This study is the first administration of GSK2793660 to humans and will evaluate the safety, tolerability, PK and PD of single oral ascending doses of GSK2793660, and of repeat oral doses of GSK2793660 in healthy subjects. The study will comprise two parts (Part A and Part B). Part A will consist of two cohorts of subjects, each taking part in a three-way cross over study, with ascending doses of GSK2793660 and placebo. Available safety, PK and PD data will be reviewed before each dose escalation. This will be followed by a food-effect arm in the cohort that received what is deemed to be the target clinical dose. Part B is planned to consist of up to two cohorts of subjects, each taking part in one 14 day repeat dose study period. Subjects will be dosed on Day 1 and then on Days 3-15. It is planned that two doses will be evaluated. The dose(s) to be tested will be selected based on safety, PK, and PD from Part A. The study is intended to provide sufficient confidence in the safety profile of the molecule and information on target engagement to allow progression to further studies.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
TRIPLE
Enrollment
33
Clear, colourless solution at a unit dose strength of 0.1 mg/mL, in a glass bottle
Size zero swedish orange capsule at a unit dose of 3 mg, 10 mg, 20 mg and 50 mg
Matching placebo to GSK2793660 solution
Matching placebo to GSK2793660 capsule
GSK Investigational Site
London, United Kingdom
Safety and tolerability of GSK2793660 as assessed by vital signs in Part A and Part B
Vital sign measurements will include systolic and diastolic blood pressure, pulse rate, respiratory rate and oral body temperature
Time frame: Part A: Screening (SCR), Day 1 (Pre-dose, 0.25 hours (h), 0.5 h, 1.5 h, 2 h, 3 h, 4 h, 12 h), Day 2 (24 h), Day 3 (48 h), Day 4 (72 h) in each period and at follow-up (7-14 days post last dose); Part B: SCR, Day 1 to Day 18 and at follow-up
Safety and tolerability of GSK2793660 as assessed by cardiac telemetry in Part A and Part B
Continuous cardiac telemetry will be performed in Part A and Part B of the study
Time frame: Part A: From 1 h pre-dose on Day 1 until 24 h post dose on Day 2 in each period. Part B: From 1 h prior to dosing on Day 3 until pre-dose on Day 5
Safety and tolerability of GSK2793660 as assessed by electrocardiograms (ECGs) in Part A and Part B
Cardiac safety will be assessed by 12-lead ECGs
Time frame: Part A: SCR, Day 1 (Pre-dose, 0.25 h, 0.5 h, 1.5 h, 2 h, 3 h, 4 h, 12 h), Day 2 (24 h), Day 3 (48 h), Day 4 (72 h) in each period and at follow-up (7-14 days post last dose); Part B: SCR, Day 1 to Day 18 and at follow-up
Safety and tolerability of GSK2793660 as assessed by laboratory data in Part A and Part B
Laboratory assessments will include hematology, clinical chemistry and urinalysis parameters
Time frame: Part A: SCR, Day -1, Day 1 (8 h), Day 2 (24 h), Day 4 (72 h) in each period and at follow-up (7-14 days post last dose); Part B: SCR, Day -1, Day 2, Day 4, Day 10, Day 15, Day 18 and at follow-up
Safety and tolerability of GSK2793660 as assessed by adverse events (AEs) in Part A and Part B
Time frame: Part A: Approximately 22- 24 weeks. Part B: Approximately 9 weeks
Composite of PK parameters for GSK2793660 in Part A and Part B
PK parameters for GSK2793660 in plasma will include: area under the plasma concentration-time curve (AUC\[0-t\], AUC\[0-infinity\]), maximum observed plasma concentration (Cmax), time to Cmax (Tmax), apparent terminal phase half-life (T1/2).
Time frame: Part A: Pre-dose, 0.25, 0.5, 1.5, 2, 3, 6, 8, 12, 16, 24, 30, 48 and 72 h; Part B: Days 1 and 15 (Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 6, 8 and 12 h), Days 2 and 16 (16, 24 and 30 h), Days 3 and 17 (48 h), Day 18 (72 h), Days 4, 7, 9, 11, 13 (pre-dose)
To evaluate biomarker activity following oral administration of GSK2793660 in Part A and Part B
Blood biomarkers that will provide information on target engagement and downstream PD activity will be assessed. Biomarker endpoints including, but not limited to, cathepsin C enzyme activity in whole blood following single dose administration. Neutrophil serine protease activity (i.e. neutrophil elastase, cathepsin G, proteinase 3 \[PR3\]) following repeat dose administration. Other endpoints may include LL37 in cell extracts and surface expression of PR3 on neutrophils following repeat dose administration.
Time frame: Part A: Pre-dose, 1 h, 2 h, 3 h, 6 h, 8 h, 12 h, 24 h, 30 h, 48 h, 72 h, 144 h in each period; Part B: Day 1 and Day 15 (Pre-dose, 1 h, 3 h, 6 h, 8 h and 12 h), Day 2 and Day 16 (24 h and 30 h), Day 3 and Day 17 (48 h), Day 18 (72 h)
Effect of food on PK of GSK2793660 in Part A
PK parameters for GSK2793660 in plasma will include: AUC(0-t), AUC(0-infinity), Cmax, Tmax, and T1/2.
Time frame: Pre-dose, 0.25, 0.5, 1.5, 2, 3, 6, 8, 12, 16, 24, 30, 48 and 72 h
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