A Study to Determine the Safety & Efficacy of ZPL-5212372 in Healthy Subjects and in Subjects With Atopic Dermatitis

Study Overview
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Brief Summary
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A Randomised, Adaptive Design, Double-Blind (3rd Party Open), Placebo Controlled, Sequential Group Study to Determine the Safety,Tolerability, Pharmacokinetics and Efficacy of Twice Daily Application of a Topical ZPL-5212372 (1.0% w/w) Ointment Administered for up to 2 Weeks in Adult Healthy Volunteers and Patients with Moderate to Severe Atopic Dermatitis

Detailed Description
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This study was a randomised, adaptive design, double blind (3rd party open), placebo controlled, sequential group study in both healthy volunteers and patients with moderate to severe AD. This study was divided into 3 separate, sequential cohorts: Cohort 1 were to assess safety, toleration and pharmacokinetics (PK) with intensive monitoring as in-patients over 7 days of dosing in healthy volunteers. Cohort 2 were to assess safety, toleration and PK with intensive monitoring as in-patients over 7 days of dosing in moderate to severe AD patients. Cohort 3 were to assess efficacy, safety, toleration and PK as out-patients over 14 days of dosing in moderate to severe AD patients. Subjects received 1.0% (w/w) ZPL-5212372 or matched placebo ointment topically, twice daily.

Official Title
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A Randomised, Double-blind, Placebo Controlled Study to Determine the Safety, Pharmacokinetics and Efficacy of Topical ZPL-5212372 Ointment Administered BID for up to 2 Weeks in Healthy Subjects and Subjects With Atopic Dermatitis.

Conditions
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Atopic Dermatitis

Intervention / Treatment
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* Drug: ZPL-5212372 1% w/w Ointment BID
* Drug: Placebo Ointment BID


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy males or females, aged between 18 and 55 years, inclusive (healthy is defined as no clinically relevant abnormalities identified by a detailed medical history, full physical examination, including blood pressure and pulse rate measurement, 12-lead ECG and clinical laboratory tests). or Males and females aged 18-65 years inclusive with physician documented history or diagnosis of atopic dermatitis for at least 6 months prior to screening. AD should be diagnosed by the Eichenfield revised criteria of Hanifin and Rajka. For Atopic Dermatitis Patients: Eczema Area and Severity Index (EASI) of ≥9 and <48 at Screening and an EASI of ≥12 and <48 at Day 1. An Investigator's Global Assessment (IGA) score ≥ 3 at both Screening and Day 1. Atopic dermatitis affecting between ≥10 to <40% BSA at Screening and ≥10% to <50% BSA on Day 1. All Subjects: Evidence of a personally signed and dated informed consent form, indicating that the subject has been informed of all pertinent aspects of the study. Exclusion Criteria: For Healthy Subjects Evidence or history of clinically significant haematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease (including drug allergies, but excluding untreated, asymptomatic, seasonal allergies at time of dosing). Have tattoos covering areas of skin to be dosed with study ointment. Subjects who are hirsute in areas of skin to be dosed with study ointment. Subjects who have received treatment with an investigational drug within 3 months prior to screening. For Atopic Dermatitis Patients: AD of such severity (EASI >48) that the subject could not comply with the demands of the study and/or the subject is not a suitable candidate for a placebo-controlled study. Have concomitant skin disease or infection (e.g. acne, impetigo) or presence of skin comorbidities in the study area to be dosed that may interfere with study assessments. Have received phototherapy (e.g. UVA, UVB or PUVA therapy), or systemic therapy (e.g. immunosuppressants [such as cyclosporine, azathioprine, methotrexate], cytostatics) known or suspected to have an effect on AD, within 4 weeks of the start of the study. All other biologics should not have been used within 3 months of the start of study. Have received systemic corticosteroids (e.g. oral, intravenous, intraarticular, rectal) within 4 weeks of the start of the study. Subjects on a stable maintenance dose (over the preceding 3 months) of inhaled or intranasal CS may participate. Patients treated with oral antihistamines or topical calcineurin inhibitors or topical steroids within 7 days of starting study; intranasal antihistamines for the treatment of allergic rhinitis are acceptable.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

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
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1a<br>ZPL-5212372 1% w/w Ointment BID | Drug: ZPL-5212372 1% w/w Ointment BID<br> <br> |
| Placebo Comparator: Cohort 1b<br>Placebo Ointment BID | Drug: Placebo Ointment BID<br> <br> |
| Experimental: Cohort 2a<br>ZPL-5212372 1% w/w Ointment BID | Drug: ZPL-5212372 1% w/w Ointment BID<br> <br> |
| Placebo Comparator: Cohort 2b<br>Placebo Ointment BID | Drug: Placebo Ointment BID<br> <br> |
| Experimental: Cohort 3a<br>ZPL-5212372 1% w/w OIntment BID | Drug: ZPL-5212372 1% w/w Ointment BID<br> <br> |
| Placebo Comparator: Cohort 3b<br>Placebo Ointment BID | Drug: Placebo Ointment BID<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline in EASI Score in Cohort 3 | The EASI is a validated tool used to measure the severity and extent of atopic eczema (Eczema Area and Severity Index). The body is divided into 4 sections of total skin area: head including neck (10%); arms including extremities (20%); trunk (30%) and legs including extremities (40%). Each area is scored and the 4 scores are combined into the final EASI. The severity parameters are measured on a scale of 0 to 3 (from none to severe). For each section, the percentage area of skin involved with eczema is estimated and transformed into an extent grade from 0 to 6, from 0% of involved skin area with eczema to 90-100% of involved skin area with eczema. The sum of all four severity parameters is calculated for each section of skin and then multiplied by the weight of the respective section. This value is then multiplied by the extent score for that body area. The EASI value can range from 0-72, a higher score indicates more severe disease. | Day 1 and Day 14 | 
| Percent Change From Baseline in EASI Score Over Time in Cohort 3 - Observed Case | The EASI is a validated tool used to measure the severity and extent of atopic eczema (Eczema Area and Severity Index). The body is divided into 4 sections of total skin area: head including neck (10%); arms including extremities (20%); trunk (30%) and legs including extremities (40%). Each area is scored and the 4 scores are combined into the final EASI. The severity parameters are measured on a scale of 0 to 3 (from none to severe). For each section, the percentage area of skin involved with eczema is estimated and transformed into an extent grade from 0 to 6, from 0% of involved skin area with eczema to 90-100% of involved skin area with eczema. The sum of all four severity parameters is calculated for each section of skin and then multiplied by the weight of the respective section. This value is then multiplied by the extent score for that body area. The EASI value can range from 0-72, a higher score indicates more severe disease. | Days 1, 5, 8, 10, and 15 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Summary of EASI-50 and EASI-75 Responders at Week 2 - Cohort 3 | The proportion of subjects who achieved EASI-50 and EASI-75 responses at Week 2 were compared between treatment groups. EASI-50 was defined as a ≥50% reduction from baseline in EASI score at Week 2. EASI-75 was defined as a ≥75% reduction from baseline in EASI score at Week 2. | Day 14 | 
| Percentage of Responders on Investigators Global Assessment in Cohort 3 | The following secondary endpoints were assessed for IGA: A subject was considered as having IGA success if they achieved a score of 'Clear' or 'Almost clear'; note, as subjects required a score of ≥3 to enter the study they must have had a reduction of ≥2 from baseline to achieve success A subject was considered as having an IGA response if they achieved a score of 'Clear' or 'Almost clear', or a reduction of ≥2 from baseline IGA was summarized for the FAS with counts and percentages by treatment at each visit. | Day 14 | 
| Change From Baseline in NRS for Pruritus at Week 2 - Observed Case in Cohort 3 | Numerical Rating Scale (NRS) for Pruritus (worst itch). The Pruritus NRS is an assessment tool that will be used to assess the subject's worst itch as a result of AD in the previous 24 hours. They will be asked the following question: On a scale of 0 (No Itching) to 10 (Itching as bad as you can imagine), please rate the WORST itching that you felt over the last 24 hours. | Day 1 to day 14 | 
| Summary of Patient Global Impression of Change and Logistic Regression of Patient Global Impression of Change in Cohort 3 | Patient Global Impression of Change (PGIC) The PGIC scores were summarised for the FAS with counts and percentages in each treatment group. All data collected were included. The PGIC was dichotomized into responders, defined as responses of 'Very Much Improved', 'Much Improved' or 'Minimally improved' and non-responders (all other responses plus missing data). | End of treatment (day 15) | 
| Change From Baseline in Body Surface Area at Week 2 - Observed Case in Cohort 3 | Body Surface Area (BSA). The percentage BSA affected was summarised at each visit, including change from baseline, by treatment group, using the Full Analysis Set. | Day 1 to day 14 |