An International, Multi-centre, Prospective, Non-controlled, Open, Single-group, 8-week Trial in Adolescent Subjects

Study Overview
=================
Brief Summary
-----------------
An international, multi-centre, prospective, non-controlled, open, single-group, 8-week trial in adolescent subjects (aged 12 to 16 years, 11 months) with scalp and body psoriasis.

Detailed Description
-----------------
A phase 2 trial evaluating the safety and efficacy of once daily use of LEO 80185 gel containing calcipotriol 50 mcg/g plus betamethasone 0.5mg/g (as dipropionate) in adolescent subjects (aged 12 to 16 years, 11 months) with scalp and body psoriasis.

Official Title
-----------------
Effect of Calcipotriol Plus Betamethasone Dipropionate Gel on the HPA Axis and Calcium Metabolism in Adolescent Subjects (Aged 12 to 16 Years, 11 Months) With Scalp and Body Psoriasis

Conditions
-----------------
Psoriasis Vulgaris

Intervention / Treatment
-----------------
* Drug: LEO 80185 gel


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria (all subjects): Clinical signs of psoriasis vulgaris on both the scalp and body (trunk and/or limbs) At SV2 and Visit 1, a clinical diagnosis of scalp and body (trunk and/or limbs) psoriasis which is: of an extent of 10 to 35% of the body surface area (excluding psoriatic lesions of the face and sensitive areas. Sensitive areas include armpits, groin, under the breasts and in other skin folds around the genitals and buttocks), and of at least moderate severity according to the investigator's global assessment of disease severity on the body. A serum albumin-corrected calcium level below the upper reference limit at SV2 Inclusion Criteria (for subjects performing HPA axis assessments): At SV2 and Visit 1, a clinical diagnosis of scalp psoriasis which is: more than or equal to 20% of the scalp area, and of at least moderate severity according to the investigator's global assessment of disease severity on the scalp. Subjects with a normal HPA axis function at SV2 including serum cortisol concentration above 5 mcg/dl before ACTH challenge and serum cortisol concentration above 18 mcg/dl 30 minutes after ACTH challenge. Inclusion Criteria (for subjects not performing HPA axis assessments): At SV2 and Visit 1, a clinical diagnosis of scalp psoriasis which is: more than or equal to 10% of the scalp area, and of at least moderate severity according to the investigator's global assessment of disease severity on the scalp. Exclusion Criteria (all subjects): Systemic treatment with biological therapies (marketed or not marketed), with a possible effect on scalp and/or body psoriasis within the following time period prior to Visit 1 and during the trial: etanercept - within 4 weeks prior to Visit 1 adalimumab, 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 Visit 1 Systemic treatment with therapies other than biologicals, with a possible effect on scalp and/or body psoriasis (e.g., retinoids, immunosuppressants, PUVA) within 4 weeks prior to Visit 1 (Day 0) or during the trial. UVB therapy within 2 weeks prior to Visit 1 or during the trial. Any topical treatment on the scalp and body (except for emollients and non-steroid medicated shampoos) within 2 weeks prior to Visit 1 or during the trial. Systemic calcium, vitamin D supplements, antacids, diuretics, antiepileptics, diphosphonates or calcitonin within 4 weeks prior to SV2 or during the trial. Planned initiation of, or changes to, concomitant medication that could affect psoriasis (e.g., betablockers, chloroquine, lithium, ACE inhibitors) during the trial. Current diagnosis of guttate, erythrodermic, exfoliative or pustular psoriasis. Subjects with any of the following conditions present on the treatment areas on scalp and/or body: 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, rosacea, acne vulgaris, acne rosacea, atrophic skin, striae atrophicae, fragility of skin veins, ichthyosis, ulcers and wounds. Other inflammatory skin diseases that may confound the evaluation of scalp and/or body psoriasis. Planned excessive exposure to sun during the trial that may affect scalp and/or body psoriasis. Known or suspected severe renal insufficiency or severe hepatic disorders. Known or suspected disorders of calcium metabolism associated with hypercalcaemia. Any clinically significant abnormality following review of screening laboratory tests (blood and urine samples), physical examination or blood pressure/heart rate measurement performed at SV2. Current participation in any other interventional clinical trial. Previously enrolled in this trial. Subjects who have received treatment with any non-marketed drug substance (i.e., an agent which has not yet been made available for clinical use following registration) within a month prior to SV1 or longer, if the class of substance required a longer wash-out as defined above (e.g., biological treatments). Subjects or parent(s) or legal guardian known or suspected of being unlikely to comply with the Clinical Trial Protocol (e.g., alcoholism, drug dependency or psychotic state). Females who are pregnant, or of child-bearing potential and wishing to become pregnant during the trial, or who are breast-feeding. Females of child-bearing potential with positive pregnancy test at SV2. Subject (or their partner) not using an adequate method of contraception according to national requirements. Exclusion Criteria (for subjects performing HPA axis assessments) A history of serious allergy, allergic asthma or serious allergic skin rash. Known or suspected hypersensitivity to any component of CORTROSYN® (including ACTH/cosyntropin/tetracosactide) Systemic treatment with corticosteroids (including inhaled and nasal steroids) within 12 weeks prior to SV2 or during the trial. Topical treatment with corticosteroids within 2 weeks prior to SV2 or during the trial. Oestrogen therapy (including contraceptives) or any other medication known to affect cortisol levels levels or HPA axis integrity within 4 weeks prior to SV2 or during the trial. Enzymatic inductors (e.g., barbiturates, phenytoin, rifampicin) within 4 weeks prior to SV2 or during the trial. Systemic or topical cytochrome P450 inhibitors (e.g., ketoconazole, itraconazole, metronidazole) within 4 weeks prior to SV2 or during the trial. Topical ketoconazole 2 weeks prior to SV2. Hypoglycemic sulfonamides within 4 weeks prior to SV2 or during the trial. Antidepressive medications within 4 weeks prior to SV2 or during the trial. Known or suspected endocrine disorder that may affect the results of the ACTH challenge test. Clinical signs or symptoms of Cushing's disease or Addison's disease. Subjects with diabetes mellitus. Known or suspected cardiac condition. Not following nocturnal sleep patterns.

Ages Eligible for Study
-----------------
Minimum Age: 12 Years
Maximum Age: 17 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LEO 80185 gel<br> | Drug: LEO 80185 gel<br> <br> |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Drug Reactions (ADRs) | Number of Adverse Drug Reactions (ADRs) | 8 weeks | 
| Subjects With Serum Cortisol Concentration of ≤18 mcg/dl at 30 Minutes After ACTH-challenge at Week 4 | Number of subjects with serum cortisol concentration of ≤18 mcg/dl at 30 minutes after ACTH-challenge at Week 4 | 30 minutes after ACTH-challenge at Week 4 | 
| Subjects With Serum Cortisol Concentration of ≤18 mcg/dl at 30 Minutes After ACTH-challenge at Week 8 | Number of subjects with serum cortisol concentration of ≤18 mcg/dl at 30 minutes after ACTH-challenge at Week 8 | 30 minutes after ACTH-challenge at Week 8 | 
| Change in Albumin-corrected Serum Calcium From Baseline to Week 4 | Change in albumin-corrected serum calcium from baseline to Week 4 | From baseline to Week 4 | 
| Change in Albumin-corrected Serum Calcium From Baseline to Week 8 | Change in albumin-corrected serum calcium from baseline to Week 8 | From baseline to Week 8 | 
| Change in Albumin-corrected Serum Calcium From Baseline to End of Treatment | Change in albumin-corrected serum calcium from baseline to end of treatment, defined as the last value recorded after baseline up to and including Week 8. | From baseline to end of treatment | 
| Change in 24-hour Urinary Calcium Excretion From Baseline to Week 4 | Change in 24-hour urinary calcium excretion from baseline to Week 4 | From baseline to Week 4 | 
| Change in 24-hour Urinary Calcium Excretion From Baseline to Week 8 | Change in 24-hour urinary calcium excretion from baseline to Week 8 | From baseline to Week 8 | 
| Change in 24-hour Urinary Calcium Excretion From Baseline to End of Treatment | Change in 24-hour urinary calcium excretion from baseline to end of treatment, defined as the last value recorded after baseline up to and including Week 8. | From baseline to end of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Events (AEs) | Number of Adverse Events (AEs) | 8 weeks | 
| Subjects With Serum Cortisol Concentration of ≤18 mcg/dl at Both 30 and 60 Minutes After ACTH-challenge at Week 4 | Number of subjects with serum cortisol concentration of ≤18 mcg/dl at both 30 and 60 minutes after ACTH-challenge at Week 4 | 30 and 60 minutes after ACTH-challenge at Week 4 | 
| Subjects With Serum Cortisol Concentration of ≤18 mcg/dl at Both 30 and 60 Minutes After ACTH-challenge at Week 8 | Number of subjects with serum cortisol concentration of ≤18 mcg/dl at both 30 and 60 minutes after ACTH-challenge at Week 8 | 30 and 60 minutes after ACTH-challenge at Week 8 | 
| Change in Urinary Calcium:Creatinine Ratio From Baseline to Week 4 | Change in urinary calcium:creatinine ratio from baseline to Week 4 | From baseline to Week 4 | 
| Change in Urinary Calcium:Creatinine Ratio From Baseline to Week 8 | Change in urinary calcium:creatinine ratio from baseline to Week 8 | From baseline to Week 8 | 
| Change in Serum Alkaline Phosphatase From Baseline to Week 4 | Change in serum alkaline phosphatase from baseline to Week 4 | From baseline to Week 4 | 
| Change in Serum Alkaline Phosphatase From Baseline to Week 8 | Change in serum alkaline phosphatase from baseline to Week 8 | From baseline to Week 8 | 
| Pharmacokinetic Evaluation AUC(0-t) | AUC(0-t) values for betamethasone dipropionate, betamethasone 17-propionate, calcipotriol, and MC1080. Betamethasone dipropionate was only detected above lower limit of quantification in 5 samples from 4 subjects, and no subjects had enough positive samples to allow calculation AUC(0-t) for betamethasone dipropionate. Betamethasone 17-propionate was only detected in 12 samples from 5 subjects, and only 2 subjects had enough positive samples to calculate AUC(0-t). The mean value of AUC(0-t) for these 2 subjects is presented for betamethasone 17-propionate. Calcipotriol and MC1080 were never detected above lower limit of quantification, therefore no PK parameters could be calculated and no data have been entered for calcipotriol and MC1080. | Week 4, blood samples taken before IMP was applied and 1, 3, and 5 hours after application of IMP | 
| Pharmacokinetic Evaluation AUC(0-infinity) | AUC(0-infinity) values for betamethasone dipropionate, betamethasone 17-propionate, calcipotriol, and MC1080. Betamethasone dipropionate was only detected above lower limit of quantification in 5 samples from 4 subjects, and no subjects had enough positive samples to allow calculation AUC(0-infinity) for betamethasone dipropionate. Betamethasone 17-propionate was only detected in 12 samples from 5 subjects, and only 2 subjects had enough positive samples to calculate AUC(0-infinity). The mean value of AUC(0-infinity) for these 2 subjects is presented for betamethasone 17-propionate. Calcipotriol and MC1080 were never detected above lower limit of quantification, therefore no PK parameters could be calculated and no data have been entered for calcipotriol and MC1080. The terms AUC(0-infinity) and AUC(all) are interchangeable, AUC(0-infinity) was used in the protocol whereas AUC(all) was used in the report. AUC(0-infinity) has been used here to be consistent with the protocol. | Week 4, blood samples taken before IMP was applied and 1, 3, and 5 hours after application of IMP | 
| Pharmacokinetic Evaluation C(Max) | C(max) values for betamethasone dipropionate, betamethasone 17-propionate, calcipotriol, and MC1080. Betamethasone dipropionate was only detected above lower limit of quantification in 5 samples from 4 subjects and betamethasone 17-propionate was only detected in 12 samples from 5 subjects, therefore pharmacokinetic profiles could not be calculated. Presented C(max) values for betamethasone dipropionate and betamethasone 17-propionate are the the single highest concentrations measured in any sample at any time. Calcipotriol and MC1080 were never detected above lower limit of quantification, therefore no PK parameters could be calculated and no data have been entered for calcipotriol and MC1080. | Week 4, blood samples taken before IMP was applied and 1, 3, and 5 hours after application of IMP | 
| Pharmacokinetic Evaluation T(Max) | T(max) values for betamethasone dipropionate, betamethasone 17-propionate, calcipotriol, and MC1080. Betamethasone dipropionate was only detected above lower limit of quantification in 5 samples from 4 subjects and betamethasone 17-propionate was only detected in 12 samples from 5 subjects. Therefore it was not possible to calculate T(max) for betamethasone dipropionate and betamethasone 17-propionate. Calcipotriol and MC1080 were never detected above lower limit of quantification, therefore no PK parameters could be calculated and no data have been entered for calcipotriol and MC1080. | Week 4, blood samples taken before IMP was applied and 1, 3, and 5 hours after application of IMP | 
| Pharmacokinetic Evaluation T(½) | T(½) values for betamethasone dipropionate, betamethasone 17-propionate, calcipotriol, and MC1080. Betamethasone dipropionate was only detected above lower limit of quantification in 5 samples from 4 subjects and betamethasone 17-propionate was only detected in 12 samples from 5 subjects, therefore it was not possible to calculate T(½) for betamethasone dipropionate or betamethasone 17-propionate. Calcipotriol and MC1080 were never detected above lower limit of quantification, therefore no PK parameters could be calculated and no data have been entered for calcipotriol and MC1080. | Week 4, blood samples taken before IMP was applied and 1, 3, and 5 hours after application of IMP | 
| Subjects With Controlled Disease According to the Investigator's Global Assessment of Disease Severity on the Body at End of Treatment | Subjects with Controlled disease (i.e., Clear or Almost clear for subjects with at least Moderate disease at baseline, Clear for subjects with Mild disease at baseline) according to the investigator's global assessment of disease severity on the body at end of treatment, defined as the last value recorded up to and including Week 8. | End of treatment | 
| Percentage Change in PASI From Baseline to End of Treatment | Percentage change in Psoriasis area and severity index (PASI) score from baseline to end of treatment, defined as the last value recorded up to and including Week 8. Psoriasis area and severity index (PASI) assesses extent and severity of clinical signs of psoriasis vulgaris. Body surface is divided in 4 ares: head (incl. neck), arms (incl. hands), trunk (incl. flexures) and legs (incl. buttocks and feet). Each area is scored from 0-6 for extent of psoriasis and from 0-4 for redness, thickness, and scaliness, and an area PASI score is calculated. The total PASI score is calculated from each area's score. The PASI score ranges from 0 (clear skin) to 72 (maximum disease), a PASI score higher than 10 generally corresponds to moderate-to-severe disease. | From baseline to end of treatment | 
| Subjects With Controlled Disease According to the Patient's Global Assessment of Disease Severity on the Body at End of Treatment | Subjects with Controlled disease (i.e., Clear or Almost clear for subjects with at least Moderate disease at baseline, Clear for subjects with Mild disease at baseline) according to the patient's global assessment of disease severity on the body at end of treatment, defined as the last value recorded up to and including Week 8. | End of treatment |