Calcipotriol/Dithranol Intensified Treatment

Transcription

1 CLINICAL STUDY REPORT Calcipotriol/Dithranol Intensified Treatment Calcipotriol intensified treatment versus Dithranol intensified treatment in patients with psoriasis vulgaris MCO 9803 NL LEO Pharma Medical Department FINAL 12-DEC

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4 MCO 9803 NL 12-DEC-2005 Page 3 of REPORT STATEMENTS 2.1 CONFIDENTIALITY STATEMENT This Clinical Study Report is the property of LEO Pharma and is a confidential document. It is not to be copied or distributed to other parties without written approval from LEO Pharma. 2.2 COMPLIANCE WITH GOOD CLINICAL PRACTICE This Clinical Study Report is designed to comply with standards issued by the International Conference on Harmonisation (ICH) (E3 Structure and Content of Clinical Study Report; E6 Good Clinical Practice; E9 Statistical Principles for Clinical Trials).

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8 MCO 9803 NL 12-DEC-2005 Page 7 of SUMMARY Name of Sponsor/Manufacturer: LEO PHARMA Name of Finished Product, if available: Location of study report in Regulatory Dossier for [..] authorities Volume: (For National Authority Use only) Daivonex ointment Name of Active Substance: Calcipotriol (50ųg/g) Page: Title of Study/Protocol Code Number: Calcipotriol intensified treatment versus Dithranol intensified treatment in patients with psoriasis vulgaris. MCO 9803 NL National Co-ordinating Investigator: Prof. Dr. Afdeling Dermatologie Academisch Ziekenhuis Nijmegen Sponsor s Medical Expert:, MD Medical Department LEO Pharma BV Hoge Mosten NH Breda The Netherlands Centre Details: 6 centres, all in The Netherlands: Publication References: None Study period details: First patient enrolled : Last patient completed : Phase of development: Phase IV Objectives/hypothesis: The primary objective was to compare the clinical efficacy of calcipotriol ointment with that of dithranol cream in an intensified treatment regimen in terms of percentage reduction in PASI from baseline to end of treatment. Secondary objectives were to compare the safety and tolerability of calcipotriol ointment with that of dithranol cream in an intensified treatment regimen and to evaluate the pharmacoeconomic implications of an intensified treatment regimen with either drug. Study Methodology: This was a national, multi-centre, prospective, randomised, open, parallel group study comparing up to 12 weeks of intensive treatment with either calcipotriol ointment (50ųg/g) or dithranol cream (in different strengths).

9 Page 8 of DEC-2005 MCO 9803 NL Name of Sponsor/Manufacturer: LEO PHARMA Name of Finished Product, if available: Location of study report in Regulatory Dossier for [..] authorities Volume: (For National Authority Use only) Daivonex ointment Name of Active Substance: Calcipotriol (50ųg/g) Page: Number of Patients enrolled: A total of 106 patients were recruited with 54 patients in the calcipotriol group and 52 patients in the dithranol group. Diagnosis and Main Criteria for patient selection: Included were patients of either sex, who had given signed informed consent before study entry, aged 18 years or above, with a clinical diagnosis of psoriasis vulgaris, amenable to treatment with topical medications, involving arms and/or trunk and/or legs. The treatment area had to be treatable with a total weekly dose of max. 100g calcipotriol ointment. PASI score for extent had to be 2 in at least one body region. Females of child-bearing potential had to have a negative pregnancy test at visit 1 and had to agree to use adequate contraception during the entire study. Patients had to be capable of and willing to attend the A.T.B. clinic during the study period. Excluded were patients with guttate, pustular, erythrodermic, or exfoliative psoriasis, as well as patients who had received systemic antipsoriatic treatment or phototherapy within the last 6 weeks, or who had used any topical antipsoriatic treatment on the body within the 2 weeks prior to study start (except for emollients and/or descaling agents (salicylic acid (5%) in petrolatum)). Furthermore, patients with planned changes in their concurrent medication that could affect their psoriasis during the study period, patients with known or suspected hypercalcaemia and patients who were hypersensitive to components of either calcipotriol ointment or dithranol cream, were excluded. In addition, pregnant patients or patients who wished to become pregnant, patients suspected of being unable to comply with the study protocol, patients who had received treatment with an investigational drug within the last 3 months or who were at the time in which the study was held participating in any other clinical trial or who had previously been randomised in this trial were excluded, as well as patients who were expected to be exposed to excessive amounts of sun or ultraviolet light during the study and patients known to be non-responding to an intensified treatment with calcipotriol or dithranol short-contact. Investigational Product: Calcipotriol 50ųg/g, ointment, applied topically, twice daily. Lot numbers:, Treatment Duration Treatment Phase: up to 12 weeks. Follow up: only in case of ongoing clinically relevant adverse events at the last study visit. Reference Therapy: Dithranol cream FNA (in different strengths: 0.05%-0.1%-0.2%-0.3%-0.4%-0.6%-0.8%- 1%-2%-3% and 5%). Applied topically, once daily. Lot numbers

10 MCO 9803 NL 12-DEC-2005 Page 9 of 141 Name of Sponsor/Manufacturer: LEO PHARMA Name of Finished Product, if available: Location of study report in Regulatory Dossier for [..] authorities Volume: (For National Authority Use only) Daivonex ointment Name of Active Substance: Calcipotriol (50ųg/g) Page: Criteria for evaluation: Efficacy: The primary response criterion was the percentage change in PASI from baseline to end of treatment. Secondary response criteria were: - the percentage change in PASI during treatment - the percentage of patients having achieved moderate improvement, marked improvement or clearance at the end of treatment according to the investigator s overall assessment and the patient s overall assessment, - the distribution of each of the investigator s and patient s overall efficacy assessment during and at end of treatment, - change in severity score for redness, thickness and scaliness from baseline to each on treatment visit and to end of treatment, - change in each of total sum score and individual clinical sign scores of the target lesion from baseline to each on treatment visit and end of treatment, - percentage of patients achieving satisfactory response (patient not requiring further active treatment at end of treatment). Safety: Any reported adverse events and patient withdrawals. Statistical Methodology. The difference between calcipotriol and dithranol for the primary efficacy criterion (percentage change in PASI from baseline to end of treatment) was calculated from an analysis of variance (ANOVA) model including centre, baseline PASI and treatment. The lower confidence limit of the difference was compared to a protocol defined lower equivalence margin of -10% to assess non-inferiority. For continuous end-points differences between treatments with corresponding 95% confidence intervals (CI) were calculated using ANOVA as described for the primary analysis. For binary variables, differences between the percentages for each treatment were calculated with 95% CI calculated using the normal approximation. The primary efficacy analysis was performed for the intention-to-treat and per protocol analysis sets. Secondary efficacy analyses were performed on the per protocol analysis set. The percentage of patients experiencing adverse events in each treatment group (safety analysis set) was compared using the Chi-squared test. The treatment groups were compared with respect to change from baseline to end of treatment for each of the 8 multi-item dimensions of SF-36 and 3 multi-item scales of the Skindex questionnaire using the Mann-Whitney U test and presenting median differences with corresponding non-parametric 95% CI.

11 Page 10 of DEC-2005 MCO 9803 NL Name of Sponsor/Manufacturer: LEO PHARMA Name of Finished Product, if available: Location of study report in Regulatory Dossier for [..] authorities Volume: (For National Authority Use only) Daivonex ointment Name of Active Substance: Calcipotriol (50ųg/g) Page: Summary/Discussion The mean age was 51.5 years (range 29 to 78) in the calcipotriol group and 50.9 years (range 25 to 83) in the dithranol group. In the calcipotriol group there were 50% males, compared to 71.2% in the dithranol group. In the calcipotriol group 17 patients (31.5%) were withdrawn from the study, compared to 11 patients (21.2%) in the dithranol group. Efficacy Results: Percentage change in PASI In the calcipotriol group, the mean PASI at baseline was 9.8 (range 3.2 to 27.0). In the dithranol group, the mean PASI at baseline was 10.1 (range 2.7 to 20.9). In the per protocol analysis set the mean percentage change in PASI from baseline to end of 12 weeks of treatment was -57.0% in the calcipotriol group and -63.6%, in the dithranol group. The difference (95% CI) between treatments (dithranol minus calcipotriol) was -6.0% (-19.0 to 7.9) (p=0.39). The 90% confidence interval for the mean difference was to 5.6. Since the lower limit of the 90% CI is outside the limit for non-inferiority of -10% there is no evidence to suggest that calcipotriol is non-inferior to dithranol. Table S1: Percentage change in PASI from baseline to end of treatment: per-protocol analysis set PASI Calcipotriol Dithranol Centre (n=46) (n=40) All patients Mean SD Minimum Maximum 71-9 Number Lower 95% CL Upper 95% CL

12 MCO 9803 NL 12-DEC-2005 Page 11 of 141 Name of Sponsor/Manufacturer: LEO PHARMA Name of Finished Product, if available: Location of study report in Regulatory Dossier for [..] authorities Volume: (For National Authority Use only) Daivonex ointment Name of Active Substance: Calcipotriol (50ųg/g) Page: Investigators overall efficacy assessment Table S2 shows the numbers and percentage of responders at the end of treatment. At the end of treatment 30 patients (65.2%) in the calcipotriol group had responded, compared to 33 patients (82.5%) in the dithranol group. The difference (95% CI) in the percentage of responders (calcipotriol dithranol) was (-35.4 to 0.8). Table S2: Investigators overall efficacy assessment, Responders/Non-Responders at End of treatment: per-protocol analysis set. (Patients having achieved a moderate improvement, a marked improvement or clearance were defined as Responders) Investigators Calcipotriol Dithranol overall efficacy (n=46) (n=40) assessment Number of Number of patients % patients % Non-Responder Responder Total Safety One serious adverse event was reported. A patient in the dithranol group was hospitalised for an exacerbation of depression which was not considered related to study medication. Thirty-seven (69.8%) patients in the calcipotriol group and 50 patients (96.2%) in the dithranol group reported at least one adverse event. There was a statistically significant difference between the treatment groups with respect to the proportion of patients who reported adverse events (p<=0.001). The odds ratio for the calcipotriol group relative to the dithranol group was 0.09 (95% CI: 0.02 to 0.43). There was also a statistically significant difference between the treatment groups with respect to the proportion of patients who reported application related skin and subcutaneous tissue adverse drug reactions (p=0.001) (Table S3). The odds ratio for the calcipotriol group relative to the dithranol group was 0.27 (95% CI: 0.12 to 0.60). Table S3: Number of patients experiencing application related skin and subcutaneous tissue disorders by preferred term: safety analysis set

13 Page 12 of DEC-2005 MCO 9803 NL Name of Sponsor/Manufacturer: LEO PHARMA Name of Finished Product, if available: Location of study report in Regulatory Dossier for [..] authorities Volume: (For National Authority Use only) Daivonex ointment Name of Active Substance: Calcipotriol (50ųg/g) Page: Preferred term 1 Calcipotriol Dithranol Treatment comparison (n=53) (n=52) Number of Number of Odds ratio (95% CI) patients % patients % P-value Application site rash Burning sensation NOS Dermatitis NOS Dry skin Erythema Impetigo NOS Inflammation NOS Koebner phenomenon Pain NOS Pain of skin Paraesthesia Pruritus NOS Psoriasis Psoriasis aggravated Rash scaly Scratch Skin burning sensation Skin disorder NOS Skin fissures Skin irritation Skin odour abnormal Total number of adverse events 2 Total number of patients (%) (0.12 to 0.60) p= ) Classification according to MedDRA version 4.1 2) Different adverse events within the same class and involving the same patient have been counted as one. A single patient could appear in multiple classes. Quality of Life There were no statistically significant differences between the calcipotriol group and dithranol group in terms of changes in Quality of Life from baseline to end of treatment (Tables S4 and S5). Table S4: Change in the 4 factors from the Skindex Quality of Life Questionnaire: randomised patients

14 MCO 9803 NL 12-DEC-2005 Page 13 of 141 Name of Sponsor/Manufacturer: LEO PHARMA Name of Finished Product, if available: Location of study report in Regulatory Dossier for [..] authorities Volume: (For National Authority Use only) Daivonex ointment Name of Active Substance: Calcipotriol (50ųg/g) Page: Calcipotriol Dithranol Difference between (n=54) (n=52) treatment groups Difference (95% CI) P-value Emotions 1 Median (-12.5 to 2.5) P=0.98 Symptoms 2 Median (-17.9 to 3.6) P=0.59 Function 1 Median (-10.0 to 2.1) P=0.54 Total score 1 Median (-11.2 to 2.6) P=0.98 1) 49 patients in the calcipotriol group and 48 patients in the dithranol group. 2) 49 patients in the calcipotriol group and 47 patients in the dithranol group. Table S5: Change in the 8 factors from the SF36 Quality of Life Questionnaire: randomised patients Calcipotriol Dithranol Difference between (n=54) (n=52) Treatment groups Difference (95% CI) P-value Physical functioning 1 Median (-6.1 to 1.1) P=0.69 Social functioning 1 Median (-12.5 to 0.0) P=0.92 Role limitations due to physical problems 2 Median (-25.0 to 0.0) P=0.85 Role limitations due to emotional problems 3 Median (-33.3 to 0.0) P=0.68 Mental Health 1 Median (-4.0 to 8.0) P=0.10 Energy/Vitality 4 Median (-10.0 to 5.0) P=0.52 Bodily Pain 1 Median (-16.0 to 2.0) P=0.80 General Health 2 Median (-10.0 to 5.0) P=0.39 1) 49 patients in the calcipotriol group and 50 patients in the dithranol group. 2) 48 patients in the calcipotriol group and 49 patients in the dithranol group. 3) 47 patients in the calcipotriol group and 50 patients in the dithranol group. 4) 48 patients in the calcipotriol group and 50 patients in the dithranol group. Conclusion

15 Page 14 of DEC-2005 MCO 9803 NL Name of Sponsor/Manufacturer: LEO PHARMA Name of Finished Product, if available: Location of study report in Regulatory Dossier for [..] authorities Volume: (For National Authority Use only) Daivonex ointment Name of Active Substance: Calcipotriol (50ųg/g) Page: Calcipotriol ointment is not at least as good as dithranol cream FNA in terms of percentage PASI reduction at end of treatment. Calcipotriol treated patients had statistically significantly fewer adverse events and adverse drug reactions than dithranol treated patients. There were no statistically significant differences between the calcipotriol group and dithranol group in terms of changes in Quality of Life from baseline to end of treatment. Calcipotriol was more cost-effective than dithranol. Report date: 12-DEC-2005

16 MCO 9803 NL 12-DEC-2005 Page 15 of SCHEDULE/CHART OF STUDY PROCEDURES Visit Week Informed consent! Quality of Life assessments!! Medical history! Pregnancy test*! Randomisation! PASI!!!!! Efficacy assessment!!!! Adverse events!!!! Concurrent medication!!!!! Supply investigational product!!!! Collect investigational product!!!! * in females of child-bearing potential It was planned for a patient to attend an ATB visit (where a nurse applied the study medication) five times during the first week and twice each week during the rest of the study.

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18 MCO 9803 NL 12-DEC-2005 Page 17 of TABLE OF CONTENTS 1 CLINICAL STUDY REPORT APPROVAL REPORT STATEMENTS CONFIDENTIALITY STATEMENT COMPLIANCE WITH GOOD CLINICAL PRACTICE STUDY AUTHENTICATION SUMMARY SCHEDULE/CHART OF STUDY PROCEDURES TABLE OF CONTENTS LIST OF ABBREVIATIONS AND DEFINITION OF TERMS LIST OF ABBREVIATIONS DEFINITION OF TERMS ETHICS INDEPENDENT ETHICS COMMITTEE (IEC) OR INSTITUTIONAL REVIEW BOARD (IRB) ETHICAL CONDUCT OF THE TRIAL PATIENT INFORMATION AND INFORMED CONSENT STUDY ADMINISTRATIVE STRUCTURE REPORT AUTHOR(S) INVESTIGATORS COMPANY PERSONNEL INSURANCE AND LIABILITY INTRODUCTION AND RATIONALE PSORIASIS VULGARIS INVESTIGATIONAL PRODUCT DESCRIPTION STUDY RATIONALE STUDY OBJECTIVES PRIMARY OBJECTIVE SECONDARY OBJECTIVES INVESTIGATIONAL PLAN STUDY DESIGN TIME SCHEDULE PATIENT NUMBERS PATIENTS SELECTION (IN- AND EXCLUSION) INCLUSION CRITERIA EXCLUSION CRITERIA WITHDRAWAL CRITERIA INVESTIGATIONAL PRODUCTS STUDY PROCEDURES ADVERSE EVENTS REPORTING OF SERIOUS ADVERSE EVENTS EFFICACY EVALUATION SAFETY EVALUATION QUALITY ASSURANCE/AUDIT DATA HANDLING STATISTICAL ANALYSIS... 61

19 Page 18 of DEC-2005 MCO 9803 NL 12 STUDY PERIOD STUDY DATES UNBLINDING OF THE STUDY STUDY POPULATION PATIENT DISPOSITION PROTOCOL DEVIATIONS EFFICACY EVALUATION DATA SETS ANALYSED DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS TREATMENT EFFICACY RESULTS USE OF-AND COMPLIANCE WITH PRESCRIBED STUDY MEDICATION SAFETY EVALUATION DURATION AND EXTENT OF EXPOSURE TO TRIAL MEDICATION ADVERSE EVENTS REPORTED DEATHS, OTHER SERIOUS ADVERSE EVENTS AND OTHER SIGNIFICANT ADVERSE EVENTS SAFETY RESULTS QUALITY OF LIFE QUESTIONNAIRES SKINDEX SF DISCUSSION SUMMARY OF RESULTS DESIGN AND CONDUCT OF THE STUDY INTERPRETATION OF STUDY RESULTS CONCLUSIONS REFERENCES LIST OF APPENDICES

20 MCO 9803 NL 12-DEC-2005 Page 19 of LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 5.1 LIST OF ABBREVIATIONS CRF GCP ICH IEC IRB LEO Case Report Form Good Clinical Practice International Conference on Harmonisation Independent Ethics Committee Institutional Review Board LEO Pharma 5.2 DEFINITION OF TERMS Adverse Drug Reaction (ADR) In the pre-approval clinical experience with a new medicinal product or its new usages, particularly as the therapeutic dose(s) may not be established: all noxious and unintended responses to a medicinal product related to any dose should be considered adverse drug reactions. The phrase responses to a medicinal product means that a causal relationship between a medicinal product and an adverse event is at least a reasonable possibility, i.e. the relationship cannot be ruled out. Regarding marketed medicinal products: a response to a drug which is noxious and unintended and which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of diseases or for modification of physiological function (see the ICH Guideline for Clinical Safety Data Management: Definitions and Standards for Expedited Reporting). Adverse Event (AE) Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An adverse event (AE) can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product (see the ICH Guideline for Clinical Safety Data Management: Definitions and Standards for Expedited Reporting). A.T.B. Arbeids- en Tijdsintensieve Behandelingen (Labour- and Time- intensive Treatments). A.T.B. visit A visit to the A.T.B. clinic where the Investigational Product is applied by a nurse. There were 5 A.T.B. visits during the first week, with subsequent visits being twice weekly. During pre-determined visits in week 0, 2, 4, 8 and 12 data on safety and efficacy were collected and recorded onto the CRF (= study visit).

21 Page 20 of DEC-2005 MCO 9803 NL Audit A systematic and independent examination of trial related activities and documents to determine whether the evaluated trial related activities were conducted, and the data were recorded, analysed and accurately reported according to the protocol, Sponsor s standard operating procedures (SOPs), Good Clinical Practice (GCP), and the applicable regulatory requirement(s). Case Report Form A printed, optical, or electronic document designed to record all of the protocol-required information to be reported to the sponsor on each trial subject. The term is synonymous for Case Record Form. Concomitant Medication Any medication taken by a subject apart from the Investigational Product(s). Contract Research Organisation (CRO) A person or an organisation (commercial, academic, or other) contracted by the Sponsor to perform one or more of a Sponsor s trial-related duties and functions. Direct Access Permission to examine, analyses, verifies, and reproduces any records and reports that are important to evaluation of a clinical trial. Any party (e.g., domestic and foreign regulatory authorities, Sponsor s monitors and auditors) with direct access should take all reasonable precautions within the constraints of the applicable regulatory requirement(s) to maintain the confidentiality of subjects identities and Sponsor s proprietary information. Enrolled Patient A patient who has signed an informed consent and been assigned a CRF number. Essential Trial Documents Documents which individually and collectively permit evaluation of the conduct of a study and the quality of the data produced. 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.

22 MCO 9803 NL 12-DEC-2005 Page 21 of 141 Good Clinical Practice (GCP) A standard for the design, conduct, performance, monitoring, auditing, recording, analyses, and reporting of clinical trials that provides assurance that the data and reported results are credible and accurate, and that the rights, integrity, and confidentiality of trial subjects are protected. Informed Consent A process by which a subject voluntarily confirms his or her willingness to participate in a particular trial, after having been informed of all aspects of the trial that are relevant to the subject s decision to participate. Informed consent is documented by means of a written, signed and dated informed consent form. Inspection The act by a regulatory authority(ies) of conducting an official review of documents, facilities, records, and any other resources that are deemed by the authority(ies) to be related to the clinical trial and that may be located at the site of the trial, at the Sponsor s and/or contract research organisation s (CRO s) facilities, or at other establishments deemed appropriate by the regulatory authority(ies). Investigational Product A pharmaceutical form of an active ingredient or placebo being tested or used as a reference in a clinical trial, including a product with a marketing authorisation when used or assembled (formulated or packaged) in a way different from the approved form, or when used for an unapproved indication, or when used to gain further information about an approved use. Investigator A person responsible for the conduct of the clinical trial at a trial site. If a team of individuals at a trial site conducts a trial, the investigator is the responsible leader of the team and may be called the principal investigator. See also Sub-investigator. Investigator Agreement A contract between LEO and an investigator specifying the conditions for the co-operation in the clinical trial and the Investigators responsibilities. Investigator s Brochure A compilation of the clinical and non clinical data on the Investigational Product(s) which is relevant to the study of the Investigational Product(s) in human subjects.

23 Page 22 of DEC-2005 MCO 9803 NL Investigator Staff Signature Form A form on which sub-investigators and other trial-related site staff sign and date and the Investigator authorises their trial-related tasks/duties. Investigator Trial File The collection of trial documents required by LEO SOPs, ICH Guidelines and/or regulatory requirements to be on file at the investigator site. Local Clinical Project Co-ordinator (LCPC) The person appointed by LEO to be LEO s national representative responsible for all aspects of a clinical trial within a country. Monitor A person appointed by the Sponsor to carry out monitoring of a clinical trial. Monitoring The act of overseeing the progress of a clinical trial, and of ensuring that it is conducted, recorded, and reported in accordance with the protocol, Standard Operating Procedures (SOPs), Good Clinical Practice (GCP), and the applicable regulatory requirement(s). Patient Identification List A summary list kept in the Investigator Trial File that records all of that investigative centre s enrolled patient s names, CRF book numbers and information to enable the patient to be contacted. Patient Screening Log A document that identifies patients/subjects who entered pre-trial screening. Patient Study Card A card given to a patient by the investigative centre at the time a patient is enrolled into the clinical trial, to identify that the patient is participating in a clinical trial. Principal Clinical Project Co-ordinator (PCPC) The person appointed by LEO to be LEO s main international representative responsible for all aspects of a clinical trial.

24 MCO 9803 NL 12-DEC-2005 Page 23 of 141 Protocol A document that describes the objective(s), design, methodology, statistical considerations, and organization of a trial. The protocol usually also gives the background and rationale for the trial, but these could be provided in other protocol referenced documents. Throughout the ICH GCP Guideline the term protocol refers to protocol and protocol amendments. Protocol Amendment A written description of a change(s) to or formal clarification of a protocol. Quality Assurance (QA) All those planned and systematic actions that are established to ensure that the trial is performed and the data are generated, documented (recorded), and reported in compliance with Good Clinical Practice (GCP) and the applicable regulatory requirement(s). Quality Control (QC) The operational techniques and activities undertaken within the quality assurance system to verify that the requirements for quality of the trial-related activities have been fulfilled. Randomisation The process of assigning trial subjects to treatment or control groups using an element of chance to determine the assignments in order to reduce bias. Randomisation Code List A list of (sequential) numbers to each of which a treatment is allocated (assigned). Treatment may be revealed as a code letter (e.g., A, B) or by directly revealing the specific treatment (Investigational Product, e.g.: Calcipotriol ointment). Serious Adverse Event (SAE) or Serious Adverse Drug Reaction (S-ADR) Any untoward medical occurrence that at any dose: results in death, is life-threatening, requires inpatient hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, requires medical or surgical intervention to prevent permanent impairment or damage. in addition, pregnancy must always be reported as a serious adverse event. (see the ICH Guideline for Clinical Safety Data Management: Definitions and Standards for Expedited Reporting). or other medically important conditions.

25 Page 24 of DEC-2005 MCO 9803 NL Site Signature Form A form on which sub-investigators and other trial-related site staff sign and date and on which the Investigator authorises their trial-related tasks/ duties. Source Data All information in original records and certified (dated and signed) copies of original records of clinical findings, observations, or other activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Source data are contained in source documents (original records or certified copies). Source Documents Original documents, data, and records (e.g., hospital records, clinical and office charts, laboratory notes, memoranda, subjects diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions certified after verification as being accurate copies, microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and records kept at the pharmacy, at the laboratories and at medico-technical departments involved in the clinical trial). Sponsor s Medical Expert A medically qualified person appointed by the Sponsor to be the sponsor s responsible person on medical questions for a trial. Statistical Analysis Plan A document that contains a more technical and detailed elaboration of the principal features of the analysis described in the protocol, and includes detailed procedures for executing the statistical analysis of the primary and secondary variables and other data. Study A synonymous term for trial. Study visit A visit during which data are collected and recorded into the CRF. Sub-investigator Any individual member of the clinical trial team designated and supervised by the investigator at a trial site to perform critical trial-related procedures and/or to make important trial-related decisions (e.g., associates, residents, research fellows). See also Investigator.

26 MCO 9803 NL 12-DEC-2005 Page 25 of 141 Treatment Code Envelope A sealed letter/envelope containing the direct information about an individual subject s treatment/investigational Product. Unexpected Adverse Drug Reaction (U-ADR) An adverse reaction, the nature or severity of which is not consistent with the applicable product information (e.g., Investigator s Brochure for an unapproved Investigational Product or package insert/summary of product characteristics for an approved product).

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28 MCO 9803 NL 12-DEC-2005 Page 27 of ETHICS 6.1 INDEPENDENT ETHICS COMMITTEE (IEC) OR INSTITUTIONAL REVIEW BOARD (IRB) The protocol and any relevant amendments were approved by/received favourable opinion from relevant Institutional Review Boards (IRB)/Independent Ethics Committees (IEC) prior to enrolment of subjects. The appropriate Regulatory Authority(ies) approved or was notified about the trial, as required. 6.2 ETHICAL CONDUCT OF THE TRIAL The trial was conducted to conform with the principles of the Declaration of Helsinki as adopted by the 18th World Medical Assembly, 1964, and subsequent amendments. The trial was conducted in accordance with the principles of GCP. Consent was obtained from the patients (or their legally acceptable representative, to record, collect, process and transfer (to EU and non-eu countries) data. Such data will be handled in accordance with the EU Data Protection Directive (95/46/EC). 6.3 PATIENT INFORMATION AND INFORMED CONSENT All patients (subjects) received written and verbal information concerning the trial. This information emphasised that participation in the trial was voluntary and that the patient could withdraw from the trial at any time and for any reason. All patients were given opportunity to ask questions and were given sufficient time to consider before consenting. The patient s signed and dated informed consent to participate in the trial was obtained prior to any trial related procedure being carried out. [a representative patient information and informed consent is provided in Appendix V] All Investigators signed an Investigator s Agreement before the study to confirm the above.

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30 MCO 9803 NL 12-DEC-2005 Page 29 of STUDY ADMINISTRATIVE STRUCTURE 7.1 REPORT AUTHOR(S) Medical Department LEO Pharma BV Hoge Mosten NH Breda The Netherlands Medical Department LEO Pharma BV Hoge Mosten NH Breda The Netherlands Medical Department LEO Pharma Longwick Road Princes Risborough Bucks HP27 9RR United Kingdom

31 Page 30 of DEC-2005 MCO 9803 NL 7.2 INVESTIGATORS NATIONAL CO-ORDINATING INVESTIGATOR Prof. Dr. Afdeling Dermatologie Academisch Ziekenhuis Nijmegen INVESTIGATORS Each participating investigator was responsible for the complete trial conduct at his/her site, and as agreed to in an Investigator Agreement signed off prior to trial initiation. If sub-investigators were delegated trial related duties, this was documented on the Investigator Staff Signature Form. The complete list of all participating (Sub) Investigators is provided in Appendices VII and VIII. 7.3 COMPANY PERSONNEL On behalf of LEO, only the Medical Director, LEO, the Medical Director, Dermatological Medical Department and the Head of Mathematical-Statistical Department, LEO were authorised to approve the Protocol and any subsequent Protocol Amendments PRINCIPAL CLINICAL PROJECT CO-ORDINATOR (PCPC) Medical Department LEO Pharma BV Hoge Mosten NH Breda The Netherlands

32 MCO 9803 NL 12-DEC-2005 Page 31 of LOCAL CLINICAL PROJECT CO-ORDINATOR (LCPC) Medical Department LEO Pharma BV Hoge Mosten NH Breda The Netherlands SPONSOR S MEDICAL EXPERT, MD Medical Department LEO Pharma BV Hoge Mosten NH Breda The Netherlands STUDY STATISTICIAN BSc MSc CStat Senior Statistician Medical Department LEO Pharma Longwick Road Princes Risborough Bucks HP27 9RR United Kingdom

33 Page 32 of DEC-2005 MCO 9803 NL MEDICAL DIRECTOR, PHARMACOVIGILANCE LEO Pharma Industriparken 55 DK-2750 Ballerup Denmark

34 MCO 9803 NL 12-DEC-2005 Page 33 of INSURANCE AND LIABILITY The patients in the present study were covered by the product and general liability insurance of LEO Pharma or LEO itself in the event of trial related injury or death, in accordance with applicable law and with the CPMP Note for Guidance on Good Clinical Practice (CPMP/ICH/135/95) of 17 July 1996.

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36 MCO 9803 NL 12-DEC-2005 Page 35 of INTRODUCTION AND RATIONALE 9.1 PSORIASIS VULGARIS Psoriasis is one of the most common chronic skin diseases, with a prevalence generally estimated at between 1.0% and 2.8% of the population [1, 2]. It is characterised by sharply marginated areas of affected skin, which appear thickened, red and scaly, and which may itch. This appearance is produced by a greatly increased rate of epidermal proliferation with impaired differentiation of the keratinocytes. Dermal blood vessels are dilated and there is infiltration of the skin with immunologically active cells [3, 4]. The pathogenesis is not yet well understood, and controversy still exists as to whether the primary abnormality resides in the epidermal keratinocytes, dermal fibroblasts, cells of the immune system, blood vessels or a combination of these [3, 4]. 9.2 INVESTIGATIONAL PRODUCT DESCRIPTION PHARMACOLOGY Calcipotriol (MC 903) is a vitamin D analogue synthesised at the research laboratories of LEO Pharma. Pre-clinical studies have demonstrated calcipotriol to have a high binding affinity for the cellular receptor of calcitriol (1α, 25 dihydroxyvitamin D 3 ), the biologically active form of vitamin D 3 [5]. Calcipotriol has been shown to be both a potent regulator of cell differentiation and an inhibitor of cell proliferation in human keratinocytes [5, 6]. Its systemic effect on calcium metabolism in rats is 100 to 200 times less than that of calcitriol [5] COMPLETED CLINICAL STUDIES WITH CALCIPOTRIOL OINTMENT IN PSORIASIS Clinical studies on calcipotriol started in A number of studies have been conducted with calcipotriol 50µg/g, and it has been shown that treatment with calcipotriol is significantly better than treatment with placebo [7]. In another study it was shown that treatment with 50 µg/g calcipotriol ointment is equally effective as treatment with 100 µg/g calcipotriol ointment. Moreover, treatment with 50 µg/g calcipotriol ointment is clinically more effective than treatment with 25 µg/g calcipotriol ointment [8]. Extensive clinical research on treatment of psoriasis with calcipotriol ointment has been performed, and calcipotriol ointment is now registered and marketed worldwide for treatment of psoriasis. Some of the results will be discussed below. Clinical results of treatment of psoriasis with calcipotriol ointment 50 µg/g or betamethasone (17-valerate) ointment 1 µg/g, were compared in two randomised, double-blind studies. In a parallel group study with 409 patients, calcipotriol was shown to be equally effective as betamethasone [9]. In a right/left comparison study with 345 patients, calcipotriol was found to be superior to betamethasone in the treatment of psoriasis vulgaris [10]. In a randomised, double-blind, parallel-group study, results of treatment for 6 weeks with either calcipotriol ointment (50 µg/g) or fluocinonide ointment 0.05% (a group III corticosteroid) were compared. The study was completed by 99 patients, and it was found that calcipotriol treatment was superior to fluocinonide treatment [11].

37 Page 36 of DEC-2005 MCO 9803 NL In another study treatment with calcipotriol ointment 50 µg/g, applied twice daily, was compared with self-treatment with short-contact dithranol. In this study, which was completed by 478 patients, calcipotriol was found to be both more effective and better accepted than short-contact dithranol. In addition, fewer adverse events were reported in the calcipotriol treatment group [12] ADVERSE EVENTS AND SAFETY FOR CALCIPOTRIOL In all studies completed so far, calcipotriol was well tolerated. The most common adverse event reported was application related lesional/perilesional irritation. Usually only mild irritation was experienced and the irritation subsided despite further treatment. Irritation was also reported for placebo treatment. Laboratory parameters showed no evidence of haemopoietic abnormalities or adverse effects on hepatic or renal function caused by calcipotriol treatment. The safety and effectiveness of both short-term and long-term calcipotriol treatment were confirmed in studies, where treatment was not allowed to exceed a total weekly dose of 100g. No significant changes in the markers of calcium and bone metabolism were found [13, 14, 15, 16, and 17]. Hypercalcaemia has been associated with excess use of calcipotriol ointment. Cases reported concerned patients who (incidentally) received treatment with weekly doses of 200g up to 770g. The serum calcium levels of all patients quickly returned to normal when treatment was stopped [18, 19, 20, and 21]. In one of those reports other causes of hypercalcaemia were not ruled out [21]. In addition, one case of hypercalcaemia has been reported to occur during treatment with an average weekly dose of less than 100 g [20]. Serum calcium levels of this patient also returned to normal after discontinuation of treatment. In summary, calcipotriol is considered to be both effective and safe in the treatment of psoriasis. Dithranol Since the beginning of the twentieth century, dithranol has been used in the treatment of psoriasis. Dithranol causes oxidative stress with production of free radicals and produces a dose dependent inflammatory reaction in the skin. The inflammatory reaction is required for dithranol to be effective. Dithranol treatment is associated with adverse events such as burning and skin irritation (mainly of uninvolved perilesional skin). Other unwanted effects are staining of the skin (temporarily) and clothing/bathroom (permanently). Dithranol therapy is started at a low concentration, which is stepwise increased depending on the patient s response to therapy. Different treatment regimens exist, of which the 24-hour in-patient treatment with dithranol in ointment or paste is considered to be the gold standard dithranol treatment. A more convenient, but less effective, treatment regimen is the so-called short-contact regimen. In this regimen, dithranol (in a cream base) is applied to the psoriasis plaques, left for minutes and washed off by taking a shower. This treatment can be given on an outpatient basis. However, skin irritation and staining are serious limitations of this treatment. Therefore, an intensified treatment regimen at a day-care centre has been developed in order to enhance the treatment effect and to reduce side effects.

38 MCO 9803 NL 12-DEC-2005 Page 37 of STUDY RATIONALE In this study, the treatment effect of calcipotriol was studied using an intensified treatment regimen. This calcipotriol treatment was compared with an intensified dithranol shortcontact treatment regimen, which is regarded as one of the most effective topical treatments for psoriasis vulgaris. The following issues were addressed: 1. Why is compliance important? 2. What is an intensified treatment regimen? 3. How does this study relate to previous studies? 4. Why an equivalence/non-inferiority design was chosen 5. Why a 12-week treatment period was chosen 6. How cost-effective are the intensified treatment regimes 1. Why is compliance important? Good compliance is essential for a therapy to be optimally effective. However, it is common knowledge that in the treatment of psoriasis vulgaris, few patients fully comply with the prescribed treatment instructions [22]. Consequently, the results obtained are often less than optimal. Thus, in order to be able to assess the maximum effect of a therapy, therapy compliance must be optimised. Knowledge of the maximum effect of a given treatment is important to make the correct decisions when treating the patients, when questions are raised such as: should treatment be changed or should patient s compliance be changed? 2. What is an intensified treatment regimen? Recently, a labour- and time intensive treatment concept has been developed, which combines treatment of the patient in a day care centre with education of the patient, aiming at improving self-treatment and treatment compliance. During the first week the patient is treated at the clinic once daily (5 times per week) and subsequently the treatments at the clinic are supervised once or twice weekly. This concept is named A.T.B., which stands for Arbeids- en Tijdsintensieve Behandelingen (English: Labour- and Timeintensive Treatments). In this study an intensified treatment regimen was chosen to ensure optimal treatment compliance.

39 Page 38 of DEC-2005 MCO 9803 NL 3. How does this study relate to previous studies? So far, various studies comparing calcipotriol with dithranol have been performed: 1. Berth-Jones et al [12] compared calcipotriol ointment with short-contact dithranol cream in an out-patient setting. They concluded that calcipotriol was more effective and better accepted than short- contact dithranol. 2. Van der Vleuten et al [23] compared, in an in-patient setting, calcipotriol ointment with dithranol in paste or petrolatum (regarded as the gold standard of topical dithranol therapy). They showed a tendency of calcipotriol being superior to dithranol and concluded that in-patient treatment with calcipotriol challenges 24-hour application with dithranol, which is considered the gold standard. The most likely explanation was an increased compliance in the in-patient setting when compared with the out-patient setting and they concluded that further studies are required to increase compliance in an out-patient setting. Therefore, this study logically fits within a range of clinical studies comparing calcipotriol with dithranol. 4. Why an equivalence design / non-inferiority design was chosen. Dithranol short-contact therapy in an intensified treatment regimen is very effective in the treatment of psoriasis; however it is associated with disadvantages like staining and irritation of the skin and staining of clothing and the bathroom. As a result, acceptance is relatively low and it can be argued that a treatment (at least) equally effective as dithranol short contact (or only slightly less effective) would be very much welcomed as an alternative. Or, in other words, if calcipotriol proves to be equally effective as dithranol or only slightly less effective in an A.T.B. setting, good reasons exist to prefer calcipotriol to dithranol. Accordingly, an equivalence/non-inferiority design is justified. 5. Why a 12-week treatment period was chosen. A regular calcipotriol ointment treatment has to be applied for six to eight weeks, in order to be optimally effective. However, long-term treatment with calcipotriol has shown that further improvement, even though relatively minor, is possible [15, 16]. For a short-contact dithranol therapy to be optimally effective, a 12-week treatment period in an A.T.B. setting is considered required (personal communication. Prof. Dr. ). Thus, in order to give both treatments a chance to a reach a maximum effect, a 12-week treatment period was chosen.

40 MCO 9803 NL 12-DEC-2005 Page 39 of How cost-effective are the intensified treatment regimens As described above, Dithranol short-contact therapy in an intensified treatment regimen is very effective in the treatment of psoriasis; however it is associated with longer nurse time and a higher quantity of medication required to obtain this treatment result. This means that if calcipotriol proves to be equally effective to dithranol, higher cost associated with dithranol makes calcipotriol a more cost-effective treatment.

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42 MCO 9803 NL 12-DEC-2005 Page 41 of STUDY OBJECTIVES 10.1 PRIMARY OBJECTIVE To compare the clinical efficacy of calcipotriol ointment with that of dithranol cream in an intensified treatment regimen in terms of percentage reduction in PASI from baseline to end of treatment SECONDARY OBJECTIVES To compare the safety and tolerability of calcipotriol ointment with that of dithranol cream in an intensified treatment regimen. To evaluate the pharmacoeconomic implications of an intensified treatment regimen with either drug.

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44 MCO 9803 NL 12-DEC-2005 Page 43 of INVESTIGATIONAL PLAN The entire Study Protocol is presented in Appendix I and the unique pages of the CRF Book are presented in Appendix II STUDY DESIGN A national multi-centre, prospective, randomised, open, parallel group study comparing up to 12 weeks of an intensified treatment regimen with either: " Calcipotriol 50 µg/g ointment, or Dithranol cream (in different strengths: 0.05% - 0.1% - 0.2% - 0.3% - 0.4% - 0.6% 0.8% - 1% - 2% - 3%). In both treatment groups, study visits took place at the start of the study (= week 0) and again after 2, 4, 8 and 12 weeks. The patient was to visit the out-patient (A.T.B.) clinic 5 times during the first week and twice weekly during the rest of the study (also see Appendix V: Protocol Labour- and Time intensive treatment). Visits other than study visits are referred to as A.T.B. visits. Patients whose psoriasis was cleared (= no evidence or very minor evidence of psoriasis remains, no further treatment required) left the study. The final study visit is defined as the visit at which the patient left the study. Treatment End of study Study Visit Time in weeks TIME SCHEDULE Planned date of inclusion of first patient: End of September 2000 Planned date of inclusion of last patient: September 2001 Planned date of completion of last patient: December PATIENT NUMBERS 110 patients were to be included and randomised (55 patients per group). This sample size would give confidence of obtaining data on an appropriate number of patients to show that calcipotriol intensified treatment was not clinically inferior to dithranol intensified treatment. The sample size calculation assumed a 5% points superiority of calcipotriol over dithranol intensified treatment and a standard deviation of 30% on reduction in PASI. When the sample size in each group was 51, a two group 0.05 one-sided t-test would have 80% power to reject the null hypothesis that the two treatments were not equivalent (the difference in mean PASI reduction, calcipotriol minus dithranol, was -10% or further from