A Study to Test the Effect of 2 Different Doses of Topical GW870086X on Atopic Dermatitis Also Including a Postive Control and a Placebo

Study Overview
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Brief Summary
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This study is a randomised, double-blind, placebo-controlled study to assess the efficacy of GW870086X cream formulation in subjects with moderate to severe atopic dermatitis. Subjects will be assigned to take 3 out of the 4 possible treatments for 21 ±2 days: GW870086X 0.2% cream, GW870086X 2% cream, FP 0.05% cream (as a positive control) and placebo cream. All subjects will be randomised to receive placebo cream. Three index lesions located on the arms and/or legs (one on each) will be identified per subject and each treatment will be applied to the same lesion.

Detailed Description
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This study is a randomised, double-blind, placebo-controlled study to assess the efficacy of GW870086X cream formulation in subjects with moderate to severe atopic dermatitis. The primary objective of this study is to assess 3 lesions using the Three Item Severity (TIS) score. The secondary objectives are to assess safety and tolerability of GW870086X, assess individual lesions using the Investigators Global Assessment (IGA) and to assess the pharmacokinetics of 21 days dosing of GW870086X administered as a cream. Twenty-five (25) subjects with atopic dermatitis will be randomised to receive placebo and 2 of the following treatments: GW870086X 0.2%, GW870086X 2%, FP 0.05% and placebo. All subjects will receive placebo. Subjects will apply all 3 treatments once daily during the 21 day treatment period. Three index lesions located on the arms and/or legs (one on each) will be identified per subject and each treatment will be applied to the same lesion throughout the 21±2 day treatment period. Each index lesion should represent the most common lesions for each patient i.e. not the most or least severe lesions.

Official Title
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A Randomised, Double-blind, Placebo-controlled Study of Topical GW870086X Formulation in Subjects With Moderate or Severe Atopic Dermatitis

Conditions
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Dermatitis, Atopic

Intervention / Treatment
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* Drug: GW870086 2.0%
* Drug: GW870086 0.2%
* Drug: FP 0.05%
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects with a diagnosis of atopic dermatitis who are otherwise healthy. Male or female between 18 and 65 years of age inclusive. A female subject is eligible to participate if she is of: • Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the protocol contraception methods if they wish to continue their HRT during the study. Male subjects with female partners of child-bearing potential must agree to use one of the protocol contraception methods. BMI within the range 19.0 - 29.0 kg/m2 (inclusive). Subjects must have body surface area (BSA) disease involvement of >5% as assessed by the rule of nines method. Patients must be willing to refrain from current active therapy for at least 10 days prior to dosing, Capable of giving written informed consent. Single QTc, QTcB < 450 msec; or QTc < 480 msec in subjects with Bundle Branch Block. AST and ALT < 2xULN; alkaline phosphatase and bilirubin ≤ 1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%). Exclusion Criteria: The subject presents with any systemic disorder, active skin disease or subjects who present with scars, moles, tattoos, body piercings, sunburn in the test area which could interfere with the assessment of lesions at screening. The subject has atopic dermatitis restricted to the face, the feet or the hands only. The subject has a current complication of atopic dermatitis for which treatment with anti-infectives are indicated. History of recent (< 6 months) active or presence of current superficial skin infections of viral aetiology The subject has been diagnosed as having contact dermatitis in area of target lesions, seborrheic dermatitis and/or occupational eczema at predilection sites of atopic dermatitis. The subject has had topical or transdermal treatments on or near the intended site of application within 14 days prior to first application of study medication. The subject has had systemic treatment for atopic dermatitis within 28 days of the first dose of study medication. Foreseeable intensive UV exposure during the study. Subjects must not be exposed to direct sunlight or skin tanning devices for the duration of the study. The subject has used topical treatment with tar or any corticosteroid within 14 days of the first dose of study medication except topical 1% hydrocortisone which may be used twice daily in patients with severe disease who require step-down therapy during the wash-out period until 3 days prior to study start, after which the hydrocortisone must be discontinued. The subject has used topical treatment with buproprion within 14 days of the first dose of study medication. History of cutaneous photodisorder. History of allergy to steroids or components of test medications. History or presence of skin (other than atopic dermatitis), hepatic or renal disease or any other condition known to interfere with absorption, distribution, metabolism or excretion of drugs. Subjects with a history of diaphoresis/excessive sweating not restricted to palms or face. A positive test for Hepatitis B or Hepatitis C antibody. Current or chronic history of liver disease, or known hepatic or biliary abnormalities. A positive pre-study drug/alcohol screen. A positive test for HIV antibody. History of regular alcohol consumption within 6 months of the study. The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer). Exposure to more than four new chemical entities within 12 months prior to the first dosing day. Use of prescription or non-prescription drugs, including vitamins, herbal and dietary supplements within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study medication, unless in the opinion of the Investigator and GSK Medical Monitor the medication will not interfere with the study procedures or compromise subject safety. Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period. Unwillingness or inability to follow the procedures outlined in the protocol. Subject is mentally or legally incapacitated. History of sensitivity to heparin or heparin-induced thrombocytopenia. Consumption of red wine, Seville oranges, grapefruit or grapefruit juice and/or pummelos, exotic citrus fruits, grapefruit hybrids or fruit juices from 7 days prior to the first dose of study medication.

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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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: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GW870086 2.0% &amp; 0.2%<br>GW870086 2.0%, GW870086 0.2% &amp; Placebo each applied to a separate specific lesion for 21±2 days. | Drug: GW870086 2.0%<br>* White to slightly colored opaque cream<br>Drug: GW870086 0.2%<br>* White to slightly colored opaque cream<br>Drug: Placebo<br>* White to slightly colored opaque cream<br>|
| Experimental: GW870086 2.0% & FP 0.05%<br>GW870086 2.0%, FP 0.05% &amp; Placebo each applied to a separate specific lesion for 21±2 days. | Drug: GW870086 2.0%<br>* White to slightly colored opaque cream<br>Drug: FP 0.05%<br>* White cream<br>Drug: Placebo<br>* White to slightly colored opaque cream<br>|
| Experimental: GW870086 0.2% & FP 0.05%<br>GW870086 0.2%, FP 0.05% &amp; Placebo each applied to a separate specific lesion for 21±2 days. | Drug: GW870086 0.2%<br>* White to slightly colored opaque cream<br>Drug: FP 0.05%<br>* White cream<br>Drug: Placebo<br>* White to slightly colored opaque cream<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline Three Item Severity (TIS) Scores Between GW870086 (0.2% and 2%) Versus Placebo at Day 22 | Three target lesions were selected and each of the 3 target lesions were assessed separately using the TIS for erythema, oedema/papulation, and excoriation using a score of 0 - 3 as 0 = absent, 1 = mild, 2 = moderate, 3 = severe. Each participant had at least 3 index lesions (=> 1square centimeter in size) with a sum score of =>4 and =< 6 for erythema, oedema/populations and excoriations using the TIS rating scale at screening. The index lesions represented common lesions i.e. not the most or least severe lesions. The total TIS score for a lesion was calculated as the sum of each of the component scores i.e. ranging from 0 (no symptoms) to 9 (severe symptoms). The values of Day 1 assessments were considered as Baseline values. The change from Baseline was calculated by subtracting the Baseline TIS score from Day 22 TIS score. | Baseline (Day 1) and Day 22 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline TIS Scores Between GW870086X (0.2% and 2%) Versus Placebo on Days 2, 3, 7 and 14 | Three target lesions were selected and each of the 3 target lesions were assessed separately using the TIS for erythema, oedema/papulation, and excoriation using a score of 0 - 3 as 0 = absent, 1 = mild, 2 = moderate, 3 = severe. Each participant had at least 3 index lesions (=> 1square centimeter in size) with a sum score of =>4 and =< 6 for erythema, oedema/populations and excoriations using the TIS rating scale at screening. The index lesions represented common lesions i.e. not the most or least severe lesions. The total TIS score for a lesion was calculated as the sum of each of the component scores i.e. may range from 0 (no symptoms) to 9 (severe symptoms). The values of Day 1 assessments were considered as Baseline values. The change from Baseline was calculated by subtracting the Baseline TIS score from Day 22 values TIS score. | Days 2, 3, 7, and 14 | 
| Number of Investigators Global Assessment (IGA) Responders on Days 2, 3, 7, 14 and 22 | Three target lesions were selected and each of the 3 target lesions were assessed separately using the IGA. The IGA was carried out by a trained dermatologist and score ranged from 0 to 5. The detailed IGA scale is as: 0-Clear: No inflammatory signs of atopic dermatitis, 1- Almost clear: Just perceptible erythema and just perceptible apulation/infiltration, 2-Mild: Mild erythema and mild papulation/infiltration, 3-Moderate: Moderate erythema, and moderate papulation/infiltration, 4-Severe: Severe erythema and severe papulation/infiltration, 5-Very Severe: Very severe erythema, and very severe papulation/infiltration with oozing/crusting. The participant was considered as responder if each lesion at timepoint, IGA score reduced by 1 grade and improved from Baseline by 2 grades. | Days 2, 3, 7, 14 and 22 | 
| Number of Participants With Any Adverse Events (AEs) and Serious Adverse Events (SAEs) | AE was defined as any untoward medical occurrence in a participant temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE include AEs those result in death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal functions, or a congenital anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered serious when, based upon appropriate medical judgment, they may jeopardize the participant and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. Number of participants with AEs and SAEs were reported. | Upto Day 21 | 
| Number of Participants With Abnormal Hematology and Clinical Chemistry Parameters of Potential Clinical Importance (PCI) | Laboratory ranges of PCI represented as multiplier of lower limit of normal [LLN]; Multipliers of upper limit of normal (ULN). Laboratory ranges of PCI for white blood cell count (0.67×LLN; 1.82×ULN), neutrophil count (0.83×ULN), hemoglobin for male (1.03×ULN) and for female (1.13×ULN), hematocrit for male (1.02×ULN) for female (1.17×ULN), platelet count (0.67×LLN; 1.57), lymphocytes (0.81×LLN), albumin (0.86 ×LLN), calcium (0.91×LLN; 1.06×ULN), glucose (0.71×LLN; 1.41×ULN), potassium (0.86×LLN; 1.10×ULN), sodium (0.96×LLN; 1.03×ULN), aspartate amino transferase (>= 2x ULN), alanine transaminase (>=2x ULN), alkaline Phosphatase (>=2x ULN), total bilirubin (>=1.5x ULN). Only those parameters for which at least one value of PCI was reported are summarized. The number of participants with PCI hematology and clinical chemistry findings at any visit during the treatment and follow-up were reported. | Up to Day 21 | 
| Number of Participants With Abnormal Electrocardiogram (ECG) of PCI | 12-lead ECG was obtained. The standard ECG criteria of PCI were 1) absolute QTc Interval, > 450 milliseconds (msec), 2) increase from Baseline in QTc > 60 msec 3) absolute PR Interval, <110 and >220 msec, 4) absolute QRS Interval, < 75 and >110 msec. The number of participants with PCI ECG findings at any visit during the treatment and follow-up were reported. | Up to Day 21 | 
| Number of Participants With Abnormal Vital Signs (Systolic and Diastolic Blood Pressure and Pulse Rate) of PCI | The PCI ranges (low and high) of the vital sign parameters were for systolic blood pressure (<85 and >160 millimeter of mercury [mmHg]), diastolic blood pressure (<45 and >100 mmHg) and heart rate (<40 and >110 beats per minute). Only those parameters for which at least one value of PCI was reported are summarized. There were no values of PCI in vital signs parameters over the course of the study. | Up to Day 21 | 
| Pharmacokinetic Parameters: Maximum Observed Concentration (Cmax) of GW870086X | Cmax was planned to be determined directly from the raw concentration-time data. The pharmacokinetic parameters were planned to be calculated by standard non-compartmental analysis using Win-Nonlin Pro-Version 5.2 or higher. | Day 7, 14 and 21 | 
| Pharmacokinetic Parameter: Time of Occurrence of Cmax (Tmax) of GW870086 | Tmax was planned to be determined directly from the raw concentration-time data. The pharmacokinetic parameters were planned to be calculated by standard non-compartmental analysis using Win-Nonlin Pro-Version 5.2 or higher. | Day 7, 14 and 21 | 
| Pharmacokintics Parameter: Area Under Curve (AUC) of GW870086 | The area under the plasma concentration-time curve to the last quantifiable concentration (AUC[0-t]) and area under the plasma concentration-time curve over the dosing interval (AUC[0-tou]) was planned to be determined using the linear trapezoidal rule for increasing concentrations and the logarithmic trapezoidal rule for decreasing concentrations. The pharmacokinetic parameters were planned to be calculated by standard non-compartmental analysis using Win-Nonlin Pro-Version 5.2 or higher. | Day 7, 14 and 21 | 
| Pharmacodynamics Endpoint: Skin Thickness and Other Markers of Atopic Dermatitis | A 4 millimeter (mm) punch skin biopsy was taken pre- and post-treatment (Day 1 and Day 21) from each of the 3 index lesions. The results were not analyzed for this outcome measure. | Day 1 and Day 22 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Atopic Dermatitis, GW870086X, TIS, IGA