy of 4 weeks of once daily use of TACLONEX ointment, containing calcipotriene 50 mcg/g plus betamethasone 0.5 mg/g (as dipropionate), in the treatment of psoriasis vulgaris on the trunk and/or limbs in adolescent patients (aged 12 to 17 years) A national, multi-centre, prospective, non-controlled, single-group, 4-week study in patients with psoriasis vulgaris on the trunk and/or limbs LEO Pharmaceutical Products Ltd. A/S MCB 0501 INT (LEO Pharma A/S) 28-MAY-2012 Clinical Development EudraCT Number:

2 MCB 0501 INT 28-MAY-2012 Page 2 of REPORT STATEMENTS APPROVAL STATEMENT On behalf of LEO, only the, LEO, and the, LEO 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: HQ, LEO LEO APPROVAL STATEMENT, INVESTIGATORS The International Co-ordinating Investigator approves the main Clinical Study Report (including appendices) by manually signing the International Co-ordinating Investigator Clinical Study Report Approval Form, which is a separate document adjoined to this report. The following person has approved this main Clinical Study Report (including appendices): International Co-ordinating Investigator

3 MCB 0501 INT 28-MAY-2012 Page 3 of 129 COMPLIANCE WITH GOOD CLINICAL PRACTICE This Clinical Study Report is designed to comply with the standards issued by the International Conference on Harmonisation (ICH) (E3 Structure and Content of Clinical Study Reports; E6 Good Clinical Practice; E9 Statistical Principles for Clinical Trials and M4 Common Technical Document). DISCLOSURE OF CLINICAL TRIAL RESULTS Results from this clinical trial will be posted on which is a publicly accessible database. TRADEMARKS TACLONEX/DAIVOBET/DOVOBET and DAIVONEX/DOVONEX are trademarks owned by LEO Pharma A/S (or its subsidiaries). 2 SYNOPSIS The synopsis of this Clinical Study Report exists as a separately approved document. MCB 0501 INT Clinical Study Report Synopsis

4 MCB 0501 INT 28-MAY-2012 Page 4 of TABLE OF CONTENTS 1 REPORT STATEMENTS SYNOPSIS TABLE OF CONTENTS... 4 TABLE OF TABLES... 8 LIST OF IN-TEXT 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 INVESTIGATORS AND TRIAL ADMINISTRATIVE STRUCTURE INTRODUCTION BACKGROUND INFORMATION PSORIASIS INVESTIGATIONAL PRODUCT DESCRIPTION STUDY RATIONALE TRIAL OBJECTIVES PRIMARY OBJECTIVE SECONDARY OBJECTIVE 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 Method of Assigning Subjects to Treatment Groups... 33

5 MCB 0501 INT 28-MAY-2012 Page 5 of Selection of Doses in the Trial Selection and Timing of Dose for each Subject Blinding Prior and Concomitant Therapy Treatment Compliance Non-Investigational Medicinal Products CORTROSYN (Cosyntropin) for Injection % Sodium Chloride Injection, USP EFFICACY AND SAFETY VARIABLES Efficacy and Safety Measurements Assessed and Flow Chart Efficacy Safety Appropriateness of Measurements Primary Safety Variables 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 Baseline characteristics Analysis of safety Analysis of efficacy General principles Determination of sample Size CHANGES IN THE CONDUCT OF THE TRIAL OR PLANNED ANALYSES TRIAL POPULATION DISPOSITION OF SUBJECTS PROTOCOL DEVIATIONS EFFICACY EVALUATION DATA SETS ANALYSED Full Analysis set Safety Analysis Set Per Protocol Analysis Set DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS Demography... 64

6 MCB 0501 INT 28-MAY-2012 Page 6 of Other Baseline Characteristics MEASUREMENT OF TREATMENT COMPLIANCE ADRENAL FUNCTION, CALCIUM METABOLISM AND CLINICAL EFFICACY Effect on Adrenal Function and Calcium Metabolism Effect on Adrenal Function Effect on Calcium Metabolism Clinical Efficacy 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 Conclusions: Effect on Adrenal Function and Calcium Metabolism, and Clinical Efficacy SAFETY EVALUATION EXTENT OF EXPOSURE ADVERSE EVENTS (AES) 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 CLINICAL LABORATORY EVALUATION Listing of Individual Laboratory Measurements by Subject and Each Abnormal Laboratory Value Evaluation of Each Laboratory Parameter... 96

7 MCB 0501 INT 28-MAY-2012 Page 7 of Laboratory values over time Individual subject changes Individual clinically significant abnormalities VITAL SIGNS, PHYSICAL FINDINGS AND OTHER OBSERVATIONS RELATED TO SAFETY SAFETY CONCLUSION DISCUSSION AND OVERALL CONCLUSIONS CONCLUSIONS TABLES, FIGURES AND GRAPHS REFERRED TO BUT NOT INCLUDED IN THE TEXT DEMOGRAPHIC DATA EFFICACY DATA REFERENCES LIST OF APPENDICES

8 MCB 0501 INT 28-MAY-2012 Page 8 of 129 TABLE OF TABLES Table 1: Identity of investigational product Table 2: Schedule/chart of trial procedures Table 3: Study period by centre: enrolled subjects Table 4: Enrolled subjects and subjects assigned treatment by centre Table 5: Age: safety analysis set and per protocol analysis set Table 6: Sex: safety analysis set and per protocol analysis set Table 7: Ethnicity: safety analysis set and per protocol analysis set Table 8: Race: safety analysis set and per protocol analysis set Table 9: Duration of psoriasis vulgaris: safety analysis set and per protocol analysis set Table 10: Investigator's assessment of extent of psoriasis on arms, trunk and legs: safety analysis set and per protocol analysis set Table 11: Modified PASI at baseline: safety analysis set and per protocol analysis set Table 12: IGA at baseline: safety analysis set and per protocol analysis set Table 13: Patient s global assessment at baseline: safety analysis set and per protocol analysis set Table 14: Concurrent diagnoses at baseline by MedDRA primary system organ class: safety analysis set and per protocol analysis set Table 15: Concomitant medication at baseline: safety analysis set and per protocol analysis set Table 16: Serum cortisol concentration at time 0 at baseline: safety analysis set and per protocol analysis set Table 17: Compliance with treatment instructions: safety analysis set and per protocol analysis set Table 18: Serum cortisol concentration <= 18 mcg/dl after ACTH challenge at Week 4: per protocol analysis set Table 19: Serum cortisol concentration at 30 and 60 minutes after ACTH challenge at baseline and Week 4: per protocol analysis set Table 20: Change in albumin-corrected serum calcium from baseline to Week 4: safety analysis set Table 21: Albumin-corrected serum calcium categorised as low, normal or high at Week 4 shown against baseline category: safety analysis set Table 22: Change in urinary calcium:creatinine ratio from baseline to Week 4: safety analysis set... 78

9 MCB 0501 INT 28-MAY-2012 Page 9 of 129 Table 23: Urinary calcium:creatinine ratio categorised as low, normal or high at Week 4 shown against baseline category: safety analysis set Table 24: Change in serum phosphorus from baseline to Week 4: safety analysis set Table 25: Serum phosphorus categorised as low, normal or high at Week 4 shown against baseline category: safety analysis set Table 26: Change in urinary phosphorus:creatinine ratio from baseline to Week 4: safety analysis set Table 27: Urinary phosphorus:creatinine ratio categorised as low, normal or high at Week 4 shown against baseline category: safety analysis set Table 28: Change in PTH from baseline to Week 4: safety analysis set Table 29: PTH categorised as low, normal or high at Week 4 shown against baseline category: safety analysis set Table 30: Controlled disease (IGA) at Week 4: full analysis set Table 31: Controlled disease (patient s global assessment) at Week 4: full analysis set Table 32: Percentage change in modified PASI from baseline to Week 4: full analysis set Table 33: Modified PASI 75 at Week 4: full analysis set Table 34: Modified PASI 50 at Week 4: full analysis set Table 35: Duration and extent of exposure to treatment: safety analysis set Table 36: Amount of study medication used: safety analysis set Table 37: Average weekly amount of study medication used: safety analysis set Table 38: Adverse events by MedDRA primary system organ class: safety analysis set Table 39: Adverse events by MedDRA primary system organ class and preferred term: safety analysis set Table 40: Causal relationship of adverse events to study medication by MedDRA primary system organ class and preferred term: safety analysis set Table 41: Adverse drug reactions by MedDRA primary system organ class and preferred term: safety analysis set Table 42: Intensity of adverse drug reactions by MedDRA primary system organ class and preferred term: safety analysis set Table 43: Lesional/perilesional adverse events by MedDRA primary system organ class and preferred term: safety analysis set Table 44: Change in haematology parameters from baseline to Week 4: safety analysis set.. 96 Table 45: Change in other biochemistry parameters from baseline to Week 4: safety analysis set Table 46: Haematology parameters categorised as low, normal or high at Week 4 against baseline category: safety analysis set

10 MCB 0501 INT 28-MAY-2012 Page 10 of 129 Table 47: Other biochemistry parameters categorised as low, normal or high at Week 4 against baseline category: safety analysis set Table 48: Presence of urinary glucose and ketones at Week 4 against presence at baseline: safety analysis set Table 49: Change in systolic blood pressure from baseline to Week 4: safety analysis set Table 50: Change in diastolic blood pressure from baseline to Week 4: safety analysis set. 109 Table 51: Change in heart rate from baseline to Week 4: safety analysis set Table 52: Reasons for withdrawal during the screening phase: enrolled subjects Table 53: Age by centre: safety analysis set and per protocol analysis set Table 54: Sex by centre: safety analysis set and per protocol analysis set Table 55: Weight: safety analysis set and per protocol analysis set Table 56: Height: safety analysis set and per protocol analysis set Table 57: BMI: safety analysis set and per protocol analysis set Table 58: Controlled disease (IGA) at Week 4 by age group: full analysis set Table 59: Controlled disease (IGA) at Week 4 by sex: full analysis set Table 60: Controlled disease (IGA) at Week 4 by baseline IGA: full analysis set Table 61: Controlled disease (IGA) at Week 4 by centre: full analysis set Table 62: Controlled disease (IGA) by visit: full analysis set Table 63: Controlled disease (patient s global assessment) by visit: full analysis set Table 64: Percentage change in modified PASI by visit: full analysis set Table 65: Modified PASI 75 by visit: full analysis set Table 66: Modified PASI 50 by visit: full analysis set

11 MCB 0501 INT 28-MAY-2012 Page 11 of 129 LIST OF IN-TEXT FIGURES Figure 1: Disposition of subjects Figure 2: Trial Analysis Sets... 63

12 MCB 0501 INT 28-MAY-2012 Page 12 of LIST OF ABBREVIATIONS AND DEFINITION OF TERMS LIST OF ABBREVIATIONS ACE ACTH ADR AE BMI BSA CRF CRO DK EC EU FDA FU GCP HPA HQ ICH ICTM IEC IGA IRB MedDRA NCTM NDA NIMP PASI PTH PUVA SAE SD SOC Angiotensin-converting enzyme Adrenocorticotropic hormone Adverse Drug Reaction Adverse Event Body Mass Index Body Surface Area Case Report Form Contract Research Organisation Denmark European Community European Union Food and Drug Administration Follow-up Good Clinical Practice Hypothalamic Pituitary Adrenal Head Quarter International Conference on Harmonisation International Clinical Trial Manager Independent Ethics Committee Investigator s global assessment Institutional Review Board Medical Dictionary for Regulatory Activities National Clinical Trial Manager New Drug Application Non-Investigational Medicinal Product Psoriasis Area and Severity Index Parathyroid hormone Psoralen plus ultraviolet light A Serious Adverse Event Standard deviation System Organ Class

13 MCB 0501 INT 28-MAY-2012 Page 13 of 129 SOP SUSAR SV UVB Standard Operating Procedure Suspected, Unexpected Serious Adverse Reaction Screening visit Ultraviolet light B DEFINITION OF TERMS Terms defined by ICH Guidelines are not mentioned here. Assessment A (cluster of) characteristic(s) measured and/or recorded for a subject. Concomitant Medication Any medication used by a subject during 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, 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. International Clinical Trial Manager (ICTM) The person appointed by LEO to be the main international representative responsible for all aspects of a clinical trial as outlined in Clinical Development SOPs. Investigator Agreement A contract between LEO and an investigator specifying the conditions for the co-operation in the clinical trial and the investigators responsibilities.

14 MCB 0501 INT 28-MAY-2012 Page 14 of 129 Investigator Staff Signature Form A form used: 1. for the investigator to delegate trial-related tasks/duties 2. for trial site staff to sign and date to accept delegation 3. for trial site staff to document signatures and initials 4. for the investigator to authorise tasks/duties delegated. Investigator Trial File The collection of trial documents required by LEO GCP SOPs, ICH Guidelines and/or regulatory requirements to be on file at the trial site. LEO LEO (no suffix): Refers to the corporate organisation of LEO Pharma. Monitor A person appointed by LEO to carry out monitoring of a clinical trial. National Clinical Trial Manager (NCTM) 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. Subject Identification List A summary list kept by the investigator in the Investigator Trial File that records the names of all subjects enrolled and the date of enrolment in the trial at that trial site, with the subject s corresponding CRF Book Number, to allow the investigator/institution to reveal the identity of any subject, if required. 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. 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.

15 MCB 0501 INT 28-MAY-2012 Page 15 of 129 Subject Screening Log A document kept by the investigator which identifies patients/subjects who entered pre-trial screening.

16 MCB 0501 INT 28-MAY-2012 Page 16 of ETHICS 5.1 INDEPENDENT ETHICS COMMITTEE (IEC) OR INSTITUTIONAL REVIEW BOARD (IRB) The Clinical Study Protocol received favourable opinion from the relevant Independent Ethics Committees (IECs)/Institutional Review Boards (IRBs). The appropriate regulatory authority approved the clinical trial, as required. A list of all IECs/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 and relevant legislation. The parent(s)/legal guardian of the subject was asked to consent that data were recorded, collected, processed and could be 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 Pharma A/S (as appended to the Clinical Study Protocol) in accordance with the EU Data protection Directive (95/46/EC) as well as any national data protection legislation. 5.3 SUBJECT INFORMATION AND INFORMED CONSENT The parent(s)/legal guardian of the subject 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. The par-

17 MCB 0501 INT 28-MAY-2012 Page 17 of 129 ent(s)/legal guardian of the subject was given an opportunity to ask questions and was given sufficient time to consider all relevant issues before consenting. Signed and dated informed consent for the subject to participate in the trial was obtained from the parent(s)/legal guardian, in accordance with regional laws or regulations, prior to any trial related procedure being carried out. The subjects also received appropriate written and verbal information, were given an opportunity to ask questions and sufficient time to consider, before providing written assent. The subject s decision not to participate or to withdraw was to be respected, even if consent was given by the parent(s)/legal guardian. At each visit subsequent to obtaining informed consent and assent, there was a brief discussion between the (sub)investigator and the subject and parent(s)/legal guardian to confirm that consent/assent was maintained. This process was documented in the subject s medical record. A representative information sheet and informed consent form are provided in Appendix

18 MCB 0501 INT 28-MAY-2012 Page 18 of INVESTIGATORS AND TRIAL ADMINISTRATIVE STRUCTURE LEO Pharma A/S was the sponsor of the clinical trial and participating LEO affiliates were authorised by the sponsor to act on behalf of the sponsor. Role International / National Co-ordinating Investigator: Name, title, affiliation, MD, Professor, USA,, LEO: MD,, LEO Pharma A/S, Industriparken 55, DK-2750 Ballerup, Denmark, LEO HQ:,, MSc,, LEO Pharma A/S, Industriparken 55, DK-2750 Ballerup, Denmark, Trial Statistician:, MSc,, LEO Pharma, Longwick Road, Princes Risborough, Bucks, HP27 9RR, UK, International Clinical Trial Manager (ICTM):, BSc,, LEO Pharma, Longwick Road, Princes Risborough, Bucks, HP27 9RR, UK, Sponsor s Medical Expert:, MD,, Medical Department, LEO Pharma A/S, Industriparken 55, DK-2750 Ballerup, Denmark,

19 MCB 0501 INT 28-MAY-2012 Page 19 of 129 Central Laboratory:, UK. Contract Research Organisation (CRO): USA., Clinical Trial Supplies:, LEO Pharma A/S, Industriparken 55, DK-2750 Ballerup, Denmark, Contract Manufacturing Organisation (CMO):, UK. Director, Global Pharmacovigilance:, LEO Pharma A/S, Industriparken 55, DK-2750 Ballerup, Denmark, Report Authors:, MD, Professor, USA,, BSc,, LEO Pharma, Longwick Road, Princes Risborough, Bucks, HP27 9RR, UK,

20 MCB 0501 INT 28-MAY-2012 Page 20 of 129, MSc,, LEO Pharma, Longwick Road, Princes Risborough, Bucks, HP27 9RR, UK,, MD,, Medical Department, LEO Pharma A/S, Industriparken 55, DK-2750 Ballerup, Denmark,, MSc, PhD,, Sweden, A list of investigators and other persons whose participation materially affected the conduct of the trial is included in Appendix

21 MCB 0501 INT 28-MAY-2012 Page 21 of INTRODUCTION 7.1 BACKGROUND INFORMATION TACLONEX ointment, containing calcipotriene 50 mcg/g plus betamethasone 0.5 mg/g (as dipropionate), is a topical therapy indicated for treatment of psoriasis vulgaris on the trunk/limbs for up to 4 weeks in adults. It first obtained marketing approval in 2001 and since then has been marketed in most European countries, Canada, Asia and South America under the tradenames DAIVOBET and DOVOBET. In January 2006, it was approved by the FDA under the tradename TACLONEX and has been marketed in the US since April It is referred to as TACLONEX ointment in this report. The present phase 2 study was undertaken as a post marketing study commitment to the FDA (for NDA ) and to address possible future requests from other Regulatory Authorities. 7.2 PSORIASIS Psoriasis is one of the most common chronic skin diseases, with a prevalence generally estimated at between 1 to 3 percent of the world s population (1). Psoriasis is a disabling disease, with a significant impact on the quality of life comparable with that observed in other chronic medical conditions such as diabetes and depression (2, 3). It is characterised by sharply marginated areas of affected skin which appear thickened, red and scaly, and may itch. This appearance is produced by a greatly increased rate of epidermal proliferation with impaired differentiation of keratinocytes. Dermal blood vessels are dilated and there is infiltration of the skin with immunologically active cells (4, 5). The pathogenesis is incompletely understood, but the disease is thought to be triggered by activation of the cellular immune system with involvement of T cells, dendritic cells, and various cytokines and chemochines (6). Psoriasis can be treated either by topical therapy, phototherapy or by systemic methods (1, 7). The commonly used topical treatments are vitamin D analogues, corticosteroids and tar products. Systemic treatments and phototherapy are generally reserved for extensive disease unresponsive to topical treatments due to concerns over toxicity (6, 7). 7.3 INVESTIGATIONAL PRODUCT DESCRIPTION TACLONEX ointment is a combination of the vitamin D analogue calcipotriene (called calcipotriol outside the US) and the corticosteroid betamethasone dipropionate. Seven large

22 MCB 0501 INT 28-MAY-2012 Page 22 of 129 Phase 3 studies (8-14), together involving more than 6,600 patients, have confirmed the efficacy and safety of TACLONEX ointment in the topical treatment of psoriasis on the trunk/limbs. The pivotal Phase 3 study (8) showed that it was significantly more effective than either betamethasone dipropionate or calcipotriene used individually. In that study, the incidence of lesional/perilesional adverse reactions with TACLONEX ointment was low, similar to that with betamethasone dipropionate and significantly lower than that with calcipotriene. The most common such reaction was pruritus, occurring in 2.7% of patients receiving TACLONEX ointment. The effect of TACLONEX ointment on adrenal function has been assessed by the ACTHchallenge test in two previous studies. In the first study, 11 patients used TACLONEX ointment for up to 4 weeks, and no patients had adrenal suppression after this time (15). In the second study, 19 patients were randomised to one of three regimens (TACLONEX ointment for 52 weeks, TACLONEX ointment and calcipotriene ointment alternating every 4 weeks for 52 weeks, TACLONEX ointment for 4 weeks followed by calcipotriene ointment for 48 weeks), with treatments used once daily as required (14). One patient in the alternating group had a serum cortisol concentration <18mcg/dL 30 minutes after ACTH-challenge at week 52, although this value was >18mcg/dL 60 minutes after ACTH-challenge. Another patient in the 4/48 week group had a serum cortisol concentration <18 mcg/dl 30 minutes after ACTH-challenge before treatment, after 4 weeks treatment with TACLONEX ointment and after a further 48 weeks treatment with calcipotriene ointment, although this value was >18 mcg/dl 60 minutes after ACTH-challenge at all three of these visits. Serum calcium was assessed in three of the phase 3 studies, and no clinically significant changes were found (11-13). 7.4 STUDY RATIONALE The aim of this study was to evaluate the safety and efficacy of TACLONEX ointment in the adolescent age group (12-17 years). TACLONEX ointment has marketing approval in many countries for the treatment of psoriasis vulgaris on the trunk/limbs in adults, i.e. patients 18 years of age and above. Prior to initiation of this trial no studies had been conducted in patients less than 18 years of age. However, about 35% of affected individuals develop the disease before the age of 20, and 25% are diagnosed between 10 and 19 years of age (16). Only 10% of psoriasis patients develop the disorder before the age of ten (16). The clinical

23 MCB 0501 INT 28-MAY-2012 Page 23 of 129 appearance of psoriasis in children (ages 2-11 years) may differ from the classical picture seen in older patients. Facial psoriasis is more common in children than in adults and may be the only site affected; guttate and flexural forms are particularly common in children (17-20). It is therefore expected that there are few children with classical psoriasis vulgaris on the trunk/limbs. Furthermore, children have a higher body surface area (BSA) to body mass ratio than adolescents and adults which increases the potential for adverse drug reactions (ADRs) due to absorption of topically applied compounds through the skin (21) and therefore limits the use of potent topical corticosteroids in this age group (22). Hence children were not enrolled into this study. To evaluate the safety of TACLONEX ointment, all adverse events (AEs) reported by the patient or observed by the investigator were recorded. In addition, any systemic absorption of the active components, betamethasone dipropionate and calcipotriene, were evaluated by assessing adrenal function and calcium metabolism, respectively. Laboratory evidence of adrenal insufficiency due to the use of topical corticosteroid treatment has been reported (23). This is due to systemic absorption of the corticosteroid, which then induces suppression of the hypothalamic-pituitary-adrenal (HPA) axis due to a negative feedback effect on the pituitary gland and the hypothalamus (23, 24). This results in a decrease in the secretion of ACTH from the pituitary gland. The adrenal glands depend on ACTH as a tropic hormone in such a way that ACTH deficiency results in a reversible inability to produce cortisol (25). Hence the adrenal glands lose the capacity to produce cortisol in response to an ACTH-challenge. Adrenal function can therefore be measured by injection of a synthetic subunit of ACTH into the patient, and then measuring the production of cortisol by the adrenal glands in response to this. A serum cortisol concentration of 18 mcg/dl or less at 30 and 60 minutes after the injection indicates adrenal suppression (24). The effect of TACLONEX ointment on adrenal function in adult patients has been assessed by the ACTH-challenge test in two previous studies (14, 15). After a total of 24 patients had received TACLONEX ointment, two had a serum cortisol concentration <18mcg/dL at 30 minutes after ACTH-challenge, although this value was >18mcg/dL at 60 minutes after ACTH-challenge; in one of these patients the same was true at the pre-treatment baseline visit. Hence subjects in the present study had an ACTH-challenge test before and after treatment. The pre-treatment test was to ensure that adrenal function was normal before starting study treatment. Serum cortisol concentrations at 60 minutes after injection were

24 MCB 0501 INT 28-MAY-2012 Page 24 of 129 measured in addition to those at 30 minutes in order to show the maximum cortisol level achieved (24). Overdosage with topical calcipotriene can cause hypercalcemia (26), due to the systemic absorption of calcipotriene, which then affects calcium metabolism as it is a vitamin D analogue. However, extensive experience with topical use of calcipotriene in psoriasis has demonstrated no significant impact on calcium metabolism when used in the recommended amounts (maximum weekly dose in adults of 100 g of a 50 mcg/g concentration). Doses up to 300 g have been used with serum calcium remaining within the normal range (26). Therefore, calcium metabolism was evaluated in the present study by measurement of serum calcium and the urinary calcium:creatinine ratio before and after treatment. The urinary excretion of calcium is most accurately assessed by the collection of a 24-hour urine sample. However, obtaining 24 hour urine collections in children is known to be difficult, and it is also expected to be difficult in adolescents. The calcium:creatinine ratio in a single voided random urine sample has been shown to correlate well with the 24-hour urinary calcium excretion (27), and this method was therefore chosen for the present study. A study has found that chronic high calcium intake did not cause a significant increase in urinary calcium, presumably because of a PTH-mediated decrease in the 1-25 (OH)2D levels which decreased the fraction of calcium absorbed (28). However, the combination of high calcium intake with vitamin D supplementation, or extreme calcium intake alone, significantly increased urinary calcium. Hence the use of calcium or vitamin D supplements was excluded in this study. The subjects had a washout period of 1-4 weeks if they were using treatments which could have an effect on the ACTH-challenge test (e.g. corticosteroids, enzymatic inductors, cytochrome P450 inhibitors, hypoglycemic sulfonamides, antidepressive medications, estrogen), calcium metabolism (e.g. vitamin D analogues) or the psoriasis to be treated with study medication (e.g. systemic/topical/ultraviolet anti-psoriatic therapy, although emollients were allowed).

25 MCB 0501 INT 28-MAY-2012 Page 25 of TRIAL OBJECTIVES 8.1 PRIMARY OBJECTIVE The primary objective of the study was to evaluate the safety of TACLONEX ointment in the treatment of psoriasis vulgaris on the trunk and/or limbs in adolescent patients (aged 12 to 17 years). 8.2 SECONDARY OBJECTIVE The secondary objective was to evaluate the efficacy of TACLONEX ointment in the treatment of psoriasis vulgaris on the trunk and/or limbs in adolescent patients (aged 12 to 17 years).

26 MCB 0501 INT 28-MAY-2012 Page 26 of INVESTIGATIONAL PLAN The entire Clinical Study Protocol is presented in Appendix and the case report form (CRF) is presented in Appendix OVERALL TRIAL DESIGN AND PLAN - DESCRIPTION This was a national, multi-centre, prospective, non-controlled, single-group, 4-week study. All subjects received TACLONEX ointment to apply once daily to psoriasis on the trunk/limbs in the evening for 4 weeks Individual Phases The study was conducted with three successive individual phases: Washout/Screening Phase Treatment Phase Follow-up Phase (if applicable) Washout/screening phase The washout/screening phase lasted for 3 days to 6 weeks, depending on the prior use of excluded treatments. There were two screening visits: screening visit 1 (SV1), and screening visit 2 (SV2). Depending on the subjects use of excluded treatments, SV1 was performed at the same time as SV2 or up to 4 weeks before SV2; SV2 was performed at 3 to 14 days before visit 1. Treatment phase The treatment phase lasted for 4 weeks. There were 3 visits: visit 1 (day 0), visit 2 (day 14) and visit 3 (day 28). Visits 2 and 3 were to be performed within ±2 days of the scheduled time relative to visit 1; if they were outside this window, the (sub)investigator was to record the reason in the subject s medical record, but LEO/Health Decisions did not need to be notified. TACLONEX ointment was applied once daily in the evening to psoriasis of the trunk/limbs excluding psoriasis on the genitals and skin folds (axillae, groin, infra mammary, and those around the buttocks). If the psoriasis cleared during the treatment phase, it was at the discretion of the (sub)investigator whether the subject continued to apply study medication or stopped applying it.

27 MCB 0501 INT 28-MAY-2012 Page 27 of 129 Follow-up phase If applicable, the treatment phase was followed by a follow-up (FU) phase consisting of Visit FU1 and/or Visit FU2. Visit FU1 was to take place 14 days after the last visit in the treatment phase, but only if there was an ongoing AE at this time of possible/probable/not assessable relationship to the study medication. At the (sub)investigator s discretion, the information required at this visit could be obtained over the telephone, and the subject did not need to make the visit. Visit FU2 was to take place 28 days after the ACTH-challenge test performed at visit 3, but only if this test showed a serum cortisol concentration 18 mcg/dl at 30 minutes after ACTHchallenge. Visits FU1 and FU2 were to be performed within ±2 days of the scheduled time; if they were outside this window, the (sub)investigator was to record the reason in the subject s medical record, but LEO/Health Decisions did not need to be notified. Overall Chart Washout/ screening phase Treatment phase Follow-up phase (if applicable) 0 to 28 days before SV2-3 to Days SV1 SV FU1 FU2 Visits 9.2 DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF CONTROL GROUPS This study evaluated the safety and efficacy of TACLONEX ointment in the treatment of psoriasis vulgaris on the trunk and/or limbs in adolescent subjects (aged 12 to 17 years). A once daily regimen for 4 weeks was chosen based on the approved application frequency and treatment duration for TACLONEX ointment in adults (8-10).

28 MCB 0501 INT 28-MAY-2012 Page 28 of 129 The maximum weekly dosage approved for adults is 100 g. To allow a safety margin, the maximum weekly dosage for this study was 60% of the maximum weekly adult dosage, i.e. 60 g. To be eligible for the study, subjects had to have an extent of psoriasis on the trunk and/or limbs of 5-30% of the BSA and a disease severity of at least moderate according to the investigator s global assessment (IGA). It was expected that many adolescent subjects with psoriasis would have less extensive and less severe disease. However, since the main purpose of the present study was to evaluate the safety of study treatment, the exposure to treatment had to be as close to maximum as possible. In order to include as few adolescent subjects as possible considering the extensive and invasive investigations in the Clinical Study Protocol, the study was non-controlled in order to expose all subjects to the study treatment. The response criteria for assessment of systemic AEs were based on objective laboratory analyses, therefore the comparison with a control group was of less relevance. Efficacy evaluation was a secondary objective and was not used to obtain confirmatory evidence of efficacy in adolescents. A target of 30 subjects providing data for the ACTH-challenge test at the end of treatment were to be enrolled in the study. This number of subjects undergoing ACTH-challenge testing had previously been accepted by the FDA as an adequate sample size. 9.3 SELECTION OF TRIAL POPULATION To be able to evaluate the safety and efficacy of TACLONEX in adolescent patients, subjects from 12 to 17 years of age with psoriasis vulgaris on the trunk and/or limbs were included in the study Inclusion Criteria 1. Aged 12 to 17 years, inclusive. 2. Either sex. 3. Any race or ethnicity.

29 MCB 0501 INT 28-MAY-2012 Page 29 of Attending a hospital out-patient clinic or the private practice of a dermatologist for treatment of psoriasis. For those attending the private practice of a dermatologist, the centre had to have experience of performing the ACTH-challenge test, and the ability/facilities to deal with allergic/anaphylactic reactions. The centre should also have close proximity, and easy access, to an acute general hospital. 5. At visit 1, a clinical diagnosis of psoriasis vulgaris on the trunk and/or limbs which was: - amenable to topical treatment with a maximum of 60 g of study medication per week, and - of an extent of 5-30% of BSA (any psoriasis on the genitals or skin folds should not be included in this calculation of extent), and - of at least a moderate severity by the investigator s global assessment. 6. At SV2, a serum cortisol concentration above 5 mcg/dl before ACTH-challenge and above 18 mcg/dl at 30 minutes after ACTH-challenge. 7. At SV2, albumin-corrected serum calcium and urinary calcium:creatinine ratio within the reference range. 8. At SV2, females of child-bearing potential had to have a negative result for a urine pregnancy test before the ACTH-challenge test and had to agree to use an adequate method of contraception according to national requirements (abstinence is an acceptable method) during the study. The contraception should have started an adequate period of time before the pregnancy test, as judged by the (sub)investigator, bearing in mind that the urine pregnancy test might not detect a pregnancy until the first missed period. 9. Following receipt of verbal and written information about the trial, the parent(s)/legal guardian of the patient had to provide signed and dated informed consent and the patient also had to provide assent, in accordance with regional laws or regulations. Such consent/assent had to be provided before any trial-related activity was carried out, including activities relating to washout periods. 10. Patients fulfilling national requirements/law for participation in this study.

30 MCB 0501 INT 28-MAY-2012 Page 30 of Exclusion Criteria 1. A history of serious allergy, serious asthma, or serious allergic skin rash. 2. A history of sensitivity to any medication (including ACTH/tetracosactide/cosyntropin), or to any component of CORTROSYN or TACLONEX ointment. 3. PUVA or Grenz ray therapy within 4 weeks prior to Visit 1 and during the study. 4. UVB therapy within 2 weeks prior to Visit 1 and during the study. 5. Systemic treatment with biological therapies with a possible effect on psoriasis vulgaris within the following time period prior to Visit 1 (or enrolment) and during the study: - etanercept - within 4 weeks prior to Visit 1 - adalimumab, alefacept, efalizumab, infliximab - within 2 months prior to Visit 1 - ustekinumab - within 4 months prior to Visit 1 - experimental products - within 4 weeks/5 half-lives (whichever is longer) prior to enrolment 6. Systemic treatment with corticosteroids (including inhaled and nasal) within 12 weeks prior to SV2 and during the study. 7. Systemic treatment with therapies other than biologicals, with a possible effect on psoriasis vulgaris (e.g., vitamin D analogues, retinoids, hydroxycarbamide, azathioprine, methotrexate, cyclosporine, other immunosuppressants) within 2 weeks prior to SV2 and during the study. 8. Any topical treatment for any disease on any body location with Class 1 to 5 corticosteroids within 2 weeks prior to SV2, with Class 6 or 7 corticosteroids or vitamin D analogues within 1 week prior to SV2, or during the study. In addition, for psoriasis of the trunk/limbs (excluding psoriasis of the genitals/skin folds), no other treatments (such as dithranol and tar) were allowed within 2 weeks prior to visit 1, except for emollient which could be used up to, but not after, visit Treatment with any of the following medications within 4 weeks prior to SV2 or during the study: enzymatic inductors (e.g., barbiturates, phenytoin, rifampicin, carbamazepine),

31 MCB 0501 INT 28-MAY-2012 Page 31 of 129 systemic or topical cytochrome P450 inhibitors (e.g., ketoconazole), hypoglycemic sulfonamides, antidepressive medications, estrogen therapy or any other medication known to affect cortisol levels or HPA-axis integrity. 10. Treatment with any non-marketed drug substance (i.e., an agent which had not yet been made available for clinical use following registration) within 4 weeks prior to enrolment, or longer if the class of substance met any of the above criteria for a longer washout (e.g., biological treatments). 11. Calcium supplements or vitamin D supplements within 4 weeks prior to SV2 and during the study. 12. Planned initiation of, or changes to, concomitant medication that could affect psoriasis vulgaris (e.g., beta-blockers, anti-malaria drugs, lithium, ACE inhibitors) after visit Planned excessive exposure of treated areas to either natural or artificial sunlight (including tanning booths, sun lamps, etc) after visit Current diagnosis of guttate, erythrodermic, exfoliative or pustular psoriasis. 15. Any of the following conditions present on the areas(s) to be treated with study medication: 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 rosacea, acne vulgaris, atrophic skin, striae atrophicae, fragility of skin veins, ichthyosis, ulcers or wounds. 16. Other inflammatory skin diseases that could confound the evaluation of psoriasis vulgaris of the trunk and/or limbs. 17. Any of the following conditions if known or suspected: severe renal insufficiency, severe hepatic disorders, disorders of calcium metabolism associated with hypercalcemia, any cardiac condition or an endocrine disorder that could affect the results of the ACTH challenge test. 18. Clinical signs or symptoms of Cushing s disease or Addison s disease.

32 MCB 0501 INT 28-MAY-2012 Page 32 of Diabetes mellitus. 20. Not following nocturnal sleep patterns (eg night-shift workers were excluded). 21. Any clinically significant abnormality in the laboratory tests, physical examination or blood pressure/heart rate measurement undertaken at SV Current participation in any other interventional clinical trial. 23. Previously enrolled in this trial. 24. Patient or parent(s)/legal guardian who, in the opinion of the investigator, was unlikely to comply with the Clinical Study Protocol (e.g., due to alcoholism, drug dependency or psychotic state). 25. Females who were pregnant, wishing to become pregnant during the study or breastfeeding Removal of Subjects from Therapy or Assessment Subjects could withdraw for any of the following reasons: medical reasons, unacceptable treatment efficacy, unacceptable AEs, emergence of exclusion criteria, voluntary withdrawal or other reasons. Subjects had to be withdrawn if they were found to have become pregnant or experienced an allergic reaction to CORTROSYN TM. Subjects who were discovered, after enrolment/randomisation, not to have fulfilled all in/exclusion criteria at time of enrolment, were to be withdrawn from the study. Such deviation(s) from the Clinical Study Protocol had to be reported to LEO (and IECs/IRBs, as appropriate) and recorded in the Clinical Study Report. If a subject withdrew at visit 2, the additional tests scheduled for visit 3 were to be done at this time (blood/urine sampling for hematology/biochemistry/urinalysis/pregnancy test, physical examination, measurement of blood pressure/heart rate), with the exception of the ACTH-challenge test.

33 MCB 0501 INT 28-MAY-2012 Page 33 of TREATMENTS Treatments Administered The investigational product in the present study was TACLONEX ointment as described in All subjects received TACLONEX ointment to apply once daily to psoriasis on the trunk/limbs in the evening for 4 weeks Identity of Investigational Product Table 1: Identity of investigational product Finished product brand name TACLONEX ointment Formulation Ointment Active ingredient name/strength Calcipotriene 50 mcg/g plus betamethasone 0.5 mg/g (as dipropionate) Excipients Mineral oil, PPG-15 stearyl ether, dl-alpha tocopherol, white petrolatum Pack size 60 g per tube Manufacturer s name LEO Pharma A/S Supplier s name LEO Pharma A/S Certifier s name Batch numbers / expiry dates / ; / ; / Method of Assigning Subjects to Treatment Groups Subjects who were found to comply with all the inclusion and exclusion criteria received treatment with TACLONEX ointment Selection of Doses in the Trial The maximum weekly dosage approved for adults is 100 g. In this study, the maximum weekly dosage was reduced to 60 g. The lowest BSA expected for a subject in this study was 75% of the average adult BSA, hence a maximum dosage in this study of 60% of the adult maximum dosage should give a reasonable safety margin.

34 MCB 0501 INT 28-MAY-2012 Page 34 of Selection and Timing of Dose for each Subject Subjects who were found to comply with all the inclusion and exclusion criteria received TACLONEX ointment to apply once daily in the evening for 4 weeks. A once daily regimen was chosen based on the approved application frequency for TACLONEX ointment in adults Blinding Not Applicable Prior and Concomitant Therapy Treatments that required washout before Visit 1/SV2/enrolment PUVA or Grenz ray therapy (4 weeks prior to Visit 1). UVB therapy (2 weeks prior to Visit 1). Systemic treatment with biological therapies with a possible effect on psoriasis vulgaris: etanercept (4 weeks prior to Visit 1), adalimumab/alefacept/efalizumab/infliximab (2 months prior to Visit 1)*, ustekinumab (4 months prior to Visit 1)*, experimental products (4 weeks/5 half lives, whichever is longer, prior to enrolment). Systemic treatment with corticosteroids, including inhaled and nasal (12 weeks prior to SV2)*. Systemic treatment with other therapies with a possible effect on psoriasis vulgaris, e.g., vitamin D analogues, retinoids, hydroxycarbamide, azathioprine, methotrexate, cyclo sporine, other immunosuppressants (2 weeks prior to SV2). Any topical treatment for any disease on any body location with Class 1 to 5 corticosteroids (2 weeks prior to SV2), or with Class 6/7 corticosteroids or vitamin D analogues (1 week prior to SV2). In addition, for psoriasis of the trunk/limbs, excluding psoriasis of the genitals/skin folds, no other treatments (such as dithranol and tar) allowed (2 weeks prior to visit 1), except for emollient (no washout required). Enzymatic inductors (e.g., barbiturates, phenytoin, rifampicin, carbamazepine), systemic or topical cytochrome P450 inhibitors (e.g., ketoconazole), hypoglycemic sulfonamides, antidepressive medications, estrogen therapy or any other medication known to affect

35 MCB 0501 INT 28-MAY-2012 Page 35 of 129 cortisol levels/hpa axis integrity (4 weeks prior to SV2). Non-marketed drug substances, i.e. an agent which had not yet been made available for clinical use following registration (4 weeks prior to enrolment, or longer if the class of substance met any of the above criteria for a longer washout, e.g. biological treatments). Calcium or vitamin D supplements (4 weeks prior to SV2). * Note: the time between SV1 and Visit 1 could not be longer than 6 weeks, and between SV1 and SV2 not longer than 4 weeks, therefore subjects receiving, or having recently received, these treatments at SV1 could not be enrolled. Treatments during the study: Treatments which could not be used during the treatment phase (Visits 1-3) were the same as those requiring a washout period, as listed previously, with the addition that the following were not allowed: Emollient on areas of psoriasis to be treated with study medication. Initiation of, or changes to, concomitant medication that could affect psoriasis vulgaris (e.g. beta-blockers, lithium, anti-malaria drugs, ACE inhibitors). Excessive exposure of treated areas to either natural or artificial sunlight (including tanning booths, sunlamps, etc). Hence psoriasis of the trunk/limbs, except for that on the genitals/skin folds, could only be treated with the study medication. Psoriasis of the genitals, skin folds, face and scalp could be treated with any topical medication except corticosteroids or vitamin D analogues. Bath oils and moisturizing soaps were allowed. Treatments during follow-up: During the follow-up phase, subjects who required a repeat ACTH-challenge test at FU2 were not to receive corticosteroid therapy (topical or systemic), enzymatic inductors, cytochrome P450 inhibitors, hypoglycemic sulfonamides, antidepressive medications, estrogen therapy, or any other medication known to affect cortisol levels/hpa axis integrity. Such subjects were also to continue to use contraception if they were of child-bearing potential. Otherwise, there were no restrictions on the use of concomitant treatment during the follow-up phase.

36 MCB 0501 INT 28-MAY-2012 Page 36 of Treatment Compliance The person responsible for dispensing the trial medication was responsible for maintaining adequate control of the investigational product and for documenting all transactions with it. The investigational product was to be stored in a safe and secure place, and proper dispensing arrangements were to be made. All investigational products supplied to and returned from the site were to be fully documented by use of drug accountability forms. At visits 2 and 3, the subject was asked if he/she had used the medication every day. If this was not the case, the number of days missed and the reason for this was recorded. At Visits 2 and 3, investigational product, including empty tubes, dispensed at the previous visit was to be returned by the subject. An inventory (Individual Drug Accountability Form) was to be kept of all trial medication given to and returned by each patient who received medication. All investigational product supplies returned from the site were to be reconciled with the Individual Drug Accountability Forms. All returned tubes were subsequently to be weighed by Catalent Pharma Solutions to determine the amount of investigational product used Non-Investigational Medicinal Products CORTROSYN (Cosyntropin) for Injection CORTROSYN, which is a commercial product for injection, was used for the ACTH challenge test. One vial contains cosyntropin 250 micrograms (equivalent to 25 IU ACTH). A detailed description of CORTROSYN is given in the Clinical Study Protocol (Appendix ) % Sodium Chloride Injection, USP A detailed description of the 0.9% Sodium Chloride Injection, USP, is given in the Clinical Study Protocol (Appendix ). It was used to reconstitute the CORTROSYN.

37 MCB 0501 INT 28-MAY-2012 Page 37 of EFFICACY AND SAFETY VARIABLES Efficacy and Safety Measurements Assessed and Flow Chart Table 2: Schedule/chart of trial procedures Phase Washout/screening Treatment Follow-up Visit SV1 SV FU1 b FU2 c Day 0 a to 28-3 to days before SV2 Informed Consent X CRF number assigned X Demographics X Inclusion/exclusion criteria X X X Concomitant medication X X X X X X Physical examination/blood pressure/heart X X e rate Hematology/biochemistry/urinalysis X X e Urine pregnancy test d X X e ACTH-challenge test X X X Adverse events X X X X X X Investigator assessments of psoriasis X X X Patient assessment of psoriasis X X X Dispensing of study medication X X Return of study medication X X Compliance check X X a. If the necessary criteria were met, SV2 could be performed at the same time as SV1. b. FU1 was for subjects who, at the last visit during the treatment phase, had ongoing AEs of a probable/possible/not assessable relationship to study medication. c. FU2 was for subjects who, at visit 3, had a serum cortisol concentration 18 mcg/dl at 30 minutes after the ACTH-challenge test. d. In female subjects of child-bearing potential. e. If the subject dropped out at visit 2, these procedures were to be performed at that time.

38 MCB 0501 INT 28-MAY-2012 Page 38 of Efficacy Investigator Assessments of Psoriasis The (sub)investigator made the following clinical assessments. Ideally, all assessments for a subject were made by the same (sub)investigator. Investigator s global assessment of disease severity At Visits 1, 2 and 3, the (sub)investigator made a global assessment of the disease severity of the psoriasis on the trunk and limbs using the 6-point scale below. This assessment represented the average lesion severity on the trunk and limbs. The assessment was based on the condition of the disease at the time of evaluation, and not in relation to the condition at a previous visit. Clear Almost clear Mild Moderate Severe Very severe Plaque thickening = no elevation or thickening over normal skin Scaling = no evidence of scaling Erythema = none or hyperpigmentation or residual red coloration Plaque thickening = none or possible thickening but difficult to ascertain whether there is a slight elevation above normal skin level Scaling = none or residual surface dryness and scaling Erythema = light pink coloration 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 elevation typically with hard or sharp edges Scaling = non-tenacious scale predominates, covering most or all of the lesions Erythema = very bright red coloration Plaque thickening = very marked elevation typically with hard or sharp edges Scaling = thick tenacious scale covers most or all of the lesions Erythema = extreme red coloration; deep red coloration Investigator s assessment of extent and severity by body region At Visits 1, 2 and 3, the (sub)investigator assessed the extent of psoriasis and the severity of the clinical signs (redness, thickness and scaliness) by body region (arms, trunk, legs).

39 MCB 0501 INT 28-MAY-2012 Page 39 of 129 The extent of psoriatic involvement was recorded for each of the three regions (arms, trunk and legs) using the following scale: 0 = no involvement 1 = < 10% 2 = 10-29% 3 = 30-49% 4 = 50-69% 5 = 70-89% 6 = % Note: arms included the hands trunk included the neck legs included the buttocks and feet The severity of the psoriasis in each of the three regions was recorded for each of the signs of redness, thickness and scaliness. For each clinical sign, a single score, reflecting the average severity of all psoriatic lesions on the given body region, was determined according to the scale below: Redness 0 = none (no erythema) 1 = mild (faint erythema, pink to very light red) 2 = moderate (definite light red erythema) 3 = severe (dark red erythema) 4 = very severe (very dark red erythema) Thickness 0 = none (no plaque elevation) 1 = mild (slight, barely perceptible elevation) 2 = moderate (definite elevation but not thick) 3 = severe (definite elevation, thick plaque with sharp edge) 4 = very severe (very thick plaque with sharp edge)

40 MCB 0501 INT 28-MAY-2012 Page 40 of 129 Scaliness 0 = none (no scaling) 1 = mild (sparse, fine scale, lesions only partially covered) 2 = moderate (coarser scales, most of lesions covered) 3 = severe (entire lesion covered with coarse scales) 4 = very severe (very thick coarse scales, possibly fissured) Investigator s assessment of the total BSA involvement At Visit 1 only, the (sub)investigator assessed the total psoriatic involvement on the arms, trunk and legs, but excluded any involvement on the skin folds or genitals, as a percentage of the total BSA. To aid this estimation, the surface of a full, flat palm (including the five digits) of the subject correlated to approximately 1% of the total BSA. The purpose of this was to obtain an estimate of the total area to be treated with study medication Patient Assessment of Psoriasis Patient s global assessment of disease severity This assessment was made at Visits 1, 2 and 3, using the 5-point scale below. The assessment was based on the condition of the disease at the time of the evaluation and not in relation to the condition at a previous visit. The patient s assessment was to be made before the (sub)investigator s assessments. The (sub)investigator explained the categories of the scale to the subject and the subject told the (sub)investigator which category to tick. Clear Very mild Mild Moderate Severe No psoriasis symptoms at all Very slight psoriasis symptoms, does not interfere with daily life Slight psoriasis symptoms, interferes with daily life only occasionally Definite psoriasis symptoms, interferes with daily life frequently Intense psoriasis symptoms, interferes or restricts daily life very frequently Safety ACTH-challenge test The ACTH-challenge test was performed at SV2 and Visit 3. If the subject dropped out at Visit 2, the ACTH-challenge test scheduled for Visit 3 was not to be performed.

41 MCB 0501 INT 28-MAY-2012 Page 41 of 129 If the result of the ACTH-challenge test at Visit 3 showed a serum cortisol concentration 18 mcg/dl at 30 minutes after the ACTH-challenge, a further ACTH-challenge test was required 28 days later at visit FU2. If the results of the ACTH-challenge test at Visit FU2 continued to show a serum cortisol concentration 18mcg/dL at 30 minutes after ACTH-challenge, further ACTH-challenge tests were to be performed, but not more often than at 4-weekly intervals, until the adrenal suppression resolved (i.e. serum cortisol concentration >18mcg/dL at 30 minutes after the ACTH-challenge). The following procedures were to be performed before the ACTH-challenge tests at SV2 and Visit 3: physical examination, blood pressure/heart rate measurement, blood/urine sampling for central laboratory analysis (hematology/biochemistry/urinalysis) and urine pregnancy test (in female patients of child-bearing potential). To perform the ACTH-challenge test, a 2.5 ml sample of venous blood was drawn at a.m. ±30 minutes. This sample was also the one on which the biochemistry analyses were performed, as detailed in Section After this, CORTROSYN TM was injected. The contents of one vial (250 mcg) was reconstituted in 2 to 5 ml of saline and injected intravenously over a 2-minute period. Two further 2.5 ml samples of venous blood were drawn exactly 30 and 60 minutes after the injection (counting from the end of the period over which the injection was given). Serum cortisol concentrations were determined for each blood sample by the Central Laboratory. The Central Laboratory provided the materials and instructions necessary for the collection and transport of the blood samples. The time of injection and of blood sampling were recorded in the CRF. For each subject, the ACTH-challenge test was to be performed at the same time of the day (including the 30 minute range) Physical examination and blood pressure/heart rate measurement At SV2 and Visit 3, the subjects had a full physical examination and measurement of blood pressure and heart rate. This was to be performed before the ACTH-challenge test that was also scheduled for these visits. If a subject dropped out at Visit 2, the physical examination and blood pressure/heart rate measurement were to be performed at this time. Any clinically significant abnormalities found in the physical examination were to be recorded.

42 MCB 0501 INT 28-MAY-2012 Page 42 of 129 Blood pressure was measured with a calibrated device using an appropriate cuff size. Subjects should be sitting for 5 minutes before measurement and two readings taken, separated by 2 minutes. Systolic and diastolic blood pressure was to be recorded in mmhg, and the disappearance of sound (Korotkoff phase V) was to be used for the diastolic reading. Blood pressure was to be measured under standardised conditions, as nearly as possible at the same time of day, with the same apparatus on the same arm and preferably by the same personnel. Heart rate was also to be measured after subjects had been sitting for 5 minutes Laboratory Assessments Central Analysis It was recommended that indwelling catheters introduced under topical anesthesia were used for the repeated blood sampling, to minimise discomfort for the subject, unless the (sub)investigator judged that there were good reasons not to. A 6.5 ml sample of venous blood and a 30 ml sample of urine were taken at SV2 and at Visit 3. The 6.5 ml sample of blood consisted of 2 ml for hematology analysis, 2.5 ml for serum biochemistry analysis and 2 ml for analysis of plasma parathyroid hormone. The samples were taken before the ACTH-challenge test that was also scheduled for these visits. Measurement of serum cortisol concentration was included in the biochemistry analysis, and this value was the baseline serum cortisol concentration for the ACTH-challenge test. If a subject dropped out at Visit 2, samples for central laboratory analysis were to be taken at this time. The Central Laboratory provided the materials and instructions necessary for the collection and transport of the samples. Phosphorus was reported instead of phosphate (according to the Clinical Study Protocol phosphate was to be reported (Appendix )), but these are equivalent measures. The following analyses were performed on the blood samples: Hematology Hemoglobin Hematocrit

43 MCB 0501 INT 28-MAY-2012 Page 43 of 129 Red blood cell count Mean corpuscular volume White blood cell count, including differential count Platelet count Serum Biochemistry Cortisol Urea Creatinine Albumin Sodium Potassium Chloride Calcium Phosphorus In addition, plasma parathyroid hormone was analysed. Urinalysis The following analyses were performed on the urine sample by dipstick test: Glucose Ketones The following were analysed quantitatively: Calcium Phosphorus Creatinine The laboratory also reported: albumin-corrected serum calcium in mmol/l using the formula: serum calcium (total) in mmol/l + (0.02 x [40-serum albumin in g/l]) the urinary calcium:creatinine ratio the urinary phosphorus:creatinine ratio If any laboratory results were abnormal, the (sub)investigator was to follow-up the subject as clinically appropriate.

44 MCB 0501 INT 28-MAY-2012 Page 44 of 129 Local Analysis A urine pregnancy test was performed at the trial site at SV2 and visit 3 in female subjects of child-bearing potential. The urine pregnancy test had to be done before the ACTHchallenge test that was scheduled for these visits. If a subject dropped out at Visit 2, the urine pregnancy test was to be performed at this time. The test kits were provided by the Central Laboratory Adverse Events (AEs) Adverse Event (AE) An AE is any untoward medical occurrence in a subject occurring after the informed consent form has been signed. The AE does not necessarily have a causal relationship with the trial treatment or trial procedures. Consequently, AEs include adverse drug reactions (ADRs), significant abnormal laboratory values and intercurrent diseases. A serious adverse event (SAE) is any untoward medical occurrence that results in death is life-threatening requires inpatient hospitalisation or prolongation of existing hospitalisation results in persistent or significant disability/incapacity or is a congenital anomaly/birth defect or other medically important conditions* ) * ) Events that may not be immediately life-threatening or result in death or hospitalisation but may jeopardise the subject or may require intervention to prevent one of the other outcomes listed in the definition above. Examples of such events are allergic broncospasm, blood dyscrasias, and convulsions. Reporting of Adverse Events Global Pharmacovigilance was responsible for the assessment of headquarter expectedness according to LEO procedures. The relevant reference document for this clinical trial was the Investigator s Brochure Taclonex Ointment in Paediatric patients, edition number 1, dated 16-JUL-2008 as agreed between the. The US Product Monograph was used as the Reference Safety Document for CORTROSYN.

45 MCB 0501 INT 28-MAY-2012 Page 45 of 129 At SV2 (after the ACTH-challenge test) and all successive visits, the subject was asked a non-leading question by the investigator: How have you felt since I saw you last? Anything new you wish to discuss?. The parent(s)/legal guardian was also asked about the subject, as appropriate. No specific symptoms were asked for. If there were no AEs to record, no further questions were asked and NO was stated. In case there were one or more AEs to record, then YES was stated and the investigator recorded the event term, intensity, duration, location for cutaneous AEs, suspected causal relationship to the investigational and non-investigational products and outcome. It was important that the investigator also observed the subject for any changes not reported by the subject or parent(s)/legal guardian, and to record these changes. All treated lesions were to be examined by the (sub)investigator for any signs of irritancy and adverse events associated with the use of topical corticosteroids, such as skin atrophy, hypopigmentation, telangiectasia and striae. Only medically qualified (sub)investigators assessed the subject for (Serious) Adverse Events. Events reported by the subject, or observed by the (sub)investigator, that fell into any of the above definitions were to be recorded on the AE page of the CRF and described in the following manner: The nature of the event was described in precise, English medical terminology (i.e., not necessarily the exact words used by the subject). Whenever possible, a specific diagnosis should be stated (e.g., allergic contact dermatitis). For cutaneous AEs the location had to be part of the AE description and was described using the following terminology: lesional/perilesional ( 2 cm from the border of lesion(s) treated with investigational product) or distant (>2 cm from the lesion border) The intensity of the event was described in terms of mild, moderate or severe according to the investigator s clinical judgement. Mild: The AE does not interfere in a significant manner with the subject s normal functioning level. It may be an annoyance.

46 MCB 0501 INT 28-MAY-2012 Page 46 of 129 Moderate: The AE produces some impairment of functioning but is not hazardous to health. It is uncomfortable and/or an embarrassment. Severe: The AE produces significant impairment of functioning or incapacitation and/or is a hazard to the patient. 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 and the noninvestigational medicinal product (NIMP) were described in terms of probable, possible, not related or not assessable according to the following: Probable: Follows a reasonable temporal sequence from administration of the investigational product/nimp Could not be reasonably explained by the subject s clinical state, environmental or toxic factors or other therapies administered to the subject Follows a known pattern of response to the investigational product/nimp Disappears or decreases on cessation or reduction in dose of the investigational product/nimp Reappears or worsens upon re-challenge. Possible: Follows a reasonable temporal sequence from administration of the investigational product/nimp Could be reasonably explained by the subject s clinical state, environmental or toxic factors or other therapies administered to the subject Follows a known pattern of response to the investigational product/nimp. Not related: Does not follow a reasonable temporal sequence from administration of the investigational product/nimp Could be reasonably explained by the patient s clinical state, environmental or toxic factors or other therapies administered to the patient Does not reappear or worsen upon rechallenge Does not follow a known pattern of response to the investigational product/nimp.

47 MCB 0501 INT 28-MAY-2012 Page 47 of 129 Not assessable: The AE cannot yet be judged otherwise because present information is insufficient or contradictory. A final judgement (i.e. probably, possibly, or not related) shall be made as more information becomes available, at the latest when the patient has completed the trial. The outcome of the event was classified and handled as follows: Recovered/resolved: (S)AE stop date was to be provided Recovering/resolving: Can be used in cases where patient is known to be clearly recovering from an event. Event is, however, not resolved yet. Follow-up required Not recovered/not resolved: Event is ongoing Follow-up required Recovered with sequelae/resolved with sequelae: Used only with persistent incapacity/life long sequelae, e.g., like blindness after diabetes mellitus, hemiparesis after stroke (S)AE stop date was to be provided Fatal: (S)AE stop date (date of death) was to be provided only for the events leading to death Unknown: Unknown to Investigator, e.g., subject lost to follow-up. Once a subject had completed the trial, the investigator was to follow-up for outcome on all non-serious AEs classified as of possible/probable/not assessable relationship to the investigational product for 14 days after the last application of investigational product or until final outcome was determined, whichever came first. Other Events to be Reported Pregnancy Pregnancy was to be reported to LEO within one working day of first knowledge using the Pregnancy Follow-up Form supplied by LEO. All pregnancies were to be followed-up until delivery or termination.

48 MCB 0501 INT 28-MAY-2012 Page 48 of 129 Serious Adverse Events Reporting of Serious Adverse Events Any SAE, related or unrelated to the investigational product or any trial procedure, after signature of the Informed Consent Form was to be reported to LEO on the (paper) Serious Adverse Event Form Clinical Trial within one working day. 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 documented 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 Global Pharmacovigilance. All other relevant reports of diagnostic procedures, hospital records, autopsy reports etc. were to be included, as applicable or upon request from Global Pharmacovigilance. The IRB(s)/IEC(s), regulatory authorities and concerned investigators were to be notified of SAEs according to current regulation and local requirements. All Suspected, Unexpected Serious Adverse Reactions (SUSARs) were subject to expedited reporting to regulatory authorities, IRB(s)/IEC(s) and all concerned investigators, unless otherwise required as per local requirements. In addition, regulatory authorities and IRB(s)/IEC(s) received Annual Safety Reports. IRB(s)/IEC(s) and investigators also were to receive Periodic Line Listings of SUSARs every 6 months or if required as per local requirements. Other safety information that could adversely affect the safety of the subjects or impact the conduct of the trial was to be reported promptly to authorities, IRB(s)/IEC(s) and investigators.

49 MCB 0501 INT 28-MAY-2012 Page 49 of 129 For all SAEs (including those ongoing at the time the subject leaves the trial and those occurring within 4 weeks of leaving the trial) the investigator was to follow-up for a final outcome and ensure all queries had been resolved. Details of follow-up was to be given (e.g. if specific treatment was required, if hospitalisation was required, etc.) Appropriateness of Measurements To evaluate the safety of TACLONEX ointment, all AEs reported by the subject or observed by the investigator were recorded. Laboratory evidence of adrenal insufficiency due to the use of topical corticosteroid treatment has been reported (23). This is due to the systemic absorption of the corticosteroid. Adrenal function can be measured by the ACTH-challenge test. Therefore, any systemic absorption of betamethasone dipropionate in the present study was evaluated using the ACTH challenge test. Overdosage with topical calcipotriene can cause hypercalcemia due to the systemic absorption of calcipotriene, which affects calcium metabolism as it is a vitamin D analogue (26). Therefore, any systemic absorption of calcipotriene in the present study was evaluated by assessing calcium metabolism by measurement of serum calcium and the urinary calcium:creatinine ratio. To evaluate the efficacy of TACLONEX ointment IGA and patient s global assessment of disease severity and modified PASI were recorded. These are accepted methods of assessing psoriasis and have been used during the clinical development programme for TACLONEX ointment Primary Safety Variables The primary response criteria were: ADRs Serum cortisol concentration of 18 mcg/dl at 30 minutes after ACTH-challenge at end of treatment Serum cortisol concentration of 18 mcg/dl at 30 and 60 minutes after ACTH-challenge at end of treatment Change in albumin-corrected serum calcium from baseline to end of treatment Change in urinary calcium:creatinine ratio from baseline to end of treatment.

50 MCB 0501 INT 28-MAY-2012 Page 50 of Drug Concentration Measurements Not Applicable 9.6 DATA QUALITY ASSURANCE LEO has implemented a system of quality assurance, including all the elements described in this report. Within this system company Standard Operating Procedures (SOPs) are implemented to ensure that clinical studies are conducted in compliance with regulatory requirements and Good Clinical Practice. Quality control is applied to each stage of data handling to ensure that data are accurate, reliable and processed correctly. Trial sites, facilities, laboratories and all data (including sources) and documentation were available for GCP audit by LEO or inspection by competent authorities. For this trial, two audits were conducted. The audit certificates are provided in Appendix Data Handling LEO, as sponsor of this trial, is responsible to the authorities for assuring the proper conduct of the trial with regard to Clinical Study Protocol adherence and validity of the data recorded on the CRFs. Monitors were assigned to serve as the principal link between (sub)investigators and LEO and to advise the investigators on the collection and maintenance of complete, legible, well organised, and easily retrievable data for the trial. In addition, they were to explain to the investigators any aspect of the (conduct of the) trial, including interpretation of the protocol, and purpose of collection of the specified data and reporting responsibilities. In this trial data were collected by means of Remote Data Capture. The investigator, or staff authorised by the investigator, were to enter subject data into an electronic CRF designed by LEO. A uniquely numbered CRF was used for each subject enrolled. Data recorded in the electronic CRF were accessible to site staff through a secure internet connection immediately after entry of data had taken place. The CRFs were to be maintained in an up-to-date condition at all times by the investigator. The investigator, or sub-investigator(s) authorised by the investigator, were to electronically sign all sections of CRFs used. This signature information (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 CRF, made by the

51 MCB 0501 INT 28-MAY-2012 Page 51 of 129 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 electronic CRF by authorised site staff in a timely manner. Data were to be entered by site staff and systematic data validation was performed through the discrepancy management system within the data collection software. Queries for discrepant data were generated either automatically by the system upon entry or generated manually by the monitor or the trial data manager. All queries, whether generated by the system or by a user, were in an electronic format. This systematic validation was made to ensure that a clean and consistent database was provided prior to the statistical analysis being performed. Central laboratory data were received directly by LEO from the central laboratory in an electronic format and batch-loaded into the database. Data were and are handled in accordance with the general terms and conditions of the authorisation granted by the Danish Data Protection Agency to LEO Pharma A/S, as required, according to the Danish Personal Act and any national legislation implementing the Data Protection Directive (95/46/EC). LEO HQ is considered data responsible for all international clinical trials sponsored by LEO. 9.7 STATISTICAL METHODS PLANNED IN THE PROTOCOL AND DETERMINATION OF SAMPLE SIZE Statistical and Analytical Plans The statistical analysis was planned in the Clinical Study Protocol (Appendix ) and further detailed in the Statistical Analysis Plan Update (SAPU) dated 08-Feb-2012 (Appendix ). All subjects enrolled into the study (i.e., signed informed consent obtained and a CRF number assigned) were to be accounted for in the report. All subjects who received study medication comprised the full analysis set and were analysed for efficacy. Exclusion from the full

52 MCB 0501 INT 28-MAY-2012 Page 52 of 129 analysis set was to be considered for subjects who applied no study medication or who provided no efficacy data following start of treatment. All subjects who applied any study medication and for whom the presence or confirmed absence of AEs was available were included in the safety analysis set and were analysed for safety, apart from the analysis of the ACTH-challenge test. For the analysis of the ACTH-challenge test, a per protocol analysis set was defined by excluding subjects from the full analysis set, who did not: apply any study medication meet inclusion criterion number 6 (concerning evidence of adrenal suppression at baseline) and/or provide any results for an ACTH-challenge test after receiving study treatment Reasons for leaving the study The reasons for leaving the study were to be presented separately for all subjects who received study medication and for all enrolled subjects who did not receive study medication Baseline characteristics Descriptive statistics of demographics and other baseline characteristics were presented for all subjects who received study medication. Demographics included age, sex, ethnicity, race, weight and height. Other baseline characteristics included duration and total BSA involvement of psoriasis vulgaris, IGA of disease severity, modified Psoriasis Area and Severity Index (PASI), patient s global assessment of disease severity, concomitant medication and concomitant diagnoses. The presentation of age and sex was also given by centre. Categorical data were summarised using the number and percentage of subjects in each category. Continuous data were summarised using the mean, median, standard deviation (SD), minimum and maximum values Analysis of safety The analysis of safety was based on the defined response criteria (as described below) for the

53 MCB 0501 INT 28-MAY-2012 Page 53 of 129 safety analysis set, apart from the analysis of the results for the ACTH-challenge test, which were based on the per-protocol analysis set. The primary response criteria were: ADRs Serum cortisol concentration of 18 mcg/dl at 30 minutes after ACTH-challenge at Visit 3 Serum cortisol concentration of 18 mcg/dl at 30 and 60 minutes after ACTH-challenge at Visit 3 Change in albumin-corrected serum calcium from baseline to end of treatment Change in urinary calcium:creatinine ratio from baseline to end of treatment. The secondary response criteria were: AEs Change in the other laboratory parameters from baseline to the end of treatment Reasons for withdrawal Change in blood pressure and heart rate from baseline to the end of treatment Adverse Events AEs were coded in accordance with the current version of the MedDRA dictionary. The AEs were presented by Preferred Terms and Primary System Organ Class. All AEs recorded during the course of the study were included in the individual subject data listings. An event was considered emergent with the study treatment if it started after the first application of the study medication or if it started before this and increased in intensity afterward. The tabulations described below only included the events that were emergent with study treatment. The number of subjects experiencing each type of AE (according to MedDRA Preferred Terms within Primary System Organ Class (SOC)) were tabulated regardless of the number of times each AE was reported by each subject. The causal relationship to trial medication for each type of AE (according to the Preferred Term) was tabulated. Where there were 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 adverse event, since that was when the investigator was in possession of most information and so best

54 MCB 0501 INT 28-MAY-2012 Page 54 of 129 able to judge causal relationship. ADRs were defined as AEs for which the investigator had not described the causal relationship to trial medication as not related. The number of subjects experiencing each type of ADR (according to the Preferred Term) was tabulated. The intensity for each type of ADR was also tabulated. Where there were several recordings of intensity for a given type of ADR, intensity was taken as the most severe recording for that ADR. Lesional/perilesional AEs were also tabulated. SAEs and AEs leading to withdrawal were to be evaluated separately, and a narrative for each was to be given ACTH-challenge test The following percentages of subjects were calculated for the per protocol analysis set: Subjects with a serum cortisol concentration 18 mcg/dl at both 30 minutes and 60 minutes after ACTH-challenge at the end of the treatment phase (week 4). Subjects with a serum cortisol concentration 18 mcg/dl at 30 minutes after ACTHchallenge at the end of the treatment phase. The following values were tabulated for the serum cortisol concentration at 30 minutes and 60 minutes after ACTH-challenge at both baseline (SV2) and end of the treatment phase: mean, median, SD, minimum, maximum and number of subjects for the per protocol analysis set. The serum cortisol concentration after 0, 30 and 60 minutes of the ACTH-challenge test and also the change in serum cortisol from time 0 to 30 and to 60 minutes at baseline and at the end of the treatment phase were to be listed for each subject with a value 18 mcg/dl at either 30 or 60 minutes post ACTH-challenge test for the per protocol analysis set and also for the safety analysis set if they differed. Values of 18 mcg/dl and lower at 30 or 60 minutes after the injection were to be flagged Laboratory Examinations For the hematology and biochemistry parameters and the urinary calcium:creatinine and phosphorus:creatinine ratios, the change from baseline (SV2) to the end of the treatment phase was tabulated displaying the mean, SD, median, minimum and maximum values and

55 MCB 0501 INT 28-MAY-2012 Page 55 of 129 number of subjects. For the albumin-corrected serum calcium and the urinary calcium: creatinine ratio, the 95% confidence interval of the mean was also presented. For the hematology and biochemistry parameters, and the urinary calcium:creatinine and phosphorus:creatinine ratios, values were categorised as low, normal or high depending on whether they were below, within or above the laboratory reference range, respectively. Shift tables were produced showing the categories at baseline (SV2) against those at the end of the treatment phase. For the urinary glucose and ketones, the values were categorised as absent or present. Shift tables were produced showing the presence/absence at baseline (SV2) against presence/ absence at the end of the treatment phase. As described in the SAPU, post-treatment unscheduled laboratory assessments were not included in the analysis Other Observations The change in mean systolic and diastolic blood pressure and in heart rate from baseline (SV2) to the end of the treatment phase was presented with mean, SD, median, minimum and maximum values and number of subjects. Clinically significant abnormalities in the physical examination at baseline (SV2) and end of treatment phase were to be presented. Any abnormalities at the end of the treatment that were not present at baseline were to be highlighted Analysis of efficacy The statistical analysis of efficacy was based on the defined response criteria for the full analysis set. The following were to be evaluated as secondary response criteria: Controlled disease (i.e., Clear or Almost clear ) according to the investigator s global assessment of disease severity at week 4. Absolute and percentage change in modified PASI from baseline (Visit 1) to week 4. Controlled disease (i.e., Clear or Very mild ) according to the patient s global assessment of disease severity at week 4. Modified PASI 75 (at least 75% reduction in modified PASI from baseline) at week 4.

56 MCB 0501 INT 28-MAY-2012 Page 56 of 129 Modified PASI 50 (at least 50% reduction in modified PASI from baseline) at week 4. The following formula was used to calculate the modified PASI: Arms 0.2 (R + T + S)E = X Trunk 0.3 (R + T + S)E = Y Legs 0.4 (R + T + S)E = Z where: R = score for redness T = score for thickness S = score for scaliness E = score for extent The sum of X + Y + Z gave the total modified PASI, which can range from 0 to The PASI used in this study was modified to exclude assessment of the head, as study treatment was not used there. The percentage of subjects who achieved controlled disease according to the IGA of disease severity at week 4 was calculated. A corresponding 95% confidence interval was determined based on a binomial distribution. The result at week 4 was presented by age group, sex, baseline disease severity and centre. The percentage of subjects who achieved controlled disease according to the IGA was also presented by visit. The percentage of subjects who achieved controlled disease according to the patient s global assessment of disease severity at week 4 was calculated. A corresponding 95% confidence interval was determined based on a binomial distribution. The percentage of subjects who achieved controlled disease according to the patient s global assessment was also presented by visit. The absolute and percentage change in modified PASI from baseline to week 4 was to be summarised using the mean, median, SD, minimum and maximum values. A corresponding 95% confidence interval for the mean percentage change was calculated based on a normal distribution. The percentage of subjects who achieved at least 75% reduction in modified PASI from baseline to week 4 was calculated. A corresponding 95% confidence interval was determined based on a binomial distribution. The percentage of subjects who achieved at least 50% reduction in modified PASI from baseline to week 4 was also calculated. A corresponding 95% confidence interval was determined based on a binomial distribution. Modified PASI 75 and PASI 50 were also presented by visit.

57 MCB 0501 INT 28-MAY-2012 Page 57 of General principles All confidence intervals were to be two-sided and presented with 95% degree of confidence. All data recorded during the course of the study were presented in individual data listings. The listings were presented and sorted by centre, subject number and visit. For tabulations on changes from baseline, baseline was defined as the last assessment performed (including unscheduled laboratory assessments) before application of study medication. For the analysis of efficacy data a last observation carried forward approach was to be used for the defined efficacy response criteria, using the last non-missing value for subjects with missing data at the week 4 visit. All efficacy data were also to be tabulated by visit using an observed cases approach (i.e. involving only those subjects who attended each specific visit). The end of treatment value for a particular laboratory parameter was defined as the last value recorded for that parameter during the treatment phase of the study. In addition, the observed cases at week 4 were tabulated for all laboratory parameters. Drop-outs and missing values were to be accounted for by the analysis of end of treatment values using a last observation carried forward approach Determination of sample Size The primary objective was to assess the safety of TACLONEX ointment. No formal sample size calculation evaluating the power of the study was performed. However, a few considerations regarding the sample size (30 subjects or more) were made as described below. The upper limit of an exact two-sided 95% confidence interval for the probability of observing a specific AE, when 0 out of 30 possible events have been observed, is 12% assuming a binomial distribution. Thirty subjects undergoing ACTH-challenge testing has previously been accepted by the FDA as an adequate sample size.

58 MCB 0501 INT 28-MAY-2012 Page 58 of 129 With 30 subjects and an assumed response rate (per cent of subjects who achieve Clear or Almost Clear at week 4 by IGA of disease severity) of about 50% (4), the confidence interval for the estimated response rate was approximately ± 18%. Each centre was to recruit a minimum number of 4 subjects. As the subjects were anticipated to be difficult to recruit, the suggested minimum number of subjects per site was based on practical considerations rather than statistical robustness of estimates given per centre. There was no maximum number of subjects per site. 9.8 CHANGES IN THE CONDUCT OF THE TRIAL OR PLANNED ANALYSES There were no protocol amendments. The statistical analyses were conducted as planned in the Statistical Analysis Plan Update, which was prepared after review of the data. The Statistical Analysis Plan Update includes minor changes from the planned data presentation and analyses presented in the Clinical Study Protocol (Appendix ). Changes from the Clinical Study Protocol in the presentation of the study results were: Baseline characteristics on both safety and per protocol analysis sets were produced as they were the analysis sets used for the primary response criteria. A table of body mass index (BMI) was presented. A table of mean serum cortisol concentration before injection of CORTROSYN at SV2 was presented. Abnormal findings from the physical examination at SV2 were added to concurrent diagnoses (unless the (sub)investigator considered them to be non-treatment-emergent AEs, in which case they were recorded as this). Any new abnormal findings from the physical examination at visit 3 were recorded as AEs. Hence the table of clinically significant abnormalities in the physical examination was not presented. Descriptive statistics for the safety analysis set were tabulated for the following: Duration and extent of exposure to study medication Amount of study medication used Average weekly amount of study medication used.

59 MCB 0501 INT 28-MAY-2012 Page 59 of 129 Compliance with treatment instructions was tabulated for the safety and per protocol analysis sets. Phosphorus was reported instead of phosphate; these are equivalent terms. For the urinary phosphorus:creatinine ratio, the 95% confidence interval of the mean change from baseline to week 4 was presented. Descriptive statistics and the 95% confidence interval of the mean change from baseline to week 4 were presented for serum phosphorus and PTH. The absolute change in modified PASI from baseline to week 4 was not presented. Reasons for leaving the study were not presented for subjects who received study medication, as all such subjects completed the study

60 MCB 0501 INT 28-MAY-2012 Page 60 of TRIAL POPULATION 10.1 DISPOSITION OF SUBJECTS A total of 56 subjects from seven centres in the USA were enrolled and screened. Of the 56 enrolled subjects, 18 withdrew after SV1 and a further five withdrew after SV2. There were no withdrawals during the treatment phase and 33 subjects completed the study. Subject disposition is illustrated in Figure 1. Reasons for withdrawal during the washout/screening phase are presented in Table 52. The visit dates are listed in Appendix , Listing 2. Figure 1: Disposition of subjects Screening visit 1 56 Screening visit inc/exc criteria not met, 2 voluntary, 1 lost to follow-up 5 5 inc/exc criteria not met Visit 1 33 Visit 2 33 Visit 3 33 The study had a duration of weeks. The first subject s first screening visit was 15-JUL and the last subject s last on-treatment visit was 05-DEC The study period by centre is shown in Table 3.

61 MCB 0501 INT 28-MAY-2012 Page 61 of 129 Table 3: Study period by centre: enrolled subjects Centre Date of first subject visit Date of last subject visit Duration of study (weeks) 11MAY MAY SEP NOV AUG AUG JUL DEC DEC FEB JUN OCT SEP MAY All enrolled subjects 15JUL DEC FEB12:15:09:17 MCB 0501 INT t1_studyp.doc The number of subjects enrolled across the seven sites ranged from 1 to 16. Enrolled subjects and subjects assigned treatment by centre are displayed in Table 4. Table 4: Enrolled subjects and subjects assigned treatment by centre Centre Total number of subjects enrolled (n=56) Total number of subjects assigned treatment TACLONEX ointment Total FEB12:15:09:47 MCB 0501 INT t2_enroll.doc 10.2 PROTOCOL DEVIATIONS There were a total of 68 deviations, the majority of which were minor. Of these 68 deviations, 7 were related to additional assessments performed, 7 to eligibility criteria, 5 to laboratory tests, 6 to informed consent, 9 to visit windows, 4 to administration of CORTROSYN injection, 25 to timing of ACTH-challenge test, and 5 to deviations not specific to a subject. The most important deviations were as follows:

62 MCB 0501 INT 28-MAY-2012 Page 62 of 129 CRF had a concurrent cardiac condition (sinus arrhythmia) in violation of exclusion criterion 17. CRF was using a topical corticosteroid (triamcinolone) on the scalp, in violation of exclusion criterion 8. CRF was taking a concurrent antidepressive medication (fluoxetine) in violation of exclusion criterion 9. CRF did not have any laboratory results from the ACTH-challenge test performed at Visit 3, and so was excluded from the per-protocol analysis set. CRF was the only subject excluded from any analysis sets, in accordance with the definitions of the analyses sets in the protocol. Subject-specific deviations are listed in Appendix Deviations which are not subjectspecific are as follows: At site two sub-investigators and a lab technician participated in the study before being properly delegated on the delegation log. At site 6 vials of saline were unaccounted for. At site a study coordinator participated in the study before receiving study training. At site a phlebotomist participated in the study before being properly delegated on the delegation log. The lot number printed on study medication labels did not match the lot number on the Certificate of Analysis. 11 EFFICACY EVALUATION 11.1 DATA SETS ANALYSED All trial sets are displayed in Figure 2. The reason for exclusion of one subject from the per protocol analysis set is listed in Appendix

63 MCB 0501 INT 28-MAY-2012 Page 63 of 129 Figure 2: Trial Analysis Sets Enrolled subjects inc/exc criteria not met, 2 voluntary, 1 lost to follow-up Subjects assigned treatment 33 Full analysis set Safety analysis set Per protocol analysis set 32 1 No ACTH-challenge test data following start of treatment (CRF Full Analysis set All 33 subjects that attended Visit 1 received treatment and were included in the full analysis set Safety Analysis Set All 33 subjects that attended Visit 1 comprised the safety analysis set. They all received treatment with trial medication, and data on the presence or confirmed absence of AEs was available for them all Per Protocol Analysis Set One subject (CRF did not provide data for the ACTH-challenge test following the start of treatment and was excluded from the per protocol analysis set. The per protocol analysis set thus consisted of 32 subjects.

64 MCB 0501 INT 28-MAY-2012 Page 64 of DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS Demographic and baseline characteristics are presented for the safety and per protocol analysis sets. Concomitant medication and concurrent diagnoses at baseline are presented for the safety and per protocol analysis sets Demography The mean age was 14.6 years and 14.7 years for the safety and per protocol analysis sets, respectively (range 12 to 17 years for both sets). Sixteen males (48.5%) and 17 females (51.5%) were included in the safety analysis set, whereas the per protocol analysis set comprised 15 males and 17 females. In the safety analysis set 11 (33.3%) subjects were reported as Hispanic or Latino and the remaining 22 (66.7%) were reported as not Hispanic or Latino. The corresponding figures for the per protocol analysis set were 10 (31.3%) and 22 (68.8%). In the safety analysis set 22 (66.7%) subjects were white, 4 (12.1%) were Black or African American, 5 (15.2%) were Asian and 2 (6.1%) were of other race (Middle Eastern and Filipino). The corresponding figures for the per protocol analysis set were 21 (65.6%), 4 (12.5%), 5 (15.6%) and 2 (6.3%). The demographics (age, sex, ethnicity, race) for the safety and per protocol analysis sets are displayed in Table 5 to Table 8. Age and sex by centre and weight, height and BMI for the safety and per protocol analysis sets are shown in Table 53 to Table 57. Table 5: Age: safety analysis set and per protocol analysis set Age (years) Safety Analysis Set Per Protocol Analysis Set (n=32) Mean SD Median Minimum Maximum Number FEB12:15:10:03 MCB 0501 INT t3_age.doc

65 MCB 0501 INT 28-MAY-2012 Page 65 of 129 Table 6: Sex: safety analysis set and per protocol analysis set Sex Safety Analysis Set Number of subjects % Per Protocol Analysis Set (n=32) Number of subjects % Male Female Total FEB12:15:19:27 MCB 0501 INT t4_sex.doc Table 7: Ethnicity: safety analysis set and per protocol analysis set Ethnicity Safety Analysis Set Number of subjects % Per Protocol Analysis Set (n=32) Number of subjects % Hispanic or Latino Not Hispanic or Latino Total FEB12:15:16:02 MCB 0501 INT t5_ethnic.doc Table 8: Race: safety analysis set and per protocol analysis set Race Safety Analysis Set Number of subjects % Per Protocol Analysis Set (n=32) Number of subjects % White Black or African American Asian Other Total MAR12:10:20:43 MCB 0501 INT t6_race.doc 1) Other: Subject Middle Eastern, subject Filipino For individual subject demographic data see Appendix

66 MCB 0501 INT 28-MAY-2012 Page 66 of Other Baseline Characteristics The mean duration of psoriasis was 4.5 and 4.6 years (range 0 to 11 years) for the safety and per protocol analysis sets, respectively. Duration of psoriasis vulgaris is shown in Table 9. Table 9: Duration of psoriasis vulgaris: safety analysis set and per protocol analysis set Duration of psoriasis (Years) Safety Analysis Set Per Protocol Analysis Set (n=32) Mean SD Median Minimum 0 0 Maximum Number FEB12:15:11:12 MCB 0501 INT t7_duration.doc The mean baseline extent of psoriasis on arms, trunk and legs was 14.2% and 13.8% of the BSA for the safety and per protocol analysis sets, respectively, and ranged between 5% and 30% of the BSA, which was in compliance with the inclusion criteria for the study. Investigator s assessment of extent of psoriasis on arms, trunk and legs at baseline is shown in Table 10. Table 10: Investigator's assessment of extent of psoriasis on arms, trunk and legs: safety analysis set and per protocol analysis set Body Surface Area (%) Safety Analysis Set Per Protocol Analysis Set (n=32) Mean SD Median Minimum 5 5 Maximum Number MAR12:15:30:21 MCB 0501 INT t8_invass.doc The mean value for modified PASI at baseline was 8.1 (range 3 to 18) for both the safety and per protocol analysis sets (Table 11).

67 MCB 0501 INT 28-MAY-2012 Page 67 of 129 Table 11: Modified PASI at baseline: safety analysis set and per protocol analysis set Modified PASI Safety Analysis Set Per Protocol Analysis Set (n=32) Mean SD Median Minimum 3 3 Maximum Number MAR12:15:32:50 MCB 0501 INT t9_mpasi.doc At baseline, approximately 91% of the subjects had moderate disease as judged by the investigator and 9% had severe disease in both analysis sets. According to the patient s global assessment a somewhat lower percentage of the subjects had moderate disease (approximately 85% and 88% for the safety and per protocol analysis sets, respectively), no subjects had severe disease and the remainder had mild or very mild disease. The IGA and patient s global assessment of disease severity at baseline are displayed in Tables 12 and Table 13, respectively. Table 12: IGA at baseline: safety analysis set and per protocol analysis set Investigator's global assessment Safety Analysis Set Number of subjects % Per Protocol Analysis Set (n=32) Number of subjects % Moderate Severe Total MAR12:15:30:40 MCB 0501 INT t10_invga.doc

68 MCB 0501 INT 28-MAY-2012 Page 68 of 129 Table 13: Patient s global assessment at baseline: safety analysis set and per protocol analysis set Patient's global assessment Safety Analysis Set Number of subjects % Per Protocol Analysis Set (n=32) Number of subjects % Very Mild Mild Moderate Total MAR12:15:31:10 MCB 0501 INT t11_patga.doc A total of 57 concurrent diagnoses at baseline from 27 subjects were reported. The most common concurrent diagnosis SOC at baseline was skin and subcutaneous tissue disorders (13 subjects). Concurrent diagnoses recorded at baseline by MedDRA primary SOC for the safety and per protocol analysis sets are shown in Table 14.

69 MCB 0501 INT 28-MAY-2012 Page 69 of 129 Table 14: Concurrent diagnoses at baseline by MedDRA primary system organ class: safety analysis set and per protocol analysis set Safety Analysis Set Per Protocol Analysis Set (n=32) System Organ Classification 1 Number of diagnoses Number of subjects % Number of diagnoses Number of subjects % Blood and lymphatic system disorders Cardiac disorders Congenital, familial and genetic disorders Gastrointestinal disorders Immune system disorders Infections and infestations Injury, poisoning and procedural complications Metabolism and nutrition disorders Musculoskeletal and connective tissue disorders Neoplasms benign, malignant and unspecified (incl cysts and polyps) Nervous system disorders Psychiatric disorders Reproductive system and breast disorders Respiratory, thoracic and mediastinal disorders Skin and subcutaneous tissue disorders Surgical and medical procedures Total number of diagnoses Total number of subjects MAR12:18:56:54 MCB 0501 INT t12 cdiag.doc 1) Classification according to MedDRA version ) Different diagnoses within the same preferred term and involving the same subject have been counted as one. A subject could appear in multiple classes.

70 MCB 0501 INT 28-MAY-2012 Page 70 of 129 The use of concomitant medication was recorded and coded according to the World Health Organisation (WHO) Anatomical Therapeutic Chemical (ATC) Classification System. At baseline a total of nine subjects were taking 15 medications and the most common were those coded in the ATC class Nervous system with six medications taken by three subjects (Table 15). Table 15: Concomitant medication at baseline: safety analysis set and per protocol analysis set ATC classification index level 1 1 Safety Analysis Set Number of Number of drugs subjects % Per Protocol Analysis Set (n=32) Number of Number of drugs subjects % ALIMENTARY TRACT AND METABOLISM CARDIOVASCULAR SYSTEM DERMATOLOGICALS GENITO URINARY SYSTEM AND SEX HORMONES MUSCULO-SKELETAL SYSTEM NERVOUS SYSTEM Total number of drugs taken 1 Total number of subjects taking drugs MAR12:18:46:39 MCB 0501 INT t13 concmed.doc 1) Drugs with the same Anatomical Therapeutic Chemical (ATC) classification level 4 code and generic name/preferred term name which have been taken by the same subject have been counted as one. The mean serum cortisol concentration prior to CORTROSYN injection at baseline was 12.6 and 12.7 mcg/dl for the safety and per protocol analysis sets, respectively. These concentrations ranged from 5.2 to 20.5 mcg/dl, and, accordingly, all subjects were above the lower limit of 5 mcg/dl as required by the inclusion criteria. The serum cortisol concentration prior to CORTROSYN injection at baseline is presented in Table 16.

71 MCB 0501 INT 28-MAY-2012 Page 71 of 129 Table 16: Serum cortisol concentration at time 0 at baseline: safety analysis set and per protocol analysis set Cortisol (mcg/dl) Safety Analysis Set Per Protocol Analysis Set (n=32) Mean SD Median Minimum Maximum Number MAR12:11:34:39 MCB 0501 INT t14_bcort.doc Individual subject data are provided in Appendix , Listing 1 (Demographic data), in Appendix , Listing 1 (IGA), Listing 2 (Patient s global assessment) and Listing 3 (Investigators s assessment of extent and severity by body region), Appendix , Listing 1 (Serum cortisol) and in Appendix , Listing 7 (Concurrent diagnoses other than study disease at baseline) and Listing 8 (Concomitant medication) MEASUREMENT OF TREATMENT COMPLIANCE All investigational product supplied to and returned from the site were fully documented by use of drug accountability forms (Section 9.4.8). The amount of study medication used, and the average weekly amount of study medication used are displayed in Table 36 and Table 37 (Section 12.1). Over the total treatment period 21 subjects were fully compliant and applied medication once daily every day. In the safety analysis set, of the twelve subjects who missed at least one application, none missed more than 20% of applications. The degree of compliance with treatment instructions is summarised in Table 17.

72 MCB 0501 INT 28-MAY-2012 Page 72 of 129 Table 17: Compliance with treatment instructions: safety analysis set and per protocol analysis set Missed any applications? Safety Analysis Set Number of subjects % Per Protocol Analysis Set (n=32) Number of subjects % No Yes: <=10% applications missed Yes: >10% to <=20% applications missed Total MAR12:11:35:03 MCB 0501 INT t15_compliance.doc For individual subject data on compliance and drug accountability, see Appendix , Listing 1 (Compliance) and Listing 2 (Drug accountability).

73 MCB 0501 INT 28-MAY-2012 Page 73 of ADRENAL FUNCTION, CALCIUM METABOLISM AND CLINICAL EFFICACY Effect on Adrenal Function and Calcium Metabolism Primary response criteria related to the effect of the study medication on adrenal function and calcium metabolism were: Serum cortisol concentration of 18 mcg/dl at 30 minutes after ACTH-challenge at end of treatment Serum cortisol concentration of 18 mcg/dl at 30 and 60 minutes after ACTH-challenge at end of treatment Change in albumin-corrected serum calcium from baseline to end of treatment Change in urinary calcium:creatinine ratio from baseline to end of treatment. For individual subject data on the adrenal function (ACTH challenge) and calcium metabolism see Appendix , Listing 1 (serum cortisol), Listing 2 (biochemistry), and Listing 4 (urinalysis) Effect on Adrenal Function None of the subjects had a serum cortisol concentration of 18 mcg/dl at either 30 or 60 minutes following ACTH challenge. The baseline and week 4 cortisol concentrations were comparable at both 30 and 60 minutes after ACTH challenge. After 30 minutes, the mean serum cortisol concentration at baseline was mcg/dl (range 18.5 to 30.6 mcg/dl) compared to mcg/dl (range 19.2 to 32.1 mcg/dl) at Week 4. After 60 minutes, the mean serum cortisol concentration at baseline was mcg/dl (range 21.4 to 36.2 mcg/dl) compared to mcg/dl (range 21.5 to 34.8 mcg/dl) at Week 4. Adrenal response to the ACTH-challenge test at week 4 is shown in Table 18. Serum cortisol concentrations at 30 and 60 minutes after ACTH challenge at baseline and week 4 are displayed in Table 19.

74 MCB 0501 INT 28-MAY-2012 Page 74 of 129 Table 18: Serum cortisol concentration <= 18 mcg/dl after ACTH challenge at Week 4: per protocol analysis set TACLONEX ointment (n=32) Serum Cortisol Concentration(mcg/dL) at Week 4 Number of subjects % 30 min after ACTH challenge test <=18 µg/dl 0 0 >18 µg/dl Total and 60 min after ACTH challenge test <=18 µg/dl 0 0 >18 µg/dl Total MAR12:12:23:47 MCB 0501 INT t16_cort18.doc

75 MCB 0501 INT 28-MAY-2012 Page 75 of 129 Table 19: Serum cortisol concentration at 30 and 60 minutes after ACTH challenge at baseline and Week 4: per protocol analysis set Serum Cortisol Concentration (mcg/dl) TACLONEX ointment (n=32) 30 min after ACTH challenge test Baseline Mean SD 3.31 Median Minimum 18.5 Maximum 30.6 Number 32 Week 4 Mean SD 3.53 Median Minimum 19.2 Maximum 32.1 Number min after ACTH challenge test Baseline Mean SD 3.62 Median Minimum 21.4 Maximum 36.2 Number 32 Week 4 Mean SD 3.86 Median Minimum 21.5 Maximum 34.8 Number 32 21MAR12:11:12:43 MCB 0501 INT t17_cort3060.doc

76 MCB 0501 INT 28-MAY-2012 Page 76 of Effect on Calcium Metabolism The mean albumin-corrected serum calcium at baseline was 2.27 mmol/l (range 2.13 to 2.48 mmol/l). The mean change in albumin-corrected serum calcium from baseline to week 4 was mmol/l (95% CI: to ). A total of 29 subjects had normal albumincorrected serum calcium values both at baseline and week 4. No subjects had values above the normal reference range at week 4. Change in albumin-corrected serum calcium from baseline to week 4 for the safety analysis set is shown in Table 20. Albumin-corrected serum calcium categorised as low, normal or high (i.e. below, within or above the laboratory reference range, respectively) at week 4 against baseline category is shown in Table 21. Table 20: Change in albumin-corrected serum calcium from baseline to Week 4: safety analysis set Visit Albumin-Corrected Serum Calcium (mmol/l) TACLONEX ointment Baseline Mean SD Median Minimum 2.13 Maximum 2.48 Number 33 Change at Week 4 Mean SD Median Minimum Maximum 0.13 Number 32 Statistical analysis 95% CI (mean) to MAR12:17:45:59 MCB 0501 INT t18_chalb.doc

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78 MCB 0501 INT 28-MAY-2012 Page 78 of 129 Table 22: Change in urinary calcium:creatinine ratio from baseline to Week 4: safety analysis set Visit Urinary calcium:creatinine ratio (mmol/g) TACLONEX ointment Baseline Mean SD Median Minimum 0.50 Maximum 5.00 Number 32 Change at Week 4 Mean SD Median Minimum Maximum Number 30 Statistical analysis 95% CI (mean) to MAR12:11:08:38 MCB 0501 INT t22_chucc.doc Table 23: Urinary calcium:creatinine ratio categorised as low, normal or high at Week 4 shown against baseline category: safety analysis set TACLONEX ointment Laboratory parameter End of treatment category 1 Baseline category 1 Low Normal High Urinary calcium:creatinine ratio Normal Unknown MAR12:17:26:26 MCB 0501 INT t23 shucc.doc 1) Number of subjects with values below, within or above the reference range. The mean serum phosphorus at baseline was 1.44 mmol/l (range 0.94 to 1.87 mmol/l). The mean change in serum phosphorus from baseline to week 4 was mmol/l (95% CI: to 0.041). Twenty-five subjects had normal serum phosphorus levels both at baseline and week 4.

79 MCB 0501 INT 28-MAY-2012 Page 79 of 129 Change in serum phosphorus from baseline to week 4 for the safety analysis set is shown in Table 24. Serum phosphorus categorised as low, normal or high (i.e. below, within or above the laboratory reference range, respectively) at week 4 against baseline category is shown in Table 25. Table 24: Change in serum phosphorus from baseline to Week 4: safety analysis set Visit Serum phosphorus (mmol/l) TACLONEX ointment Baseline Mean SD Median Minimum 0.94 Maximum 1.87 Number 33 Change at Week 4 Mean SD Median Minimum Maximum 0.29 Number 32 Statistical analysis 95% CI (mean) to MAR12:17:48:44 MCB 0501 INT t20_chsp.doc Table 25: Serum phosphorus categorised as low, normal or high at Week 4 shown against baseline category: safety analysis set TACLONEX ointment Laboratory parameter End of treatment category 1 Baseline category 1 Low Normal High Serum phosphorus Normal High MAR12:17:24:31 MCB 0501 INT t21 shsp.doc 1) Number of subjects with values below, within or above the reference range.

80 MCB 0501 INT 28-MAY-2012 Page 80 of 129 The mean urinary phosphorus:creatinine ratio at baseline was mmol/g (range 1.29 to mmol/g). The mean change in urinary phosphorus:creatinine ratio from baseline to week 4 was mmol/g (95% CI: to 6.380). Six of the 23 subjects that had a normal urinary phosphorus:creatinine ratio at baseline, had high values at week 4. Seven of the eight subjects that had low, high or unknown values at baseline had normal values at week 4. Change in urinary phosphorus:creatinine ratio from baseline to week 4 for the safety analysis set is shown in Table 26. Urinary phosphorus:creatinine ratio categorised as low, normal or high (i.e. below, within or above the laboratory reference range, respectively) at week 4 against baseline category is shown in Table 27. Table 26: Change in urinary phosphorus:creatinine ratio from baseline to Week 4: safety analysis set Visit Urinary phosphorus:creatinine ratio (mmol/g) TACLONEX ointment Baseline Mean SD Median Minimum 1.29 Maximum Number 32 Change at Week 4 Mean SD Median Minimum Maximum Number 30 Statistical analysis 95% CI (mean) to MAR12:17:52:04 MCB 0501 INT t24_chupc.doc

81 MCB 0501 INT 28-MAY-2012 Page 81 of 129 Table 27: Urinary phosphorus:creatinine ratio categorised as low, normal or high at Week 4 shown against baseline category: safety analysis set TACLONEX ointment Laboratory parameter End of treatment category 1 Baseline category 1 Low Normal High Urinary phosphorus:creatinine ratio Low Normal High Unknown MAR12:17:27:52 MCB 0501 INT t25_shupc.doc 1) Number of subjects with values below, within or above the reference range. The mean PTH at baseline was 3.5 pmol/l (range 1.6 to 5.9 pmol/l). The mean change in PTH from baseline to week 4 was 0.04 pmol/l (95% CI: to 0.64). All subjects had normal PTH levels at baseline and all but one (low value) had normal values at week 4. One subject (CRF had a slight decrease in PTH after treatment, but there was no relevant change in serum or urinary calcium. Change in PTH from baseline to week 4 for the safety analysis set is shown in Table 28. PTH categorised as low, normal or high (i.e. below, within or above the laboratory reference range, respectively) at week 4 against baseline category is shown in Table 29.

82 MCB 0501 INT 28-MAY-2012 Page 82 of 129 Table 28: Change in PTH from baseline to Week 4: safety analysis set Visit PTH, Intact (pmol/l) TACLONEX ointment Baseline Mean 3.51 SD 1.17 Median 3.08 Minimum 1.6 Maximum 5.9 Number 33 Change at Week 4 Mean 0.04 SD 1.62 Median Minimum -2.3 Maximum 4.5 Number 31 Statistical analysis 95% CI (mean) to MAR12:17:54:39 MCB 0501 INT t26_chpth.doc Table 29: PTH categorised as low, normal or high at Week 4 shown against baseline category: safety analysis set TACLONEX ointment Laboratory parameter End of treatment category 1 Baseline category 1 Low Normal High PTH, Intact Normal MAR12:17:29:17 MCB 0501 INT t27 shpth.doc 1) Number of subjects with values below, within or above the reference range Clinical Efficacy The percentage of subjects with controlled disease (i.e. clear or almost clear ) at week 4 was 60.6% (95% CI: 43.9% to 77.3%) according to IGA (Table 30). The percentage of

83 MCB 0501 INT 28-MAY-2012 Page 83 of 129 subjects with controlled disease (i.e. clear or very mild ) at week 4 was 69.7% (95% CI: 54.0% to 85.4%) according to the patient s global assessment (Table 31). Controlled disease by IGA at week 4 for the full analysis set is presented by age group, sex, baseline IGA of disease severity and centre, respectively, in Table 58 to Table 61. Controlled disease by visit by IGA and patient s global assessment, respectively, is shown in Table 62 and Table 63. Table 30: Controlled disease (IGA) at Week 4: full analysis set TACLONEX ointment Controlled disease Number of subjects % Controlled Non-controlled Total Statistical analysis 95% CI (%) 43.9 to MAR12:17:41:24 MCB 0501 INT t28_controlled_iga.doc Table 31: Controlled disease (patient s global assessment) at Week 4: full analysis set TACLONEX ointment Controlled disease Number of subjects % Controlled Non-controlled Total Statistical analysis 95% CI (%) 54.0 to MAR12:17:43:04 MCB 0501 INT t29_controlled_pga.doc The mean percentage change in modified PASI from baseline to week 4 was -72.5% (95% CI: to -63.9). At week 4, 51.5% of subjects had at least 75% reduction in modified PASI and 84.8% of subjects had at least 50% reduction in modified PASI from baseline.

84 MCB 0501 INT 28-MAY-2012 Page 84 of 129 Percentage change in modified PASI from baseline to week 4 for the full analysis set is displayed in Table 32. Modified PASI 75 and 50 at week 4 are shown in Table 33 and Table 34. Percentage change in modified PASI by visit is presented in Table 64. Modified PASI 75 and modified PASI 50 by visit are shown in Table 65 and Table 66. Table 32: Percentage change in modified PASI from baseline to Week 4: full analysis set Percentage change in modified PASI TACLONEX ointment Mean SD 24.2 Median Minimum Maximum 3.6 Number 33 Statistical analysis 95% CI (mean) to MAR12:14:23:24 MCB 0501 INT t30_mpasi.doc Table 33: Modified PASI 75 at Week 4: full analysis set TACLONEX ointment Modified PASI 75 Number of subjects % Yes No Total Statistical analysis 95% CI (%) 34.5 to MAR12:18:04:19 MCB 0501 INT t31_mpasi75.doc

85 MCB 0501 INT 28-MAY-2012 Page 85 of 129 Table 34: Modified PASI 50 at Week 4: full analysis set TACLONEX ointment Modified PASI 50 Number of subjects % Yes No Total Statistical analysis 95% CI (%) 72.6 to MAR12:13:11:53 MCB 0501 INT t32_mpasi50.doc For individual subject data on IGA and patient s global assessment see Appendix , Listing 1 (IGA) and Listing 2 (Patient s global assessment). For individual subject data used for calculation of modified PASI see Appendix , Listing 3 (Investigator s assessment of extent and severity by body region) Statistical/Analytical Issues The analyses were conducted according to the Clinical Study Protocol and the SAPU Adjustments for covariates Not applicable Handling of dropouts or missing data There were no drop-outs in the study. One subject (CRF did not provide data for the ACTH-challenge test at week 4. The ACTH-challenge test response for this subject was treated as missing, and the subject was excluded from the per protocol analysis set. No LOCF approach as planned in the protocol was employed for the efficacy and laboratory analyses as all subjects completed the study Interim analyses and data monitoring Not applicable

86 MCB 0501 INT 28-MAY-2012 Page 86 of Multi-site clinical trials Four of the five primary response criteria were laboratory tests. The laboratory measurements were all made at a central laboratory. Therefore the potential variability between sites for laboratory tests was reduced to a minimum Multiple comparison/multiplicity Not applicable Use of an efficacy subset of subjects Not applicable Active-control studies intended to show equivalence Not applicable Examination of subgroups Not applicable Tabulation of Individual Response Data Individual subject response data are available in Appendix and Appendix Drug Dose, Drug Concentration, and Relationships to Response Not applicable Drug-Drug and Drug-Disease Interactions Not applicable By-Subject Displays No by-subject displays have been outlined.

87 MCB 0501 INT 28-MAY-2012 Page 87 of Conclusions: Effect on Adrenal Function and Calcium Metabolism, and Clinical Efficacy There was no evidence of adrenal suppression following study treatment. There were no clinically significant mean changes in albumin-corrected serum calcium or urinary calcium:creatinine ratio, and no cases of hypercalcaemia were reported. One subject had an increase in urinary calcium:creatinine ratio, and a relationship to study treatment cannot be excluded. The efficacy level in the study suggests that TACLONEX ointment is effective in the treatment of psoriasis vulgaris in adolescents.

88 MCB 0501 INT 28-MAY-2012 Page 88 of SAFETY EVALUATION 12.1 EXTENT OF EXPOSURE The mean duration of treatment was 4 weeks and the extent of exposure to treatment was 133 subject-treatment-weeks. The duration and extent of exposure to treatment with TACLONEX ointment is tabulated in Table 35 and was calculated for all subjects in the safety analysis set. Table 35: Duration and extent of exposure to treatment: safety analysis set Duration (weeks) TACLONEX ointment Mean 4.0 SD 0.2 Minimum 3.7 Maximum 4.4 Number 33 Extent of exposure to treatment(subjecttreatment-weeks) MAR12:12:24:33 MCB 0501 INT t33 durexp.doc The mean amount of study medication used was 59.1 g (range 8.3 to g) during the first 2 weeks, 56.8 g (range 7.4 to g) during the second 2 weeks and g (range 30.6 to g) for the total treatment period. The mean weekly amount of study drug used was 28.8 g (range 4.4 to 54.2 g) during the first 2 weeks and 28.5 g (range 3.7 to 66.1 g) in the second 2 weeks. The mean weekly amount used in the total treatment period was 29.6 g (range 8.1 to 55.8 g). The amount of study medication used per visit interval is shown in Table 36. The amount of study medication used per week is shown in Table 37.

89 MCB 0501 INT 28-MAY-2012 Page 89 of 129 Table 36: Amount of study medication used: safety analysis set Visit interval Amount used 1 (g) TACLONEX ointment Visit 1 to Visit 2 (2 weeks) Mean 59.1 SD 37.4 Median 57.2 Minimum 8.3 Maximum Number 2 30 Visit 2 to Visit 3 (2 weeks) Mean 56.8 SD 36.7 Median 49.4 Minimum 7.4 Maximum Number 2 32 Visit 1 to End of Treatment Mean SD 70.2 Median Minimum 30.6 Maximum Number MAR12:10:22:52 MCB 0501 INT t34_totamt.doc 1) Calculated by subtracting the weight of the used tubes from the mean normal weight of full tubes. Negative weights have been set to zero. 2) Only subjects who returned all dispensed tubes provided data.

90 MCB 0501 INT 28-MAY-2012 Page 90 of 129 Table 37: Average weekly amount of study medication used: safety analysis set Visit interval Average weekly amount 1 (g) TACLONEX ointment Visit 1 to Visit 2 (2 weeks) Mean 28.8 SD 17.6 Median 27.6 Minimum 4.4 Maximum 54.2 Number 2 30 Visit 2 to Visit 3 (2 weeks) Mean 28.5 SD 18.5 Median 27.7 Minimum 3.7 Maximum 66.1 Number 2 32 Visit 1 to End of Treatment Mean 29.6 SD 17.0 Median 29.4 Minimum 8.1 Maximum 55.8 Number MAR12:10:26:32 MCB 0501 INT t35_avgamt.doc 1) Calculated by subtracting the weight of the used tubes from the mean normal weight of full tubes. Negative weights have been set to zero. 2) Only subjects who returned all dispensed tubes provided data. For individual subject data on exposure see Appendix , Listing 1 (Compliance) and Listing 2 (Drug accountability) ADVERSE EVENTS (AES) Brief Summary of Adverse Events A total of 16 AEs were reported by 11 (33.3%) subjects. The most commonly affected SOCs were Infections and infestations and Nervous system disorders with four subjects each. There were two ADRs (headache and pruritus), both of mild intensity, and considered possibly related to treatment by the (sub)investigator. There were no SAEs or withdrawals due to AEs in the study.

91 MCB 0501 INT 28-MAY-2012 Page 91 of Display of Adverse Events The AEs are summarised by SOC in Table 38 and by SOC and preferred term in Table 39. Table 38: Adverse events by MedDRA primary system organ class: safety analysis set TACLONEX ointment System Organ Class 1 Number of subjects % Blood and lymphatic system disorders General disorders and administration site conditions Infections and infestations Injury, poisoning and procedural complications Nervous system disorders Respiratory, thoracic and mediastinal disorders Skin and subcutaneous tissue disorders Total number of adverse events 2 16 Total number of subjects MAR12:10:54:03 MCB 0501 INT t36 aesoc.doc 1) 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.

92 MCB 0501 INT 28-MAY-2012 Page 92 of 129 Table 39: Adverse events by MedDRA primary system organ class and preferred term: safety analysis set TACLONEX ointment System Organ Class Preferred Term 1 Number of subjects % Blood and lymphatic system disorders Lymphadenopathy General disorders and administration site conditions Pyrexia Infections and infestations Body tinea Gastroenteritis viral Upper respiratory tract infection Injury, poisoning and procedural complications Joint sprain Nervous system disorders Headache Tension headache Respiratory, thoracic and mediastinal disorders Cough Skin and subcutaneous tissue disorders Pruritus Rash papular Total number of adverse events 2 16 Total number of subjects MAR12:11:21:27 MCB 0501 INT t37_aept.doc 1) 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 Analysis of Adverse Events Two AEs were classified as possibly related to treatment and all other AEs were classified as not related to treatment (Table 40). Hence there were two ADRs (headache and pruritus) as shown in Table 41, and both were of mild intensity (Table 42). There were three lesional/ perilesional AEs, one event of pruritus (possibly related to treatment) and two of rash papular (not related to treatment) as shown in Table 43.

93 MCB 0501 INT 28-MAY-2012 Page 93 of 129 Table 40: Causal relationship of adverse events to study medication by MedDRA primary system organ class and preferred term: safety analysis set TACLONEX ointment System Organ Class Preferred Term 1 Not related Possible Probable Blood and lymphatic system disorders Lymphadenopathy General disorders and administration site conditions Pyrexia Infections and infestations Body tinea Gastroenteritis viral Upper respiratory tract infection Injury, poisoning and procedural complications Joint sprain Nervous system disorders Headache Tension headache Respiratory, thoracic and mediastinal disorders Cough Skin and subcutaneous tissue disorders Pruritus Rash papular Total number of adverse events MAR12:12:55:48 MCB 0501 INT t38 aerel.doc 1) 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.

94 MCB 0501 INT 28-MAY-2012 Page 94 of 129 Table 41: Adverse drug reactions by MedDRA primary system organ class and preferred term: safety analysis set TACLONEX ointment System Organ Class Preferred Term 1 Number of subjects % Nervous system disorders Headache Skin and subcutaneous tissue disorders Pruritus Total number of drug reactions 2 2 Total number of subjects MAR12:12:59:33 MCB 0501 INT t39 adrpt.doc 1) 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. Table 42: Intensity of adverse drug reactions by MedDRA primary system organ class and preferred term: safety analysis set TACLONEX ointment System Organ Class Preferred Term 1 Mild Moderate Severe Nervous system disorders Headache Skin and subcutaneous tissue disorders Pruritus Total number of adverse drug reactions MAR12:11:50:07 MCB 0501 INT t40 adrint.doc 1) 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.

95 MCB 0501 INT 28-MAY-2012 Page 95 of 129 Table 43: Lesional/perilesional adverse events by MedDRA primary system organ class and preferred term: safety analysis set TACLONEX ointment System Organ Class Preferred Term 1 Number of subjects % Skin and subcutaneous tissue disorders Pruritus Rash papular Total number of adverse events 2 3 Total number of subjects MAR12:12:17:09 MCB 0501 INT t41 aeptlp.doc 1) 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 Listing of Adverse Events by Subject For individual subject data on AEs see Appendix DEATHS, OTHER SERIOUS ADVERSE EVENTS AND OTHER SIGNIFICANT ADVERSE EVENTS No deaths, other SAEs or other significant AEs were observed in the study CLINICAL LABORATORY EVALUATION Listing of Individual Laboratory Measurements by Subject and Each Abnormal Laboratory Value For individual subject data on laboratory assessments see Appendix , Listing 1 (serum cortisol), Listing 2 (biochemistry), Listing 3 (haematology), Listing 4 (urinalysis), Listing 5 (urine pregnancy test). In addition, abnormal laboratory values are available in Listing 6.

96 MCB 0501 INT 28-MAY-2012 Page 96 of Evaluation of Each Laboratory Parameter Laboratory measurements related to the analysis of effect on adrenal function and calcium metabolism (serum cortisol, albumin-corrected serum calcium, serum phosphorus, plasma PTH and urinary calcium:creatinine and phosphorus:creatinine ratios) are reported separately (Section 11.4) Laboratory values over time The change in haematology parameters and in other biochemistry parameters, not reported in Section 11.4, from baseline to week 4 are summarised in Table 44 and Table 45, respectively. There were only minor mean changes from baseline to week 4 in the parameters listed. Table 44: Change in haematology parameters from baseline to Week 4: safety analysis set Laboratory parameter Visit TACLONEX ointment Hemoglobin (g/l) Baseline Mean SD 14.3 Median Minimum 108 Maximum 165 Number 33 Change at Week 4 Mean -1.4 SD 7.6 Median -2.0 Minimum -17 Maximum 18 Number 31 Hematocrit (Proportion of 1.0) Baseline Mean SD Median Minimum Maximum Number 33 Change at Week 4 Mean SD Median Minimum Maximum Number 31 12MAR12:17:07:02 MCB 0501 INT t42_chhaem.doc Continued...

97 MCB 0501 INT 28-MAY-2012 Page 97 of 129 Table 44: Change in haematology parameters from baseline to Week 4: safety analysis set Laboratory parameter Visit TACLONEX ointment Erythrocytes (10^12/L) Baseline Mean SD Median Minimum 3.96 Maximum 5.99 Number 33 Change at Week 4 Mean SD Median Minimum Maximum 0.57 Number 31 Mean corpuscular volume (FL) Baseline Mean SD 6.09 Median Minimum 67.9 Maximum 99.0 Number 33 Change at Week 4 Mean SD 1.36 Median 0.00 Minimum -4.9 Maximum 2.5 Number 31 12MAR12:17:07:02 MCB 0501 INT t42_chhaem.doc Continued...

98 MCB 0501 INT 28-MAY-2012 Page 98 of 129 Table 44: Change in haematology parameters from baseline to Week 4: safety analysis set Laboratory parameter Visit TACLONEX ointment Leukocytes (10^9/L) Baseline Mean 7.21 SD 2.41 Median 6.40 Minimum 3.7 Maximum 14.5 Number 33 Change at Week 4 Mean SD 1.34 Median Minimum -3.9 Maximum 1.6 Number 31 Neutrophils (10^9/L) Baseline Mean 4.38 SD 1.96 Median 4.10 Minimum 1.6 Maximum 10.9 Number 33 Change at Week 4 Mean SD 1.42 Median Minimum -5.3 Maximum 1.5 Number 31 12MAR12:17:07:02 MCB 0501 INT t42_chhaem.doc Continued...

99 MCB 0501 INT 28-MAY-2012 Page 99 of 129 Table 44: Change in haematology parameters from baseline to Week 4: safety analysis set Laboratory parameter Visit TACLONEX ointment Lymphocytes (10^9/L) Baseline Mean 2.19 SD 0.69 Median 2.30 Minimum 1.0 Maximum 4.6 Number 33 Change at Week 4 Mean SD 0.54 Median 0.00 Minimum -1.2 Maximum 1.5 Number 31 Monocytes (10^9/L) Baseline Mean 0.42 SD 0.24 Median 0.40 Minimum 0.1 Maximum 1.3 Number 33 Change at Week 4 Mean SD 0.20 Median 0.00 Minimum -0.7 Maximum 0.6 Number 31 12MAR12:17:07:02 MCB 0501 INT t42_chhaem.doc Continued...

100 MCB 0501 INT 28-MAY-2012 Page 100 of 129 Table 44: Change in haematology parameters from baseline to Week 4: safety analysis set Laboratory parameter Visit TACLONEX ointment Eosinophils (10^9/L) Baseline Mean 0.22 SD 0.17 Median 0.20 Minimum 0.0 Maximum 0.7 Number 33 Change at Week 4 Mean SD 0.17 Median 0.00 Minimum -0.5 Maximum 0.5 Number 31 Basophils (10^9/L) Baseline Mean 0.01 SD 0.03 Median 0.00 Minimum 0.0 Maximum 0.1 Number 33 Change at Week 4 Mean SD 0.02 Median 0.00 Minimum -0.1 Maximum 0.0 Number 31 12MAR12:17:07:02 MCB 0501 INT t42_chhaem.doc Continued...

101 MCB 0501 INT 28-MAY-2012 Page 101 of 129 Table 44: Change in haematology parameters from baseline to Week 4: safety analysis set Laboratory parameter Visit TACLONEX ointment Platelet count (10^9/L) Baseline Mean SD 96.3 Median Minimum 148 Maximum 641 Number 32 Change at Week 4 Mean -8.2 SD 46.4 Median 1.5 Minimum -172 Maximum 68 Number 30 12MAR12:17:07:02 MCB 0501 INT t42_chhaem.doc

102 MCB 0501 INT 28-MAY-2012 Page 102 of 129 Table 45: Change in other biochemistry parameters from baseline to Week 4: safety analysis set Laboratory parameter Visit TACLONEX ointment Blood Urea Nitrogen (mmol/l) Baseline Mean 4.45 SD 1.07 Median 4.28 Minimum 3.2 Maximum 8.6 Number 33 Change at Week 4 Mean SD 1.44 Median Minimum -3.6 Maximum 3.6 Number 32 Creatinine (umol/l) Baseline Mean 66.4 SD 17.4 Median 61.9 Minimum 44 Maximum 115 Number 33 Change at Week 4 Mean -4.1 SD 15.4 Median -4.4 Minimum -62 Maximum 35 Number 32 20MAR12:17:59:00 MCB 0501 INT t44_chbiochem.doc Continued...

103 MCB 0501 INT 28-MAY-2012 Page 103 of 129 Table 45: Change in other biochemistry parameters from baseline to Week 4: safety analysis set Laboratory parameter Visit TACLONEX ointment Albumin (g/l) Baseline Mean 45.5 SD 2.2 Median 45.0 Minimum 40 Maximum 50 Number 33 Change at Week 4 Mean -0.8 SD 3.2 Median -1.0 Minimum -12 Maximum 4 Number 32 Sodium (mmol/l) Baseline Mean SD 1.9 Median Minimum 135 Maximum 144 Number 33 Change at Week 4 Mean -0.2 SD 2.1 Median 0.0 Minimum -5 Maximum 5 Number 32 20MAR12:17:59:00 MCB 0501 INT t44_chbiochem.doc Continued...

104 MCB 0501 INT 28-MAY-2012 Page 104 of 129 Table 45: Change in other biochemistry parameters from baseline to Week 4: safety analysis set Laboratory parameter Visit TACLONEX ointment Potassium (mmol/l) Baseline Mean 4.27 SD 0.30 Median 4.30 Minimum 3.7 Maximum 5.2 Number 33 Change at Week 4 Mean 0.00 SD 0.42 Median 0.10 Minimum -1.2 Maximum 1.1 Number 32 Chloride (mmol/l) Baseline Mean SD 2.2 Median Minimum 99 Maximum 111 Number 33 Change at Week 4 Mean -0.5 SD 2.3 Median -1.0 Minimum -4 Maximum 6 Number 32 20MAR12:17:59:00 MCB 0501 INT t44_chbiochem.doc Continued...

105 MCB 0501 INT 28-MAY-2012 Page 105 of 129 Table 45: Change in other biochemistry parameters from baseline to Week 4: safety analysis set Laboratory parameter Visit TACLONEX ointment Calcium (mmol/l) Baseline Mean SD Median Minimum 2.18 Maximum 2.58 Number 33 Change at Week 4 Mean SD Median Minimum Maximum 0.18 Number 32 20MAR12:17:59:00 MCB 0501 INT t44_chbiochem.doc Individual subject changes The haematology parameters categorised as low, normal or high (according to whether they are below, within or above the laboratory reference range, respectively) at week 4 against baseline category are shown in Table 46. Other biochemistry parameters, not reported in Section 11.4, categorised as low, normal or high at week 4 against baseline category are shown in Table 47. The presence of urinary glucose and ketones at week 4 against presence at baseline is displayed in Table 48. The number of subjects with shifts from within the reference range to a high or low value was small and did not indicate a trend towards increasing or decreasing values on treatment.

106 MCB 0501 INT 28-MAY-2012 Page 106 of 129 Table 46: Haematology parameters categorised as low, normal or high at Week 4 against baseline category: safety analysis set TACLONEX ointment Laboratory parameter End of treatment category 1 Baseline category 1 Low Normal High Hemoglobin Low Normal High Hematocrit Low Normal Erythrocytes Normal High Mean corpuscular volume Low Normal Leukocytes Low Normal High Neutrophils Low Normal High Lymphocytes Low Normal Monocytes Normal High Eosinophils Normal High Basophils Normal Platelet count Low Normal High Unknown MAR12:17:30:57 MCB 0501 INT t43 shhaem.doc 1) Number of subjects with laboratory parameters below, within or above the reference range.

107 MCB 0501 INT 28-MAY-2012 Page 107 of 129 Table 47: Other biochemistry parameters categorised as low, normal or high at Week 4 against baseline category: safety analysis set TACLONEX ointment Laboratory parameter End of treatment category 1 Baseline category 1 Low Normal High Blood Urea Nitrogen Normal High Creatinine Normal High Albumin Normal Sodium Normal Potassium Normal Chloride Normal High Calcium Normal MAR12:17:32:11 MCB 0501 INT t45 shbiochem.doc 1) Number of subjects with laboratory parameters below, within or above the reference range.

108 MCB 0501 INT 28-MAY-2012 Page 108 of 129 Table 48: Presence of urinary glucose and ketones at Week 4 against presence at baseline: safety analysis set TACLONEX ointment Laboratory parameter End of treatment category 1 Baseline category 1 Absent Present Glucose Absent 33 0 Ketones Absent MAR12:17:33:36 MCB 0501 INT t46 shglucket.doc 1) Present = Trace or 1+, 2+, Individual clinically significant abnormalities There were no individual clinically significant abnormalities with regards to the laboratory parameters assessed VITAL SIGNS, PHYSICAL FINDINGS AND OTHER OBSERVATIONS RELATED TO SAFETY The changes in vital signs from baseline to end of treatment were minor. Change in vital signs from baseline to week 4 are summarised in Table 49 (systolic blood pressure), Table 50 (diastolic blood pressure), and Table 51 (heart rate).

109 MCB 0501 INT 28-MAY-2012 Page 109 of 129 Table 49: Change in systolic blood pressure from baseline to Week 4: safety analysis set Systolic Blood Pressure (mmhg) TACLONEX ointment Baseline Mean SD 10.2 Median Minimum Maximum Number 33 Change at Week 4 Mean -2.0 SD 7.9 Median -1.5 Minimum Maximum 11.5 Number 33 08MAR12:14:57:58 MCB 0501 INT t47_chsysbp.doc Table 50: Change in diastolic blood pressure from baseline to Week 4: safety analysis set Diastolic Blood Pressure (mmhg) TACLONEX ointment Baseline Mean 68.7 SD 9.6 Median 69.5 Minimum 51.0 Maximum 83.0 Number 33 Change at Week 4 Mean 0.4 SD 7.4 Median 1.0 Minimum Maximum 17.0 Number 33 08MAR12:15:01:43 MCB 0501 INT t48_chdiabp.doc

110 MCB 0501 INT 28-MAY-2012 Page 110 of 129 Table 51: Change in heart rate from baseline to Week 4: safety analysis set Heart Rate (bpm) TACLONEX ointment Baseline Mean 74.2 SD 8.9 Median 74.0 Minimum 58 Maximum 92 Number 33 Change at Week 4 Mean 2.8 SD 12.0 Median 4.0 Minimum -20 Maximum 24 Number 33 08MAR12:15:12:53 MCB 0501 INT t49_chhr.doc For individual subject data see Appendix , Listing 11 (vital signs) SAFETY CONCLUSION TACLONEX ointment was well tolerated with few ADRs, no SAEs and no withdrawals.

111 MCB 0501 INT 28-MAY-2012 Page 111 of DISCUSSION AND OVERALL CONCLUSIONS The aim of this study was to evaluate the safety and efficacy of TACLONEX ointment in the adolescent age group (12-17 years inclusive). At the time of initiation, this was the first study in patients less than 18 years of age despite the fact that 35% of affected individuals develop the disease before the age of 20, and that 25% are diagnosed between 10 and 19 years of age (16). The study was conducted as planned in the Clinical Study Protocol. There were no protocol amendments and only minor changes to the planned analyses. A total of 33 subjects between 12 and 17 years of age inclusive with psoriasis vulgaris were treated with TACLONEX ointment. They all received 4 weeks treatment, and 32 provided data for the ACTH-challenge test at week 4, therefore meeting the required number of 30. Twenty-two (67%) subjects were white and the remaining 11 (33%) subjects were either Black or African American (4 subjects), Asian (5 subjects) or of other race (2 subjects; Middle Eastern and Filipino). Eleven (33%) subjects were reported as Hispanic or Latino and 22 (67%) were reported as not Hispanic or Latino. This distribution of race and ethnicity is unusual for psoriasis studies. This was a small, non-controlled study where the primary objective was to assess safety of TACLONEX ointment. Thus the number of subjects was not based on a formal size calculation. However, a few considerations regarding the sample size (30 subjects) were made. The upper limit of an exact two-sided 95% confidence interval for the probability of observing a specific AE, when 0 out of 30 possible events have been observed, is 12% assuming a binomial distribution. Thirty subjects undergoing ACTH-challenge testing has previously been accepted by the FDA as an adequate sample size. To evaluate the safety of TACLONEX ointment, all AEs were recorded and any systemic absorption of the active components, betamethasone dipropionate and calcipotriene, were evaluated by assessing adrenal function and calcium metabolism, respectively. None of the subjects had a serum cortisol concentration of 18 mcg/dl at either 30 or 60 minutes following ACTH challenge at week 4, hence there was no laboratory evidence of adrenal suppression following study treatment.

112 MCB 0501 INT 28-MAY-2012 Page 112 of 129 There were no clinically significant mean changes in albumin corrected serum calcium or urinary calcium:creatinine ratio from baseline to week 4, and no subject had albumin corrected serum calcium above the reference range at week 4. One subject had an increase in urinary calcium:creatinine ratio, and a relationship to study treatment cannot be excluded. There were no individual clinically significant abnormalities in the biochemistry or haematology parameters assessed. A total of 11 subjects (33%) experienced AEs. This is in line with the AE profile in 4-week studies on adults where 24%, 30% and 27% of the subjects reported AEs, respectively (8,11,12). There were no SAEs or withdrawals due to AEs in the study, and only two subjects had one ADR each (headache and pruritus, both of mild intensity). Lesional/perilesional AEs in this study were one event of pruritus (possibly related to treatment) and two of rash papular (not related to treatment). Hence one subject (3.0%) had a lesional/perilesional ADR. This corresponds to a figure of 6.0% in the pivotal Phase 3 study in adults, where the most common lesional/perilesional ADR was pruritus (8). However the numbers in the present study were low, so comparisons should be interpreted with caution. The changes in vital signs from baseline to end of treatment were minor. The mean amount of TACLONEX ointment used per week was 29.6 g (range 8.1 to 55.8 g). This corresponds to a figure of 33.5 g in the pivotal Phase 3 study in adults (8). Evaluation of efficacy was a secondary objective, and the study was not designed to obtain evidence of efficacy. Even so, the efficacy of TACLONEX ointment in this small, noncontrolled study on 33 adolescent subjects was comparable to that observed in the pivotal Phase 3 study in adults (8). In the present study the percentage of subjects with controlled disease (i.e. clear or almost clear ) after 4 weeks of treatment was 61% according to IGA. The mean percentage reduction in modified PASI from baseline to week 4 was 72.5%. In the pivotal Phase 3 study in adults the percentage of subjects with controlled disease at week 4 was 56% according to IGA and the mean percentage reduction in modified PASI from baseline to week 4 was 71.3%. The similar outcome for efficacy in the two studies suggests that TACLONEX ointment is as effective in adolescents as it is in adults.

113 MCB 0501 INT 28-MAY-2012 Page 113 of CONCLUSIONS There was no evidence of adrenal suppression following study treatment. There were no clinically significant mean changes in albumin-corrected serum calcium or urinary calcium:creatinine ratio, and no cases of hypercalcaemia were reported. One subject had an increase in urinary calcium:creatinine ratio, and a relationship to study treatment cannot be excluded. TACLONEX ointment was well tolerated with few ADRs, no SAEs and no withdrawals. The efficacy level in the study suggests that TACLONEX ointment is effective in the treatment of psoriasis vulgaris in adolescents. In conclusion, in this small, non-controlled study TACLONEX ointment appeared to be safe and effective in the treatment of psoriasis vulgaris in adolescents.

114 MCB 0501 INT 28-MAY-2012 Page 114 of TABLES, FIGURES AND GRAPHS REFERRED TO BUT NOT INCLUDED IN THE TEXT 14.1 DEMOGRAPHIC DATA Table 52: Reasons for withdrawal during the screening phase: enrolled subjects CRF N Centre Reason for withdrawal details <5% bsa on trunk/extremities <5% bsa affected by psoriasis No active psoriatic lesions currently Not meet exclusion criteria 16. Not meet exclusion criteria 15 and 16. Withdrew consent Subject has only mild psoriasis per investigator assessment while not on any treatment for psoriasis Subject was lost to follow-up during the screening phase of the study. Failed inclusion criteria 6, acth labs not in the acceptable range. (ie pre-acth level not greater than 5, and 30 minute level not greater than 18). Failed protocol inculsion criteria 7-urinary calcium/creatinine ratio not within reference range. Subject failed inclusion criteria 5-did not have moderate psoriasis or at least 5% bsa. Subject failed inclusion criteria 5-did not have from 5-30%bsa of psoriasis. Failed inclusion criteria 5-did not have at least 5% body surface area Did not have psoriasis Per monitor each pt that signed consent was 'enrolled' in study. this pt came in at sv1 signed consent but did not have sufficient bsa.returned 7/29/09 still did not have enought bsa Subjectalbumin corrected serum out of range at sv2 and redrawn but remained out of range. unable to enroll. Not enought bsa to meet inclusion criteria Withdrew consent during screening After signing consent and on careful examination of skin, subject was deemed to have mixed psoriasis, guttate and plaque,also taking welbuterin for depression Did not have sufficient bsa to qualify Patient violated exclusion criteria 15 (pityriasis rosacea on trunk) Patient with a current diagnosis of guttate psoriasis. Acth challenge test was unable to be completed due to unable to do blood draw due to bad veins and was not able to draw labs at appropriate time periods. 13MAR12:12:47:31 MCB 0501 INT t50 reaswdscr.doc

115 MCB 0501 INT 28-MAY-2012 Page 115 of 129 Table 53: Age by centre: safety analysis set and per protocol analysis set Centre Age (years) Safety Analysis Set Per Protocol Analysis Set (n=32) Mean SD Median Minimum Maximum Number 1 1 Mean SD Median Minimum Maximum Number 3 2 Mean SD Median Minimum Maximum Number 5 5 Mean SD Median Minimum Maximum Number Mean SD Median Minimum Maximum Number MAR12:14:57:57 MCB 0501 INT t51_agecentre.doc Continued...

116 MCB 0501 INT 28-MAY-2012 Page 116 of 129 Table 53: Age by centre: safety analysis set and per protocol analysis set Centre Age (years) Safety Analysis Set Per Protocol Analysis Set (n=32) Mean SD Median Minimum Maximum Number Mean SD Median Minimum Maximum Number 2 2 All Centres Mean SD Median Minimum Maximum Number MAR12:14:57:57 MCB 0501 INT t51_agecentre.doc

117 MCB 0501 INT 28-MAY-2012 Page 117 of 129 Table 54: Sex by centre: safety analysis set and per protocol analysis set Centre Sex Safety Analysis Set Number of subjects % Per Protocol Analysis Set (n=32) Number of subjects % Male Total Male Female Total Male Female Total Male Female Total Female Total Male Female Total Female Total All centres Male Female Total MAR12:16:06:33 MCB 0501 INT t52 sexcentre.doc

118 MCB 0501 INT 28-MAY-2012 Page 118 of 129 Table 55: Weight: safety analysis set and per protocol analysis set Weight (kg) Safety Analysis Set Per Protocol Analysis Set (n=32) Mean SD Median Minimum Maximum Number MAR12:16:20:42 MCB 0501 INT t53_weight.doc Table 56: Height: safety analysis set and per protocol analysis set Height (cm) Safety Analysis Set Per Protocol Analysis Set (n=32) Mean SD Median Minimum Maximum Number MAR12:16:40:52 MCB 0501 INT t54_height.doc Table 57: BMI: safety analysis set and per protocol analysis set BMI (kg/m2) Safety Analysis Set Per Protocol Analysis Set (n=32) Mean SD Median Minimum Maximum Number MAR12:16:50:27 MCB 0501 INT t55_bmi.doc

119 MCB 0501 INT 28-MAY-2012 Page 119 of EFFICACY DATA Table 58: Controlled disease (IGA) at Week 4 by age group: full analysis set TACLONEX ointment Age Group (years) Controlled disease Number of subjects % 12 to 14 Controlled Non-controlled Total to 17 Controlled Non-controlled Total MAR12:11:51:32 MCB 0501 INT t56 iga agegrp.doc Table 59: Controlled disease (IGA) at Week 4 by sex: full analysis set TACLONEX ointment Sex Controlled disease Number of subjects % Male Controlled Non-controlled Total Female Controlled Non-controlled Total MAR12:17:46:23 MCB 0501 INT t57 iga sexgrp.doc

120 MCB 0501 INT 28-MAY-2012 Page 120 of 129 Table 60: Controlled disease (IGA) at Week 4 by baseline IGA: full analysis set TACLONEX ointment Baseline IGA Controlled disease Number of subjects % Moderate Controlled Non-controlled Total Severe Controlled Non-controlled Total MAR12:10:44:27 MCB 0501 INT t58 iga base.doc

121 MCB 0501 INT 28-MAY-2012 Page 121 of 129 Table 61: Controlled disease (IGA) at Week 4 by centre: full analysis set TACLONEX ointment Centre Controlled disease Number of subjects % Controlled Total Controlled Non-controlled Total Controlled Non-controlled Total Controlled Non-controlled Total Controlled Total Controlled Non-controlled Total Controlled Total All Centres Controlled Non-controlled Total MAR12:12:46:22 MCB 0501 INT t59_iga_centre.doc

122 MCB 0501 INT 28-MAY-2012 Page 122 of 129 Table 62: Controlled disease (IGA) by visit: full analysis set TACLONEX ointment Visit Controlled disease Number of subjects % Visit 1 (Baseline) Non-controlled Total Visit 2 (Week 2) Controlled Non-controlled Total Visit 3 (Week 4) Controlled Non-controlled Total MAR12:11:10:17 MCB 0501 INT t60 iga visit.doc Table 63: Controlled disease (patient s global assessment) by visit: full analysis set TACLONEX ointment Visit Controlled disease Number of subjects % Visit 1 (Baseline) Controlled Non-controlled Total Visit 2 (Week 2) Controlled Non-controlled Total Visit 3 (Week 4) Controlled Non-controlled Total MAR12:11:30:47 MCB 0501 INT t61 pga visit.doc

123 MCB 0501 INT 28-MAY-2012 Page 123 of 129 Table 64: Percentage change in modified PASI by visit: full analysis set Visit Percentage change in modified PASI TACLONEX ointment Visit 1 (Baseline) Mean 8.1 SD 4.1 Median 6.7 Minimum 3.0 Maximum 18.0 Number 33 Visit 2 (Week 2) Mean SD 23.0 Median Minimum Maximum 0.0 Number 33 Visit 3 (Week 4) Mean SD 24.2 Median Minimum Maximum 3.6 Number 33 12MAR12:15:01:56 MCB 0501 INT t62_mpasi_visit.doc Table 65: Modified PASI 75 by visit: full analysis set TACLONEX ointment Visit Achieved modified PASI 75 Number of subjects % Visit 2 (Week 2) Yes No Total Visit 3 (Week 4) Yes No Total MAR12:12:18:11 MCB 0501 INT t63 mpasi75 visit.doc

124 MCB 0501 INT 28-MAY-2012 Page 124 of 129 Table 66: Modified PASI 50 by visit: full analysis set TACLONEX ointment Visit Achieved modified PASI 50 Number of subjects % Visit 2 (Week 2) Yes No Total Visit 3 (Week 4) Yes No Total MAR12:12:24:32 MCB 0501 INT t64 mpasi50 visit.doc

125 MCB 0501 INT 28-MAY-2012 Page 125 of REFERENCES 1. Greaves MW, Weinstein GD. Treatment of psoriasis. N Engl J Med 1995; 332: Rapp SR, Feldman SR, Exum ML, Fleischer AB, Reboussin DM. Psoriasis causes as much disablity as other major medical diseases. J Am Acad Dermatol 1999; 41: Gelfand JM, Feldman SR, Stern RS, Thomas J, Rolstad T, Margolis DJ. Determinants of quality of life in patients with psoriasis: a study from the US population. J Am Acad Dermatol 2004; 51 (5): Christophers E, Schubert C. Psoriasis. In: Thody AJ, Friedmann PS, editors. Scientific basis of dermatology, a physiological approach. London: Churchill Livingstone; p Bos JD. The pathomechanisms of psoriasis; the skin immune system and cyclosporin. Br J Dermatol 1988; 118: Lowes MA, Bowcock AM, Krueger JG. Pathogenesis and therapy of psoriasis. Nature 2007; 445: Gawkrodger DJ on behalf of the Therapy Guidelines and Audit Subcommittee of the British Association of Dermatologists. Current management of psoriasis. J Derm Treat 1997; 8: Kaufmann R, Bibby AJ, Bissonnette R, Cambazard F, Chu AC, Decroix J et al. A new calcipotriol/betamethasone dipropionate formulation (Daivobet TM ) is an effective oncedaily treatment for psoriasis vulgaris. Dermatology 2002; 205: Kragballe K, Noerrelund KL, Lui H, Ortonne JP, Wozel G, Uurasmaa T et al. Efficacy of once-daily treatment regimens with calcipotriol/betamethasone dipropionate ointment and calcipotriol ointment in psoriasis vulgaris. Br J Dermatol 2004; 150: Ortonne JP, Kaufmann R, Lecha M, Goodfield M. Efficacy of treatment with calcipotriol/betamethasone dipropionate followed by calcipotriol alone compared with tacalcitol for the treatment of psoriasis vulgaris: a randomised, double-blind trial. Dermatology 2004; 209: Papp KA, Guenther L, Boyden B, Larsen FG, Harvima RJ, Guilhou JJ et al. Early onset of action and efficacy of a combination of calcipotriene and betamethasone dipropionate in the treatment of psoriasis. J Am Acad Dermatol 2003; 48: Douglas WS, Poulin Y, Decroix J, Ortonne JP, Mrowietz U, Gulliver W et al. A new calcipotriol/betamethasone formulation with rapid onset of action was superior to monotherapy with betamethasone dipropionate or calcipotriol in psoriasis vulgaris. Acta Derm Venerol 2002; 82:

126 MCB 0501 INT 28-MAY-2012 Page 126 of Guenther L, Cambazard F, van de Kerkhof PCM, Snellman E, Kragballe K, Chu AC et al. Efficacy and safety of a new combination of calcipotriol and betamethasone dipropionate (once or twice daily) compared to calcipotriol (twice daily) in the treatment of psoriasis vulgaris: a randomized, double-blind, vehicle-controlled clinical trial. Br J Dermatol 2002; 147: Kragballe K, Austad J, Barnes L, Bibby A, Brassinne M de la, Cambazard F et al. A 52- week randomized safety study of a calcipotriol/betamethasone dipropionate twocompound product (Dovobet /Daivobet /Taclonex ) in the treatment of psoriasis vulgaris. Br J Dermatol 2006; 154: Effect of calcipotriol/betamethasone dipropionate ointment compared to betamethasone dipropionate ointment on the HPA axis in patients with psoriasis vulgaris. LEO Study Number MCB 0201 FR, Aster PC Report dated 1 July Farber EM, Nall ML. The natural history of psoriasis in 5,600 patients. Dermatologica 1974; 148: Farber EM, Nall L. Childhood psoriasis. Cutis 1999; 64: Rogers M. Childhood psoriasis. Curr Opin Pediatr 2002; 14: Leman J, Burden D. Psoriasis in children. A guide to its diagnosis and management Paediatr Drugs 2001; 3: Morris A, Rogers M, Fischer G, Williams K. Childhood psoriasis: A clinical review of 1262 cases. Pediatr Dermatol 2001; 18: Garzon MC. Diagnosis and management of psoriasis and pityriasis lichenoides in children. Dermatol Therapy 1997; 2: Drake LA, Ceilley RI, Cornelison RL, Dobes WA, Dorner W, Goltz RW, et al. Guidelines of care for psoriasis. J Am Acad Dermatol 1993; 28: Levin C, Maibach HI. Topical corticosteroid-induced adrenocortical insufficiency. Am J Clin Dermatol 2002; 3: Forest MG. Adrenal function tests. In: Ranke MB (ed): Diagnostics of endocrine function in children and adolescents. Basel, Karger, 2003, pp Grinspoon SK, Biller BMK. Clinical Review 62. Laboratory assessment of adrenal insufficiency. J Clin Endocrin Metabolism 1994; 79: Bourke JF, Berth-Jones J, Iqbal SJ, Hutchinson PE. High-dose topical calcipotriol in the treatment of extensive psoriasis vulgaris. Br J Dermatol 1993; 129: Gokce C, Gokce O, Baydinc C, Ilhan N, Alasehirli E, Ozkucuk F. Use of random urine samples to estimate total urinary calcium and phosphate excretion. Arch Intern Med 1991; 151:

127 MCB 0501 INT 28-MAY-2012 Page 127 of Pacifici R, Vered I, McMurtry C, Smith S, Muckerman J, Delebar C, et al. Effect of Ca and vitamin D supplementation on urinary calcium excretion in an adult female population. J Am Coll Nutr 1987; 6: 430 (Abstr 35).

128 MCB 0501 INT 28-MAY-2012 Page 128 of LIST OF APPENDICES App. No. Appendix Date of appendix Enclosed/ N.A STUDY INFORMATION Protocol and protocol amendments 11-APR-2012 Enclosed Sample case report form (unique pages only) 12-APR-2012 Enclosed List of IECs or IRBs (plus the name of the committee 12-APR-2012 Enclosed Chair if required by the regulatory authority) - Representative written information for subject and sample consent forms List and description of investigators and other 13-APR-2012 Enclosed important participants in the trial, including brief (1 page) CVs or equivalent summaries of training and experience relevant to the performance of the clinical trial Signatures of principal or coordinating investigator(s) 12-APR-2012 Enclosed or sponsor s responsible medical officer, depending on the regulatory authority's requirement Listing of subjects receiving test 18-MAY-2012 Enclosed drug(s)/investigational product(s) from specific batches, where more than one batch was used Randomisation scheme and codes (subject identification N.A. and treatment assigned) Audit certificates (if available) 12-APR-2012 Enclosed Documentation of statistical methods 23-MAY-2012 Enclosed Documentation of inter-laboratory standardisation N.A. methods and quality assurance procedures if used Publications based on the trial N.A Important publications referenced in the report Links to the references are found in Section

129 MCB 0501 INT 28-MAY-2012 Page 129 of SUBJECT DATA LISTINGS Discontinued subjects 18-MAY-2012 Enclosed Protocol deviations 23-MAY-2012 Enclosed Subjects excluded from the per protocol analysis 14-MAY-2012 Enclosed Demographic data 14-MAY-2012 Enclosed Compliance and/or drug concentration data 14-MAY-2012 Enclosed Individual efficacy response data 21-MAY-2012 Enclosed Adverse event listings 15-MAY-2012 Enclosed Listing of individual laboratory measurements by subject 18-MAY Enclosed Additional subject data listings 18-MAY-2012 Enclosed 16.3 CASE REPORT FORMS CRFs for deaths, other serious adverse events and N.A. withdrawals for AE Other CRFs submitted Available upon request.

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