Effect of LEO 90100 on the HPA Axis and Calcium Metabolism in Subjects With Extensive Psoriasis VulgarisExtensive Psoriasis Vulgaris

Study Overview
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Brief Summary
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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.

Detailed Description
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The purpose of the present study is to assess the systemic safety of LEO 90100. Although LEO 90100 contains the same active ingredients in the same concentration as DAIVOBET/DOVOBET/TACLONEX ointment, the degree of absorption of the active ingredients from the new formulation may differ. Systemic safety will be assessed through the effect of LEO 90100 on calcium metabolism and HPA axis function under maximum use conditions (i.e., in subjects with very extensive psoriasis on the trunk, limbs and scalp, using up to 120g per week of LEO 90100 for up to 4 weeks). Data from this study, together with the measurements of albumin-corrected serum calcium and the calcium:creatinine ratio in spot urine samples in the planned phase 2 and 3 studies in the development program for LEO 90100, are expected to provide adequate information with respect to the systemic safety of LEO 90100.

Official Title
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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

Conditions
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Psoriasis Vulgaris

Intervention / Treatment
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* Drug: LEO 90100


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed and dated informed consent obtained prior to any trial related activities (including any washout period) Age 18 years or above Either sex Any race or ethnicity Any skin type Attending a hospital out-patient clinic or the private practice of a dermatologist for treatment of psoriasis vulgaris At SV2 and Day 0 (Visit 1), a clinical diagnosis of psoriasis vulgaris of at least 6 months duration involving the trunk and/or limbs and the scalp which is; amenable to topical treatment with a maximum of 120g of study medication per week of an extent of between 15 and 30% of the body surface area (BSA) excluding psoriatic lesions of the face, genitals and skin folds including at least 30% scalp involvement of at least a moderate disease severity according to the investigators global assessment (IGA) At SV2, a normal HPA axis function including a serum cortisol concentration above 5 mcg/dl before ACTH-challenge and above 18 mcg/dl 30 minutes after ACTH-challenge At SV2, an albumin-corrected serum calcium below the upper reference range limit At SV2, females of child-bearing potential must have a negative urine pregnancy result Females of child-bearing potential must agree to use a highly effective method of contraception during the study. A highly effective method of birth control is defined as one which results in a low failure rate (less than 1% per year) Able to communicate with the investigator and understand and comply with the requirements of the study Exclusion Criteria: A history of allergic asthma, serious allergy or serious allergic skin rash Known or suspected hypersensitivity to component(s) of LEO 90100 or CORTROSYN (including cosyntropin/tetracosactide) Systemic treatment with corticosteroids (including inhaled and nasal steroids) within 12 weeks prior to SV2 Systemic treatment with biological therapies (whether marketed or not marketed), with a possible effect on psoriasis vulgaris within the following time period prior to Day 0 (Visit 1); etanercept - within 4 weeks adalimumab, alefacept, infliximab - within 8 weeks ustekinumab - within 16 weeks other products - within 4 weeks/5 half-lives (whichever is longer) Subjects who have received treatment with any non-marketed drug substance (i.e. a drug which has not yet been made available for clinical use following registration) within 4 weeks/5 half-lives (whichever is longer) prior to Day 0 (Visit 1) Systemic treatment with all other therapies with a possible effect on psoriasis vulgaris (e.g. retinoids, methotrexate, cyclosporine and other immunosuppressants) within 4 weeks prior to Day 0 (Visit 1) PUVA therapy within 4 weeks prior to Day 0 (Visit 1) UVB therapy within 2 weeks prior to day 0 (Visit 1). Topical treatment with corticosteroids or vitamin D analogues on any body location within 2 weeks prior to SV2 Any topical treatment of psoriasis vulgaris on the trunk, limbs or scalp (except for emollients and non-medicated shampoos) within 2 weeks prior to Day 0 (Visit 1) Planned initiation of, or changes to, concomitant medication that could affect psoriasis vulgaris (e.g., betablockers, antimalarials, lithium, ACE inhibitors) during the study Oral calcium supplements, vitamin D supplements, bisphosphonates or calcitonin within 4 weeks prior to SV2. Note: Stable doses of oral vitamin D supplementation ≤400 IU/day is permitted provided there are no dose adjustments during the study period Planned initiation of, or changes to concomitant medication that could affect calcium metabolism (e.g. antacids, thiazide and/or loop diuretics, antiepileptics) during the study Planned excessive exposure of area(s) to be treated with study medication to either natural or artificial sunlight (including tanning booths, sunlamps etc.) during the study Oestrogen therapy (including contraceptives), antidepressant medications and any other medication known to affect cortisol levels or HPA axis integrity within 4 weeks prior to SV2 Cytochrome P450 3A4 (CYP 3A4) inducers (e.g., barbiturates, phenytoin, rifampicin) within 4 weeks prior to SV2 Systemic cytochrome P450 3A4 (CYP 3A4) inhibitors (e.g., ketoconazole, itraconazole, metronidazole) within 4 weeks prior to SV2 Topical cytochrome P450 3A4 (CYP 3A4) inhibitors (e.g., ketoconazole) within 2 weeks prior to SV2 Non-nocturnal sleep patterns (e.g. night shift workers) Any of the following conditions, whether known or suspected: depression and endocrine disorders (e.g. Cushing's disease, Addison's disease, diabetes mellitus) known to affect cortisol levels or HPA axis integrity disorders of calcium metabolism associated with hypercalcaemia cardiac disorders associated with abnormal QT intervals or rhythm disturbances including clinically significant bradycardia or tachycardia severe renal insufficiency severe hepatic disorders Any clinically significant abnormality following blood pressure/heart rate measurement or review of screening laboratory tests (blood and spot urine samples) collected at SV2 Any clinically significant abnormality following physical examination at SV1 Current diagnosis of guttate, erythrodermic, exfoliative or pustular psoriasis Any of the following conditions present on the study treatment areas (trunk, limbs and scalp): viral (e.g., herpes or varicella) lesions of the skin, fungal and bacterial skin infections, parasitic infections, skin manifestations in relation to syphilis or tuberculosis, acne vulgaris, atrophic skin, striae atrophicae, fragility of skin veins, ichthyosis, ulcers and wounds Other inflammatory skin disorders (e.g. seborrhoeic dermatitis and contact dermatitis) that may confound the evaluation of psoriasis vulgaris Current participation in any other interventional clinical trial Previously enrolled in this trial Known or suspected of not being able to comply with the trial protocol (e.g., alcoholism, drug dependency or psychotic state) Females who are pregnant, wishing to become pregnant during the study or who are breast-feeding

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LEO 90100<br> | Drug: LEO 90100<br>* Calcipotriol 50 mcg/g (as hydrate) and betamethasone 0.5 mg/g (as dipropionate)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Subjects With Serum Cortisol Concentration of ≤18 mcg/dl at 30 Minutes After Adrenocorticotrophic Hormone-challenge (ACTH-challenge) | HPA-axis testing by means of the rapid standard-dose cosyntropin test (ACTH-challenge test) for detection of adrenal suppression. | Day 28 | 
| Change in Albumin-corrected Serum Calcium From Baseline to Day 28 | The effect of LEO 90100 on calcium metabolism was evaluated based on change in albumin-corrected serum calcium from Baseline to Day 28. | Baseline and Day 28 | 
| Change in 24-hour Urinary Calcium Excretion From Baseline to Day 28 | The effect of LEO 90100 on calcium metabolism was evaluated based on change in 24-hour urinary calcium excretion from Baseline to Day 28 in 24-hour. | Baseline and Day 28 | 
| Change in 24-hour Urinary Calcium:Creatinine Ratio From Baseline to Day 28 | The effect of LEO 90100 on calcium metabolism was evaluated based on change in urinary calcium:creatinine ratio from Baseline to Day 28. | Baseline and Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Serum Cortisol Concentration of ≤18 mcg/dl at 30 and 60 Minutes After ACTH-challenge at Day 28 | Serum cortisol concentrations at 30 and 60 minutes after injection were measured in order to assess the maximum stimulated cortisol level achieved. Potential adrenal suppression was indicated if the serum cortisol concentration is ≤18mcg/dl at 30 minutes after the injection. | Day 28 | 
| Number of Participants With an Adverse Drug Reaction (ADR) | Adverse drug reactions (ADRs) were defined as adverse events for which the investigator has not described the causal relationship to investigational medication as not related. | Baseline to Day 28 | 
| Change in Serum Phosphate From Baseline to Day 28 | The effect of LEO 90100 on calcium metabolism was evaluated based on change in serum phosphate from Baseline to Day 28. | Baseline and Day 28 | 
| Change in 24-hour Urinary Phosphate Excretion From Baseline to Day 28 | The effect of LEO 90100 on calcium metabolism was evaluated based on change in 24-hour urinary phosphate excretion from Baseline to Day 28. | Baseline and Day 28 | 
| Change in Urinary Phosphate: Creatinine Ratio From Baseline to Day 28 | The effect of LEO 90100 on calcium metabolism was evaluated based on change in urinary phosphate:creatinine ratio from Baseline to Day 28. | Baseline and Day 28 | 
| Change in Serum Alkaline Phosphatase (ALP) From Baseline to Day 28 | The effect of LEO 90100 on calcium metabolism was evaluated based on change in serum ALP from Baseline to Day 28. | Baseline and Day 28 | 
| Change in Plasma Parathyroid Hormone (PTH) From Baseline to Day 28 | The effect of LEO 90100 on calcium metabolism was evaluated based on change in plasma PTH from Baseline to Day 28. | Baseline and Day 28 | 
| Change in Blood Pressure From Baseline to Day 28 | The effect of LEO 90100 on calcium metabolism was evaluated based on vital sign assessments (blood pressure). | Baseline and Day 28 | 
| Change in Heart Rate From Baseline to Day 28 | The effect of LEO 90100 on calcium metabolism was evaluated based on vital sign assessments (heart rate). | Baseline and Day 28 | 
| Number of Subjects Who Discontinued From the Study | Number of subjects who discontinued from the study due to adverse events. | Baseline to Day 28 | 
| Pharmacokinetic Evaluation Cmax | The following PK parameters will be calculated, if possible, for each assayed compound based on the obtained plasma concentrations: AUC0-t AUC0-∞ Cmax Tmax T½ If it is not possible to calculate the above PK parameters, samples with plasma concentration above lower limit of quantification (LLOQ) will be presented. All subjects but 1 had plasma concentration of calcipotriol below the LLOQ (lower limit of quantification), and thus it was not possible to calculate group mean of the derived PK parameter based on one sample. Provided values for calcipotriol Cmax are derived from that 1 subject. | 4 weeks / 28 days | 
| Pharmacokinetic Evaluation AUClast | The following PK parameters will be calculated, if possible, for each assayed compound based on the obtained plasma concentrations: AUC0-t AUC0-∞ Cmax Tmax T½ If it is not possible to calculate the above PK parameters, samples with plasma concentration above lower limit of quantification (LLOQ) will be presented. All subjects but 1 had plasma concentration of calcipotriol below the LLOQ (lower limit of quantification), and thus it was not possible to calculate group mean of the derived PK parameter based on one sample. Provided values for calcipotriol AUClast are derived from that 1 subject. | 4 weeks / 28 days | 
| Pharmacokinetic Evaluation AUCinf | The following PK parameters will be calculated, if possible, for each assayed compound based on the obtained plasma concentrations: AUC0-t AUC0-∞ Cmax Tmax T½ If it is not possible to calculate the above PK parameters, samples with plasma concentration above lower limit of quantification (LLOQ) will be presented. | 4 weeks / 28 days | 
| Pharmacokinetic Evaluation Tmax | The following PK parameters will be calculated, if possible, for each assayed compound based on the obtained plasma concentrations: AUC0-t AUC0-∞ Cmax Tmax T½ If it is not possible to calculate the above PK parameters, samples with plasma concentration above lower limit of quantification (LLOQ) will be presented. All subjects but 1 had plasma concentration of calcipotriol below the LLOQ (lower limit of quantification), and thus it was not possible to calculate group mean of the derived PK parameter based on one sample. Provided values for calcipotriol Tmax are derived from that 1 subject. | 4 weeks / 28 days | 
| Pharmacokinetic Evaluation T1/2 | The following PK parameters will be calculated, if possible, for each assayed compound based on the obtained plasma concentrations: AUC0-t AUC0-∞ Cmax Tmax T½ If it is not possible to calculate the above PK parameters, samples with plasma concentration above lower limit of quantification (LLOQ) will be presented. | 4 weeks / 28 days | 
| Efficacy Evaluation | The percentage of subjects who achieved 'controlled disease' (i.e., Clear or Almost clear) according to the Investigator's Global Assessment (IGA) of disease severity on the trunk, limbs and scalp at Days 28 (Visit 3) and End of treatment (EoT) were presented. | 4 weeks I 28 days and End of treatment |