A 12-Day Randomized, Blinded, Vehicle and Active Comparator-Controlled Study to Determine the Efficacy and Safety of Six Concentrations of Topical E6201 Gel in Subjects With Psoriasis Vulgaris

Study Overview
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Brief Summary
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The purpose of this study is to investigate the efficacy, safety, tolerability and the concentration/response relationship of E6201 in subjects with psoriasis vulgaris.

Detailed Description
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This is a single center, randomized, blinded, intra-individual comparison in two sequential cohorts of 15 subjects each (30 subjects in total) in an outpatient setting, in which each subject simultaneously receives five topical treatments (3 active, 1 vehicle, and 1 positive control) within one or two psoriatic plaques. Treatments consisted of 3 concentrations of E6201 gel, a negative control (gel vehicle), and a positive control (0.005% calcipotriene cream). The different concentrations of E6201 gel and vehicle control were double-blinded, while the calciprotriene cream was single-blinded. Cohort 2 participants were not dosed until all participants in Cohort 1 completed treatment and safety data were collected and evaluated.

Official Title
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A 12-Day Randomized, Blinded, Vehicle and Active Comparator-Controlled Study to Determine the Efficacy and Safety of Six Concentrations of Topical E6201 Gel in Subjects With Psoriasis Vulgaris

Conditions
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Psoriasis Vulgaris

Intervention / Treatment
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* Drug: 0.03% E6201
* Drug: 0.1% E6201
* Drug: 0.2% E6201
* Drug: 0.005% E6201
* Drug: 0.01% E6201
* Drug: 0.05% E6201
* Other: Placebo - 0.03% gel vehicle
* Other: Placebo - 0.1% gel vehicle
* Other: Placebo - 0.2% gel vehicle
* Other: Placebo - 0.05% gel vehicle
* Other: Placebo - 0.01% gel vehicle
* Other: Placebo - 0.05% gel vehicle
* Drug: Calcipotriene


Participation Criteria
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Eligibility Criteria
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Inclusion: Chronic stable plaque psoriasis with one or two stable psoriatic plaques(s) suitable in size and location for five separate treatment fields to be assessed within it. Males and females aged between 18 and 75 years of age The general physical examination should be normal (excluding the skin examination for psoriasis) unless the Investigator considers an abnormality not to be clinically significant with regard to the study Females of childbearing potential must have a negative serum beta-human chorionic gonadotropin at Visit 1 (Screening) and a negative urine pregnancy test prior to starting study drug(s) (Visit 2). Female subjects of childbearing potential must agree to be abstinent or to use a highly effective method of contraception throughout the study period and for 30 days after the last dose of study drug. Provide written informed consent Willing and able to comply with all aspects of the protocol Exclusion: Any clinically significant skin diseases other then chronic stable plaque psoriasis Other types of psoriasis than chronic stable plaque variant eg, guttate, pustular, erythodermic, etc An unstable course of the disease defined as flare(s) in the previous month Subjects who used any concommitant topical treatment for the psoriatic plaque(s) to be studied (other than emollients or salicylic acid) within 8 weeks before the Baseline visit eg corticosteroids or topical immunomodulators, anthralin (dithranil), vitamin D derivatives, ultraviolet-light therapy including sunbathing , or retinoids. Subjects who used any of the following systemic treatments within 12 weeks before the Baseline visit eg: corticosteroids or adrenocorticotrophic hormone analogs, retinoids such as acitretin or isotretinoin, cyclosporin, interferon, methotrexate, other immuno-suppressive/immunomodulating drugs, psoralen and ultraviolet A therapy, or biologics Subjects planning on significant exposure to sun (sun-bathing) Treatment with systemic or locally acting medications which might counter or influence the study aim (eg monoamine oxidase inhibitors, anti-epileptic drugs, anti-psychotic drugs) or medications which are known to provoke or aggravate psoriasis, eg Beta-blockers, antimalarial drugs, and lithium within two weeks before the Baseline visit Subject is a dependent person, ie, a relative/family member of the Investigator and/or is a member of the Investigator's staff Clinical study participation with any investigational drug less than 30 days prior to study entry or planning to receive an investigational drug during the study period

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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
Allocation: Randomized
Intervention Model: Parallel Assignment


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>Three concentrations of E6201 topical gel (0.03%, 0.1%, and 0.2%) and active comparator, calcipotriene cream (0.005%), were applied once daily for 12 days to specific test fields determined at Baseline. The 3 concentrations of E6201 gel were dosed first in Cohort 1 to establish the safety and tolerability prior to dosing in Cohort 2. | Drug: 0.03% E6201<br>* Topical 0.03% E6201 gel was applied once daily to individual specific regions of the psoriatic plaque.<br>Drug: 0.1% E6201<br>* Topical 0.1% E6201 gel was applied once daily to individual specific regions of the psoriatic plaque.<br>Drug: 0.2% E6201<br>* Topical 0.2% E6201 gel was applied once daily to individual specific regions of the psoriatic plaque.<br>Other: Placebo - 0.03% gel vehicle<br>* Topical 0.03% gel vehicle (negative control) was applied once daily to individual specific regions of the psoriatic plaque.<br>Other: Placebo - 0.1% gel vehicle<br>* Topical 0.1% gel vehicle (negative control) was applied once daily to individual specific regions of the psoriatic plaque.<br>Other: Placebo - 0.2% gel vehicle<br>* Topical 0.2% gel vehicle (negative control) was applied once daily to individual specific regions of the psoriatic plaque.<br>Drug: Calcipotriene<br>* Topical 0.005% calcipotriene (positive control) was applied once daily to individual specific regions of the psoriatic plaque.<br>* Other names: Daivonex;|
| Experimental: Cohort 2<br>Three concentrations of E6201 topical gel (0.005%, 0.01%, and 0.05%) and active comparator, calcipotriene cream (0.005%), were applied once daily for 12 days to specific test fields determined at Baseline. Cohort 2 participants were not dosed until all participants in Cohort 1 completed treatment and safety data were collected and evaluated. | Drug: 0.005% E6201<br>* Topical 0.005% E6201 gel was applied once daily to individual specific regions of the psoriatic plaque.<br>Drug: 0.01% E6201<br>* Topical 0.01% E6201 gel was applied once daily to individual specific regions of the psoriatic plaque.<br>Drug: 0.05% E6201<br>* Topical 0.05% E6201 gel was applied once daily to individual specific regions of the psoriatic plaque.<br>Other: Placebo - 0.05% gel vehicle<br>* Topical 0.005% gel vehicle (negative control) was applied once daily to individual specific regions of the psoriatic plaque.<br>Other: Placebo - 0.01% gel vehicle<br>* Topical 0.01% gel vehicle (negative control) was applied once daily to individual specific regions of the psoriatic plaque.<br>Other: Placebo - 0.05% gel vehicle<br>* Topical 0.05% gel vehicle (negative control) was applied once daily to individual specific regions of the psoriatic plaque.<br>Drug: Calcipotriene<br>* Topical 0.005% calcipotriene (positive control) was applied once daily to individual specific regions of the psoriatic plaque.<br>* Other names: Daivonex;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Summary Statistics and Primary Pairwise Comparison (Vehicle-E6201) of Area Under the Curve (AUC) for the Baseline-Corrected Thickness of the Psoriatic Infiltrate | The AUC was based on the baseline-corrected thickness of the psoriatic infiltrate (20 megahertz (MHz) Sonographic measurement) at specified days for each treatment field calculated by applying the linear trapezoidal rule. Sonographic measurements were performed using a 20 MHz high-frequency sonograph. Serial A-scans were composed and represented on a monitor as a section of the skin. A lateral resolution of approximately 200 um and an axial resolution of 80 um were possible. Dependent on the echo patterns, components of the epidermis, dermis, and subcutis were represented. Therefore, exact measurement of skin thickness was possible. The inflammatory psoriatic infiltrate was seen as a clearly definable echo lucent band below the entrance echo. The thickness of the echo lucent psoriatic band was determined. The thickness was measured in micrometers (um) and was denoted as T. | Day 0 (Baseline), Day 8 (Visit 10), and Day 12 (End of Treatment) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Thickness of the Psoriatic Infiltrate From Baseline to End of Treatment (Day 12/Discontinuation) | Psoriatic infiltrate thickness was determined by 20 MHz Sonographic measurements using a 20 MHz high-frequency sonograph. Serial-A scans were composed and represented on a monitor as a section of the skin. A lateral resolution of approximately 200 um and an axial resolution of 80 um were possible. Dependent on the echo patterns, components of the epidermis, dermis, and subcutis were represented. Therefore exact measurement of the skin thickness was possible. The inflammatory psoriatic infiltrate was seen as a clearly definable echo lucent back below the entrance echo. The thickness of the echo lucent psoriatic band was determined. Comparisons were made with the untreated plaque(s) beneath the hydrocolloid dressing. Baseline was defined as Visit 2 (Day 0). Least Squares Means (LSM) and Confidence Intervals (CI) were obtained from ANCOVA model with factors for treatment and baseline psoriatic infiltrate thickness as a continuous covariate. | Day 12/Discontinuation (Visit 14/End of Treatment) | 
| Change in Thickness of the Psoriatic Infiltrate From Baseline to Day 8 | Psoriatic infiltrate thickness was determined by 20 MHz Sonographic measurements using a 20 MHz high-frequency sonograph. Serial-A scans were composed and represented on a monitor as a section of the skin. A lateral resolution of approximately 200 um and an axial resolution of 80 um were possible. Dependent on the echo patterns, components of the epidermis, dermis, and subcutis were represented. Therefore exact measurement of the skin thickness was possible. The inflammatory psoriatic infiltrate was seen as a clearly definable echo lucent back below the entrance echo. The thickness of the echo lucent psoriatic band was determined. Comparisons were made with the untreated plaque(s) beneath the hydrocolloid dressing. Baseline was defined as Visit 2 (Day 0). LSM and CI were obtained from ANCOVA model with factors for treatment and baseline psoriatic infiltrate thickness as a continuous covariate. | Day 8 (Visit 10) | 
| Clinical (Global) Assessment of Efficacy at Day 12/Discontinuation | Clinical (global) assessment of the test fields was performed using a 5-point score: -1 = worsened, 0 = unchanged (no effect), 1 = slight improvement, 2 = clear improvement but not completely healed, and 3 = completely healed. Comparisons were made with the untreated plaque(s) beneath the hydrocolloid dressing. Clinically apparent differences in erythema and infiltration contributed to the global assessment. Baseline was defined as Visit 2 (Day 0). | Day 12/Discontinuation (Visit 14/End of Treatment) | 
| Clinical (Global) Assessment of Efficacy on Day 8 | Clinical (global) assessment of the test fields was performed using a 5-point score: -1 = worsened, 0 = unchanged (no effect), 1 = slight improvement, 2 = clear improvement but not completely healed, and 3 = completely healed. Comparisons were made with the untreated plaque(s) beneath the hydrocolloid dressing. Clinically apparent differences in erythema and infiltration contributed to the global assessment. Baseline was defined as Visit 2 (Day 0). | Day 8 (Visit 10) | 
| Overview of Treatment-Emergent Adverse Events (TEAEs) | TEAEs were defined as an adverse event (AE) that emerged during treatment, having been absent at pretreatment (baseline), or re-emerged during treatment, having been present at baseline but stopped prior to treatment, or worsened in severity during treatment relative to the pretreatment state, when the AE was continuous. Safety variables included TEAEs including skin reactions, diascopy and biopsy findings, clinical laboratory parameters, vital signs, and physical examinations. For Cohort 2, special attention was given to a close, daily monitoring of the application site for signs of skin irritation. Any suspected ecchymoses or petechiae were to be followed up with a diascopy test that was to be documented with digital photographs. Any positive diascopy test was to be followed up by biopsy for skin ultrastructural analysis (if agreed to by the participant, sponsor, and investigator). Few adverse events occurred in more than one treatment group. | From first dose of study treatment up to 30 days after the last dose, or until resolution, whichever came first, or up to approximately 10 months. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Psoriasis vulgaris