First-time-in-Human (FTIH) Study to Evaluate Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single (in Both Fed and Fasted States) or Repeat Doses of GSK3358699

ID: NCT03426995
Status: Not yet recruiting
Phase: Phase 1
Start Date: March 12, 2018
First Submitted: February 02, 2018
Last Updated: February 22, 2018
Results: N/A
Organization: GlaxoSmithKline
Sponsors & Collaborators: GlaxoSmithKline
Location: N/A
Conditions: Arthritis, Rheumatoid
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Study Description

Brief Summary

This FTIH study, intends to identify the doses of GSK3358699, which are well tolerated by the subjects whilst delivering a robust pharmacodynamic (PD) response. This study will evaluate the safety, tolerability, pharmacokinetic (PK) and PD profile of single (in both fed and fasted states) and multiple ascending doses of GSK3358699 in healthy male subjects within a pre-defined and controlled pharmacodynamic and pharmacokinetic range for each cohort. It also intends to understand the effect of GSK3358699 on systemic markers of inflammation following low dose in vivo lipopolysaccharide (LPS) or Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) challenge and local inflammation in cantharidin-induced blisters. The study has been carefully designed to explore the in vivo biology of the target and the potential for the study drug to become a transformative medicine for subjects in multiple immuno-inflammatory disease indications.The study will be conducted in three Parts. Total duration for participation will be approximately 23 weeks for Part A, 9 weeks for Part B and 12 weeks for Part C. The study will be conducted in up to 80 subjects.

Detailed Description

Condition or disease Intervention/treatment Phase

Arthritis, Rheumatoid

Drug: Placebo
Other Names
Drug: GSK3358699
Other Names
Biological: GM-CSF
Other Names
Biological: LPS
Other Names
Other: Cantharidin
Other Names
Phase 1

Tracking Information

First Submitted DateFebruary 02, 2018
Last Update Posted DateFebruary 22, 2018
Anticipated Start DateMarch 12, 2018
Anticipated Completion DateAugust 05, 2019
Anticipated Primary Completion DateMay 30, 2019
Results First Submitted DateN/A
Received Results Disposit DateN/A

Current Primary Outcome Measures

  • Part A: Number of subjects with adverse events (AEs) and Serious adverse events (SAEs) [Time Frame: Up to 17 weeks]

    An AE is any untoward medical occurrence in a subject or clinical investigation subject, 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/incapacity, Is a congenital anomaly/birth defect, medical judgement and is associated with liver injury or liver impartment

  • Part B: Number of subjects with AEs and SAEs [Time Frame: Up to 4 weeks]

    An AE is any untoward medical occurrence in a subject or clinical investigation subject, 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/incapacity, Is a congenital anomaly/birth defect, medical judgement and is associated with liver injury or liver impartment.

  • Part C: Number of subjects with AEs and SAEs [Time Frame: Up to 7 weeks]

    An AE is any untoward medical occurrence in a subject or clinical investigation subject, 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/incapacity, Is a congenital anomaly/birth defect, medical judgement and is associated with liver injury or liver impartment.

  • Part A: Number of subjects with abnormal clinical chemistry parameter's as measure of safety [Time Frame: Up to 12 weeks]

    Blood samples will be collected and processed to measure the number of subjects with abnormal blood urea nitrogen (BUN), C-reactive protein (CRP), creatinine, glucose, sodium, potassium, calcium, Aspartate Aminotransferase, (AST)/ Serum Glutamic-Oxaloacetic Transaminase (SGOT), alanine aminotransferase (ALT/SGPT), alkaline phosphatase (ALP) levels, total and direct bilirubin, cholesterol, triglycerides, total protein, low density lipoprotein, high density lipoprotein and albumin.

  • Part B: Number of subjects with abnormal clinical chemistry parameter's as measure of safety [Time Frame: Up to 4 weeks]

    Blood samples will be collected and processed to measure the number of subjects with abnormal BUN, CRP, creatinine, glucose, sodium, potassium, calcium, AST/SGOT, ALT/SGPT, ALP levels, total and direct bilirubin, cholesterol, triglycerides, total protein, low density lipoprotein, high density lipoprotein and albumin.

  • Part C: Number of subjects with abnormal clinical chemistry parameter's as measure of safety [Time Frame: Up to 2 weeks]

    Blood samples will be collected and processed to measure the number of subjects with abnormal BUN, CRP, creatinine, glucose, sodium, potassium, calcium, AST/SGOT, ALT/SGPT, ALP levels, total and direct bilirubin, cholesterol (fasting), triglycerides, total protein, low density lipoprotein, high density lipoprotein and albumin.

  • Part A: Number of subjects with abnormal hematology parameter's as measure of safety [Time Frame: Up to 12 weeks]

    Blood samples will be collected and processed to measure the number of subjects with abnormal platelet counts, red blood cells (RBC) count, white blood cells (WBC) count (absolute), hemoglobin, hematocrit, percent reticulocytes, RBC indices (mean corpuscle volume [MCV], mean corpuscle hemoglobin [MCH] and differential WBC count (neutrophils, lymphocytes, monocytes, eosinophils, and basophils) and clotting parameter's like activated partial thromboplastin time (APTT), pro-thrombin (PT) times, and fibrinogen.

  • Part B: Number of subjects with abnormal hematology parameter's as measure of safety [Time Frame: Up to 4 weeks]

    Blood samples will be collected and processed to measure the number of subjects with abnormal platelet counts, RBC count, WBC count (absolute), hemoglobin, hematocrit, percent reticulocytes, RBC indices MCV, MCH and differential WBC count (neutrophils, lymphocytes, monocytes, eosinophils, and basophils) and clotting parameter's APTT, PT times, and fibrinogen.

  • Part C: Number of subjects with abnormal hematology parameter's as measure of safety [Time Frame: Up to 2 weeks]

    Blood samples will be collected and processed to measure the number of subjects with abnormal platelet counts, RBC count, WBC count (absolute), hemoglobin, hematocrit, percent reticulocytes, RBC indices MCV, MCH and differential WBC count (neutrophils, lymphocytes, monocytes, eosinophils, and basophils) and clotting parameter's APTT, PT times, and fibrinogen.

  • Part A: Number of subjects with abnormal urinalysis parameter's as measure of safety [Time Frame: Up to 12 weeks]

    Urine samples will be collected to evaluate specific gravity, pH, glucose, protein, blood, ketones by dipstick along with microscopic examination if blood or protein is abnormal.

  • Part B: Number of subjects with abnormal urinalysis parameter's as measure of safety [Time Frame: Up to 4 weeks]

    Urine samples will be collected to evaluate specific gravity, pH, glucose, protein, blood, ketones by dipstick along with microscopic examination if blood or protein is abnormal.

  • Part C: Number of subjects with abnormal urinalysis parameter's as measure of safety [Time Frame: Up to 2 weeks]

    Urine samples will be collected to evaluate specific gravity, pH, glucose, protein, blood, ketones by dipstick along with microscopic examination if blood or protein is abnormal.

  • Part A: Number of subjects with abnormal 12 lead electrocardiograms (ECGs) findings [Time Frame: Up to 12 weeks]

    Triplicate 12-lead ECGs will be obtained prior to blood draws and dosing. Single ECGs will be taken at other time points.

  • Part C: Number of subjects with abnormal vital signs-respiratory rate [Time Frame: Up to 7 weeks]

    The number of subjects with abnormal respiratory rate values will be reported

  • Part B: Number of subjects with abnormal vital signs-respiratory rate [Time Frame: Up to 4 weeks]

    The number of subjects with abnormal respiratory rate values will be reported

  • Part A: Number of subjects with abnormal vital signs-respiratory rate [Time Frame: Up to 17 weeks]

    The number of subjects with abnormal respiratory rate values will be reported

  • Part C: Number of subjects with abnormal vital signs-heart rate [Time Frame: Up to 7 weeks]

    The number of subjects with abnormal heart rate values will be reported

  • Part B: Number of subjects with abnormal vital signs-heart rate [Time Frame: Up to 4 weeks]

    The number of subjects with abnormal heart rate values will be reported

  • Part A: Number of subjects with abnormal vital signs-heart rate [Time Frame: Up to 17 weeks]

    The number of subjects with abnormal heart rate values will be reported

  • Part C: Number of subjects with abnormal vital signs-temperature [Time Frame: Up to 7 weeks]

    The number of subjects with abnormal temperature values will be reported.

  • Part B: Number of subjects with abnormal vital signs-temperature [Time Frame: Up to 4 weeks]

    The number of subjects with abnormal temperature values will be reported.

  • Part A: Number of subjects with abnormal vital signs-temperature [Time Frame: Up to 17 weeks]

    The number of subjects with abnormal temperature values will be reported.

  • Part C: Number of subjects with abnormal vital signs-systolic and diastolic blood pressure [Time Frame: Up to 7 weeks]

    The number of subjects with abnormal systolic and diastolic blood pressure values will be reported.

  • Part B: Number of subjects with abnormal vital signs-systolic and diastolic blood pressure [Time Frame: Up to 4 weeks]

    The number of subjects with abnormal systolic and diastolic blood pressure values will be reported.

  • Part A: Number of subjects with abnormal vital signs-systolic and diastolic blood pressure [Time Frame: Up to 17 weeks]

    The number of subjects with abnormal systolic and diastolic blood pressure values will be reported.

  • Part C: Number of subjects with abnormal 12 lead ECG findings [Time Frame: Up to 2 weeks]

    Triplicate 12-lead ECGs will be obtained prior to blood draws and dosing. Single ECGs will be taken at other time points.

  • Part B: Number of subjects with abnormal 12 lead ECGs findings [Time Frame: Up to 4 weeks]

    Triplicate 12-lead ECGs will be obtained prior to blood draws and dosing. Single ECGs will be taken at other time points.

Original Primary Outcome Measures

Not Available

Current Secondary Outcome Measures

  • Part A: Area under the plasma concentration (AUC) from time zero (pre-dose) to last time of quantifiable concentration (AUC[0-t]) for Gsk3358699 [Time Frame: Day 1 (pre-dose, 15, and 30 minutes, 1 hour, 2 ,4, 6, 8, 12 hour), Day 2 (24 hour), Day 3 (48 hour) in each period]

    Blood samples will be collected for measurement of GSK3358699 concentrations in plasma.

  • Part B: AUC (0-t) for GSK3358699 [Time Frame: Day 1 (pre-dose, 15, 30 minutes; 1,2,4,6,8,12 hour; Day 2 (24 hour), Day 3 (48 hour) in each period]

    Blood samples will be collected at specified time points for PK analysis

  • Part C: AUC (0-t) for GSK3358699 [Time Frame: On Day 1 samples will be taken at pre-dose, 15 and 30 minutes, 1 hour, 2, 4, 6, 8, 12 and 24 hour post-dose, Pre-dose samples Days 4, 8 and 12 and for Day 14 (pre-dose, 15 and 30 minutes, 1 hour, 2, 4, 6, 8, 12 hour) Day 15 and Day 16.]

    Blood samples will be collected at specified time points for PK analysis

  • Part A: AUC pre dose to infinite (inf) time (AUC [0-inf]) of GSK3358699 [Time Frame: Day 1 (pre-dose, 15, and 30 minutes, 1 hour, 2 ,4, 6, 8, 12 hour), Day 2 (24 hour), Day 3 (48 hour) in each period]

    Blood samples will be collected at specified time points for PK analysis

  • Part B: AUC (0-inf) time of GSK3358699 [Time Frame: Day 1 (pre-dose, 15, 30 minutes; 1 hour, 2,4, 6, 8, 12 hour; Day 2 (24 hour), Day 3 (48 hour) in each period]

    Blood samples will be collected at specified time points for PK analysis

  • Part C: AUC (0-inf) time of GSK3358699 [Time Frame: On Day 1 samples will be taken at pre-dose, 15 and 30 minutes, 1 hour, 2, 4, 6, 8, 12 and 24 hour post-dose, Pre-dose samples Days 4, 8 and 12 and for Day 14 (pre-dose, 15 and 30 minutes, 1 hour, 2, 4, 6, 8, 12 hour) Day 15 and Day 16.]

    Blood samples will be collected at specified time points for PK analysis

  • Part A: Maximum plasma concentration (Cmax) of GSK3358699 [Time Frame: Day 1 (pre-dose, 15, and 30 minutes, 1 hour, 2 ,4, 6, 8, 12 hour), Day 2 (24 hour), Day 3 (48 hour) in each period]

    Blood samples will be collected at specified time points for PK analysis

  • Part B: Cmax of GSK3358699 [Time Frame: Day 1 (pre-dose, 15, 30 minutes; 1 hour, 2,4, 6, 8, 12 hour; Day 2 (24 hour), Day 3 (48 hour) in each period]

    Blood samples will be collected at specified time points for PK analysis

  • Part C: Cmax of GSK3358699 [Time Frame: On Day 1 samples will be taken at pre-dose, 15 and 30 minutes, 1 hour, 2, 4, 6, 8, 12 and 24 hour post-dose, Pre-dose samples Days 4, 8 and 12 and for Day 14 (pre-dose, 15 and 30 minutes, 1 hour, 2, 4, 6, 8, 12 hour) Day 15 and Day 16.]

    Blood samples will be collected at specified time points for PK analysis

  • Part A: Time to maximum plasma concentration (tmax) of GSK3358699 [Time Frame: Day 1 (pre-dose, 15, and 30 minutes, 1 hour, 2 ,4, 6, 8, 12 hour), Day 2 (24 hour), Day 3 (48 hour) in each period]

    Blood samples will be collected at specified time points for PK analysis

  • Part B: tmax of GSK3358699 [Time Frame: Day 1 (pre-dose, 15, 30 minutes; 1 hour, 2,4, 6, 8, 12 hour; Day 2 (24 hour), Day 3 (48 hour) in each period]

    Blood samples will be collected at specified time points for PK analysis

  • Part C: tmax of GSK3358699 [Time Frame: On Day 1 samples will be taken at pre-dose, 15 and 30 minutes, 1 hour, 2, 4, 6, 8, 12 and 24 hour post-dose, Pre-dose samples Days 4, 8 and 12 and for Day 14 (pre-dose, 15 and 30 minutes, 1 hour, 2, 4, 6, 8, 12 hour) Day 15 and Day 16.]

    Blood samples will be collected at specified time points for PK analysis

  • Part A: Terminal elimination half-life (t1/2) of GSK3358699 in plasma [Time Frame: Day 1 (pre-dose, 15, and 30 minutes, 1 hour, 2 ,4, 6, 8, 12 hour), Day 2 (24 hour), Day 3 (48 hour) in each period]

    Blood samples will be collected at specified time points for PK analysis

  • Part B: t1/2 of GSK3358699 in plasma [Time Frame: Day 1 (pre-dose, 15, 30 minutes; 1 hour, 2,4, 6, 8, 12 hour; Day 2 (24 hour), Day 3 (48 hour) in each period]

    Blood samples will be collected at specified time points for PK analysis

  • Part C: t1/2 of GSK3358699 in plasma [Time Frame: On Day 1 samples will be taken at pre-dose, 15 and 30 minutes, 1 hour, 2, 4, 6, 8, 12 and 24 hour post-dose, Pre-dose samples Days 4, 8 and 12 and for Day 14 (pre-dose, 15 and 30 minutes, 1 hour, 2, 4, 6, 8, 12 hour) Day 15 and Day 16.]

    Blood samples will be collected at specified time points for PK analysis

  • Part A: AUC pre-dose to 24 hours post-dose: AUC (0-24) for GSK3358699 [Time Frame: Day 1 (pre-dose, 15, and 30 minutes, 1 hour, 2 ,4, 6, 8, 12 hour), Day 2 (24 hour), Day 3 (48 hour) in each period]

    Blood samples will be collected at specified time points for PK analysis

  • Part B: AUC (0-24) for GSK3358699 [Time Frame: Day 1 (pre-dose, 15, 30 minutes; 1 hour, 2,4, 6, 8, 12 hour; Day 2 (24 hour), Day 3 (48 hour) in each period]

    Blood samples will be collected at specified time points for PK analysis

  • Part C: AUC (0-24) for GSK3358699 [Time Frame: On Day 1 samples will be taken at pre-dose, 15 and 30 minutes, 1 hour, 2, 4, 6, 8, 12 and 24 hour post-dose, Pre-dose samples Days 4, 8 and 12 and for Day 14 (pre-dose, 15 and 30 minutes, 1 hour, 2, 4, 6, 8, 12 hour) Day 15 and Day 16.]

    Blood samples will be collected at specified time points for PK analysis

  • Part A: AUC (0-t) for GSK3206944 [Time Frame: Day 1 (pre-dose, 15, and 30 minutes, 1 hour, 2 ,4, 6, 8, 12 hour), Day 2 (24 hour), Day 3 (48 hour) in each period]

    Blood samples will be collected at specified time points for PK analysis

  • Part B: AUC (0-t) for GSK3206944 [Time Frame: Day 1 (pre-dose, 15, 30 minutes; 1 hour, 2,4, 6, 8, 12 hour; Day 2 (24 hour), Day 3 (48 hour) in each period]

    Blood samples will be collected at specified time points for PK analysis

  • Part C: AUC(0-t) for GSK3206944 [Time Frame: On Day 1 samples will be taken at pre-dose, 15 and 30 minutes, 1 hour, 2, 4, 6, 8, 12 and 24 hour post-dose, Pre-dose samples Days 4, 8 and 12 and for Day 14 (pre-dose, 15 and 30 minutes, 1 hour, 2, 4, 6, 8, 12 hour) Day 15 and Day 16.]

    Blood samples will be collected at specified time points for PK analysis

  • Part A: AUC (0-inf) of GSK3206944 [Time Frame: Day 1 (pre-dose, 15, and 30 minutes, 1 hour, 2 ,4, 6, 8, 12 hour), Day 2 (24 hour), Day 3 (48 hour) in each period]

    Blood samples will be collected at specified time points for PK analysis.

  • Part B: AUC (0-inf) of GSK3206944 [Time Frame: Day 1 (pre-dose, 15, 30 minutes; 1 hour, 2,4, 6, 8, 12 hour; Day 2 (24 hour), Day 3 (48 hour) in each period]

    Blood samples will be collected at specified time points for PK analysis

  • Part C: AUC (0-inf) of GSK3206944 [Time Frame: On Day 1 samples will be taken at pre-dose, 15 and 30 minutes, 1 hour, 2, 4, 6, 8, 12 and 24 hour post-dose, Pre-dose samples Days 4, 8 and 12 and for Day 14 (pre-dose, 15 and 30 minutes, 1 hour, 2, 4, 6, 8, 12 hour) Day 15 and Day 16.]

    Blood samples will be collected at specified time points for PK analysis

  • Part A: Cmax of GSK3206944 [Time Frame: Day 1 (pre-dose, 15, and 30 minutes, 1 hour, 2 ,4, 6, 8, 12 hour), Day 2 (24 hour), Day 3 (48 hour) in each period]

    Blood samples will be collected at 6 mL, per timepoint for measurement of GSK3206944 concentrations in plasma (approximately 1 mL per time-point up to and including 6 hours post dose and approximately 2 mL per time-point after 6 hours post-dose

  • Part B: Cmax of GSK3206944 [Time Frame: Day 1 (pre-dose, 15, 30 minutes; 1 hour, 2,4, 6, 8, 12 hour; Day 2 (24 hour), Day 3 (48 hour) in each period]

    Blood samples will be collected at specified time points for PK analysis

  • Part C: Cmax of GSK3206944 [Time Frame: On Day 1 samples will be taken at pre-dose, 15 and 30 minutes, 1 hour, 2, 4, 6, 8, 12 and 24 hour post-dose, Pre-dose samples Days 4, 8 and 12 and for Day 14 (pre-dose, 15 and 30 minutes, 1 hour, 2, 4, 6, 8, 12 hour) Day 15 and Day 16.]

    Blood samples will be collected at specified time points for PK analysis

  • Part A: tmax of GSK3206944 [Time Frame: Day 1 (pre-dose, 15, and 30 minutes, 1 hour, 2 ,4, 6, 8, 12 hour), Day 2 (24 hour), Day 3 (48 hour) in each period]

    Blood samples will be collected at specified time points for PK analysis.

  • Part B: tmax of GSK3206944 [Time Frame: Day 1 (pre-dose, 15, 30 minutes; 1 hour, 2,4, 6, 8, 12 hour; Day 2 (24 hour), Day 3 (48 hour)]

    Blood samples will be collected at specified time points for PK analysis

  • Part C: tmax of GSK3206944 [Time Frame: On Day 1 samples will be taken at pre-dose, 15 and 30 minutes, 1 hour, 2, 4, 6, 8, 12 and 24 hour post-dose, Pre-dose samples Days 4, 8 and 12 and for Day 14 (pre-dose, 15 and 30 minutes, 1 hour, 2, 4, 6, 8, 12 hour) Day 15 and Day 16.]

    Blood samples will be collected at specified time points for PK analysis

  • Part A: t1/2 of GSK3206944 in plasma [Time Frame: Day 1 (pre-dose, 15, and 30 minutes, 1 hour, 2 ,4, 6, 8, 12 hour), Day 2 (24 hour), Day 3 (48 hour)]

    Blood samples will be collected at specified time points for PK analysis

  • Part B: t1/2 of GSK3206944 in plasma [Time Frame: Day 1 (pre-dose, 15, 30 minutes; 1 hour, 2,4, 6, 8, 12 hour; Day 2 (24 hour), Day 3 (48 hour)]

    Blood samples will be collected at specified time points for PK analysis

  • Part C: t1/2 of GSK3206944 in plasma [Time Frame: On Day 1 samples will be taken at pre-dose, 15 and 30 minutes, 1 hour, 2, 4, 6, 8, 12 and 24 hour post-dose, Pre-dose samples Days 4, 8 and 12 and for Day 14 (pre-dose, 15 and 30 minutes, 1 hour, 2, 4, 6, 8, 12 hour) Day 15 and Day 16.]

    Blood samples will be collected at specified time points for PK analysis

  • Part A: AUC (0-24) for GSK3206944 [Time Frame: Day 1 (pre-dose, 15, and 30 minutes, 1 hour, 2 ,4, 6, 8, 12 hour), Day 2 (24 hour), Day 3 (48 hour)]

    Blood samples will be collected at specified time points for PK analysis

  • Part B: AUC (0-24) for GSK3206944 [Time Frame: Day 1 (pre-dose, 15, 30 minutes; 1 hour, 2,4, 6, 8, 12 hour; Day 2 (24 hour), Day 3 (48 hour)]

    Blood samples will be collected at specified time points for PK analysis

  • Part C: AUC (0-24) for GSK3206944 [Time Frame: On Day 1 samples will be taken at pre-dose, 15 and 30 minutes, 1 hour, 2, 4, 6, 8, 12 and 24 hour post-dose, Pre-dose samples Days 4, 8 and 12 and for Day 14 (pre-dose, 15 and 30 minutes, 1 hour, 2, 4, 6, 8, 12 hour) Day 15 and Day 16.]

    Blood samples will be collected at specified time points for PK analysis

  • Part A: Monocyte intracellular concentration of GSK3206944 [Time Frame: Day 1 (1 hour, 4 and 8 hour), Day 2 (24 hour), and Day 3 (48 hour)]

    Blood samples will be collected into sodium heparin tubes for the isolation of monocytes and for measurement of GSK3206944 concentrations in monocytes

  • Part B: Monocyte intracellular concentration of GSK3206944 [Time Frame: Day 1 (1 hour,4 hour, 8 hour), Day 2 (24 hour), Day 3 (48 hour)]

    Blood samples will be collected into sodium heparin tubes for the isolation of monocytes and for measurement of GSK3206944 concentrations in monocytes

  • Part C: Monocyte intracellular concentration of GSK3206944 [Time Frame: Day 1 (1, 4 and 8 hour), Pre dose on Days 4-12, Day 14 (1, 4 and 8 hour), Day 15 (24 hour), Day 16 (48 hour)]

    Blood samples will be collected into sodium heparin tubes for the isolation of monocytes and for measurement of GSK3206944 concentrations in monocytes

  • Part A: Plasma concentrations of monocyte chemoattractant protein (MCP)-1, in blood stimulated ex vivo with lipopolysaccharide (LPS) over time [Time Frame: Day -1, Day 1 (pre-dose, 1 hour, 4, 8, and 12 hour); Day 2 (24 hour), and Day 3 (48 hour)]

    Whole blood samples of 1 mL will be collected in TruCulture tubes, containing LPS and incubated for 24 hours, post which the inflammatory mediator will be analyzed.

  • Part A: Plasma concentrations of interleukin (IL)-6 in blood stimulated ex vivo with LPS over time [Time Frame: Day -1, Day 1 (pre-dose, 1 hour, 4, 8, and 12 hour); Day 2 (24 hour), and Day 3 (48 hour)]

    Whole blood samples of 1 mL will be collected in TruCulture tubes, containing LPS and incubated for 24 hours, post which the inflammatory mediator will be analyzed.

  • Part A: Plasma concentrations of monocyte chemoattractant protein tumor necrosis factor (TNF) in blood stimulated ex vivo with LPS over time [Time Frame: Day -1, Day 1 (pre-dose, 1 hour, 4, 8, and 12 hour); Day 2 (24 hour), and Day 3 (48 hour)]

    Whole blood samples of 1 mL will be collected in TruCulture tubes, containing LPS and incubated for 24 hours, post which the inflammatory mediator will be analyzed.

  • Part B: Plasma concentrations of MCP-1, in blood stimulated ex vivo with LPS over time [Time Frame: Day -1, Day 1 (pre-dose, 1 hour,4, 8, 12 hour), Day 2 (24 hour) and Day 3 (48 hour)]

    Whole blood samples of 1 mL will be collected in TruCulture tubes, containing LPS and incubated for 24 hours, post which the inflammatory mediator will be analyzed.

  • Part B: Plasma concentrations of IL-6 in blood stimulated ex vivo with LPS over time [Time Frame: Day -1, Day 1 (pre-dose, 1 hour,4, 8, 12 hour), Day 2 (24 hour) and Day 3 (48 hour)]

    Whole blood samples of 1 mL will be collected in TruCulture tubes, containing LPS and incubated for 24 hours, post which the inflammatory mediator will be analyzed.

  • Part B: Plasma concentrations of monocyte chemoattractant protein TNF in blood stimulated ex vivo with LPS over time [Time Frame: Day -1, Day 1 (pre-dose, 1 hour,4, 8, 12 hour), Day 2 (24 hour) and Day 3 (48 hour)]

    Whole blood samples of 1 mL will be collected in TruCulture tubes, containing LPS and incubated for 24 hours, post which the inflammatory mediator will be analyzed.

  • Part C: Plasma concentrations of MCP-1, in blood stimulated ex vivo with LPS over time [Time Frame: Day -1, 1,2,4,8,12 and Day 14.]

    Whole blood samples of 1 mL will be collected in TruCulture tubes, containing LPS and incubated for 24 hours, post which the inflammatory mediator will be analyzed.

  • Part C: Plasma concentrations of IL-6 in blood stimulated ex vivo with LPS over time [Time Frame: Day -1, 1,2,4,8,12 and Day 14.]

    Whole blood samples of 1 mL will be collected in TruCulture tubes, containing LPS and incubated for 24 hours, post which the inflammatory mediator will be analyzed.

  • Part C: Plasma concentrations of monocyte chemoattractant protein TNF in blood stimulated ex vivo with LPS over time [Time Frame: Day -1, 1, 2, 4, 8, 12 and Day 14.]

    Whole blood samples of 1 mL will be collected in TruCulture tubes, containing LPS and incubated for 24 hours, post which the inflammatory mediator will be analyzed.

Original Secondary Outcome Measures

Not Available

Study Design

Brief TitleFirst-time-in-Human (FTIH) Study to Evaluate Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single (in Both Fed and Fasted States) or Repeat Doses of GSK3358699
Official TitleA Randomised, Double-blind (Sponsor Open), Placebo-controlled, Three Part Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single (in Both Fed and Fasted States) or Repeat Doses of GSK3358699 in Healthy Male Participants
Brief Summary

This FTIH study, intends to identify the doses of GSK3358699, which are well tolerated by the subjects whilst delivering a robust pharmacodynamic (PD) response. This study will evaluate the safety, tolerability, pharmacokinetic (PK) and PD profile of single (in both fed and fasted states) and multiple ascending doses of GSK3358699 in healthy male subjects within a pre-defined and controlled pharmacodynamic and pharmacokinetic range for each cohort. It also intends to understand the effect of GSK3358699 on systemic markers of inflammation following low dose in vivo lipopolysaccharide (LPS) or Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) challenge and local inflammation in cantharidin-induced blisters. The study has been carefully designed to explore the in vivo biology of the target and the potential for the study drug to become a transformative medicine for subjects in multiple immuno-inflammatory disease indications.The study will be conducted in three Parts. Total duration for participation will be approximately 23 weeks for Part A, 9 weeks for Part B and 12 weeks for Part C. The study will be conducted in up to 80 subjects.

Detailed Description

Study TypeInterventional
Study PhasePhase 1
Estimated Enrollment
80
Allocation
Randomized
Interventional Model
Crossover Assignment
Masking
Double
Primary Purpose
Treatment
Conditions
Arthritis, Rheumatoid
Target Follow-Up Duration N/A
Biospecimen:
N/A
Sampling MethodN/A
Study PopulationN/A
Intervention
Drug: Placebo

Placebo will be administered as a matching oral solution or matching capsule to study drug GSK3358699, during Part A and C once daily

Other Names
Drug: GSK3358699

GSK3358699, will be administered from 1 mg to 45 mg as an oral solution (1 to 10 mg) or as a capsule (10 to 45 mg), in Part A, B and Part C once daily.

Other Names
Biological: GM-CSF

The GM-CSF will be administered as an intravenous infusion to subjects as 60 microgram per meter^2 in Part A (Day 1) and Part C (Day 14).This will be administered for 2 hours approximately, no later than 24 hours post -dose of the GSK3358699 or placebo in Part C

Other Names
Biological: LPS

LPS will be administered as an intravenous injection to subjects not exceeding 0.75 nanogram per kilogram in Part A (Day 1) and Part C (Day 14). This will be administered no later than 24 hours post -dose of the GSK3358699 or placebo in Part C.

Other Names
Other: Cantharidin

This will be applied as a topical application with 0.7% cantharidin liquid which will be diluted with acetone to 0.2%.

Other Names
Study Groups/Cohorts
GSK3358699, Part A, Cohort 1
Part A will comprise of 4 TPs. The subjects in this cohort will receive GSK3358699, as single escalation dose, during TP (1 to 3) with planned escalated doses as 1 mg, 10 mg and 35 mg. Dose of 1 mg will be given as solution and doses of 10 mg and 35 mg, will be given as a capsule. Each TP will be of 1 day and separated by a washout period of 14-days. Post completion of the dose-escalation TPs, an additional dosing TP 4 will be included where the subjects from each TP (1 to 3), will receive control blisters induced on forearm (0.2 % cantharidin) at Day -10. The subjects in cohort 1 will receive GSK3358699 at a dose level already given in TP 1-3, and will then receive an intravenous in vivo LPS challenge at a dose not exceeding 0.75 nanogram per kilogram post administration of GSK3358699. The subjects will then have blisters induced on the forearm approximately 20 minutes after the challenge. LPS dose will be based on data of study 207654.

GSK3358699, Part A, Cohort 2
Part A will comprise of 4 TPs. The subjects in this cohort will receive GSK3358699, as single escalation dose during TP (1 to 3) with planned escalated doses as 3 mg, 20 mg and 45 mg. Dose of 3 mg will be given as solution and that of 20 and 45 mg, as capsule. Each TP will be of 1 day and separated by a washout period of 14-days. Post completion of the dose-escalation TPs, an additional dosing TP 4 will be included where the subjects from each TP (1 to 3), will receive control blisters induced on forearm (0.2 % cantharidin) at Day -10. The subjects in cohort 2 will receive GSK3358699 at a dose level already given in TP 1-3, and will then receive 60 microgram per meter^2 of in vivo GM CSF challenge as an intravenous infusion during TP 4, post administration of GSK3358699. The subjects will then have blisters induced on the forearm approximately 20 minutes after the challenge GM-CSF infusion. GM-CSF dose will be based on data of study 207654.

Placebo, Part A, Cohort 1
Part A will comprise of 4 TPs. The subjects in this cohort will receive matching Placebo solution to the study drug GSK3358699 solution for 1 mg and a matching placebo capsule to the study drug GSK3358699, 10 mg and 35 mg capsule, during TP (1 to 3). Each TP will be of 1 day and separated by a washout period of 14-days. Post completion of the dose-escalation TPs, an additional dosing TP 4 will be included where the subjects from each TP (1 to 3), will receive control blisters induced on forearm (0.2 % cantharidin) at Day -10. The subjects in cohort 1 will receive Placebo at a dose level already given in TP 1-3, and will then receive an intravenous in vivo LPS challenge at a dose not exceeding 0.75 nanogram per kilogram post administration of Placebo. The subjects will then have blisters induced on the forearm approximately 20 minutes after the challenge. LPS dose will be based on data of study 207654.

Placebo, Part A, Cohort 2
Part A will comprise of 4 TPs. The subjects in this cohort will receive matching Placebo solution to the study drug GSK3358699 solution for 3 mg and a matching placebo capsule to the study drug GSK3358699, for 20 and 45 mg capsule, during TP (1 to 3). Each TP will be of 1 day and separated by a washout period of 14-days. Post completion of the dose-escalation TPs, an additional dosing TP 4 will be included where the subjects from each TP (1 to 3), will receive control blisters induced on forearm (0.2 % cantharidin) at Day -10. The subjects in cohort 2 will receive Placebo at a dose level already given in TP 1-3, and will then receive 60 microgram per meter^2 of in vivo GM CSF challenge as an intravenous infusion during TP 4, post administration of Placebo. The subjects will then have blisters induced on the forearm approximately 20 minutes after the challenge GM-CSF infusion. GM-CSF dose will be based on data of study 207654.

GSK3358699, Part B
The subjects in this arm will receive single oral dose of GSK3358699, at a dose level evaluated in Part A, following either fed or fasted condition. This cohort intended to evaluate the effect of food.

GSK3358699, Part C
The dose level for the first cohort in Part C will be decided following completion of Part A of the study for GSK3358699. The subjects in this arm will constitute 3 cohorts each (cohort 4 to 6), where the subjects will receive GSK3358699, as one repeat dose treatment once daily for 14-consecutive days. Subjects will have control blisters induced on the forearm (0.2% cantharidin) on Day -10. On the Day 14 of each cohort, each subject will receive an intravenous in vivo LPS challenge at a dose not exceeding 0.75 nanogram per kilogram or an intravenous infusion of GM-CSF, in vivo as 60 microgram per meter^2. The administration of LPS or GM CSF will be followed by blister induction on forearm (0.2 % cantharidin).

Placebo, Part C
The subjects in this cohort will receive a matching placebo to GSK3358699, Part C, as a single oral dose once daily for 14 consecutive days. The subjects in this arm will constitute 3 cohorts each (cohort 4 to 6), where the subjects will receive placebo, as one repeat dose treatment once daily for 14-consecutive days. Subjects will have control blisters induced on the forearm (0.2% cantharidin) on Day -10. On the Day 14 of each cohort, each subject will receive an intravenous in vivo LPS challenge at a dose not exceeding 0.75 nanogram per kilogram or an intravenous infusion of GM-CSF, in vivo as 60 microgram per meter^2. The administration of LPS or GM CSF will be followed by blister induction on forearm (0.2 % cantharidin).

Study Arms
Experimental GSK3358699, Part A, Cohort 1
Part A will comprise of 4 TPs. The subjects in this cohort will receive GSK3358699, as single escalation dose, during TP (1 to 3) with planned escalated doses as 1 mg, 10 mg and 35 mg. Dose of 1 mg will be given as solution and doses of 10 mg and 35 mg, will be given as a capsule. Each TP will be of 1 day and separated by a washout period of 14-days. Post completion of the dose-escalation TPs, an additional dosing TP 4 will be included where the subjects from each TP (1 to 3), will receive control blisters induced on forearm (0.2 % cantharidin) at Day -10. The subjects in cohort 1 will receive GSK3358699 at a dose level already given in TP 1-3, and will then receive an intravenous in vivo LPS challenge at a dose not exceeding 0.75 nanogram per kilogram post administration of GSK3358699. The subjects will then have blisters induced on the forearm approximately 20 minutes after the challenge. LPS dose will be based on data of study 207654.
Drug : GSK3358699
GSK3358699, will be administered from 1 mg to 45 mg as an oral solution (1 to 10 mg) or as a capsule (10 to 45 mg), in Part A, B and Part C once daily.

Experimental GSK3358699, Part A, Cohort 1
Part A will comprise of 4 TPs. The subjects in this cohort will receive GSK3358699, as single escalation dose, during TP (1 to 3) with planned escalated doses as 1 mg, 10 mg and 35 mg. Dose of 1 mg will be given as solution and doses of 10 mg and 35 mg, will be given as a capsule. Each TP will be of 1 day and separated by a washout period of 14-days. Post completion of the dose-escalation TPs, an additional dosing TP 4 will be included where the subjects from each TP (1 to 3), will receive control blisters induced on forearm (0.2 % cantharidin) at Day -10. The subjects in cohort 1 will receive GSK3358699 at a dose level already given in TP 1-3, and will then receive an intravenous in vivo LPS challenge at a dose not exceeding 0.75 nanogram per kilogram post administration of GSK3358699. The subjects will then have blisters induced on the forearm approximately 20 minutes after the challenge. LPS dose will be based on data of study 207654.
Biological : LPS
LPS will be administered as an intravenous injection to subjects not exceeding 0.75 nanogram per kilogram in Part A (Day 1) and Part C (Day 14). This will be administered no later than 24 hours post -dose of the GSK3358699 or placebo in Part C.

Experimental GSK3358699, Part A, Cohort 1
Part A will comprise of 4 TPs. The subjects in this cohort will receive GSK3358699, as single escalation dose, during TP (1 to 3) with planned escalated doses as 1 mg, 10 mg and 35 mg. Dose of 1 mg will be given as solution and doses of 10 mg and 35 mg, will be given as a capsule. Each TP will be of 1 day and separated by a washout period of 14-days. Post completion of the dose-escalation TPs, an additional dosing TP 4 will be included where the subjects from each TP (1 to 3), will receive control blisters induced on forearm (0.2 % cantharidin) at Day -10. The subjects in cohort 1 will receive GSK3358699 at a dose level already given in TP 1-3, and will then receive an intravenous in vivo LPS challenge at a dose not exceeding 0.75 nanogram per kilogram post administration of GSK3358699. The subjects will then have blisters induced on the forearm approximately 20 minutes after the challenge. LPS dose will be based on data of study 207654.
Other : Cantharidin
This will be applied as a topical application with 0.7% cantharidin liquid which will be diluted with acetone to 0.2%.

Experimental GSK3358699, Part A, Cohort 2
Part A will comprise of 4 TPs. The subjects in this cohort will receive GSK3358699, as single escalation dose during TP (1 to 3) with planned escalated doses as 3 mg, 20 mg and 45 mg. Dose of 3 mg will be given as solution and that of 20 and 45 mg, as capsule. Each TP will be of 1 day and separated by a washout period of 14-days. Post completion of the dose-escalation TPs, an additional dosing TP 4 will be included where the subjects from each TP (1 to 3), will receive control blisters induced on forearm (0.2 % cantharidin) at Day -10. The subjects in cohort 2 will receive GSK3358699 at a dose level already given in TP 1-3, and will then receive 60 microgram per meter^2 of in vivo GM CSF challenge as an intravenous infusion during TP 4, post administration of GSK3358699. The subjects will then have blisters induced on the forearm approximately 20 minutes after the challenge GM-CSF infusion. GM-CSF dose will be based on data of study 207654.
Other : Cantharidin
This will be applied as a topical application with 0.7% cantharidin liquid which will be diluted with acetone to 0.2%.

Experimental GSK3358699, Part A, Cohort 2
Part A will comprise of 4 TPs. The subjects in this cohort will receive GSK3358699, as single escalation dose during TP (1 to 3) with planned escalated doses as 3 mg, 20 mg and 45 mg. Dose of 3 mg will be given as solution and that of 20 and 45 mg, as capsule. Each TP will be of 1 day and separated by a washout period of 14-days. Post completion of the dose-escalation TPs, an additional dosing TP 4 will be included where the subjects from each TP (1 to 3), will receive control blisters induced on forearm (0.2 % cantharidin) at Day -10. The subjects in cohort 2 will receive GSK3358699 at a dose level already given in TP 1-3, and will then receive 60 microgram per meter^2 of in vivo GM CSF challenge as an intravenous infusion during TP 4, post administration of GSK3358699. The subjects will then have blisters induced on the forearm approximately 20 minutes after the challenge GM-CSF infusion. GM-CSF dose will be based on data of study 207654.
Biological : GM-CSF
The GM-CSF will be administered as an intravenous infusion to subjects as 60 microgram per meter^2 in Part A (Day 1) and Part C (Day 14).This will be administered for 2 hours approximately, no later than 24 hours post -dose of the GSK3358699 or placebo in Part C

Experimental GSK3358699, Part A, Cohort 2
Part A will comprise of 4 TPs. The subjects in this cohort will receive GSK3358699, as single escalation dose during TP (1 to 3) with planned escalated doses as 3 mg, 20 mg and 45 mg. Dose of 3 mg will be given as solution and that of 20 and 45 mg, as capsule. Each TP will be of 1 day and separated by a washout period of 14-days. Post completion of the dose-escalation TPs, an additional dosing TP 4 will be included where the subjects from each TP (1 to 3), will receive control blisters induced on forearm (0.2 % cantharidin) at Day -10. The subjects in cohort 2 will receive GSK3358699 at a dose level already given in TP 1-3, and will then receive 60 microgram per meter^2 of in vivo GM CSF challenge as an intravenous infusion during TP 4, post administration of GSK3358699. The subjects will then have blisters induced on the forearm approximately 20 minutes after the challenge GM-CSF infusion. GM-CSF dose will be based on data of study 207654.
Drug : GSK3358699
GSK3358699, will be administered from 1 mg to 45 mg as an oral solution (1 to 10 mg) or as a capsule (10 to 45 mg), in Part A, B and Part C once daily.

Experimental GSK3358699, Part B
The subjects in this arm will receive single oral dose of GSK3358699, at a dose level evaluated in Part A, following either fed or fasted condition. This cohort intended to evaluate the effect of food.
Drug : GSK3358699
GSK3358699, will be administered from 1 mg to 45 mg as an oral solution (1 to 10 mg) or as a capsule (10 to 45 mg), in Part A, B and Part C once daily.

Experimental GSK3358699, Part C
The dose level for the first cohort in Part C will be decided following completion of Part A of the study for GSK3358699. The subjects in this arm will constitute 3 cohorts each (cohort 4 to 6), where the subjects will receive GSK3358699, as one repeat dose treatment once daily for 14-consecutive days. Subjects will have control blisters induced on the forearm (0.2% cantharidin) on Day -10. On the Day 14 of each cohort, each subject will receive an intravenous in vivo LPS challenge at a dose not exceeding 0.75 nanogram per kilogram or an intravenous infusion of GM-CSF, in vivo as 60 microgram per meter^2. The administration of LPS or GM CSF will be followed by blister induction on forearm (0.2 % cantharidin).
Drug : GSK3358699
GSK3358699, will be administered from 1 mg to 45 mg as an oral solution (1 to 10 mg) or as a capsule (10 to 45 mg), in Part A, B and Part C once daily.

Experimental GSK3358699, Part C
The dose level for the first cohort in Part C will be decided following completion of Part A of the study for GSK3358699. The subjects in this arm will constitute 3 cohorts each (cohort 4 to 6), where the subjects will receive GSK3358699, as one repeat dose treatment once daily for 14-consecutive days. Subjects will have control blisters induced on the forearm (0.2% cantharidin) on Day -10. On the Day 14 of each cohort, each subject will receive an intravenous in vivo LPS challenge at a dose not exceeding 0.75 nanogram per kilogram or an intravenous infusion of GM-CSF, in vivo as 60 microgram per meter^2. The administration of LPS or GM CSF will be followed by blister induction on forearm (0.2 % cantharidin).
Biological : GM-CSF
The GM-CSF will be administered as an intravenous infusion to subjects as 60 microgram per meter^2 in Part A (Day 1) and Part C (Day 14).This will be administered for 2 hours approximately, no later than 24 hours post -dose of the GSK3358699 or placebo in Part C

Experimental GSK3358699, Part C
The dose level for the first cohort in Part C will be decided following completion of Part A of the study for GSK3358699. The subjects in this arm will constitute 3 cohorts each (cohort 4 to 6), where the subjects will receive GSK3358699, as one repeat dose treatment once daily for 14-consecutive days. Subjects will have control blisters induced on the forearm (0.2% cantharidin) on Day -10. On the Day 14 of each cohort, each subject will receive an intravenous in vivo LPS challenge at a dose not exceeding 0.75 nanogram per kilogram or an intravenous infusion of GM-CSF, in vivo as 60 microgram per meter^2. The administration of LPS or GM CSF will be followed by blister induction on forearm (0.2 % cantharidin).
Biological : LPS
LPS will be administered as an intravenous injection to subjects not exceeding 0.75 nanogram per kilogram in Part A (Day 1) and Part C (Day 14). This will be administered no later than 24 hours post -dose of the GSK3358699 or placebo in Part C.

Experimental GSK3358699, Part C
The dose level for the first cohort in Part C will be decided following completion of Part A of the study for GSK3358699. The subjects in this arm will constitute 3 cohorts each (cohort 4 to 6), where the subjects will receive GSK3358699, as one repeat dose treatment once daily for 14-consecutive days. Subjects will have control blisters induced on the forearm (0.2% cantharidin) on Day -10. On the Day 14 of each cohort, each subject will receive an intravenous in vivo LPS challenge at a dose not exceeding 0.75 nanogram per kilogram or an intravenous infusion of GM-CSF, in vivo as 60 microgram per meter^2. The administration of LPS or GM CSF will be followed by blister induction on forearm (0.2 % cantharidin).
Other : Cantharidin
This will be applied as a topical application with 0.7% cantharidin liquid which will be diluted with acetone to 0.2%.

Placebo Comparator Placebo, Part A, Cohort 1
Part A will comprise of 4 TPs. The subjects in this cohort will receive matching Placebo solution to the study drug GSK3358699 solution for 1 mg and a matching placebo capsule to the study drug GSK3358699, 10 mg and 35 mg capsule, during TP (1 to 3). Each TP will be of 1 day and separated by a washout period of 14-days. Post completion of the dose-escalation TPs, an additional dosing TP 4 will be included where the subjects from each TP (1 to 3), will receive control blisters induced on forearm (0.2 % cantharidin) at Day -10. The subjects in cohort 1 will receive Placebo at a dose level already given in TP 1-3, and will then receive an intravenous in vivo LPS challenge at a dose not exceeding 0.75 nanogram per kilogram post administration of Placebo. The subjects will then have blisters induced on the forearm approximately 20 minutes after the challenge. LPS dose will be based on data of study 207654.
Biological : LPS
LPS will be administered as an intravenous injection to subjects not exceeding 0.75 nanogram per kilogram in Part A (Day 1) and Part C (Day 14). This will be administered no later than 24 hours post -dose of the GSK3358699 or placebo in Part C.

Placebo Comparator Placebo, Part A, Cohort 1
Part A will comprise of 4 TPs. The subjects in this cohort will receive matching Placebo solution to the study drug GSK3358699 solution for 1 mg and a matching placebo capsule to the study drug GSK3358699, 10 mg and 35 mg capsule, during TP (1 to 3). Each TP will be of 1 day and separated by a washout period of 14-days. Post completion of the dose-escalation TPs, an additional dosing TP 4 will be included where the subjects from each TP (1 to 3), will receive control blisters induced on forearm (0.2 % cantharidin) at Day -10. The subjects in cohort 1 will receive Placebo at a dose level already given in TP 1-3, and will then receive an intravenous in vivo LPS challenge at a dose not exceeding 0.75 nanogram per kilogram post administration of Placebo. The subjects will then have blisters induced on the forearm approximately 20 minutes after the challenge. LPS dose will be based on data of study 207654.
Drug : Placebo
Placebo will be administered as a matching oral solution or matching capsule to study drug GSK3358699, during Part A and C once daily

Placebo Comparator Placebo, Part A, Cohort 1
Part A will comprise of 4 TPs. The subjects in this cohort will receive matching Placebo solution to the study drug GSK3358699 solution for 1 mg and a matching placebo capsule to the study drug GSK3358699, 10 mg and 35 mg capsule, during TP (1 to 3). Each TP will be of 1 day and separated by a washout period of 14-days. Post completion of the dose-escalation TPs, an additional dosing TP 4 will be included where the subjects from each TP (1 to 3), will receive control blisters induced on forearm (0.2 % cantharidin) at Day -10. The subjects in cohort 1 will receive Placebo at a dose level already given in TP 1-3, and will then receive an intravenous in vivo LPS challenge at a dose not exceeding 0.75 nanogram per kilogram post administration of Placebo. The subjects will then have blisters induced on the forearm approximately 20 minutes after the challenge. LPS dose will be based on data of study 207654.
Other : Cantharidin
This will be applied as a topical application with 0.7% cantharidin liquid which will be diluted with acetone to 0.2%.

Placebo Comparator Placebo, Part A, Cohort 2
Part A will comprise of 4 TPs. The subjects in this cohort will receive matching Placebo solution to the study drug GSK3358699 solution for 3 mg and a matching placebo capsule to the study drug GSK3358699, for 20 and 45 mg capsule, during TP (1 to 3). Each TP will be of 1 day and separated by a washout period of 14-days. Post completion of the dose-escalation TPs, an additional dosing TP 4 will be included where the subjects from each TP (1 to 3), will receive control blisters induced on forearm (0.2 % cantharidin) at Day -10. The subjects in cohort 2 will receive Placebo at a dose level already given in TP 1-3, and will then receive 60 microgram per meter^2 of in vivo GM CSF challenge as an intravenous infusion during TP 4, post administration of Placebo. The subjects will then have blisters induced on the forearm approximately 20 minutes after the challenge GM-CSF infusion. GM-CSF dose will be based on data of study 207654.
Drug : Placebo
Placebo will be administered as a matching oral solution or matching capsule to study drug GSK3358699, during Part A and C once daily

Placebo Comparator Placebo, Part A, Cohort 2
Part A will comprise of 4 TPs. The subjects in this cohort will receive matching Placebo solution to the study drug GSK3358699 solution for 3 mg and a matching placebo capsule to the study drug GSK3358699, for 20 and 45 mg capsule, during TP (1 to 3). Each TP will be of 1 day and separated by a washout period of 14-days. Post completion of the dose-escalation TPs, an additional dosing TP 4 will be included where the subjects from each TP (1 to 3), will receive control blisters induced on forearm (0.2 % cantharidin) at Day -10. The subjects in cohort 2 will receive Placebo at a dose level already given in TP 1-3, and will then receive 60 microgram per meter^2 of in vivo GM CSF challenge as an intravenous infusion during TP 4, post administration of Placebo. The subjects will then have blisters induced on the forearm approximately 20 minutes after the challenge GM-CSF infusion. GM-CSF dose will be based on data of study 207654.
Biological : GM-CSF
The GM-CSF will be administered as an intravenous infusion to subjects as 60 microgram per meter^2 in Part A (Day 1) and Part C (Day 14).This will be administered for 2 hours approximately, no later than 24 hours post -dose of the GSK3358699 or placebo in Part C

Placebo Comparator Placebo, Part A, Cohort 2
Part A will comprise of 4 TPs. The subjects in this cohort will receive matching Placebo solution to the study drug GSK3358699 solution for 3 mg and a matching placebo capsule to the study drug GSK3358699, for 20 and 45 mg capsule, during TP (1 to 3). Each TP will be of 1 day and separated by a washout period of 14-days. Post completion of the dose-escalation TPs, an additional dosing TP 4 will be included where the subjects from each TP (1 to 3), will receive control blisters induced on forearm (0.2 % cantharidin) at Day -10. The subjects in cohort 2 will receive Placebo at a dose level already given in TP 1-3, and will then receive 60 microgram per meter^2 of in vivo GM CSF challenge as an intravenous infusion during TP 4, post administration of Placebo. The subjects will then have blisters induced on the forearm approximately 20 minutes after the challenge GM-CSF infusion. GM-CSF dose will be based on data of study 207654.
Other : Cantharidin
This will be applied as a topical application with 0.7% cantharidin liquid which will be diluted with acetone to 0.2%.

Placebo Comparator Placebo, Part C
The subjects in this cohort will receive a matching placebo to GSK3358699, Part C, as a single oral dose once daily for 14 consecutive days. The subjects in this arm will constitute 3 cohorts each (cohort 4 to 6), where the subjects will receive placebo, as one repeat dose treatment once daily for 14-consecutive days. Subjects will have control blisters induced on the forearm (0.2% cantharidin) on Day -10. On the Day 14 of each cohort, each subject will receive an intravenous in vivo LPS challenge at a dose not exceeding 0.75 nanogram per kilogram or an intravenous infusion of GM-CSF, in vivo as 60 microgram per meter^2. The administration of LPS or GM CSF will be followed by blister induction on forearm (0.2 % cantharidin).
Other : Cantharidin
This will be applied as a topical application with 0.7% cantharidin liquid which will be diluted with acetone to 0.2%.

Placebo Comparator Placebo, Part C
The subjects in this cohort will receive a matching placebo to GSK3358699, Part C, as a single oral dose once daily for 14 consecutive days. The subjects in this arm will constitute 3 cohorts each (cohort 4 to 6), where the subjects will receive placebo, as one repeat dose treatment once daily for 14-consecutive days. Subjects will have control blisters induced on the forearm (0.2% cantharidin) on Day -10. On the Day 14 of each cohort, each subject will receive an intravenous in vivo LPS challenge at a dose not exceeding 0.75 nanogram per kilogram or an intravenous infusion of GM-CSF, in vivo as 60 microgram per meter^2. The administration of LPS or GM CSF will be followed by blister induction on forearm (0.2 % cantharidin).
Biological : LPS
LPS will be administered as an intravenous injection to subjects not exceeding 0.75 nanogram per kilogram in Part A (Day 1) and Part C (Day 14). This will be administered no later than 24 hours post -dose of the GSK3358699 or placebo in Part C.

Placebo Comparator Placebo, Part C
The subjects in this cohort will receive a matching placebo to GSK3358699, Part C, as a single oral dose once daily for 14 consecutive days. The subjects in this arm will constitute 3 cohorts each (cohort 4 to 6), where the subjects will receive placebo, as one repeat dose treatment once daily for 14-consecutive days. Subjects will have control blisters induced on the forearm (0.2% cantharidin) on Day -10. On the Day 14 of each cohort, each subject will receive an intravenous in vivo LPS challenge at a dose not exceeding 0.75 nanogram per kilogram or an intravenous infusion of GM-CSF, in vivo as 60 microgram per meter^2. The administration of LPS or GM CSF will be followed by blister induction on forearm (0.2 % cantharidin).
Drug : Placebo
Placebo will be administered as a matching oral solution or matching capsule to study drug GSK3358699, during Part A and C once daily

Placebo Comparator Placebo, Part C
The subjects in this cohort will receive a matching placebo to GSK3358699, Part C, as a single oral dose once daily for 14 consecutive days. The subjects in this arm will constitute 3 cohorts each (cohort 4 to 6), where the subjects will receive placebo, as one repeat dose treatment once daily for 14-consecutive days. Subjects will have control blisters induced on the forearm (0.2% cantharidin) on Day -10. On the Day 14 of each cohort, each subject will receive an intravenous in vivo LPS challenge at a dose not exceeding 0.75 nanogram per kilogram or an intravenous infusion of GM-CSF, in vivo as 60 microgram per meter^2. The administration of LPS or GM CSF will be followed by blister induction on forearm (0.2 % cantharidin).
Biological : GM-CSF
The GM-CSF will be administered as an intravenous infusion to subjects as 60 microgram per meter^2 in Part A (Day 1) and Part C (Day 14).This will be administered for 2 hours approximately, no later than 24 hours post -dose of the GSK3358699 or placebo in Part C

Arm Intervention/Treatment
Experimental GSK3358699, Part A, Cohort 1
Part A will comprise of 4 TPs. The subjects in this cohort will receive GSK3358699, as single escalation dose, during TP (1 to 3) with planned escalated doses as 1 mg, 10 mg and 35 mg. Dose of 1 mg will be given as solution and doses of 10 mg and 35 mg, will be given as a capsule. Each TP will be of 1 day and separated by a washout period of 14-days. Post completion of the dose-escalation TPs, an additional dosing TP 4 will be included where the subjects from each TP (1 to 3), will receive control blisters induced on forearm (0.2 % cantharidin) at Day -10. The subjects in cohort 1 will receive GSK3358699 at a dose level already given in TP 1-3, and will then receive an intravenous in vivo LPS challenge at a dose not exceeding 0.75 nanogram per kilogram post administration of GSK3358699. The subjects will then have blisters induced on the forearm approximately 20 minutes after the challenge. LPS dose will be based on data of study 207654.
Drug : GSK3358699
Experimental GSK3358699, Part A, Cohort 1
Part A will comprise of 4 TPs. The subjects in this cohort will receive GSK3358699, as single escalation dose, during TP (1 to 3) with planned escalated doses as 1 mg, 10 mg and 35 mg. Dose of 1 mg will be given as solution and doses of 10 mg and 35 mg, will be given as a capsule. Each TP will be of 1 day and separated by a washout period of 14-days. Post completion of the dose-escalation TPs, an additional dosing TP 4 will be included where the subjects from each TP (1 to 3), will receive control blisters induced on forearm (0.2 % cantharidin) at Day -10. The subjects in cohort 1 will receive GSK3358699 at a dose level already given in TP 1-3, and will then receive an intravenous in vivo LPS challenge at a dose not exceeding 0.75 nanogram per kilogram post administration of GSK3358699. The subjects will then have blisters induced on the forearm approximately 20 minutes after the challenge. LPS dose will be based on data of study 207654.
Biological : LPS
Experimental GSK3358699, Part A, Cohort 1
Part A will comprise of 4 TPs. The subjects in this cohort will receive GSK3358699, as single escalation dose, during TP (1 to 3) with planned escalated doses as 1 mg, 10 mg and 35 mg. Dose of 1 mg will be given as solution and doses of 10 mg and 35 mg, will be given as a capsule. Each TP will be of 1 day and separated by a washout period of 14-days. Post completion of the dose-escalation TPs, an additional dosing TP 4 will be included where the subjects from each TP (1 to 3), will receive control blisters induced on forearm (0.2 % cantharidin) at Day -10. The subjects in cohort 1 will receive GSK3358699 at a dose level already given in TP 1-3, and will then receive an intravenous in vivo LPS challenge at a dose not exceeding 0.75 nanogram per kilogram post administration of GSK3358699. The subjects will then have blisters induced on the forearm approximately 20 minutes after the challenge. LPS dose will be based on data of study 207654.
Other : Cantharidin
Experimental GSK3358699, Part A, Cohort 2
Part A will comprise of 4 TPs. The subjects in this cohort will receive GSK3358699, as single escalation dose during TP (1 to 3) with planned escalated doses as 3 mg, 20 mg and 45 mg. Dose of 3 mg will be given as solution and that of 20 and 45 mg, as capsule. Each TP will be of 1 day and separated by a washout period of 14-days. Post completion of the dose-escalation TPs, an additional dosing TP 4 will be included where the subjects from each TP (1 to 3), will receive control blisters induced on forearm (0.2 % cantharidin) at Day -10. The subjects in cohort 2 will receive GSK3358699 at a dose level already given in TP 1-3, and will then receive 60 microgram per meter^2 of in vivo GM CSF challenge as an intravenous infusion during TP 4, post administration of GSK3358699. The subjects will then have blisters induced on the forearm approximately 20 minutes after the challenge GM-CSF infusion. GM-CSF dose will be based on data of study 207654.
Other : Cantharidin
Experimental GSK3358699, Part A, Cohort 2
Part A will comprise of 4 TPs. The subjects in this cohort will receive GSK3358699, as single escalation dose during TP (1 to 3) with planned escalated doses as 3 mg, 20 mg and 45 mg. Dose of 3 mg will be given as solution and that of 20 and 45 mg, as capsule. Each TP will be of 1 day and separated by a washout period of 14-days. Post completion of the dose-escalation TPs, an additional dosing TP 4 will be included where the subjects from each TP (1 to 3), will receive control blisters induced on forearm (0.2 % cantharidin) at Day -10. The subjects in cohort 2 will receive GSK3358699 at a dose level already given in TP 1-3, and will then receive 60 microgram per meter^2 of in vivo GM CSF challenge as an intravenous infusion during TP 4, post administration of GSK3358699. The subjects will then have blisters induced on the forearm approximately 20 minutes after the challenge GM-CSF infusion. GM-CSF dose will be based on data of study 207654.
Biological : GM-CSF
Experimental GSK3358699, Part A, Cohort 2
Part A will comprise of 4 TPs. The subjects in this cohort will receive GSK3358699, as single escalation dose during TP (1 to 3) with planned escalated doses as 3 mg, 20 mg and 45 mg. Dose of 3 mg will be given as solution and that of 20 and 45 mg, as capsule. Each TP will be of 1 day and separated by a washout period of 14-days. Post completion of the dose-escalation TPs, an additional dosing TP 4 will be included where the subjects from each TP (1 to 3), will receive control blisters induced on forearm (0.2 % cantharidin) at Day -10. The subjects in cohort 2 will receive GSK3358699 at a dose level already given in TP 1-3, and will then receive 60 microgram per meter^2 of in vivo GM CSF challenge as an intravenous infusion during TP 4, post administration of GSK3358699. The subjects will then have blisters induced on the forearm approximately 20 minutes after the challenge GM-CSF infusion. GM-CSF dose will be based on data of study 207654.
Drug : GSK3358699
Experimental GSK3358699, Part B
The subjects in this arm will receive single oral dose of GSK3358699, at a dose level evaluated in Part A, following either fed or fasted condition. This cohort intended to evaluate the effect of food.
Drug : GSK3358699
Experimental GSK3358699, Part C
The dose level for the first cohort in Part C will be decided following completion of Part A of the study for GSK3358699. The subjects in this arm will constitute 3 cohorts each (cohort 4 to 6), where the subjects will receive GSK3358699, as one repeat dose treatment once daily for 14-consecutive days. Subjects will have control blisters induced on the forearm (0.2% cantharidin) on Day -10. On the Day 14 of each cohort, each subject will receive an intravenous in vivo LPS challenge at a dose not exceeding 0.75 nanogram per kilogram or an intravenous infusion of GM-CSF, in vivo as 60 microgram per meter^2. The administration of LPS or GM CSF will be followed by blister induction on forearm (0.2 % cantharidin).
Drug : GSK3358699
Experimental GSK3358699, Part C
The dose level for the first cohort in Part C will be decided following completion of Part A of the study for GSK3358699. The subjects in this arm will constitute 3 cohorts each (cohort 4 to 6), where the subjects will receive GSK3358699, as one repeat dose treatment once daily for 14-consecutive days. Subjects will have control blisters induced on the forearm (0.2% cantharidin) on Day -10. On the Day 14 of each cohort, each subject will receive an intravenous in vivo LPS challenge at a dose not exceeding 0.75 nanogram per kilogram or an intravenous infusion of GM-CSF, in vivo as 60 microgram per meter^2. The administration of LPS or GM CSF will be followed by blister induction on forearm (0.2 % cantharidin).
Biological : GM-CSF
Experimental GSK3358699, Part C
The dose level for the first cohort in Part C will be decided following completion of Part A of the study for GSK3358699. The subjects in this arm will constitute 3 cohorts each (cohort 4 to 6), where the subjects will receive GSK3358699, as one repeat dose treatment once daily for 14-consecutive days. Subjects will have control blisters induced on the forearm (0.2% cantharidin) on Day -10. On the Day 14 of each cohort, each subject will receive an intravenous in vivo LPS challenge at a dose not exceeding 0.75 nanogram per kilogram or an intravenous infusion of GM-CSF, in vivo as 60 microgram per meter^2. The administration of LPS or GM CSF will be followed by blister induction on forearm (0.2 % cantharidin).
Biological : LPS
Experimental GSK3358699, Part C
The dose level for the first cohort in Part C will be decided following completion of Part A of the study for GSK3358699. The subjects in this arm will constitute 3 cohorts each (cohort 4 to 6), where the subjects will receive GSK3358699, as one repeat dose treatment once daily for 14-consecutive days. Subjects will have control blisters induced on the forearm (0.2% cantharidin) on Day -10. On the Day 14 of each cohort, each subject will receive an intravenous in vivo LPS challenge at a dose not exceeding 0.75 nanogram per kilogram or an intravenous infusion of GM-CSF, in vivo as 60 microgram per meter^2. The administration of LPS or GM CSF will be followed by blister induction on forearm (0.2 % cantharidin).
Other : Cantharidin
Placebo Comparator Placebo, Part A, Cohort 1
Part A will comprise of 4 TPs. The subjects in this cohort will receive matching Placebo solution to the study drug GSK3358699 solution for 1 mg and a matching placebo capsule to the study drug GSK3358699, 10 mg and 35 mg capsule, during TP (1 to 3). Each TP will be of 1 day and separated by a washout period of 14-days. Post completion of the dose-escalation TPs, an additional dosing TP 4 will be included where the subjects from each TP (1 to 3), will receive control blisters induced on forearm (0.2 % cantharidin) at Day -10. The subjects in cohort 1 will receive Placebo at a dose level already given in TP 1-3, and will then receive an intravenous in vivo LPS challenge at a dose not exceeding 0.75 nanogram per kilogram post administration of Placebo. The subjects will then have blisters induced on the forearm approximately 20 minutes after the challenge. LPS dose will be based on data of study 207654.
Biological : LPS
Placebo Comparator Placebo, Part A, Cohort 1
Part A will comprise of 4 TPs. The subjects in this cohort will receive matching Placebo solution to the study drug GSK3358699 solution for 1 mg and a matching placebo capsule to the study drug GSK3358699, 10 mg and 35 mg capsule, during TP (1 to 3). Each TP will be of 1 day and separated by a washout period of 14-days. Post completion of the dose-escalation TPs, an additional dosing TP 4 will be included where the subjects from each TP (1 to 3), will receive control blisters induced on forearm (0.2 % cantharidin) at Day -10. The subjects in cohort 1 will receive Placebo at a dose level already given in TP 1-3, and will then receive an intravenous in vivo LPS challenge at a dose not exceeding 0.75 nanogram per kilogram post administration of Placebo. The subjects will then have blisters induced on the forearm approximately 20 minutes after the challenge. LPS dose will be based on data of study 207654.
Drug : Placebo
Placebo Comparator Placebo, Part A, Cohort 1
Part A will comprise of 4 TPs. The subjects in this cohort will receive matching Placebo solution to the study drug GSK3358699 solution for 1 mg and a matching placebo capsule to the study drug GSK3358699, 10 mg and 35 mg capsule, during TP (1 to 3). Each TP will be of 1 day and separated by a washout period of 14-days. Post completion of the dose-escalation TPs, an additional dosing TP 4 will be included where the subjects from each TP (1 to 3), will receive control blisters induced on forearm (0.2 % cantharidin) at Day -10. The subjects in cohort 1 will receive Placebo at a dose level already given in TP 1-3, and will then receive an intravenous in vivo LPS challenge at a dose not exceeding 0.75 nanogram per kilogram post administration of Placebo. The subjects will then have blisters induced on the forearm approximately 20 minutes after the challenge. LPS dose will be based on data of study 207654.
Other : Cantharidin
Placebo Comparator Placebo, Part A, Cohort 2
Part A will comprise of 4 TPs. The subjects in this cohort will receive matching Placebo solution to the study drug GSK3358699 solution for 3 mg and a matching placebo capsule to the study drug GSK3358699, for 20 and 45 mg capsule, during TP (1 to 3). Each TP will be of 1 day and separated by a washout period of 14-days. Post completion of the dose-escalation TPs, an additional dosing TP 4 will be included where the subjects from each TP (1 to 3), will receive control blisters induced on forearm (0.2 % cantharidin) at Day -10. The subjects in cohort 2 will receive Placebo at a dose level already given in TP 1-3, and will then receive 60 microgram per meter^2 of in vivo GM CSF challenge as an intravenous infusion during TP 4, post administration of Placebo. The subjects will then have blisters induced on the forearm approximately 20 minutes after the challenge GM-CSF infusion. GM-CSF dose will be based on data of study 207654.
Drug : Placebo
Placebo Comparator Placebo, Part A, Cohort 2
Part A will comprise of 4 TPs. The subjects in this cohort will receive matching Placebo solution to the study drug GSK3358699 solution for 3 mg and a matching placebo capsule to the study drug GSK3358699, for 20 and 45 mg capsule, during TP (1 to 3). Each TP will be of 1 day and separated by a washout period of 14-days. Post completion of the dose-escalation TPs, an additional dosing TP 4 will be included where the subjects from each TP (1 to 3), will receive control blisters induced on forearm (0.2 % cantharidin) at Day -10. The subjects in cohort 2 will receive Placebo at a dose level already given in TP 1-3, and will then receive 60 microgram per meter^2 of in vivo GM CSF challenge as an intravenous infusion during TP 4, post administration of Placebo. The subjects will then have blisters induced on the forearm approximately 20 minutes after the challenge GM-CSF infusion. GM-CSF dose will be based on data of study 207654.
Biological : GM-CSF
Placebo Comparator Placebo, Part A, Cohort 2
Part A will comprise of 4 TPs. The subjects in this cohort will receive matching Placebo solution to the study drug GSK3358699 solution for 3 mg and a matching placebo capsule to the study drug GSK3358699, for 20 and 45 mg capsule, during TP (1 to 3). Each TP will be of 1 day and separated by a washout period of 14-days. Post completion of the dose-escalation TPs, an additional dosing TP 4 will be included where the subjects from each TP (1 to 3), will receive control blisters induced on forearm (0.2 % cantharidin) at Day -10. The subjects in cohort 2 will receive Placebo at a dose level already given in TP 1-3, and will then receive 60 microgram per meter^2 of in vivo GM CSF challenge as an intravenous infusion during TP 4, post administration of Placebo. The subjects will then have blisters induced on the forearm approximately 20 minutes after the challenge GM-CSF infusion. GM-CSF dose will be based on data of study 207654.
Other : Cantharidin
Placebo Comparator Placebo, Part C
The subjects in this cohort will receive a matching placebo to GSK3358699, Part C, as a single oral dose once daily for 14 consecutive days. The subjects in this arm will constitute 3 cohorts each (cohort 4 to 6), where the subjects will receive placebo, as one repeat dose treatment once daily for 14-consecutive days. Subjects will have control blisters induced on the forearm (0.2% cantharidin) on Day -10. On the Day 14 of each cohort, each subject will receive an intravenous in vivo LPS challenge at a dose not exceeding 0.75 nanogram per kilogram or an intravenous infusion of GM-CSF, in vivo as 60 microgram per meter^2. The administration of LPS or GM CSF will be followed by blister induction on forearm (0.2 % cantharidin).
Other : Cantharidin
Placebo Comparator Placebo, Part C
The subjects in this cohort will receive a matching placebo to GSK3358699, Part C, as a single oral dose once daily for 14 consecutive days. The subjects in this arm will constitute 3 cohorts each (cohort 4 to 6), where the subjects will receive placebo, as one repeat dose treatment once daily for 14-consecutive days. Subjects will have control blisters induced on the forearm (0.2% cantharidin) on Day -10. On the Day 14 of each cohort, each subject will receive an intravenous in vivo LPS challenge at a dose not exceeding 0.75 nanogram per kilogram or an intravenous infusion of GM-CSF, in vivo as 60 microgram per meter^2. The administration of LPS or GM CSF will be followed by blister induction on forearm (0.2 % cantharidin).
Biological : LPS
Placebo Comparator Placebo, Part C
The subjects in this cohort will receive a matching placebo to GSK3358699, Part C, as a single oral dose once daily for 14 consecutive days. The subjects in this arm will constitute 3 cohorts each (cohort 4 to 6), where the subjects will receive placebo, as one repeat dose treatment once daily for 14-consecutive days. Subjects will have control blisters induced on the forearm (0.2% cantharidin) on Day -10. On the Day 14 of each cohort, each subject will receive an intravenous in vivo LPS challenge at a dose not exceeding 0.75 nanogram per kilogram or an intravenous infusion of GM-CSF, in vivo as 60 microgram per meter^2. The administration of LPS or GM CSF will be followed by blister induction on forearm (0.2 % cantharidin).
Drug : Placebo
Placebo Comparator Placebo, Part C
The subjects in this cohort will receive a matching placebo to GSK3358699, Part C, as a single oral dose once daily for 14 consecutive days. The subjects in this arm will constitute 3 cohorts each (cohort 4 to 6), where the subjects will receive placebo, as one repeat dose treatment once daily for 14-consecutive days. Subjects will have control blisters induced on the forearm (0.2% cantharidin) on Day -10. On the Day 14 of each cohort, each subject will receive an intravenous in vivo LPS challenge at a dose not exceeding 0.75 nanogram per kilogram or an intravenous infusion of GM-CSF, in vivo as 60 microgram per meter^2. The administration of LPS or GM CSF will be followed by blister induction on forearm (0.2 % cantharidin).
Biological : GM-CSF

Recruitment Information

Recruitment Status:Not yet recruiting
Enrollment80
Completion DateAugust 05, 2019
Eligibility Criteria: Inclusion Criteria:
- Subjects must be 18 to 45 years of age inclusive, at the time of signing the informed consent.
- Subjects must be overtly healthy as determined by medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring.
- Body weight must be > = 50 kilogram (kg) and body mass index (BMI) within the range 18.5-35.0 kg per square meter (kg/m^2) (inclusive).
- Male subjects agreeing to use contraceptive methods during the treatment period and for at least 91 days, after the last dose of study treatment and refrain from donating sperm during this period.
- Capable of giving informed consent.

Exclusion Criteria:
- Current or chronic history of pancreatitis, diabetes mellitus or impaired glucose tolerance, gastrointestinal disease, liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones), anaphylaxis, and /or anaphylactoid (resembling anaphylaxis) reactions [Sampson et al 2006], cardiac disease including clinically significant ventricular arrhythmias or long QT syndrome, renal disease where clinically significant (minor abnormalities may be permitted base on discussion between investigator and medical monitor), respiratory disease or conditions including but not limited to asthma, chronic obstructive pulmonary disease (COPD), and bronchiectasis and any current respiratory infection (childhood asthma is not an exclusion criterion), sensitivity or severe allergic responses to any of the challenge agents or cantharidin, or components thereof or a history of drug or other allergy that, in the opinion of the Investigator or GlaxoSmithKline (GSK) Medical Monitor, contraindicates their participation; frequent vasovagal syncope, surgery requiring general anaesthetic or significant trauma in 3 months leading to study enrolment, relevant skin conditions (e.g. recent history of eczema or recurrent eczema, keloid, skin allergies, psoriasis, atopic dermatitis, and vitiligo) which in the opinion of the investigator could pose safety issues or cause interference with study procedures, sepsis, coagulation disorders, peripheral edema, lymphangitis, lymphedema, pleural or pericardial effusion, hemorrhage (eg sub-arachnoid) or hemophilia or a related bleeding disorder.
- History of malignancies e.g. recurrent basal cell carcinoma, hematological malignancy.
- Presence on either forearm of tattoos, naevi, hypertrophic scars, keloids, hyper- or hypo- pigmentation that may, in the opinion of the Investigator, interfere with study assessments. Subjects with very fair skin, very dark skin, excessive hair or any skin abnormalities that may, in the opinion of the Investigator, interfere with study assessments.
- Family history of premature cardiovascular disease or long QT syndrome.
- QT interval with Fridericia's correction (QTcF) > 450 millisecond (msec), based on averaged QTcF values of triplicate ECGs obtained over a brief recording period.
- Unable or unwilling to refrain from taking prescription or non-prescription drugs (including vitamins and dietary or herbal supplements) within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) before the start of study treatment until completion of the follow-up visit. Paracetamol, at a dose of <= 2 grams per day was permitted for use anytime during the study. Other concomitant medications will be considered on case by case basis.
- The subjects have participated in a clinical trial and had received an investigational product within time period following first dosing in the current study in 90 days; 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer) or currently in a study of an investigational device.
- Exposure to more than four new chemical entities within 12 months prior to the first dosing day.
- Previous exposure to intravenous lipopolysaccharide (LPS) in a clinical research setting (for Part A and C subjects only).
- Prior participation in the enabling study 207654.
- Alanine transaminase (ALT) >1.5x upper limit of normal (ULN).
- Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
- Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test result at screening or within 3 months prior to first dose of study treatment.
- A positive pre-study drug/alcohol screen.
- A positive test for human immunodeficiency virus (HIV) antibody.
- Persistent abnormal C-reactive protein (CRP) levels at screening
- Persistent clinically significant abnormal white cell count (WCC) levels at screening (if clinically significant abnormality is detected, WCC can be retested as clinically indicated)
- Platelets < 150 x 10^9 per liter (L).
- Triglycerides > = 2.3 millimole per liter (mmol/L).
- Total cholesterol >=5.2 mmol/L.
- Random glucose > = 11.1 mmol/L.
- Urinary cotinine levels indicative of smoking or history or regular use of tobacco- or nicotine-containing products within 3 months prior to screening.
- History of regular alcohol consumption within 6 months of the study defined as: an average weekly intake of >14 units. One unit is equivalent to 8 gram of alcohol: a half-pint (approximately 240 milliliter [mL]) of beer, 1 glass (125 mL) of wine or 1 (25 mL).
- Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period.
- Unable to comply with precautions to minimize phototoxicity risk.
GenderMale
Age18 Years to 45 Years
Accepts Healthy VolunteersAccepts Healthy Volunteers
Contacts
Listed Location Countries
Not Available

Administrative Information

NCT Number:NCT03426995
Other Study ID Numbers
207546
Has Data Monitoring CommitteeNo
U.S. FDA-regulated Product Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Device Product Not Approved or Cleared by U.S. FDA: No
IPD Sharing Statement
Not Available
Responsible Party,
Study Sponsor
GlaxoSmithKline
Collaborators
Not Available
Investigators
Study Director
GSK Clinical Trials
GlaxoSmithKline