This document has been downloaded from \v v.. w.leo-pharma.com subject to the terms of use state on the webs1te. It contains data and results regarding approved and non-approved uses, formulations or treatment regimens, and it is provided for transparency and informational purposes only. The content does not reflect the complete results from all studies related to a product. As a document of scientific nature it is not to be see,n as a recomme,ndation or advice regarding the use of any products and you must always consult the specific prescribing information approved for the product prior to any prescription or use. Clinical Study Report Synopsis Effect of LEO 90100 on the HPA axis and Calcium Metabolism in Subjects with Extensive Psoriasis Vulgaris A Phase 2 Maximal Use Systemic Exposure (MUSE) study evaluating the safety and efficacy of LEO 90100 used once daily in subjects with extensive psoriasis vulgaris A national, multi-centre, prospective, non-controlled, open, single-group, 4-week clinical study in subjects with extensive psoriasis vulgaris LEO Pharma A/S Clinical Development and Safety LEO 90100-30 17-DEC-2013
LEO 90100-30 17-DEC-2013 Page 2 of 5 Clinical Study Report Synopsis Statement Approval Statement, Sponsor The following persons have approved this Clinical Study Report Synopsis on behalf of LEO Pharma A/S using electronic signatures: Biostatistics and Data Management Medical Department Approval Statement, Investigator The Co-ordinating Investigator approves the Clinical Study Report Synopsis 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 Clinical Study Report Synopsis:, MD Co-ordinating Investigator
LEO 90100-30 17-DEC-2013 Page 3 of 5 SYNOPSIS Name of Sponsor/Company: LEO Pharma A/S Name of Finished Product: LEO 90100 aerosol foam Name of Active Ingredient: Calcipotriol + Betamethasone dipropionate Title of Trial: Effect of LEO 90100 on the HPA axis and Calcium Metabolism in Subjects with Extensive Psoriasis Vulgaris Investigators: The international co-ordinating investigator was Research, 425 St. Mary Avenue, Winnipeg, Manitoba, R3C 0N2, Canada., MD, Winnipeg Clinic Dermatology Trial Centre(s): The study was conducted at 8 sites located in Canada. Publication(s) based on the trial: None at the time of this report. Trial Period: First subject enrolled: 4-Jun-2012 Last subject last visit: 2-May-2013 Phase of Development: Phase 2 Objectives: Primary: To evaluate the effect of once daily use of LEO 90100 on the hypothalamic-pituitary-adrenal (HPA) axis and calcium metabolism in subjects with extensive psoriasis vulgaris. Secondary: To evaluate other safety aspects of LEO 90100 used once daily in subjects with extensive psoriasis vulgaris. To assess the pharmacokinetic (PK) profile of the active components and major metabolites of LEO 90100 following topical application under maximal use conditions. To evaluate the efficacy of LEO 90100 used once daily in extensive psoriasis vulgaris. Methodology: A national, multi-centre, prospective, non-controlled, open, single-group, 4-week study in subjects with extensive psoriasis vulgaris. Subjects received once daily topical treatment with LEO 90100 on all lesions on the trunk, limbs and scalp (excluding skin folds, face, and genitals) for up to 4 weeks. The study consisted of a screening period (up to 56 days) followed by a 28 day treatment phase, and a 28 day follow-up phase. Screening visits were performed at Day-56 to -7 (SV1), and between Day -7 and Day-3 (SV2). Treatment start was Day 0 (Visit 1). On-treatment visits were Days 14 and 28 (Visits 2 and 3). Subjects classified as Clear (according to IGA at Day 14 (Visit 2)) were allowed to stop treatment at the investigator s discretion. Subjects remained in the study and were to attend Day 28 (Visit 3). If their psoriasis reappeared subjects were advised to reinitiate the treatment without consulting the investigator. HPA axis testing by means of the rapid standard-dose cosyntropin test was conducted at baseline (SV2) and at Day 28 (Visit 3). Serum cortisol levels were evaluated before stimulation and 30 and 60 minutes after stimulation. Effect on calcium metabolism was evaluated by measurements of albumin corrected serum calcium, serum phosphate and ALP, plasma PTH, 24 hour urinary excretion of calcium, phosphate, creatinine, as well as urinary calcium:creatinine and phosphate:creatinine ratios at baseline (SV2) and Day 28 (Visit 3). Plasma levels of calcipotriol and betamethasone dipropionate and their main metabolites (MC1080 and betamethasone 17-propionate, respectively) were determined. Plasma samples were collected for PK at baseline (SV2) prior to the ACTH challenge test. Pre-dose trough samples were collected on Day 14 (Visit 2) and Day 28 (Visit 3) and then up to 7 hours post-application of study treatment at Day 28 (Visit 3). Adverse events were recorded at all visits except Day -56 to -7 (SV1). Psoriasis on the body was assessed by the investigator s global assessment of disease severity (IGA) at Day -7 to -3 (SV2) and Day 28 (Visit 3). Number of Subjects (Planned and Analysed): It was planned to include at least 30 subjects to ensure 20 evaluable subjects completing 28 days of treatment who undergo both the ACTH challenge test and analysis of calcium metabolism after treatment. A total of 37 subjects were enrolled and started treatment with LEO 90100; 35 subjects completed the trial as per protocol.
LEO 90100-30 17-DEC-2013 Page 4 of 5 Name of Sponsor/Company: LEO Pharma A/S Name of Finished Product: LEO 90100 aerosol foam Name of Active Ingredient: Calcipotriol + Betamethasone dipropionate Diagnosis and Main Criteria for Inclusion: Subjects of either sex, aged 18 years or above with psoriasis vulgaris involving trunk and/or limbs and scalp amenable to topical treatment with a maximum of 120 g of study medication per week, with a total extent on scalp and trunk/limbs of 15-30% of body surface area (BSA) excluding face, genitals and skin folds, and including at least 30% scalp involvement. Disease severity on the trunk/limbs graded as at least moderate according to the IGA. Normal HPA axis function at baseline and albumin corrected serum calcium below the upper limit of the reference range. Investigational Product, Dose and Mode of Administration, Batch Number: LEO 90100, aerosol, foam containing calcipotriol (as hydrate) 50 mcg/g plus betamethasone 0.5 mg/g (as dipropionate), 30 g per can, applied topically once daily to psoriasis lesions on the trunk and/or the limbs and the scalp up to maximum 120 g aerosol, foam per week. Batch number: 113727401 / 07-2013 Duration of Treatment: 4 weeks Reference Therapy, Dose and Mode of Administration, Batch Number: Not applicable Criteria for Evaluation: Primary endpoints: The adrenal response to ACTH stimulation test defined as serum cortisol concentration obtained after 30 minutes at Day 28. Also the change in albumin-corrected serum calcium, 24-hour urinary calcium excretion and urinary calcium:creatinine ratio from baseline SV2 to Day 28 (Visit 3). Secondary endpoints were: subjects with serum cortisol concentration of 18 mcg/dl at 30 and 60 minutes after ACTHchallenge at Day 28 (Visit 3), change from baseline (SV2) to Day 28 (Visit 3) in serum phosphate, 24-hour urinary phosphate excretion, urinary phosphate:creatinine ratio, serum alkaline phosphatase (ALP) or plasma parathyroid hormone (PTH), other laboratory parameters, blood pressure and heart rate, adverse events, adverse drug reactions, local safety and tolerability parameters and reasons for withdrawal from the study.. Efficacy: Subjects with controlled disease ( clear or almost clear ) according to the IGA at Day 28. Pharmacokinetics: The following PK parameters were planned to be calculated, if possible, for each assayed compound (i.e., calcipotriol, betamethasone dipropionate, MC1080 and betamethasone 17-propionate) based on the obtained plasma concentrations: Area under the curve from time zero to last measurable concentration (AUC0-t,), area under the curve from time zero to infinity (AUC0- ), maximum plasma concentration (Cmax), Time to maximum plasma concentration (tmax) and apparent elimination half life (t½). Statistical Methods: The analysis of the ACTH challenge test was based on the per-protocol analysis set (n=35), AE and laboratory data were analysed using the safety analysis set (n=37) and the efficacy analysis was based on the full analysis set (n=37). The change in albumin-corrected serum calcium, 24-hour urinary calcium excretion and urinary calcium:creatinine ratio from baseline (SV2) to Day 28 (Visits 3) was calculated. For treatment-emergent AEs the number of subjects experiencing each AE (preferred term) and the percentage of subjects with AEs was tabulated. Laboratory values and vital signs were listed, flagged for values outside the reference ranges and summarised by visit where appropriate for observed values and changes from baseline (SV2). The frequency of subjects who achieved controlled disease according to the IGA was calculated. The pharmacokinetic parameters (AUC 0-t, AUC 0-, C max, t max and t ½ ) were estimated where scientifically valid and summary statistics given as appropriate for each compound.
LEO 90100-30 17-DEC-2013 Page 5 of 5 Name of Sponsor/Company: LEO Pharma A/S Name of Finished Product: LEO 90100 aerosol foam Name of Active Ingredient: Calcipotriol + Betamethasone dipropionate Summary Conclusions Study Population: 37 subjects were treated with at least one application/dose of investigational product and 35 subjects completed the trial. Pharmacodynamics, pharmacokinetics and efficacy summary: Effect on the HPA axis Following once daily application of LEO 90100 on the scalp and body, no subjects showed adrenal suppression as indicated by a 30 minute post-stimulation cortisol level 18 mcg/dl at Day 28. All subjects showed normal response to ACTH challenge test at both 30 and 60 minutes at Day 28. Effect on calcium metabolism There was no significant mean change from baseline to Day 28 in albumin-corrected serum calcium, 24-hour urinary calcium excretion or the urinary calcium:creatinine ratio. No subjects developed elevated serum or urinary calcium levels above the normal range following treatment with LEO 90100. Furthermore, there was no clinically relevant mean change in the other serum and urinary parameters assessed in the study for the evaluation of calcium metabolism including serum phosphate, serum alkaline phosphatase (ALP), plasma parathyroid hormone (PTH), 24-hour urinary phosphate excretion and urinary phosphate:creatinine ratio. Likewise there were no individual changes of concern in any of these parameters. Pharmacokinetics Plasma concentrations of betamethasone dipropionate, calcipotriol, and its metabolite MC1080 were below the lower limit of assay quantitation in the majority of subjects. Plasma concentrations of betamethasone 17-propionate were quantifiable in 27 out of 35 subjects. The mean plasma betamethasone 17 propionate C max was 148 pg/ml (range: 30.2 to 1133 pg/ml). Mean plasma betamethasone 17 propionate AUC last was 68.4 h*pg/ml (range: 18.5 to 4254 h*pg/ml). No significant accumulation of plasma betamethasone dipropionate, betamethasone 17-propionate, calcipotriol or MC1080 was observed in subjects with extensive psoriasis vulgaris after once daily topical application of LEO 90100 for up to 28 days. Efficacy At end of treatment, 17 subjects (46 %) had controlled disease (clear or almost clear) according to IGA. Safety Summary: No death, serious adverse events or discontinuations/withdrawals due to adverse events were reported Apart from one case of probably treatment-related severe erythema, the few adverse events observed were all nonlesional/perilesional, unrelated to treatment and mostly mild There were no clinically significant changes in clinical laboratory parameters or vital signs Conclusion: None of the 35 subjects with extensive psoriasis vulgaris of the body and scalp treated with LEO 90100 once daily for 4 weeks showed adrenal suppression as indicated by a 30 minute post-stimulation cortisol level 18 mcg/dl at Day 28. There was no evidence of an effect of LEO 90100 on calcium metabolism based on evaluation of serum and 24-hour urinary calcium parameters. LEO 90100 was safe and well tolerated
LEO 90100-30 Clinical Study Report Synopsis 17-Dec-2013- English ELECTRONIC SIGNATURES Electronic signahtre made within edoc LEO by LEO Pharma AIS employees or employees of any LEO Pharma AIS affiliate located anywhere in the world, are to be considered to be legally binding equivalent of traditional handwritten signahtres. Meaning of Signature Biostatistics Approval 20-Dec-2013 21:07 GMT+Ol - Department, Medical Approval 23-Dec-2013 11:46 GMT+Ol