A Study to Evaluate Pharmacokinetic (PK), Safety and Tolerability of GSK2894512 in Healthy Adult Subjects

Phase 1

Withdrawn

• Conditions: Psoriasis
• Interventions: Drug: GSK2894512 1% CREAM; Drug: GSK2894512 MATCHING VEHICLE CREAM

• Registration Number: NCT03201978
• Lead Sponsor: GlaxoSmithKline

Brief Summary

GSK2894512 (trans-isomer) is a fully synthetic, non-steroidal anti-inflammatory agent. This study is being conducted to evaluate the PK, safety and tolerability of GSK2894512 cream, 1 percent administered topically to healthy adult subjects. PK parameters obtained in this study will be used to support the design of future maximum use PK (MUPK) studies in subjects with atopic dermatitis (AD) and plaque psoriasis or psoriasis (PSO). This is a phase 1, randomized, double-blind, vehicle-controlled, 3-period, sequential, inpatient study consists of a Screening visit, 3 treatment periods and a follow-up visit. GSK2894512 cream, 1 percent (or matching vehicle) will be administered sequentially in the treatment periods. Period 1 will include once daily repeated topical applications on approximately 5000 centimeter (cm) \^2 intact non-occluded skin area for 21 days. Period 2 will include once daily repeated topical applications on approximately 5000 cm\^2 intact occluded skin area for 21 days. Period 3 will include a single topical application on up to 400 cm\^2 gently taped-stripped skin area. Each treatment regimen will be followed by washout period for approximately 21 days, except for Treatment Period 3. Approximately 26 healthy adult subjects will be enrolled in to the study. Total duration of participation in this study will be approximately 18 weeks.

Detailed Description

Not available

Basic Information
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Recruitment & Eligibility
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Study & Design

Study Timeline

• Study First Submitted: 2017-06-27
• Study First Submitted QC: 2017-06-27
• Study First Posted: 2017-06-28
• Status Verified: 2017-11
• Last Update Submitted: 2017-11-27
• Last Update Posted: 2017-11-29
• Study Start: 2017-12-14
• Primary Completion: 2018-05-15
• Study Completion: 2018-05-15

Recruitment & Eligibility

• Status: WITHDRAWN
• Sex: All
• Target Recruitment: Not specified

Inclusion Criteria

Not provided

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Exclusion Criteria

• A history of ongoing serious illness or medical, physical, or psychiatric condition(s) that, in the investigator's opinion, may interfere with the subject's completion of the study.
• A history or presence of skin disorders (e.g., irritant contact dermatitis); history or presence of hypertrophic scarring tissue or keloid formation in scars or needle puncture sites; a tattoo, body piercing or branding located on the study medication application site; excessive body hair that in the Investigator's opinion, may interfere with the areas designated for study medication application.
• Presence or history of AD or PSO.
• Presence of erosions, lacerations, abrasions, dermatitis or any other lesion on the lower legs that could increase absorption of GSK2894512.
• Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
• Subject has a history of hyperhidrosis.
• Subject had a major surgery within 8 weeks prior to Baseline (Day -1) or has a major surgery planned during the study.
• Known hypersensitivity to GSK2894512 or excipients of the study treatments, or a history of drug or other allergy that, in the opinion of the investigator, contraindicates participation.
• Abnormal aspartate aminotransferase (AST), alanine aminotransferase (ALT) or bilirubin values at screening
• Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C virus (HCV) antibody and human immunodeficiency virus (HIV) antibody test results at screening.
• Presence of out-of-range cardiac interval (PR <110 millisecond (msec), PR >220 msec, QRS <60msec, QRS >119msec and QTcF > 450msec) on the screening ECG (average of the triplicate ECG) or other clinically significant ECG abnormalities.
• Any history of latent or active tuberculosis (TB) and/or prophylaxis for tuberculosis according to the TB Medical History screening questionnaire.
• Subjects who took an investigational product (in another clinical trial) in the previous 30 days before day 1 of this study.
• Use of any medicated topical product on the same areas as study medication applications within 2 weeks prior to admission to clinical research center (CRC) on Day -1 and throughout each inpatient treatment period.
• Use of any topical products (apart from medicated topical products), except soap and gentle cleansers (example, moisturizers), on the same areas as study medication applications within 2 days prior to admission to CRC on Day -1 and throughout each inpatient treatment period.
• Positive findings of urine drug screen (example, amphetamine, barbiturates, benzodiazepines, cocaine, cannabinoids, opiates, and phencyclidine [PCP]).
• Maintenance therapy with any drug or significant history of drug dependency or alcohol abuse (>3 units of alcohol per day, intake of excessive alcohol, acute or chronic)
• Subjects who have already participated in this clinical study.
• Subjects who donated 50 milliliter (mL) or more of blood in the previous 30 days before day 1 of this study. Donation of 500 mL or more of blood (Canadian Blood Services, Hema-Quebec, clinical studies, etc.) in the previous 60 days before Day 1 of this study.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
GSK2894512 cream group	GSK2894512 1% CREAM	Subjects will receive once daily topical repeated application on approximately 5000 cm\^2 intact non-occluded skin for 21 days in period 1 followed by once daily on 5000 cm\^2 intact occluded skin for 21 days in period 2 (after approximately 21 days of washout period), followed by a single topical application on up to 400 cm\^2 gently tape stripped skin area in period 3.
Vehicle cream group	GSK2894512 MATCHING VEHICLE CREAM	Subjects will receive once daily topical repeated application on approximately 5000 cm\^2 intact non-occluded skin for 21 days in period 1 followed by once daily on 5000 cm\^2 intact occluded skin for 21 days in period 2 (after approximately 21 days of washout period), followed by a single topical application on up to 400 cm\^2 gently tape stripped skin area in period 3.

Primary Outcome Measures

Name	Time	Method
Area under the plasma concentration-time curve from time zero to the end of the dosing interval (AUC [0-tau]) of GSK2894512	Days 1, 7, 14, 21: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16 hours; Days 2, 3, 8, 9, 15, 16, 22, 23: Pre-dose, in Period-1 and 2. Period-3: Day 1: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16, 24, 48 hours	Blood sample will be collected at the indicated time points to evaluate PK profile of GSK2894512.
Plasma concentrations of GSK2894512 (trans-isomer)	Days 1, 7, 14, 21: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16 hours; Days 2, 3, 8, 9, 15, 16, 22, 23: Pre-dose, in Period-1 and 2. Period-3: Day 1: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16, 24, 48 hours	Blood samples will be collected at the indicated time points to evaluate plasma concentration of GSK2894512 (trans-isomer).
Area under the plasma concentration-time curve from time zero to the last measurable concentration (AUC [0-t) of GSK2894512	Days 1, 7, 14, 21: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16 hours; Days 2, 3, 8, 9, 15, 16, 22, 23: Pre-dose, in Period-1 and 2. Period-3: Day 1: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16, 24, 48 hours	Blood sample will be collected at the indicated time points to evaluate PK profile of GSK2894512.
Maximum observed serum concentration (Cmax) of GSK2894512	Days 1, 7, 14, 21: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16 hours; Days 2, 3, 8, 9, 15, 16, 22, 23: Pre-dose, in Period-1 and 2. Period-3: Day 1: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16, 24, 48 hours	Blood sample will be collected at the indicated time points to evaluate PK profile of GSK2894512.
Time of maximum concentration observed (tmax) of GSK2894512	Days 1, 7, 14, 21: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16 hours; Days 2, 3, 8, 9, 15, 16, 22, 23: Pre-dose, in Period-1 and 2. Period-3: Day 1: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16, 24, 48 hours	Blood sample will be collected at the indicated time points to evaluate PK profile of GSK2894512.
Apparent terminal phase half life (t1/2) of GSK2894512	Days 1, 7, 14, 21: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16 hours; Days 2, 3, 8, 9, 15, 16, 22, 23: Pre-dose, in Period-1 and 2. Period-3: Day 1: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16, 24, 48 hours	Blood sample will be collected at the indicated time points to evaluate PK profile of GSK2894512.
Trough concentration at the end of the dosing interval (Ctau) of GSK2894512	Days 1, 7, 14, 21: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16 hours; Days 2, 3, 8, 9, 15, 16, 22, 23: Pre-dose, in Period-1 and 2. Period-3: Day 1: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16, 24, 48 hours	Blood sample will be collected at the indicated time points to evaluate PK profile of GSK2894512.
Accumulation ratio (Ro) of GSK2894512	Days 1, 7, 14, 21: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16 hours; Days 2, 3, 8, 9, 15, 16, 22, 23: Pre-dose, in Period-1 and 2. Period-3: Day 1: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16, 24, 48 hours	Blood sample will be collected at the indicated time points to evaluate PK profile of GSK2894512.

Secondary Outcome Measures

Name	Time	Method
Number of subjects with any adverse events (AEs) and serious AEs (SAEs)	Up to 14 weeks	An AE is any untoward medical occurrence in a clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is defined as any untoward medical occurrence that: results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, other important medical events judged by physician that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the subject or may require medical or surgical intervention to prevent one of the other outcomes listed in this definition.
Number of subjects with abnormal vital sign findings	Up to 13 weeks	Vital sign parameters including systolic and diastolic blood pressure, heart rate (HR) and body temperature will be evaluated. Vital sign measurements will be preceded by at least 5 minutes of rest (supine or seated) for the subject in a quiet setting.
Number of subjects with abnormal electrocardiogram (ECG) findings	Up to 13 weeks	Triplicate 12-lead ECG will be obtained using an ECG machine that automatically calculates the HR and measures PR, QRS, QT, and QT interval corrected for heart rate according to Fridericia's formula (QTcF) intervals on Days -1, 3, 9, 16 and 23 in Period-1 and 2; and on Days -1 and 3 in Period-3.
Number of subjects with abnormal findings in digital holter monitoring	Up to 13 weeks	Continuous digital 12-lead ECGs will be recorded using 12-lead Holter/12-lead ECG recorder from 1 hour prior to dosing to 24 hours after dosing on Days 1, 2, 7, 8, 14, 15, 21 and 22 in period-1 and 2; and on Days 1 and 2 in Period-3.
Number of subjects with abnormal findings in physical examination	Up to 13 weeks	Complete physical examination will include review of head and neck, heart, lungs, abdomen, skin, general appearance, height and weight.
Number of subjects with abnormal clinical laboratory findings	Up to 13 weeks	Serum chemistry, hematological and urine analysis parameters will be evaluated.
Assessment of degree of local irritation as a measure of local tolerability	Up to 14 weeks	Dermal reactions like erythema, edema, papules at test sites will be visually assessed. Degree of local irritation will be assessed to determine tolerability of topical application of GSK2894512 cream. if a subject is found to meet a dermal response graded 4 (definite edema) and above indicated in Erythema and Dermal Response Grading Scale, the study medication applications will be discontinued. Grade \<4 will be recorded as an AE.