A Dose-Finding Study of GSK2894512 Cream in Subjects With Atopic Dermatitis (AD)

The IGA is a clinical tool for assessing the current state/severity of a participant's AD. It is a static 5-point morphological assessment of overall disease severity, as determined by the investigator, using the clinical characteristics of erythema, infiltration, papulation, oozing, and crusting as guidelines. The percentage of participants who have an IGA score of clear or almost clear at Week 12 and a minimum 2 grade improvement from Baseline to Week 12 in IGA score was presented. . The analysis was performed on ITT Population which comprised of all randomized participants.

NRS is a 11-point tool ranging from 0 (absent) to 10 (worst imaginable) to assess the severity of 11 disease-related signs and symptoms including itching, discoloration, bleeding, oozing, cracking, scaling, flaking, dry/rough, painful, burning, and stinging. Participants were asked to complete the self-administered sign and symptom severity diary containing NRS using a recall period of the past 24 hours. Question 1 of the diary was used to assess itch. Mean change from Baseline to Week 12 in weekly average of daily itch/pruritus based on the NRS was presented using mean and standard deviation (SD). Baseline was defined as the latest assessment prior to first dose and Change from Baseline was defined as post-dose weekly average value minus Baseline value.

NRS is a 11-point tool ranging from 0 (absent) to 10 (worst imaginable) to assess the severity of 11 disease-related signs and symptoms including itching, discoloration, bleeding, oozing, cracking, scaling, flaking, dry/rough, painful, burning, and stinging. Participants were asked to complete the self-administered sign and symptom severity diary containing NRS using a recall period of the past 24 hours. Question 1 of the diary was used to assess itch. Mean percent change in weekly average of daily itch/pruritus based on the NRS was presented using mean and SD from Baseline to Week 12. Baseline was defined as the latest assessment prior to first dose and Change from Baseline was defined as post-dose weekly average value minus Baseline value.

NRS is a 11-point tool ranging from 0 (absent) to 10 (worst imaginable) to assess the severity of 11 disease-related signs and symptoms including itching, discoloration, bleeding, oozing, cracking, scaling, flaking, dry/rough, painful, burning, and stinging. Participants were asked to complete the self-administered sign and symptom severity diary containing NRS using a recall period of the past 24 hours. Question 1 of the diary was used to assess itch. Percentage of participants who achieved a minimum 3-point improvement in itch/pruritus (NRS) from Baseline to each study visit were measured. Baseline was defined as the latest assessment prior to first dose. Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles).

The EASI scoring system is a standard clinical tool for assessing the severity of AD that takes into account the overall severity of erythema, infiltration/papulation, excoriation, and lichenification, as well as the extent of BSA affected with AD. These 4 clinical signs were graded on a 4-point scale (0 [absent] to 3 [severe]) for each of the 4 specified body regions (head and neck, upper extremities, lower extremities, and trunk). Body area involvement ranged from 0 (0%) to 6 (90-100%). Total EASI score was calculated as a sum of scores of all 4 specified body region. Range for EASI total score is 0 (absent) to 72 (severe). Baseline was defined as the latest assessment prior to first dose and change from Baseline was defined as post dose visit value minus Baseline value. Mean change from Baseline was presented in the form of mean and SD. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

The EASI scoring system is a standard clinical tool for assessing the severity of AD that takes into account the overall severity of erythema, infiltration/papulation, excoriation, and lichenification, as well as the extent of BSA affected with AD. These 4 clinical signs were graded on a 4-point scale (0 [absent] to 3 [severe]) for each of the 4 specified body regions (head and neck, upper extremities, lower extremities, and trunk). Body area involvement ranged from 0 (0%) to 6 (90-100%). Total EASI score was calculated as a sum of scores of all 4 specified body region. Range for EASI total score is 0 (absent) to 72 (severe). Baseline was defined as the latest assessment prior to first dose and change from Baseline was defined as post dose visit value minus Baseline value. Mean percent change from Baseline was presented in the form of mean and SD. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

The IGA is a clinical tool for assessing the current state/severity of a participant's AD. It is a static 5-point morphological assessment of overall disease severity, as determined by the investigator, using the clinical characteristics of erythema, infiltration, papulation, oozing, and crusting as guidelines. IGA is made without reference to previous scores. The percentage of participants with a minimum 2-grade improvement in IGA score from Baseline at Week 1, Week 2, Week 4, Week 8, Week 12, Week 14 (follow up 1), Week 16 (follow up 2) and early withdrawal (EW) visit was presented in the form of mean and SD. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

The IGA is a clinical tool for assessing the current state/severity of a participant's AD. It is a static 5-point morphological assessment of overall disease severity, as determined by the investigator, using the clinical characteristics of erythema, infiltration, papulation, oozing, and crusting as guidelines. IGA is made without reference to previous scores. The percentage of participants with an IGA score of 0 or 1 at Week 1, Week 2, Week 4, Week 8, Week 12, Week 14 (follow up 1), Week 16 (follow up 2) and EW visit was presented in the form of mean and SD. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

The EASI scoring system is a standard clinical tool for assessing the severity of AD that takes into account the overall severity of erythema, infiltration/papulation, excoriation, and lichenification, as well as the extent of BSA affected with AD. These 4 clinical signs were graded on a 4-point scale for each of the 4 specified body regions (head and neck, upper extremities, lower extremities, and trunk). Percentage of participants with >=50 percent improvement in EASI score from Baseline to Week 1, Week 2, Week 4, Week 8, Week 12, Week 14 (follow up 1), Week 16 (follow up 2) and EW were presented and statistical analysis was performed using a repeated measures factorial logistic regression model. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

The EASI scoring system is a standard clinical tool for assessing the severity of AD that takes into account the overall severity of erythema, infiltration/papulation, excoriation, and lichenification, as well as the extent of BSA affected with AD. These 4 clinical signs were graded on a 4-point scale for each of the 4 specified body regions (head and neck, upper extremities, lower extremities, and trunk). Percentage of participants with >=75 percent improvement in EASI score from Baseline to Week 1, Week 2, Week 4, Week 8, Week 12, Week 14 (follow up 1), Week 16 (follow up 2) and EW were presented and statistical analysis was performed using a repeated measures factorial logistic regression model. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

A target lesion of at least 3 centimeter square (cm^2) was selected at Baseline. The severity of the following signs: erythema, induration/papulation, lichenification, oozing/crusting, and scaling was assessed on a 4-point scale ranging from 0 (absent) to 3 (severe), with higher values indicating greater severity of symptoms. TSS (maximum score 15) was calculated based on these signs. Mean change from Baseline in TSS at Week 1, Week 2, Week 4, Week 8, Week 12, Week 14 (follow up 1), Week 16 (follow up 2) and EW visit was presented using mean and SD. Baseline value was defined as the latest assessment prior to first dose and change from Baseline was defined as post dose visit value minus Baseline value. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

A target lesion of at least 3 cm^2 was selected at Baseline. The severity of the following signs: erythema, induration/papulation, lichenification, oozing/crusting, and scaling was assessed on a 4-point scale ranging from 0 (absent) to 3 (severe) , with higher values indicating greater severity of symptoms. TSS (maximum score 15) was calculated based on these signs. Mean percent change from Baseline in TSS at Week 1, Week 2, Week 4, Week 8, Week 12, Week 14 (follow up 1), Week 16 (follow up 2) and EW visit was presented using mean and SD. Baseline value was defined as the latest assessment prior to first dose and change from Baseline was defined as post dose visit value minus Baseline value. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

The severity of the following signs: erythema, induration/papulation, lichenification, oozing/crusting, and scaling was assessed on a 4-point scale ranging from 0 (absent) to 3 (severe) and TSS (maximum score 15) was calculated based on these signs. Mean change from Baseline in individual signs of TSS was presented using mean and SD. Baseline value was defined as the latest assessment prior to first dose and change from Baseline was defined as post dose visit value minus Baseline value. If the participant had more than 3 missing days during the week, then the weekly average was not calculated and treated as missing data and excluded from the analysis. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

The severity of the following signs: erythema, induration/papulation, lichenification, oozing/crusting, and scaling was assessed on a 4-point scale ranging from 0 (absent) to 3 (severe) and TSS (maximum score 15) was calculated based on these signs. Mean percent change from Baseline in individual signs of TSS was presented using mean and SD. Baseline value was defined as the latest assessment prior to first dose and change from Baseline was defined as post dose visit value minus Baseline value. NA indicates that data were not available. If the participant had more than 3 missing days during the week, then the weekly average was not calculated and treated as missing data and excluded from the analysis. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

The extent of BSA affected by AD is a general indicator of disease severity and the assessment of BSA with AD was performed separately for four body surface regions: the head (h), the upper extremities (u), the trunk (t) and the lower extremities (l), corresponding to 10, 20, 30, and 40 percent of the total body area, respectively. Mean change from Baseline in percent BSA was presented using mean and SD at Week 1, Week 2, Week 4, Week 8, Week 12, Week 14 (follow up 1), Week 16 (follow up 2) and EW visit. Baseline was defined as the latest assessment prior to first dose and change from Baseline was defined as post dose visit value minus Baseline value. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

The IGA is a clinical tool for assessing the current state/severity of a participant's AD. It is a static 5-point morphological assessment of overall disease severity, as determined by the investigator, using the clinical characteristics of erythema, infiltration, papulation, oozing, and crusting as guidelines. IGA is made without reference to previous scores. Score ranges from 0 (clear) to 4 (severe). Higher values represent a severe disease. Mean change from Baseline in IGA score was presented using mean and SD at Week 1, Week 2, Week 4, Week 8, Week 12, Week 14 (follow up 1), Week 16 (follow up 2) and EW visit. Baseline was defined as the latest assessment prior to first dose and change from Baseline was defined as post dose visit value minus Baseline value. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

The IGA is a clinical tool for assessing the current state/severity of a participant's AD. It is a static 5-point morphological assessment of overall disease severity, as determined by the investigator, using the clinical characteristics of erythema, infiltration, papulation, oozing, and crusting as guidelines. IGA is made without reference to previous scores. The percentage of participants who have an IGA score of clear or almost clear and a minimum 2 grade improvement from Baseline to each study visit in IGA score was presented. The statistical analysis was performed using a repeated measures factorial logistic regression model with covariates for dose, frequency of administration, and study day as well as a dose by frequency interaction term. The analysis was performed on ITT Population which comprised of all randomized participants. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category title).

An AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability, is a congenital anomaly/ birth effect, other situations and is associated with liver injury or impaired liver function. Treatment emergent AEs (TEAE) is defined as AE occurred on or after study treatment start date and on or before last visit. Number of participants with AEs and serious TEAEs were presented. The analysis was performed on Safety population which comprised of all participants who receive at least one dose of study treatment.

Participants were asked to use a 5-point tolerability scale from 0 (none) to 4 (severe) to assess the presence and degree of burning/stinging and itching at the application sites that has generally been experienced following application of the study treatment. The score represented an 'average' across all application sites. A score of 3 or 4 was reported as an AE. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

Blood samples were collected to evaluate change from Baseline in albumin and total protein values at Baseline throughout the 12 weeks of study treatment and follow up visit 1 at Week 14. Baseline values were taken at Day 1 and change from Baseline was defined as post-dose visit value minus Baseline value. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles). Mean and SD were measured.

Blood samples were collected to evaluate change from Baseline in Alk.phosph., ALT, AST and GGT values at Baseline throughout the 12 weeks of study treatment and follow up visit 1 at Week 14. Baseline values were taken at Day 1 and change from Baseline was defined as post-dose visit value minus Baseline value. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles). Mean and SD were measured.

Blood samples were collected to evaluate change from Baseline in direct and total bilirubin, creatinine and urate values at Baseline throughout the 12 weeks of study treatment and follow up visit 1 at Week 14. Baseline values were taken at Day 1 and change from Baseline was defined as post-dose visit value minus Baseline value. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles). Mean and SD were measured.

Blood samples were collected to evaluate change from Baseline in calcium, chloride, CO2, glucose, potassium, sodium and BUN values at Baseline throughout the 12 weeks of study treatment and follow up visit 1 at Week 14. Baseline values were taken at Day 1 and change from Baseline was defined as post-dose visit value minus Baseline value. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles). Mean and SD were measured.

Blood samples were collected from participants for evaluation of clinical chemistry parameters by Potential Clinical Importance Criteria from Baseline to Week 14, EW and any visit post-screen. The vital signs included alk.phosph., ALT, AST, bilirubin, calcium, CO2, creatinine, glucose and potassium. Baseline was defined as the latest assessment prior to the first dose. Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles).

Blood samples were collected to evaluate change from Baseline in basophils, eosinophils, lymphocytes, monocytes, neutrophils, platelet and leukocytes and values at Baseline throughout the 12 weeks of study treatment and follow up visit 1 at Week 14. Baseline values were taken at Day 1 and change from Baseline was defined as post-dose visit value minus Baseline value. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles). Mean and SD were measured.

Blood samples were collected to evaluate change from Baseline in hematocrit and values at Baseline throughout the 12 weeks of study treatment and follow up visit 1 at Week 14. Baseline values were taken at Day 1 and change from Baseline was defined as post-dose visit value minus Baseline value. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles). Mean and SD were measured.

Blood samples were collected to evaluate change from Baseline in hemoglobin and MCHC and values at Baseline throughout the 12 weeks of study treatment and follow up visit 1 at Week 14. Baseline values were taken at Day 1 and change from Baseline was defined as post-dose visit value minus Baseline value. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles). Mean and SD were measured.

Blood samples were collected to evaluate change from Baseline in MCH and values at Baseline throughout the 12 weeks of study treatment and follow up visit 1 at Week 14. Baseline values were taken at Day 1 and change from Baseline was defined as post-dose visit value minus Baseline value. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles). Mean and SD were measured.

Blood samples were collected to evaluate change from Baseline in MCV and values at Baseline throughout the 12 weeks of study treatment and follow up visit 1 at Week 14. Baseline values were taken at Day 1 and change from Baseline was defined as post-dose visit value minus Baseline value. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles). Mean and SD were measured.

Blood samples were collected to evaluate change from Baseline in erythrocytes and values at Baseline throughout the 12 weeks of study treatment and follow up visit 1 at Week 14. Baseline values were taken at Day 1 and change from Baseline was defined as post-dose visit value minus Baseline value. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles). Mean and SD were measured.

Blood samples were collected from participants for evaluation of hematology parameters by Potential Clinical Importance Criteria from Baseline to Week 14, EW and any visit post-screen. The vital signs included hematocrit, hemoglobin, lymphocytes, neutrophils, platelet and leukocytes. Baseline was defined as the latest assessment prior to the first dose. Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles).

Blood samples were collected to evaluate change from Baseline in total T lympho, B lympho, T and B NK cells and (Foxp3) values at Baseline throughout the 12 weeks of study treatment. The immunophenotyping parameters included cluster of differentiation (CD)19, CD3, CD3+CD8+, CD3+CD4+, CD16+CD56+, CD3+CD4+CD25+CD127, CD3+CD4+foxP3+CD25+CD127 and T and NK lympho. CD3, CD3+CD8+ and CD3+CD4+ were also evaluated by using treg flow cytometry (cyto). Baseline was defined as the latest assessment prior to the first dose. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles). Mean and SD were measured.

Blood samples were collected from participants for evaluation of immunophenotyping parameters by Potential Clinical Importance Criteria at Baseline, Week 4, Week 8, Week 12 nd any visit post-screen. The immunophenotyping parameters included CD 19, CD3, CD3+CD8+, CD3+CD4+, CD16+CD56+, CD3+CD4+CD25+CD127, CD3+CD4+foxP3+CD25+CD127 and T and NK lympho. CD3, CD3+CD8+ and CD3+CD4+ were also evaluated by using treg flow cyto. Baseline was defined as the latest assessment prior to the first dose. Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles).

Blood samples were collected to evaluate change from Baseline in IgA, IgG, IM values at Baseline throughout the 12 weeks of study treatment. Baseline values were taken at Day 1 and change from Baseline was defined as post-dose visit value minus Baseline value. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles). Mean and SD were measured.

Blood samples were collected from participants for evaluation of immunoglobulin data outside the reference range at Baseline, Week 4, Week 8, Week 12 and any visit post-screen. The immunoglobulin parameters included IgA, IgG and Ig M. Baseline was defined as the latest assessment prior to the first dose. Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles).

SBP and DBP were measured from Baseline up to follow up Visit 1 at Week 14 in semi-supine position after at least 5 minutes of rest. The Baseline value was taken at Day 1 and change from Baseline was defined as post dose visit value minus Baseline value. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles). Mean and SD were measured.

Pulse rate were measured from Baseline up to follow up Visit 1 at Week 14 in semi-supine position after at least 5 minutes of rest. The Baseline value was taken at Day 1 and change from Baseline was defined as post dose visit value minus Baseline value. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles). Mean and SD were measured.

Temperature were measured from Baseline up to follow up Visit 1 at Week 14 in semi-supine position after at least 5 minutes of rest. The Baseline value was taken at Day 1 and change from Baseline was defined as post dose visit value minus Baseline value. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles). Mean and SD were measured.

Blood samples were collected from participants for evaluation of vital signs by Potential Clinical Importance Criteria from Baseline to Week 14, EW and any visit post-screen. The vital signs included SBP, DBP and pulse rate. Baseline was defined as the latest assessment prior to the first dose. Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles).

Single measurements of 12-lead ECGs were obtained at Baseline , Week 1, Week 12, Week 14 (follow up 1), EW and at any time post-screen using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and corrected QT (QTc). Baseline was defined as the latest assessment prior to the first dose. For multiple ECGs at one visit, or "Any visit post-screen", a participant was categorized as "Abnormal" if >=1 assessment was abnormal. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).