Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Study of Single and Repeated Doses of Topical GSK1278863

Phase 1

Completed

Conditions: Wound Healing

Interventions: Drug: GSK1278863
Drug: Placebo

Registration Number: NCT01831804

Lead Sponsor: GlaxoSmithKline

Brief Summary: This is a randomized, placebo-controlled, single-blind (subjects and investigators will be blinded, GSK internal personnel will not be blinded), parallel-group, two part (Part A, Part B) trial in healthy volunteers and subjects with diabetic foot ulcers. Part A is designed to evaluate single applications of GSK1278863 in one cohort of healthy volunteers (intact skin) and approximately 3 cohorts of diabetic subjects. Part B is designed to evaluate first single, and then repeat applications of GSK1278863 in diabetics, both in the clinic and by subjects at home. Part B will include approximately 3 cohorts in which the concentration of drug applied will be determined by pharmacokinetic data from Part A and earlier cohorts in Part B.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 65

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Cohort 1 Part A	GSK1278863	Healthy subjects in this arm will receive single applications of GSK1278863 or placebo (with 6:2 ratio) on intact skin in two escalating dosing periods each separated by 10 days. The first application will be with a single dose of 0.3 mg and second application will be single dose of 3 mg.
Cohort 1 Part A	Placebo	Healthy subjects in this arm will receive single applications of GSK1278863 or placebo (with 6:2 ratio) on intact skin in two escalating dosing periods each separated by 10 days. The first application will be with a single dose of 0.3 mg and second application will be single dose of 3 mg.
Cohort 2 Part A	GSK1278863	Subjects with diabetic foot ulcer (DFU) will receive a single application of GSK1278863 or placebo (with 6:2 ratio) in two dosing periods separated by 10 days. The first application will be made on intact skin and second application directly on DFU. Dose will be based on wound area and review from previous cohort data.
Cohort 2 Part A	Placebo	Subjects with diabetic foot ulcer (DFU) will receive a single application of GSK1278863 or placebo (with 6:2 ratio) in two dosing periods separated by 10 days. The first application will be made on intact skin and second application directly on DFU. Dose will be based on wound area and review from previous cohort data.
Cohort 3 Part A	GSK1278863	Subjects with DFU will receive single application of GSK1278863 or placebo directly on DFU. Dose will be based on wound area and review from previous cohort data.
Cohort 4 Part A	Placebo	Subjects with DFU will receive a single application of GSK1278863 or placebo (with 6:2 ratio) in two dosing periods separated by 10 days. The first application will be made on DFU and second application on intact skin. Dose will be based on wound area and review from previous cohort data.
Cohort 5 Part B	Placebo	Subjects with DFU will receive Standard of care (SOC) up to 15 days and then will be randomized to one of the three arms: GSK1278863 + SOC, or SOC only, or placebo + SOC with ratio of 12:2:2. Doses for the cohorts in Part B will be determined from safety, tolerability and PK data from Part A. subjects will first be given a single application of GSK1278863 or placebo at the dose chosen for that cohort, followed by a 7-day washout period, and then repeat applications for 14 days, starting on Day 8.
Cohort 3 Part A	Placebo	Subjects with DFU will receive single application of GSK1278863 or placebo directly on DFU. Dose will be based on wound area and review from previous cohort data.
Cohort 6 Part B	Placebo	Subjects with DFU will receive Standard of care (SOC) up to 15 days and then will be randomized to one of the three arms: GSK1278863 + SOC, or SOC only, or placebo + SOC with ratio of 12:2:2. Doses for the cohorts in Part B will be determined from safety, tolerability and PK data from Part A. subjects will first be given a single application of GSK1278863 or placebo at the dose chosen for that cohort, followed by a 7-day washout period, and then repeat applications for 14 days, starting on Day 8.
Cohort 7 Part B	Placebo	Subjects with DFU will receive Standard of care (SOC) up to 15 days and then will be randomized to one of the three arms: GSK1278863 + SOC, or SOC only, or placebo + SOC with ratio of 12:2:2. Doses for the cohorts in Part B will be determined from safety, tolerability and PK data from Part A. subjects will first be given a single application of GSK1278863 or placebo at the dose chosen for that cohort, followed by a 7-day washout period, and then repeat applications for 14 days, starting on Day 8.
Cohort 4 Part A	GSK1278863	Subjects with DFU will receive a single application of GSK1278863 or placebo (with 6:2 ratio) in two dosing periods separated by 10 days. The first application will be made on DFU and second application on intact skin. Dose will be based on wound area and review from previous cohort data.
Cohort 5 Part B	GSK1278863	Subjects with DFU will receive Standard of care (SOC) up to 15 days and then will be randomized to one of the three arms: GSK1278863 + SOC, or SOC only, or placebo + SOC with ratio of 12:2:2. Doses for the cohorts in Part B will be determined from safety, tolerability and PK data from Part A. subjects will first be given a single application of GSK1278863 or placebo at the dose chosen for that cohort, followed by a 7-day washout period, and then repeat applications for 14 days, starting on Day 8.
Cohort 7 Part B	GSK1278863	Subjects with DFU will receive Standard of care (SOC) up to 15 days and then will be randomized to one of the three arms: GSK1278863 + SOC, or SOC only, or placebo + SOC with ratio of 12:2:2. Doses for the cohorts in Part B will be determined from safety, tolerability and PK data from Part A. subjects will first be given a single application of GSK1278863 or placebo at the dose chosen for that cohort, followed by a 7-day washout period, and then repeat applications for 14 days, starting on Day 8.
Cohort 6 Part B	GSK1278863	Subjects with DFU will receive Standard of care (SOC) up to 15 days and then will be randomized to one of the three arms: GSK1278863 + SOC, or SOC only, or placebo + SOC with ratio of 12:2:2. Doses for the cohorts in Part B will be determined from safety, tolerability and PK data from Part A. subjects will first be given a single application of GSK1278863 or placebo at the dose chosen for that cohort, followed by a 7-day washout period, and then repeat applications for 14 days, starting on Day 8.

Primary Outcome Measures

Name	Time	Method
Area Under the Concentration-time Curve From Time Zero (Pre-dose) Extrapolated to Infinite Time [AUC(0-inf)] of GSK1278863 (Part A)	Pre-dose and 0.25, 0.5, 1, 2, 4, 8, 12, 24, 48 and 72hrs post-dose	The pharmacokinetic parameters were calculated by standard non-compartmental analysis according to current working practices and using WinNonlin Version 5.2 or higher. All calculations of non-compartmental parameters were based on actual sampling times. AUC (0-inf) could not be determined as data was below the limit of quantification.
Area Under the Concentration-time Curve From Time Zero (Pre-dose) to Last Time of Quantifiable Concentration Within a Participant Across All Treatments [AUC(0-t)] of GSK1278863 (Part A)	Pre-dose and 0.25, 0.5, 1, 2, 4, 8, 12, 24, 48 and 72 hrs post-dose	The pharmacokinetic parameters were calculated by standard non-compartmental analysis according to current working practices and using WinNonlin Version 5.2 or higher. All calculations of non-compartmental parameters were based on actual sampling times. AUC (0-t) could not be determined as data was below the limit of quantification.
Number of Participants With Abnormal Nurse/Physician Observation (Part B)	Up to a maximum of 53 days (Start of study treatment through final follow up 2 [28-32 days post last dose])	A brief physical assessments of the skin, lungs, cardiovascular system, and abdomen (liver and spleen) were planned to be performed by qualified licensed, medical professional (i.e., physician, physician assistant, or nurse practitioner) but was not performed. Since data was not collected, no analysis was performed.
AUC(0-inf) of GSK1278863 (Part B)	Pre-dose and 2 hrs on Day 1 and 7; pre-dose, 1, 2,4, 8, 12 and 24 hrs post-dose on Day 14	The pharmacokinetic parameters were calculated by standard non-compartmental analysis according to current working practices and using WinNonlin Version 5.2 or higher. All calculations of non-compartmental parameters were based on actual sampling times. AUC (0-inf) could not be determined as data was below the limit of quantification.
Number of Participants With AEs and SAEs Following Repeat Dose Administration (Part B)	Up to a maximum of 53 days (Start of study treatment through final follow up 2 [28-32 days post last dose])	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. An SAE is any untoward medical occurrence that, at any dose: 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; or is associated with liver injury and impaired liver function.
Number of Participants With Clinically Significant 12-lead ECG Measurement Following Repeat Dose Administrations (Part B)	Up to a maximum of 53 days (Start of study treatment through final follow up 2 [28-32 days post last dose])	ECG measurements were taken with the participants in supine position for at least 5 minutes. The number of participants with clinically significant abnormal ECG measurement following single dose administration for worst case post-Baseline visit has been presented.
Number of Participants With Clinical Chemistry Values Outside the Clinical Concern Range (Part A)	Day 1 (pre-dose and 48 hours) in period 1; Day 1 (48 hours) in period 2	Chemistry parameters assessed were: Blood urea nitrogen (BUN), creatinine, fasting glucose, sodium, creatine phosphokinase (CPK), potassium, chloride, total carbon dioxide (CO2), calcium, glycosylated hemoglobin (HbA1C), Aspartate aminotransferase (AST), Alanine aminotransferase (ALT), Gamma glutamyltransferase (GGT), Alkaline phosphatase (ALP), High sensitivity C-reactive protein (hsCRP), total and direct bilirubin, uric acid, albumin and total protein. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles). When a high or low value was reported, all values are presented for that time point and parameter.
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) Following Single Dose Administration (Part A)	Up to a maximum of 75 days (Start of study treatment through final follow up 2 [28-32 days post last dose])	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. An SAE is any untoward medical occurrence that, at any dose: 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; or is associated with liver injury and impaired liver function.
Number of Participants With Clinically Significant 12-lead Electrocardiograms (ECGs) Measurement Following Single Dose Administrations (Part A)	Up to a maximum of 75 days (Start of study treatment through final follow up 2 [28-32 days post last dose])	ECG measurements were taken with the participants in supine position for at least 5 minutes. The number of participants with clinically significant abnormal ECG measurement following single dose administration for worst case post-Baseline visit has been presented.
Number of Participants With Vital Sign Data Outside Clinical Concern Range Following Single Dose Administration (Part A)	Day 1 (pre-dose and 48 hours) of Periods 1 and 2	Vital sign measurements included systolic blood pressure (SBP) and diastolic blood pressure (DBP). Vital signs were measured after the participants rested in a supine or semi-supine position for 5 minutes prior to the procedure. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles). When a high or low value was reported, all values are presented for that time point and parameter.
Number of Participants With Clinical Chemistry Values Outside the Clinical Concern Range (Part B)	Days 1 and 7 (pre-dose) and Day 14 (24 hours)	Chemistry parameters assessed were: Blood urea nitrogen (BUN), creatinine, fasting glucose, sodium, creatine phosphokinase (CPK), potassium, chloride, total carbon dioxide (CO2), calcium, glycosylated hemoglobin (HbA1C), Aspartate aminotransferase (AST), Alanine aminotransferase (ALT), Gamma glutamyltransferase (GGT), Alkaline phosphatase (ALP), High sensitivity C-reactive protein (hsCRP), total and direct bilirubin, uric acid, albumin and total protein. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles). When a high or low value was reported, all values are presented for that time point and parameter.
Maximum Observed Concentration (Cmax) of GSK1278863 (Part A)	Pre-dose and 0.25, 0.5, 1, 2, 4, 8, 12, 24, 48 and 72 hrs post-dose	The pharmacokinetic (PK) parameters were calculated by standard non-compartmental analysis according to current working practices and using WinNonlin Version 5.2 or higher. All calculations of non-compartmental parameters were based on actual sampling times. Cmax could not be determined as data was below the limit of quantification.
Cmax of GSK1278863 (Part B)	Pre-dose and 2 hrs on Day 1 and 7; pre-dose, 1, 2,4, 8, 12 and 24 hrs post-dose on Day 14	The pharmacokinetic parameters were calculated by standard non-compartmental analysis according to current working practices and using WinNonlin Version 5.2 or higher. All calculations of non-compartmental parameters were based on actual sampling times. Cmax could not be determined as data was below the limit of quantification.
Time of Occurrence of Cmax (Tmax) of GSK1278863 (Part A)	Pre-dose and 0.25, 0.5, 1, 2, 4, 8, 12, 24, 48 and 72hrs post-dose	The pharmacokinetic parameters were calculated by standard non-compartmental analysis according to current working practices and using WinNonlin Version 5.2 or higher. All calculations of non-compartmental parameters were based on actual sampling times. Tmax could not be determined as data was below the limit of quantification.
Apparent Terminal Elimination Half-life (t1/2) of GSK1278863 (Part A)	Pre-dose and 0.25, 0.5, 1, 2, 4, 8, 12, 24, 48 and 72hrs post-dose	The pharmacokinetic parameters were calculated by standard non-compartmental analysis according to current working practices and using WinNonlin Version 5.2 or higher. All calculations of non-compartmental parameters were based on actual sampling times. t1/2 could not be determined as data was below the limit of quantification.
Lag Time Before Observation of Drug Concentrations in Sampled Matrix (Tlag) (Part A)	Pre-dose and 0.25, 0.5, 1, 2, 4, 8, 12, 24, 48 and 72hrs post-dose	The pharmacokinetic parameters were calculated by standard non-compartmental analysis according to current working practices and using WinNonlin Version 5.2 or higher. All calculations of non-compartmental parameters were based on actual sampling times. Tlag could not be determined as data was below the limit of quantification.
Number of Participants With Vital Sign Data Outside Clinical Concern Range Following Repeat Dose Administration (Part B)	Days 1 and 7 (pre-dose), Day 14 (24 hours)	Vital sign measurements included systolic blood pressure (SBP) and diastolic blood pressure (DBP). Vital signs were measured after the participants rested in a supine or semi-supine position for 5 minutes prior to the procedure. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles). When a high or low value was reported, all values are presented for that time point and parameter.
Number of Participants With Abnormal Nurse/Physician Observation (Part A)	Up to a maximum of 75 days (Start of study treatment through final follow up 2 [28-32 days post last dose])	A brief physical assessments of the skin, lungs, cardiovascular system, and abdomen (liver and spleen) were planned to be performed by qualified licensed, medical professional (i.e., physician, physician assistant, or nurse practitioner) but was not performed.Since data was not collected, no analysis was performed.
Number of Participants With Hematology Values Outside the Clinical Concern Range (Part A)	Day 1 (pre-dose)	Hematology parameters assessed were: platelet count, red blood cell count, white blood cell count, hemoglobin, reticulocyte count, hematocrit, absolute neutrophil count (ANC), monocytes, lymphocytes, eosinophils, basophils, mean corpuscular volume, mean corpuscular hemoglobin, and mean corpuscular hemoglobin concentration. When a high or low value was reported, all values are presented for that time point and parameter.
Number of Participants With Hematology Data Outside the Clinical Concern Range (Part B)	Day 1 (pre-dose)	Hematology parameters assessed were: platelet count, red blood cell count, white blood cell count, hemoglobin, reticulocyte count, hematocrit, neutrophils, monocytes, lymphocytes, eosinophils, basophils, mean corpuscular volume, mean corpuscular hemoglobin, and mean corpuscular hemoglobin concentration. When a high or low value was reported, all values are presented for that time point and parameter.
Tmax of GSK1278863 (Part B)	Pre-dose and 2 hrs on Day 1 and 7; pre-dose, 1, 2,4, 8, 12 and 24 hrs post-dose on Day 14	The pharmacokinetic parameters were calculated by standard non-compartmental analysis according to current working practices and using WinNonlin Version 5.2 or higher. All calculations of non-compartmental parameters were based on actual sampling times. Tmax could not be determined as data was below the limit of quantification.
t1/2 of GSK1278863 (Part B)	Pre-dose and 2 hrs on Day 1 and 7; pre-dose, 1, 2,4, 8, 12 and 24 hrs post-dose on Day 14	The pharmacokinetic parameters were calculated by standard non-compartmental analysis according to current working practices and using WinNonlin Version 5.2 or higher. All calculations of non-compartmental parameters were based on actual sampling times. t1/2 could not be determined as data was below the limit of quantification.
AUC(0-t) of GSK1278863 (Part B)	Pre-dose and 2 hrs on Day 1 and 7; pre-dose, 1, 2,4, 8, 12 and 24 hrs post-dose on Day 14	The pharmacokinetic parameters were calculated by standard non-compartmental analysis according to current working practices and using WinNonlin Version 5.2 or higher. All calculations of non-compartmental parameters were based on actual sampling times. AUC (0-t) could not be determined as data was below the limit of quantification.
Lag Time Before Observation of Drug Concentrations in Sampled Matrix (Tlag) (Part B)	Pre-dose and 2 hrs on Day 1 and 7; pre-dose, 1, 2,4, 8, 12 and 24 hrs post-dose on Day 14	The pharmacokinetic parameters were calculated by standard non-compartmental analysis according to current working practices and using WinNonlin Version 5.2 or higher. All calculations of non-compartmental parameters were based on actual sampling times. Tlag could not be determined as data was below the limit of quantification.