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

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.

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