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

Sponsor
GlaxoSmithKline (Industry)
Overall Status
Terminated
CT.gov ID
NCT03426995
Collaborator
(none)
48
1
8
13.6
3.5

Study Details

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.

Condition or Disease Intervention/Treatment Phase
  • Drug: Placebo
  • Drug: GSK3358699
  • Biological: GM-CSF
  • Biological: LPS
  • Other: Cantharidin
Phase 1

Detailed Description

Subjects who are enrolled in the dose escalation treatment Periods of Part A may choose to only take part in the dose escalation treatment Periods 1-3, or may choose to also take part in the challenge Treatment Period (Period 4). If a subject chooses to participate in the dose escalation treatment Periods 1-3 only, or does not (at screening) meet the eligibility criteria specific to challenges (treatment Period 4), a new subject will be recruited for treatment Period 4 only and will be regarded as a replacement subject. The study will be conducted in three Parts. Total duration for participation will be approximately 19 weeks for subjects taking part in all three dose escalation treatment Periods and 23 weeks if a subject takes part in all four treatment Periods of Part A. For replacement subjects only taking part in the challenge treatment Period (Period 4), approximate study duration will be 10 weeks. Total duration for participation will be approximately 9 weeks for Part B and 12 weeks for Part C. The study will be conducted in up to 80 subjects.

Study Design

Study Type:
Interventional
Actual Enrollment :
48 participants
Allocation:
Randomized
Intervention Model:
Crossover Assignment
Intervention Model Description:
Study will be conducted as Part A, B and C. Part A will consist of 2-interlocking cohorts, where each subject will receive maximum 2-single ascending oral doses of GSK3358699 and 1 dose of placebo, in Treatment Periods (TP) 1 to 3. In TP 4 subjects will receive GSK3358699, dose evaluated in TP (1 to 3) or placebo, with cantharidin induced blisters and either LPS or GM-CSF in vivo challenge. Part B will comprise of single cohort taking part in two-way cross over, with open label phase where each subject will receive single oral dose of GSK3358699 (based on Part A), under fed and fasted conditions in each TP. Part C will consist of 3 cohorts with multiple ascending doses, with every cohort having one repeat dose TP with 14 days of daily dosing of either GSK3358699 or placebo. Subjects on Day 14 will receive cantharidin induced blisters with either LPS or GM-CSF in vivo challenge. An optional, cohort 7 may be included for further dose evaluation of GSK3358699 or alternate dosing schedule.Study will be conducted as Part A, B and C. Part A will consist of 2-interlocking cohorts, where each subject will receive maximum 2-single ascending oral doses of GSK3358699 and 1 dose of placebo, in Treatment Periods (TP) 1 to 3. In TP 4 subjects will receive GSK3358699, dose evaluated in TP (1 to 3) or placebo, with cantharidin induced blisters and either LPS or GM-CSF in vivo challenge. Part B will comprise of single cohort taking part in two-way cross over, with open label phase where each subject will receive single oral dose of GSK3358699 (based on Part A), under fed and fasted conditions in each TP. Part C will consist of 3 cohorts with multiple ascending doses, with every cohort having one repeat dose TP with 14 days of daily dosing of either GSK3358699 or placebo. Subjects on Day 14 will receive cantharidin induced blisters with either LPS or GM-CSF in vivo challenge. An optional, cohort 7 may be included for further dose evaluation of GSK3358699 or alternate dosing schedule.
Masking:
Double (Participant, Investigator)
Masking Description:
This will be a double blind (sponsor open) study with respect to allocation of GSK3358699 or placebo to subjects. All site staff will be blinded with the exception of un-blinded pharmacists. Investigators will be un-blinded with respect to the LPS and GM-CSF allocation. The food effect part of the study (Part B) will be open-label
Primary Purpose:
Treatment
Official Title:
A 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
Actual Study Start Date :
Mar 13, 2018
Actual Primary Completion Date :
May 2, 2019
Actual Study Completion Date :
May 2, 2019

Arms and Interventions

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 (NCT03306589).

Drug: GSK3358699
GSK3358699, will be administered from 1 mg to 45 mg as an oral solution (1 to 10 mg) or as a capsule (3 to 45 mg), in Part A, B and Part C once daily.

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: 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 (NCT03306589).

Drug: GSK3358699
GSK3358699, will be administered from 1 mg to 45 mg as an oral solution (1 to 10 mg) or as a capsule (3 to 45 mg), in Part A, B and Part C once daily.

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: 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 (NCT03306589).

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

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: 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 (NCT03306589).

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

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

Experimental: Part B, GSK3358699 under Fasted followed by Fed conditions

The subjects in this arm will receive single oral dose of GSK3358699, at a dose level evaluated in Part A, under fasted condition in TP1 followed by fed condition in TP2. 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 (3 to 45 mg), in Part A, B and Part C once daily.

Experimental: Part B, GSK3358699 under Fed followed by Fasted conditions

The subjects in this arm will receive single oral dose of GSK3358699, at a dose level evaluated in Part A, under fed condition in TP1 followed by fasted condition in TP2. 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 (3 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 (3 to 45 mg), in Part A, B and Part C once daily.

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

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: 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).

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

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

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

Outcome Measures

Primary Outcome Measures

  1. Part A: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) [Up to Day 193]

    An adverse event (AE) is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, important medical events that may jeopardize the participant or require medical or surgical intervention to prevent one of the outcomes listed before. Safety Population consisted of all randomized participants who took at least 1 dose of study treatment.

  2. Part B: Number of Participants With AEs and SAEs [Up to Day 30]

    An AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, important medical events that may jeopardize the participant or require medical or surgical intervention to prevent one of the outcomes listed before.

  3. Part C: Number of Participants With AEs and SAEs [Up to Day 49]

    An AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, important medical events that may jeopardize the participant or require medical or surgical intervention to prevent one of the outcomes listed before.

  4. Part A: Number of Participants With Worst Case Chemistry Results by Potential Clinical Importance (PCI) Criteria Post-Baseline Relative to Baseline [Up to Day 193]

    Blood samples were collected for analysis of clinical chemistry parameters. PCI ranges were <30 grams per liter (g/L) (albumin), <2 or >2.75 millimoles/L (mmol/L) (calcium), >1.3* upper limit of normal (ULN) mmol/L (creatinine), <3 or >9 mmol/L (glucose), <3 or >5.5 mmol/L (potassium), and <130 or >150 mmol/L (sodium). Participants were counted in worst case category that their value changes to (low, within range or no change or high), unless there is no change in their category. Participants whose laboratory value category was unchanged (e.g., High to High), or whose value became within range, were recorded in To within Range or No Change (NC) category. Participants were counted twice if participant had values that changed To Low and To High, so the percentages may not add to 100%.

  5. Part A: Number of Participants With Worst Case Chemistry Results Relative to Normal Range Post-Baseline Relative to Baseline [Up to Day 193]

    Clinical chemistry parameters assessed were alanine aminotransferase(ALT)(<10 or >50 international units per liter[IU/L]),alkaline phosphatase(ALP)(<40 or >129 IU/L),aspartate aminotransferase(AST)(<0 or >37 IU/L),cholesterol(<2.3 or >4.9 mmol/L),direct bilirubin(DB)(<0 or >5 micromoles[mcmol]/L),high density lipoprotein (DL)(<0.9 or >1.5 mmol/L),C-reactive protein(CRP)(<0.0 or >5.0mg/liter),low DL(<0 or >3.0 mmol/L), total bilirubin (<0 or >20 mcmol/L),total protein(<63 or >83 grams/L),triglycerides(<0 or >2.3 mmol/L) and blood urea nitrogen(BUN)(<4.76 or >23.24 mg/deciliter).Participants were counted in worst case category that their value changes to (low, normal or high), unless there is NC in their category.Participants whose laboratory value category was unchanged(e.g.,High to High) or whose value became normal, are recorded in "To Normal or NC" category.Participants were counted twice if participant had values that changed To Low and To High, so percentages may not add to 100%.

  6. Part B: Number of Participants With Worst Case Chemistry Results by PCI Criteria Post-Baseline Relative to Baseline [Up to Day 30]

    Blood samples were planned to be collected to analyze the chemistry parameters.

  7. Part B: Number of Participants With Worst Case Chemistry Results Relative to Normal Range Post-Baseline Relative to Baseline [Up to Day 30]

    Blood samples were planned to be collected to analyze the chemistry parameters.

  8. Part C: Number of Participants With Worst Case Chemistry Results by PCI Criteria Post-Baseline Relative to Baseline [Up to Day 28]

    Blood samples were collected for analysis of chemistry parameters. PCI ranges were <30 g/L (albumin), <2 or >2.75 mmol/L (calcium), >1.3* ULN mmol/L (creatinine), <3 or >9 mmol/L (glucose), <3 or >5.5 mmol/L (potassium), and <130 or >150 mmol/L (sodium). Participants were counted in worst case category that their value changes to (low, within range or no change or high), unless there is no change in their category. Participants whose laboratory value category was unchanged (e.g., High to High), or whose value became within range, were recorded in To within Range or No Change category. Participants were counted twice if participant had values that changed To Low and To High, so the percentages may not add to 100%.

  9. Part C: Number of Participants With Worst Case Chemistry Results Relative to Normal Range Post-Baseline Relative to Baseline [Up to Day 28]

    Clinical chemistry parameters assessed were ALT (<10 or >50 IU/L), ALP (<40 or >129 IU/L), AST (<0 or >37 IU/L), cholesterol (<2.3 or >4.9 mmol/L), DB (<0 or >5 mcmol/L), high DL (<0.9 or >1.5 mmol/L), CRP (<0.0 or >5.0 mg/liter), low DL (<0 or >3.0 mmol/L), total bilirubin (<0 or >20 mcmol/L), total protein (<63 or >83 grams/L), triglycerides (<0 or >2.3 mmol/L) and BUN (<4.76 or >23.24 mg/deciliter). Participants were counted in worst case category that their value changes to (low, normal or high), unless there is NC in their category. Participants whose laboratory value category was unchanged (e.g., High to High) or whose value became normal, are recorded in "To Normal or NC" category. Participants were counted twice if participant had values that changed To Low and To High, so percentages may not add to 100%.

  10. Part A: Number of Participants With Worst Case Hematology Results by PCI Criteria Post-Baseline Relative to Baseline [Up to Day 193]

    Blood samples collected for analysis of hematology parameters. PCI ranges were >0.54 proportion of red blood cells in blood (hematocrit), >180 grams/liter (hemoglobin), <0.8 *10^9 cells/L (lymphocyte count), <1.5 *10^9 cells/L (total absolute neutrophil count [ANC]), <100 or >550 *10^9 cells/L (platelet count), and <3 or >20*10^9 cells/L (white blood cell [WBC] count). Participants were counted in worst case category that their value changes to (low, within range or no change or high), unless there is no change in their category. Participants whose laboratory value category was unchanged (e.g., High to High), or whose value became within range, were recorded in To within Range or No Change category. Participants were counted twice if the participant had values that changed To Low and To High, so the percentages may not add to 100%.

  11. Part A: Number of Participants With Worst Case Hematology Results Relative to Normal Range Post-Baseline Relative to Baseline [Up to Day 193]

    Hematology parameters assessed were activated partial thromboplastin time (APTT) (<25 or >37 seconds), basophil count (<0.0 or >0.1*10^9 cells/L), eosinophil count (<0.0 or >0.4*10^9 cells/L), fibrinogen (<1.5 or >4.0 g/L), mean corpuscle hemoglobin (MCH) (<26.0 or >33.5 picogram), mean corpuscle volume (MCV) (<80 or >99 femtoliter), monocyte count (<0.2 or >1.0*10^9 cells/L), prothrombin time (PT) (<10 or >12 seconds), red blood cell (RBC) count (<4.4 or >5.8*10^12 cells/L) and reticulocyte count (<0.38 or >2.64 percentage of reticulocytes). Participants were counted in worst case category that their value changes to (low, normal or high), unless there is NC in their category. Participants whose laboratory value category was unchanged (e.g., High to High) or whose value became normal, are recorded in "To Normal or NC" category. Participants were counted twice if participant had values that changed To Low and To High, so percentages may not add to 100%.

  12. Part B: Number of Participants With Worst Case Hematology Results by PCI Criteria Post-Baseline Relative to Baseline [Up to Day 30]

    Blood samples were planned to be collected to analyze hematology parameters.

  13. Part B: Number of Participants With Worst Case Hematology Results Relative to Normal Range Post-Baseline Relative to Baseline [Up to Day 30]

    Blood samples were planned to be collected to analyze hematology parameters.

  14. Part C: Number of Participants With Worst Case Hematology Results by PCI Criteria Post-Baseline Relative to Baseline [Up to Day 28]

    Blood samples were collected for analysis of hematology parameters. PCI ranges were >0.54 proportion of red blood cells in blood (hematocrit), >180 grams/liter (hemoglobin), <0.8*10^9 cells/L (lymphocyte count), <1.5*10^9 cells/L (total ANC), <100 or >550*10^9 cells/L (platelet count), and <3 or >20*10^9 cells/L (WBC count). Participants were counted in worst case category that their value changes to (low, within range or no change or high), unless there is no change in their category. Participants whose laboratory value category was unchanged (e.g., High to High), or whose value became within range, were recorded in To within Range or No Change category. Participants were counted twice if the participant had values that changed To Low and To High, so the percentages may not add to 100%.

  15. Part C: Number of Participants With Worst Case Hematology Results Relative to Normal Range Post-Baseline Relative to Baseline [Up to Day 28]

    Hematology parameters assessed were APTT (<25 or >37 seconds), basophil count (<0.0 or >0.1*10^9 cells/L), eosinophil count (<0.0 or >0.4*10^9 cells/L), fibrinogen (<1.5 or >4.0 g/L), MCH (<26.0 or >33.5 picogram), MCV (<80 or >99 femtoliter), monocyte count (<0.2 or >1.0*10^9 cells/L), PT (<10 or >12 seconds), RBC count (<4.4 or >5.8*10^12 cells/L) and reticulocyte count (<0.38 or >2.64 percentage of reticulocytes). Participants were counted in worst case category that their value changes to (low, normal or high), unless there is NC in their category. Participants whose laboratory value category was unchanged (e.g., High to High) or whose value became normal, are recorded in "To Normal or NC" category. Participants were counted twice if participant had values that changed To Low and To High, so percentages may not add to 100%.

  16. Part A: Number of Participants With Abnormal Urinalysis Parameters [Up to Day 193]

    Urine samples were collected from participants for analyzing the following urine parameters: potential of hydrogen (pH) and glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocytes levels by dipstick. Urine samples showing any abnormality were sent for microscopic examination to detect the presence of RBC, WBC, cellular casts, granular casts, hyaline casts, and were counted as cells per high-power field (cells/HPF). Number of participants with abnormal urinalysis result by microscopic examination have been presented.

  17. Part B: Number of Participants With Abnormal Urinalysis Parameters [Up to Day 30]

    Urine samples were planned to be collected to analyze urine parameters.

  18. Part C: Number of Participants With Abnormal Urinalysis Parameters [Up to Day 28]

    Urine samples were collected from participants for analyzing the following urine parameters: pH and glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocytes levels by dipstick. Urine samples showing any abnormality were sent for microscopic examination to detect the presence of RBC, WBC, cellular casts, granular casts, hyaline casts, and were counted as cells/HPF. Number of participants with abnormal urinalysis result by microscopic examination have been presented.

  19. Part A: Number of Participants With Worst Case Vital Sign Results by PCI Criteria Post-Baseline Relative to Baseline [Up to Day 193]

    Vital signs included systolic blood pressure(SBP), diastolic blood pressure(DBP), heart rate, respiratory rate and body temperature and were measured in a semi-supine position after 5 minutes rest. PCI ranges were, SBP (millimeters of mercury [mmHg]): <85 (low) or >160 (high), DBP (mmHg): <45 (low) or >100 (high), heart rate (beats per minute): <40 (low) or >110 (high), respiration rate (breaths per minute): <11(low) or >20(high) and body temperature (degrees Celsius) <35.5 (low) or >38.0 (high). Participants were counted in the worst case category that their value changes to (low, within range or no change, or high), unless there is no change in their category. Participants whose vital signs value category was unchanged (e.g., High to High), or whose value became within range, were recorded in the "To within Range or No Change" category. Participants were counted twice if the participant had values that changed "To Low" and "To High", so the percentages may not add to 100%.

  20. Part B: Number of Participants With Worst Case Vital Sign Results by PCI Criteria Post-Baseline Relative to Baseline [Up to Day 30]

    Vital signs were planned to be measured in a semi-supine position after 5 minutes of rest.

  21. Part C: Number of Participants With Worst Case Vital Sign Results by PCI Criteria Post-Baseline Relative to Baseline [Up to Day 49]

    Vital signs included SBP, DBP, heart rate, respiratory rate and body temperature and were measured in a semi-supine position after 5 minutes rest. PCI ranges were, SBP (mmHg): <85 (low) or >160 (high), DBP (mmHg): <45 (low) or >100 (high), heart rate (beats per minute): <40 (low) or >110 (high), respiration rate (breaths per minute): <11 (low) or >20 (high) and body temperature (degrees Celsius) <35.5 (low) or >38.0 (high). Participants were counted in the worst case category that their value changes to (low, within range or no change, or high), unless there is no change in their category. Participants whose vital signs value category was unchanged (e.g., High to High), or whose value became within range, were recorded in the "To within Range or No Change" category. Participants were counted twice if the participant had values that changed "To Low" and "To High", so the percentages may not add to 100%.

  22. Part A: Number of Participants With Worst Case Post-Baseline Abnormal Electrocardiogram (ECG) Findings [Up to Day 193]

    Twelve lead ECGs were obtained using an ECG machine that automatically calculated the heart rate and measured PR, QRS, QT, and QT interval corrected using the Fridericia's formula (QTcF) intervals. Abnormal findings were categorized as clinically significant (CS) and not clinically significant (NCS). Clinically significant abnormal findings are those which are not associated with the underlying disease, unless judged by the investigator to be more severe than expected for the participant's condition. Data for number of participants with worst case post-Baseline abnormal ECG findings have been presented.

  23. Part B: Number of Participants With Worst Case Post-Baseline Abnormal ECG Findings [Up to Day 30]

    Twelve lead ECGs were planned to be performed to measure PR interval, QRS duration, QT interval and QTcF.

  24. Part C: Number of Participants With Worst Case Post-Baseline Abnormal ECG Findings [Up to Day 28]

    Twelve lead ECGs were obtained using an ECG machine that automatically calculated the heart rate and measured PR, QRS, QT, and QTcF intervals. Abnormal findings were categorized as clinically significant and not clinically significant. Clinically significant abnormal findings are those which are not associated with the underlying disease, unless judged by the investigator to be more severe than expected for the participant's condition. Data for number of participants with worst case post-Baseline abnormal ECG findings have been presented.

Secondary Outcome Measures

  1. Part A: Plasma Concentrations of GSK3358699 [Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose in each treatment period]

    Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3358699. Pharmacokinetic (PK) parameters were calculated using standard non-compartmental analysis. PK Population consisted of all participants in the Safety Population who received an active dose and for whom a PK sample was obtained and analyzed.

  2. Part B: Plasma Concentrations of GSK3358699 [Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose in each treatment period]

    Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of GSK3358699.

  3. Part C: Plasma Concentrations of GSK3358699 [Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12 and 24 hours; Days 4, 8 and 12: Pre-dose; Day 14: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose]

    Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3358699. PK parameters were calculated using standard non-compartmental analysis.

  4. Part A: Area Under the Plasma Concentration Curve From Time Zero to Last Time of Quantifiable Concentration (AUC[0-t]) of GSK3358699 [Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose in each treatment period]

    Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3358699. PK parameters were calculated using standard non-compartmental analysis.

  5. Part B: AUC(0-t) of GSK3358699 [Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose in each treatment period]

    Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of GSK3358699.

  6. Part C: AUC(0-t) of GSK3358699 [Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12 and 24 hours; Day 14: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose]

    Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3358699. PK parameters were calculated using standard non-compartmental analysis.

  7. Part A: Area Under the Plasma Concentration Curve From Time Zero to Infinity (AUC[0-infinity]) of GSK3358699 [Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose in each treatment period]

    Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3358699. PK parameters were calculated using standard non-compartmental analysis.

  8. Part B: AUC(0-infinity) of GSK3358699 [Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose in each treatment period]

    Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of GSK3358699.

  9. Part C: AUC(0-infinity) of GSK3358699 [Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12 and 24 hours; Day 14: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose]

    Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3358699. PK parameters were calculated using standard non-compartmental analysis.

  10. Part A: Area Under the Plasma Concentration Curve From Time Zero to 24 Hours (AUC[0-24]) of GSK3358699 [Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12 and 24 hours post-dose in each treatment period]

    Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3358699. PK parameters were calculated using standard non-compartmental analysis.

  11. Part B: AUC(0-24) of GSK3358699 [Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12 and 24 hours post-dose in each treatment period]

    Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of GSK3358699.

  12. Part C: AUC(0-24) of GSK3358699 [Days 1 and 14: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, and 24 hours post-dose]

    Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3358699. PK parameters were calculated using standard non-compartmental analysis.

  13. Part A: Maximum Plasma Concentration (Cmax) of GSK3358699 [Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose in each treatment period]

    Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3358699. PK parameters were calculated using standard non-compartmental analysis.

  14. Part B: Cmax of GSK3358699 [Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose in each treatment period]

    Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of GSK3358699.

  15. Part C: Cmax of GSK3358699 [Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12 and 24 hours; Day 14: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose]

    Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3358699. PK parameters were calculated using standard non-compartmental analysis.

  16. Part A: Time to Cmax (Tmax) of GSK3358699 [Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose in each treatment period]

    Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3358699. PK parameters were calculated using standard non-compartmental analysis.

  17. Part B: Tmax of GSK3358699 [Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose in each treatment period]

    Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of GSK3358699.

  18. Part C: Tmax of GSK3358699 [Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12 and 24 hours; Day 14: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose]

    Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3358699. PK parameters were calculated using standard non-compartmental analysis.

  19. Part A: Apparent Terminal Phase Half-life (t1/2) of GSK3358699 [Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose in each treatment period]

    Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3358699. PK parameters were calculated using standard non-compartmental analysis.

  20. Part B: t1/2 of GSK3358699 [Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose in each treatment period]

    Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of GSK3358699.

  21. Part C: t1/2 of GSK3358699 [Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12 and 24 hours; Day 14: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose]

    Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3358699. PK parameters were calculated using standard non-compartmental analysis.

  22. Part A: Plasma Concentrations of GSK3206944 [Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose in each treatment period]

    Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3206944. PK parameters were calculated using standard non-compartmental analysis. GSK3206944 is a metabolite of GSK3358699.

  23. Part B: Plasma Concentrations of GSK3206944 [Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose in each treatment period]

    Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of GSK3206944. GSK3206944 is a metabolite of GSK3358699.

  24. Part C: Plasma Concentrations of GSK3206944 [Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12 and 24 hours; Days 4, 8 and 12: Pre-dose; Day 14: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose]

    Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3206944. PK parameters were calculated using standard non-compartmental analysis. GSK3206944 is a metabolite of GSK3358699.

  25. Part A: AUC(0-t) of GSK3206944 [Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose in each treatment period]

    Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3206944. PK parameters were calculated using standard non-compartmental analysis. GSK3206944 is a metabolite of GSK3358699.

  26. Part B: AUC(0-t) of GSK3206944 [Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose in each treatment period]

    Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of GSK3206944. GSK3206944 is a metabolite of GSK3358699.

  27. Part C: AUC(0-t) of GSK3206944 [Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12 and 24 hours; Day 14: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose]

    Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3206944. PK parameters were calculated using standard non-compartmental analysis. GSK3206944 is a metabolite of GSK3358699.

  28. Part A: AUC(0-infinity) of GSK3206944 [Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose in each treatment period]

    Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3206944. PK parameters were calculated using standard non-compartmental analysis. GSK3206944 is a metabolite of GSK3358699.

  29. Part B: AUC(0-infinity) of GSK3206944 [Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose in each treatment period]

    Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of GSK3206944. GSK3206944 is a metabolite of GSK3358699.

  30. Part C: AUC(0-infinity) of GSK3206944 [Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12 and 24 hours; Day 14: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose]

    Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3206944. PK parameters were calculated using standard non-compartmental analysis. GSK3206944 is a metabolite of GSK3358699.

  31. Part A: AUC(0-24) of GSK3206944 [Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12 and 24 hours post-dose in each treatment period]

    Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3206944. PK parameters were calculated using standard non-compartmental analysis. GSK3206944 is a metabolite of GSK3358699.

  32. Part B: AUC(0-24) of GSK3206944 [Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12 and 24 hours post-dose in each treatment period]

    Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of GSK3206944. GSK3206944 is a metabolite of GSK3358699.

  33. Part C: AUC(0-24) of GSK3206944 [Days 1 and 14: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, and 24 hours post-dose]

    Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3206944. PK parameters were calculated using standard non-compartmental analysis. GSK3206944 is a metabolite of GSK3358699.

  34. Part A: Cmax of GSK3206944 [Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose in each treatment period]

    Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3206944. PK parameters were calculated using standard non-compartmental analysis. GSK3206944 is a metabolite of GSK3358699.

  35. Part B: Cmax of GSK3206944 [Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose in each treatment period]

    Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of GSK3206944. GSK3206944 is a metabolite of GSK3358699.

  36. Part C: Cmax of GSK3206944 [Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12 and 24 hours; Day 14: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose]

    Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3206944. PK parameters were calculated using standard non-compartmental analysis. GSK3206944 is a metabolite of GSK3358699.

  37. Part A: Tmax of GSK3206944 [Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose in each treatment period]

    Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3206944. PK parameters were calculated using standard non-compartmental analysis. GSK3206944 is a metabolite of GSK3358699.

  38. Part B: Tmax of GSK3206944 [Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose in each treatment period]

    Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of GSK3206944. GSK3206944 is a metabolite of GSK3358699.

  39. Part C: Tmax of GSK3206944 [Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12 and 24 hours; Day 14: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose]

    Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3206944. PK parameters were calculated using standard non-compartmental analysis. GSK3206944 is a metabolite of GSK3358699.

  40. Part A: t1/2 of GSK3206944 [Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose in each treatment period]

    Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3206944. PK parameters were calculated using standard non-compartmental analysis. GSK3206944 is a metabolite of GSK3358699.

  41. Part B: t1/2 of GSK3206944 [Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose in each treatment period]

    Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of GSK3206944. GSK3206944 is a metabolite of GSK3358699.

  42. Part C: t1/2 of GSK3206944 [Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12 and 24 hours; Day 14: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose]

    Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3206944. PK parameters were calculated using standard non-compartmental analysis. GSK3206944 is a metabolite of GSK3358699.

  43. Part A: Monocyte Intracellular Concentration of GSK3206944 [Day 1: 1, 4, 8, 24 and 48 hours post-dose in each treatment period]

    Blood samples were collected into sodium heparin tubes for the isolation of monocytes and for measurement of GSK3206944 concentrations in monocytes. GSK3206944 is a metabolite of GSK3358699.

  44. Part B: Monocyte Intracellular Concentration of GSK3206944 [Day 1: 1, 4, 8, 24 and 48 hours post-dose in each treatment period]

    Blood samples were planned to be collected into sodium heparin tubes for the isolation of monocytes and for measurement of GSK3206944 concentrations in monocytes. GSK3206944 is a metabolite of GSK3358699.

  45. Part C: Monocyte Intracellular Concentration of GSK3206944 [Days 1 and 13: 1, 4 and 8 hour; Days 4, 8 and 12: Pre-dose; Day 14: 1, 4, 8, 24 and 48 hours post-dose]

    Blood samples were collected into sodium heparin tubes for the isolation of monocytes and for measurement of GSK3206944 concentrations in monocytes. GSK3206944 is a metabolite of GSK3358699.

  46. Part A: Absolute Values of Monocyte Chemotactic Protein (MCP)-1, Interleukin (IL)6, Tumor Necrosis Factor (TNF) Alpha in Blood After Ex-vivo Lipopolysaccharide (LPS) Activation [Day 1: 1, 4, 8, 12, 24 and 48 hours]

    Whole blood samples of 1 milliliter (mL) were collected in TruCulture tubes, containing LPS and incubated for 24 hours, post which the inflammatory mediators (MCP-1, IL-6 and TNF alpha) were analyzed.

  47. Part B: Absolute Values of MCP-1, IL6, TNF Alpha in Blood After Ex-vivo LPS Activation [Day 1: 1, 4, 8, 12, 24 and 48 hours]

    Whole blood samples were planned to be collected in TruCulture tubes, containing LPS and incubated for 24 hours, post which the inflammatory mediators (MCP-1, IL6 and TNF alpha) were planned to be analyzed.

  48. Part C: Absolute Values of MCP-1, IL6, TNF Alpha in Blood After Ex-vivo LPS Activation [Day 1: 1, 4 and 8 hours; Days 2, 4, 8 and 12: Pre-dose; Day 13: Pre-dose, 1, 4 and 8 hours; Day 14: Pre-dose, Pre-LPS challenge, 1, 4, 8, 24 and 48 hours]

    Whole blood samples of 1 mL were collected in TruCulture tubes, containing LPS and incubated for 24 hours, post which the inflammatory mediators (MCP-1, IL-6 and TNF alpha) were analyzed.

Eligibility Criteria

Criteria

Ages Eligible for Study:
18 Years to 65 Years
Sexes Eligible for Study:
Male
Accepts Healthy Volunteers:
Yes

Inclusion Criteria: - Subjects enrolled into the study, where they will be administered LPS or GM-CSF challenge, must be 18 to 55 years of age inclusive, at the time of signing the informed consent. Subjects enrolled into the study where they will not be administered LPS or GM-CSF challenge must be 18 to 65 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. - For subjects receiving cantharidin: 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 received an investigational product within the following time period prior to the first dosing day in the study: 30 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. - Alanine transaminase (ALT) >1.5x upper limit of normal (ULN) at screening. - Bilirubin

1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%) at screening. - 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 at screening. - A positive test for human immunodeficiency virus (HIV) antibody at screening. - Persistent clinically significant 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) at screening. - Fasted Triglycerides >3.4 millimole per liter (mmol/L) at screening. - Fasted Total cholesterol >7.7 mmol/L at screening. - Random glucose > = 11.1 mmol/L at screening. - 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.

Contacts and Locations

Locations

Site City State Country Postal Code
1 GSK Investigational Site Cambridge United Kingdom CB2 2GG

Sponsors and Collaborators

  • GlaxoSmithKline

Investigators

  • Study Director: GSK Clinical Trials, GlaxoSmithKline

Study Documents (Full-Text)

More Information

Publications

None provided.
Responsible Party:
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT03426995
Other Study ID Numbers:
  • 207546
  • 2017-003997-15
First Posted:
Feb 9, 2018
Last Update Posted:
Dec 2, 2020
Last Verified:
Oct 1, 2020
Individual Participant Data (IPD) Sharing Statement:
Yes
Plan to Share IPD:
Yes
Studies a U.S. FDA-regulated Drug Product:
No
Studies a U.S. FDA-regulated Device Product:
No
Additional relevant MeSH terms:

Study Results

Participant Flow

Recruitment Details This was a randomized, double-blind, placebo-controlled, 3-part study. Part A was single ascending dose crossover with 2 interlocking cohorts(1 and 2);Part B was planned to be a single dose, open-label, 2-way crossover in fed, fasted conditions(Cohort3);Part C was repeat dose design in sequential cohorts(4,5) and cohorts 6 to 8 were planned.
Pre-assignment Detail A total 48 participants were enrolled in this study. Part B and Part C (Cohorts 6 to 8) were not initiated as the study was terminated early due to strategic reasons following emergence of new data. Hence, no participants were enrolled in Part B and Part C (Cohorts 6 to 8).
Arm/Group Title Part A: Cohort 1- Sequence PCEP Part A: Cohort 1- Sequence PCER Part A: Cohort 1- Sequence APEP Part A: Cohort 1- Sequence APER Part A: Cohort 1- Sequence ACPP Part A: Cohort 1- Sequence ACPR Part A: Cohort 2- Sequence PDFP Part A: Cohort 2- Sequence PDFR Part A: Cohort 2- Sequence BPFP Part A: Cohort 2- Sequence BPFR Part A: Cohort 2- Sequence BDPP Part A: Cohort 2- Sequence BDPR Part B: Cohort 3- GSK3358699 Fed + GSK3358699 Fasted Part B: Cohort 3- GSK3358699 Fasted + GSK3358699 Fed Part C: Cohort 4 and 5- Placebo RD Part C: Cohort 4 and 5- GSK3358699 10 mg RD Part C: Cohort 6- GSK3358699 or Placebo RD Part C: Cohort 7- GSK3358699 or Placebo RD Part C: Cohort 8- GSK3358699 or Placebo RD
Arm/Group Description Participants in Part A Cohort 1 were planned to receive a single dose (SD) of placebo (Treatment P) on Day 1 in treatment Period 1. Participants were received a SD of GSK3358699 10 milligram (mg) (Treatment C) on Day 1 in treatment Period 2; followed by a SD of GSK3358699 40 mg (Treatment E) on Day 1 in treatment Period 3. On Day 1 of treatment Period 4, participants were administered a SD of placebo (Treatment P) followed by intravenous (IV) administration of in vivo lipopolysaccharide (LPS) challenge at a dose of 0.75 nanograms per kilogram (ng/kg) and further treated with 0.2 percent (%) cantharidin for induction of blisters on the forearm. GSK3358699 and placebo were administered via the oral route. There was a washout period of 14 days between each treatment period. Participants in Part A Cohort 1 received a SD of placebo (Treatment P) on Day 1 in treatment Period 1; followed by a SD of GSK3358699 10 mg (Treatment C) on Day 1 in treatment Period 2; followed by a SD of GSK3358699 40 mg (Treatment E) on Day 1 in treatment Period 3. On Day 1 of treatment Period 4, participants were administered a SD of GSK3358699 25 mg (Treatment R) followed by IV administration of in vivo LPS challenge at a dose of 0.75 ng/kg and further treated with 0.2% cantharidin for induction of blisters on the forearm. GSK3358699 and placebo were administered via the oral route. There was a washout period of 14 days between each treatment period. Participants in Part A Cohort 1 received a SD of GSK3358699 1 mg (Treatment A) on Day 1 in treatment Period 1; followed by a SD of placebo (Treatment P) on Day 1 in treatment Period 2; followed by a SD of GSK3358699 40 mg (Treatment E) on Day 1 in treatment Period 3. On Day 1 of treatment Period 4, participants were administered a SD of placebo (Treatment P) followed by IV administration of in vivo LPS challenge at a dose of 0.75 ng/kg and further treated with 0.2% cantharidin for induction of blisters on the forearm. GSK3358699 and placebo were administered via the oral route. There was a washout period of 14 days between each treatment period. Participants in Part A Cohort 1 received a SD of GSK3358699 1 mg (Treatment A) on Day 1 in treatment Period 1; followed by a SD of placebo (Treatment P) on Day 1 in treatment Period 2; followed by a SD of GSK3358699 40 mg (Treatment E) on Day 1 in treatment Period 3. On Day 1 of treatment Period 4, participants were administered a SD of GSK3358699 25 mg (Treatment R) followed by IV administration of in vivo LPS challenge at a dose of 0.75 ng/kg and further treated with 0.2% cantharidin for induction of blisters on the forearm. GSK3358699 and placebo were administered via the oral route. There was a washout period of 14 days between each treatment period. Participants in Part A Cohort 1 received a SD of GSK3358699 1 mg (Treatment A) on Day 1 in treatment Period 1; followed by a SD of GSK3358699 10 mg (Treatment C) on Day 1 in treatment Period 2; followed by a SD of placebo (Treatment P) on Day 1 in treatment Period 3. On Day 1 of treatment Period 4, participants were administered a SD of placebo (Treatment P) followed by IV administration of in vivo LPS challenge at a dose of 0.75 ng/kg and further treated with 0.2% cantharidin for induction of blisters on the forearm. GSK3358699 and placebo were administered via the oral route. There was a washout period of 14 days between each treatment period. Participants in Part A Cohort 1 received a SD of GSK3358699 1 mg (Treatment A) on Day 1 in treatment Period 1; followed by a SD of GSK3358699 10 mg (Treatment C) on Day 1 in treatment Period 2; followed by a SD of placebo (Treatment P) on Day 1 in treatment Period 3. On Day 1 of treatment Period 4, participants were administered a SD of GSK3358699 25 mg (Treatment R) followed by IV administration of in vivo LPS challenge at a dose of 0.75 ng/kg and further treated with 0.2% cantharidin for induction of blisters on the forearm. GSK3358699 and placebo were administered via the oral route. There was a washout period of 14 days between each treatment period. Participants in Part A Cohort 2 received a SD of placebo (Treatment P) on Day 1 in treatment Period 1; followed by a SD of GSK3358699 20 mg (Treatment D) on Day 1 in treatment Period 2; followed by a SD of GSK3358699 30 mg (Treatment F) on Day 1 in treatment Period 3. On Day 1 of treatment Period 4, participants were administered a SD of placebo (Treatment P) followed by IV administration of in vivo administration of Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) at a dose of 60 micrograms per meter square (mcg/m^2) and further treated with 0.2% cantharidin for induction of blisters on the forearm. GSK3358699 and placebo were administered via the oral route. There was a washout period of 14 days between each treatment period. Participants in Part A Cohort 2 received a SD of placebo (Treatment P) on Day 1 in treatment Period 1; followed by a SD of GSK3358699 20 mg (Treatment D) on Day 1 in treatment Period 2; followed by a SD of GSK3358699 30 mg (Treatment F) on Day 1 in treatment Period 3. On Day 1 of treatment Period 4, participants were administered a SD of GSK3358699 25 mg (Treatment R) followed by IV administration of in vivo administration of GM-CSF at a dose of 60 mcg/m^2 and further treated with 0.2% cantharidin for induction of blisters on the forearm. GSK3358699 and placebo were administered via the oral route. There was a washout period of 14 days between each treatment period. Participants in Part A Cohort 2 received a SD of GSK3358699 3 mg (Treatment B) on Day 1 in treatment Period 1; followed by a SD of placebo (Treatment P) on Day 1 in treatment Period 2; followed by a SD of GSK3358699 30 mg (Treatment F) on Day 1 in treatment Period 3. On Day 1 of treatment Period 4, participants were administered a SD of placebo (Treatment P) followed by IV administration of in vivo administration of GM-CSF at a dose of 60 mcg/m^2 and further treated with 0.2% cantharidin for induction of blisters on the forearm. GSK3358699 and placebo were administered via the oral route. There was a washout period of 14 days between each treatment period. Participants in Part A Cohort 2 were planned to receive a SD of GSK3358699 3 mg (Treatment B) on Day 1 in treatment Period 1.Participants were received a SD of placebo (Treatment P) on Day 1 in treatment Period 2; followed by a SD of GSK3358699 30 mg (Treatment F) on Day 1 in treatment Period 3. On Day 1 of treatment Period 4, participants were administered a SD of GSK3358699 25 mg (Treatment R) followed by IV administration of in vivo administration of GM-CSF at a dose of 60 mcg/m^2 and further treated with 0.2% cantharidin for induction of blisters on the forearm. GSK3358699 and placebo were administered via the oral route. There was a washout period of 14 days between each treatment period. Participants in Part A Cohort 2 received a SD of GSK3358699 3 mg (Treatment B) on Day 1 in treatment Period 1; followed by a SD of GSK3358699 20 mg (Treatment D) on Day 1 in treatment Period 2; followed by a SD of placebo (Treatment P) on Day 1 in treatment Period 3. On Day 1 of treatment Period 4, participants were administered a SD of placebo (Treatment P) followed by IV administration of in vivo administration of GM-CSF at a dose of 60 mcg/m^2 and further treated with 0.2% cantharidin for induction of blisters on the forearm. GSK3358699 and placebo were administered via the oral route. There was a washout period of 14 days between each treatment period. Participants in Part A Cohort 2 received a SD of GSK3358699 3 mg (Treatment B) on Day 1 in treatment Period 1; followed by a SD of GSK3358699 20 mg (Treatment D) on Day 1 in treatment Period 2; followed by a SD of placebo (Treatment P) on Day 1 in treatment Period 3. On Day 1 of treatment Period 4, participants were administered a SD of GSK3358699 25 mg (Treatment R) followed by IV administration of in vivo administration of GM-CSF at a dose of 60 mcg/m^2 and further treated with 0.2% cantharidin for induction of blisters on the forearm. GSK3358699 and placebo were administered via the oral route. There was a washout period of 14 days between each treatment period. Participants in Part B Cohort 3 were planned to receive a SD of GSK3358699 under fed conditions on Day 1 in treatment Period 1; followed by a SD of GSK3358699 under fasted conditions on Day 1 in treatment Period 2. There was a planned washout period of 14 days between each treatment period. Participants in Part B Cohort 3 were planned to receive a SD of GSK3358699 under fasted conditions on Day 1 in treatment Period 1; followed by a SD of GSK3358699 under fed conditions on Day 1 in treatment Period 2. There was a planned washout period of 14 days between each treatment period. Participants received once daily repeat dose (RD) of placebo on Days 1 to 14. In Cohort 4, on Day 14, participants were administered an IV in vivo LPS challenge at a dose of 0.75 ng/kg or an IV infusion of GM-CSF, in vivo at a dose of 60 mcg/m^2. The administration of LPS or GM-CSF was followed by blister induction on forearm (0.2% cantharidin). Participants received once daily repeat dose of GSK3358699 10 mg on Days 1 to 14. In Cohort 4, on Day 14, participants were administered an IV in vivo LPS challenge at a dose of 0.75 ng/kg or an IV infusion of GM-CSF, in vivo at a dose of 60 mcg/m^2. The administration of LPS or GM-CSF was followed by blister induction on forearm (0.2% cantharidin). Participants in Part C Cohort 6 were planned to receive once daily repeat dose of GSK3358699 or placebo on Days 1 to 14. Participants in Part C Cohort 7 were planned to receive once daily repeat dose of GSK3358699 or placebo on Days 1 to 14. Participants in Part C Cohort 8 were planned to receive once daily repeat dose of GSK3358699 or placebo on Days 1 to 14. On Day 14, participants were planned to receive an IV in vivo LPS challenge at a dose of 0.75 ng/kg or an IV infusion of GM-CSF, in vivo as 60 mcg/m^2. The administration of LPS or GM-CSF was planned to be followed by blister induction on forearm (0.2% cantharidin).
Period Title: Part A: Cohort 1-Period 1 (Day1)
STARTED 0 2 1 2 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0
COMPLETED 0 2 0 2 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0
NOT COMPLETED 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Period Title: Part A: Cohort 1-Period 1 (Day1)
STARTED 0 2 0 2 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0
COMPLETED 0 2 0 2 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0
NOT COMPLETED 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Period Title: Part A: Cohort 1-Period 1 (Day1)
STARTED 1 2 1 2 1 3 0 0 0 0 0 0 0 0 0 0 0 0 0
COMPLETED 1 2 1 2 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0
NOT COMPLETED 0 0 0 0 1 2 0 0 0 0 0 0 0 0 0 0 0 0 0
Period Title: Part A: Cohort 1-Period 1 (Day1)
STARTED 1 2 1 2 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0
COMPLETED 1 2 1 2 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0
NOT COMPLETED 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Period Title: Part A: Cohort 1-Period 1 (Day1)
STARTED 1 2 1 2 1 2 0 0 0 0 0 0 0 0 0 0 0 0 0
COMPLETED 1 2 1 2 1 2 0 0 0 0 0 0 0 0 0 0 0 0 0
NOT COMPLETED 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Period Title: Part A: Cohort 1-Period 1 (Day1)
STARTED 1 2 1 2 1 2 0 0 0 0 0 0 0 0 0 0 0 0 0
COMPLETED 1 2 1 2 1 2 0 0 0 0 0 0 0 0 0 0 0 0 0
NOT COMPLETED 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Period Title: Part A: Cohort 1-Period 1 (Day1)
STARTED 1 2 1 2 1 2 0 0 0 0 0 0 0 0 0 0 0 0 0
COMPLETED 1 2 1 2 1 2 0 0 0 0 0 0 0 0 0 0 0 0 0
NOT COMPLETED 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Period Title: Part A: Cohort 1-Period 1 (Day1)
STARTED 0 0 0 0 0 0 1 2 1 0 1 1 0 0 0 0 0 0 0
COMPLETED 0 0 0 0 0 0 1 2 1 0 1 1 0 0 0 0 0 0 0
NOT COMPLETED 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Period Title: Part A: Cohort 1-Period 1 (Day1)
STARTED 0 0 0 0 0 0 1 2 1 0 1 1 0 0 0 0 0 0 0
COMPLETED 0 0 0 0 0 0 1 2 1 0 1 1 0 0 0 0 0 0 0
NOT COMPLETED 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Period Title: Part A: Cohort 1-Period 1 (Day1)
STARTED 0 0 0 0 0 0 1 2 1 2 1 2 0 0 0 0 0 0 0
COMPLETED 0 0 0 0 0 0 1 2 1 2 1 2 0 0 0 0 0 0 0
NOT COMPLETED 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Period Title: Part A: Cohort 1-Period 1 (Day1)
STARTED 0 0 0 0 0 0 1 2 1 2 1 2 0 0 0 0 0 0 0
COMPLETED 0 0 0 0 0 0 1 2 1 2 1 2 0 0 0 0 0 0 0
NOT COMPLETED 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Period Title: Part A: Cohort 1-Period 1 (Day1)
STARTED 0 0 0 0 0 0 1 2 1 2 1 2 0 0 0 0 0 0 0
COMPLETED 0 0 0 0 0 0 1 2 1 2 1 2 0 0 0 0 0 0 0
NOT COMPLETED 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Period Title: Part A: Cohort 1-Period 1 (Day1)
STARTED 0 0 0 0 0 0 1 2 1 2 1 2 0 0 0 0 0 0 0
COMPLETED 0 0 0 0 0 0 1 2 1 2 1 2 0 0 0 0 0 0 0
NOT COMPLETED 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Period Title: Part A: Cohort 1-Period 1 (Day1)
STARTED 0 0 0 0 0 0 1 3 1 2 1 2 0 0 0 0 0 0 0
COMPLETED 0 0 0 0 0 0 1 2 1 2 0 2 0 0 0 0 0 0 0
NOT COMPLETED 0 0 0 0 0 0 0 1 0 0 1 0 0 0 0 0 0 0 0
Period Title: Part A: Cohort 1-Period 1 (Day1)
STARTED 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
COMPLETED 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
NOT COMPLETED 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Period Title: Part A: Cohort 1-Period 1 (Day1)
STARTED 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
COMPLETED 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
NOT COMPLETED 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Period Title: Part A: Cohort 1-Period 1 (Day1)
STARTED 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
COMPLETED 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
NOT COMPLETED 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Period Title: Part A: Cohort 1-Period 1 (Day1)
STARTED 0 0 0 0 0 0 0 0 0 0 0 0 0 0 11 14 0 0 0
COMPLETED 0 0 0 0 0 0 0 0 0 0 0 0 0 0 2 2 0 0 0
NOT COMPLETED 0 0 0 0 0 0 0 0 0 0 0 0 0 0 9 12 0 0 0

Baseline Characteristics

Arm/Group Title Part A: Cohort 1- Sequence PCEP Part A: Cohort 1- Sequence PCER Part A: Cohort 1- Sequence APEP Part A: Cohort 1- Sequence APER Part A: Cohort 1- Sequence ACPP Part A: Cohort 1- Sequence ACPR Part A: Cohort 2- Sequence PDFP Part A: Cohort 2- Sequence PDFR Part A: Cohort 2- Sequence BPFP Part A: Cohort 2- Sequence BPFR Part A: Cohort 2- Sequence BDPP Part A: Cohort 2- Sequence BDPR Part B: Cohort 3- GSK3358699 Fed + GSK3358699 Fasted Part B: Cohort 3- GSK3358699 Fasted + GSK3358699 Fed Part C: Cohort 4 and 5- Placebo RD Part C: Cohort 4 and 5- GSK3358699 10 mg RD Part C: Cohort 6- GSK3358699 or Placebo RD Part C: Cohort 7- GSK3358699 or Placebo RD Part C: Cohort 8- GSK3358699 or Placebo RD Total
Arm/Group Description Participants in Part A Cohort 1 were planned to receive a single dose (SD) of placebo (Treatment P) on Day 1 in treatment Period 1. Participants were received a SD of GSK3358699 10 milligram (mg) (Treatment C) on Day 1 in treatment Period 2; followed by a SD of GSK3358699 40 mg (Treatment E) on Day 1 in treatment Period 3. On Day 1 of treatment Period 4, participants were administered a SD of placebo (Treatment P) followed by intravenous (IV) administration of in vivo lipopolysaccharide (LPS) challenge at a dose of 0.75 nanograms per kilogram (ng/kg) and further treated with 0.2 percent (%) cantharidin for induction of blisters on the forearm. GSK3358699 and placebo were administered via the oral route. There was a washout period of 14 days between each treatment period. Participants in Part A Cohort 1 received a SD of placebo (Treatment P) on Day 1 in treatment Period 1; followed by a SD of GSK3358699 10 mg (Treatment C) on Day 1 in treatment Period 2; followed by a SD of GSK3358699 40 mg (Treatment E) on Day 1 in treatment Period 3. On Day 1 of treatment Period 4, participants were administered a SD of GSK3358699 25 mg (Treatment R) followed by IV administration of in vivo LPS challenge at a dose of 0.75 ng/kg and further treated with 0.2% cantharidin for induction of blisters on the forearm. GSK3358699 and placebo were administered via the oral route. There was a washout period of 14 days between each treatment period. Participants in Part A Cohort 1 received a SD of GSK3358699 1 mg (Treatment A) on Day 1 in treatment Period 1; followed by a SD of placebo (Treatment P) on Day 1 in treatment Period 2; followed by a SD of GSK3358699 40 mg (Treatment E) on Day 1 in treatment Period 3. On Day 1 of treatment Period 4, participants were administered a SD of placebo (Treatment P) followed by IV administration of in vivo LPS challenge at a dose of 0.75 ng/kg and further treated with 0.2% cantharidin for induction of blisters on the forearm. GSK3358699 and placebo were administered via the oral route. There was a washout period of 14 days between each treatment period. Participants in Part A Cohort 1 received a SD of GSK3358699 1 mg (Treatment A) on Day 1 in treatment Period 1; followed by a SD of placebo (Treatment P) on Day 1 in treatment Period 2; followed by a SD of GSK3358699 40 mg (Treatment E) on Day 1 in treatment Period 3. On Day 1 of treatment Period 4, participants were administered a SD of GSK3358699 25 mg (Treatment R) followed by IV administration of in vivo LPS challenge at a dose of 0.75 ng/kg and further treated with 0.2% cantharidin for induction of blisters on the forearm. GSK3358699 and placebo were administered via the oral route. There was a washout period of 14 days between each treatment period. Participants in Part A Cohort 1 received a SD of GSK3358699 1 mg (Treatment A) on Day 1 in treatment Period 1; followed by a SD of GSK3358699 10 mg (Treatment C) on Day 1 in treatment Period 2; followed by a SD of placebo (Treatment P) on Day 1 in treatment Period 3. On Day 1 of treatment Period 4, participants were administered a SD of placebo (Treatment P) followed by IV administration of in vivo LPS challenge at a dose of 0.75 ng/kg and further treated with 0.2% cantharidin for induction of blisters on the forearm. GSK3358699 and placebo were administered via the oral route. There was a washout period of 14 days between each treatment period. Participants in Part A Cohort 1 received a SD of GSK3358699 1 mg (Treatment A) on Day 1 in treatment Period 1; followed by a SD of GSK3358699 10 mg (Treatment C) on Day 1 in treatment Period 2; followed by a SD of placebo (Treatment P) on Day 1 in treatment Period 3. On Day 1 of treatment Period 4, participants were administered a SD of GSK3358699 25 mg (Treatment R) followed by IV administration of in vivo LPS challenge at a dose of 0.75 ng/kg and further treated with 0.2% cantharidin for induction of blisters on the forearm. GSK3358699 and placebo were administered via the oral route. There was a washout period of 14 days between each treatment period. Participants in Part A Cohort 2 received a SD of placebo (Treatment P) on Day 1 in treatment Period 1; followed by a SD of GSK3358699 20 mg (Treatment D) on Day 1 in treatment Period 2; followed by a SD of GSK3358699 30 mg (Treatment F) on Day 1 in treatment Period 3. On Day 1 of treatment Period 4, participants were administered a SD of placebo (Treatment P) followed by IV administration of in vivo administration of Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) at a dose of 60 micrograms per meter square (mcg/m^2) and further treated with 0.2% cantharidin for induction of blisters on the forearm. GSK3358699 and placebo were administered via the oral route. There was a washout period of 14 days between each treatment period. Participants in Part A Cohort 2 received a SD of placebo (Treatment P) on Day 1 in treatment Period 1; followed by a SD of GSK3358699 20 mg (Treatment D) on Day 1 in treatment Period 2; followed by a SD of GSK3358699 30 mg (Treatment F) on Day 1 in treatment Period 3. On Day 1 of treatment Period 4, participants were administered a SD of GSK3358699 25 mg (Treatment R) followed by IV administration of in vivo administration of GM-CSF at a dose of 60 mcg/m^2 and further treated with 0.2% cantharidin for induction of blisters on the forearm. GSK3358699 and placebo were administered via the oral route. There was a washout period of 14 days between each treatment period. Participants in Part A Cohort 2 received a SD of GSK3358699 3 mg (Treatment B) on Day 1 in treatment Period 1; followed by a SD of placebo (Treatment P) on Day 1 in treatment Period 2; followed by a SD of GSK3358699 30 mg (Treatment F) on Day 1 in treatment Period 3. On Day 1 of treatment Period 4, participants were administered a SD of placebo (Treatment P) followed by IV administration of in vivo administration of GM-CSF at a dose of 60 mcg/m^2 and further treated with 0.2% cantharidin for induction of blisters on the forearm. GSK3358699 and placebo were administered via the oral route. There was a washout period of 14 days between each treatment period. Participants in Part A Cohort 2 were planned to receive a SD of GSK3358699 3 mg (Treatment B) on Day 1 in treatment Period 1.Participants were received a SD of placebo (Treatment P) on Day 1 in treatment Period 2; followed by a SD of GSK3358699 30 mg (Treatment F) on Day 1 in treatment Period 3. On Day 1 of treatment Period 4, participants were administered a SD of GSK3358699 25 mg (Treatment R) followed by IV administration of in vivo administration of GM-CSF at a dose of 60 mcg/m^2 and further treated with 0.2% cantharidin for induction of blisters on the forearm. GSK3358699 and placebo were administered via the oral route. There was a washout period of 14 days between each treatment period. Participants in Part A Cohort 2 received a SD of GSK3358699 3 mg (Treatment B) on Day 1 in treatment Period 1; followed by a SD of GSK3358699 20 mg (Treatment D) on Day 1 in treatment Period 2; followed by a SD of placebo (Treatment P) on Day 1 in treatment Period 3. On Day 1 of treatment Period 4, participants were administered a SD of placebo (Treatment P) followed by IV administration of in vivo administration of GM-CSF at a dose of 60 mcg/m^2 and further treated with 0.2% cantharidin for induction of blisters on the forearm. GSK3358699 and placebo were administered via the oral route. There was a washout period of 14 days between each treatment period. Participants in Part A Cohort 2 received a SD of GSK3358699 3 mg (Treatment B) on Day 1 in treatment Period 1; followed by a SD of GSK3358699 20 mg (Treatment D) on Day 1 in treatment Period 2; followed by a SD of placebo (Treatment P) on Day 1 in treatment Period 3. On Day 1 of treatment Period 4, participants were administered a SD of GSK3358699 25 mg (Treatment R) followed by IV administration of in vivo administration of GM-CSF at a dose of 60 mcg/m^2 and further treated with 0.2% cantharidin for induction of blisters on the forearm. GSK3358699 and placebo were administered via the oral route. There was a washout period of 14 days between each treatment period. Participants in Part B Cohort 3 were planned to receive a SD of GSK3358699 under fed conditions on Day 1 in treatment Period 1; followed by a SD of GSK3358699 under fasted conditions on Day 1 in treatment Period 2. There was a planned washout period of 14 days between each treatment period. Participants in Part B Cohort 3 were planned to receive a SD of GSK3358699 under fasted conditions on Day 1 in treatment Period 1; followed by a SD of GSK3358699 under fed conditions on Day 1 in treatment Period 2. There was a planned washout period of 14 days between each treatment period. Participants received once daily RD of placebo on Days 1 to 14. In Cohort 4, on Day 14, participants were administered an IV in vivo LPS challenge at a dose of 0.75 ng/kg or an IV infusion of GM-CSF, in vivo at a dose of 60 mcg/m^2. The administration of LPS or GM-CSF was followed by blister induction on forearm (0.2% cantharidin). Participants received once daily repeat dose of GSK3358699 10 mg on Days 1 to 14. In Cohort 4, on Day 14, participants were administered an IV in vivo LPS challenge at a dose of 0.75 ng/kg or an IV infusion of GM-CSF, in vivo at a dose of 60 mcg/m^2. The administration of LPS or GM-CSF was followed by blister induction on forearm (0.2% cantharidin). Participants in Part C Cohort 6 were planned to receive once daily repeat dose of GSK3358699 or placebo on Days 1 to 14. Participants in Part C Cohort 7 were planned to receive once daily repeat dose of GSK3358699 or placebo on Days 1 to 14. Participants in Part C Cohort 8 were planned to receive once daily repeat dose of GSK3358699 or placebo on Days 1 to 14. On Day 14, participants were planned to receive an IV in vivo LPS challenge at a dose of 0.75 ng/kg or an IV infusion of GM-CSF, in vivo as 60 mcg/m^2. The administration of LPS or GM-CSF was planned to be followed by blister induction on forearm (0.2% cantharidin). Total of all reporting groups
Overall Participants 1 2 2 2 2 4 1 3 1 2 1 2 0 0 11 14 0 0 0 48
Age, Customized (Count of Participants)
<=18 years
0
0%
1
50%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
NaN
0
NaN
1
9.1%
>18 and <65 years
1
100%
1
50%
2
100%
2
100%
2
100%
4
100%
1
100%
3
100%
1
100%
2
100%
1
100%
2
100%
11
Infinity
14
Infinity
47
427.3%
>=65 years
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
NaN
0
NaN
0
0%
Sex: Female, Male (Count of Participants)
Female
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
NaN
0
NaN
0
0%
Male
1
100%
2
100%
2
100%
2
100%
2
100%
4
100%
1
100%
3
100%
1
100%
2
100%
1
100%
2
100%
11
Infinity
14
Infinity
48
436.4%
Race/Ethnicity, Customized (Count of Participants)
Black or African American
0
0%
0
0%
0
0%
0
0%
0
0%
1
25%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
1
Infinity
0
NaN
2
18.2%
White-White/Caucasian/European Heritage
1
100%
2
100%
2
100%
2
100%
2
100%
3
75%
1
100%
3
100%
1
100%
2
100%
1
100%
1
50%
10
Infinity
14
Infinity
45
409.1%
Multiple
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
1
50%
0
NaN
0
NaN
1
9.1%

Outcome Measures

1. Primary Outcome
Title Part A: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
Description An adverse event (AE) is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, important medical events that may jeopardize the participant or require medical or surgical intervention to prevent one of the outcomes listed before. Safety Population consisted of all randomized participants who took at least 1 dose of study treatment.
Time Frame Up to Day 193

Outcome Measure Data

Analysis Population Description
Safety Population.
Arm/Group Title Part A: Placebo SD Part A: GSK3358699 1 mg SD Part A: GSK3358699 3 mg SD Part A: GSK3358699 10 mg SD Part A: GSK3358699 20 mg SD Part A: GSK3358699 25 mg SD Part A: GSK3358699 30 mg SD Part A: GSK3358699 40 mg SD
Arm/Group Description Participants in Part A received a SD of placebo on Day 1 in either treatment Period 1, 2 and 3. On Day 1 of treatment Period 4, participants were administered a SD of placebo followed by IV administration of in vivo LPS challenge at a dose of 0.75 ng/kg for induction of blisters on the forearm in Cohort 1 and in Cohort 2, participants were administered with IV administration of in vivo GM-CSF challenge at a dose of 60 mcg/m^2 and further treated with 0.2% cantharidin for induction of blisters on the forearm. Placebo were administered via the oral route. Participants in Part A received a SD of GSK3358699 1 mg on Day 1 in treatment Period 1. Participants in Part A received a SD of GSK3358699 3 mg on Day 1 in treatment Period 1. Participants in Part A received a SD of GSK3358699 10 mg on Day 1 in treatment Period 2. Participants in Part A received a SD of GSK3358699 20 mg on Day 1 in treatment Period 2. Participants in Part A received a SD of GSK3358699 25 mg on Day 1 in treatment Period 4. On Day 1, participants were administered a SD of GSK3358699 25 mg followed by IV administration of in vivo LPS challenge at a dose of 0.75 ng/kg for induction of blisters on the forearm in Cohort 1 and in Cohort 2, participants were administered with IV administration of in vivo GM-CSF challenge at a dose of 60 mcg/m^2 and further treated with 0.2% cantharidin for induction of blisters on the forearm. GSK3358699 were administered via the oral route. Participants in Part A received a SD of GSK3358699 30 mg on Day 1 in treatment Period 3. Participants in Part A received a SD of GSK3358699 40 mg on Day 1 in treatment Period 3.
Measure Participants 23 5 3 6 6 12 6 6
AEs
8
800%
2
100%
3
150%
2
100%
3
150%
8
200%
4
400%
3
100%
SAEs
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
2. Primary Outcome
Title Part B: Number of Participants With AEs and SAEs
Description An AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, important medical events that may jeopardize the participant or require medical or surgical intervention to prevent one of the outcomes listed before.
Time Frame Up to Day 30

Outcome Measure Data

Analysis Population Description
Safety Population. Data was not collected as no participants were enrolled in Part B.
Arm/Group Title Part B: Cohort 3- GSK3358699 Fed + GSK3358699 Fasted Part B: Cohort 3- GSK3358699 Fasted + GSK3358699 Fed
Arm/Group Description Participants in Part B Cohort 3 were planned to receive a SD of GSK3358699 under fed conditions on Day 1 in treatment Period 1; followed by a SD of GSK3358699 under fasted conditions on Day 1 in treatment Period 2. There was a planned washout period of 14 days between each treatment period. Participants in Part B Cohort 3 were planned to receive a SD of GSK3358699 under fasted conditions on Day 1 in treatment Period 1; followed by a SD of GSK3358699 under fed conditions on Day 1 in treatment Period 2. There was a planned washout period of 14 days between each treatment period.
Measure Participants 0 0
3. Primary Outcome
Title Part C: Number of Participants With AEs and SAEs
Description An AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, important medical events that may jeopardize the participant or require medical or surgical intervention to prevent one of the outcomes listed before.
Time Frame Up to Day 49

Outcome Measure Data

Analysis Population Description
Safety Population. Data was not collected for Cohorts 6 to 8 as no participants were enrolled.
Arm/Group Title Part C: Cohort 4 and 5- Placebo RD Part C: Cohort 4 and 5- GSK3358699 10 mg RD Part C: Cohort 6- GSK3358699 or Placebo RD Part C: Cohort 7- GSK3358699 or Placebo RD Part C: Cohort 8- GSK3358699 or Placebo RD
Arm/Group Description Participants received once daily RD of placebo on Days 1 to 14. In Cohort 4, on Day 14, participants were administered an IV in vivo LPS challenge at a dose of 0.75 ng/kg or an IV infusion of GM-CSF, in vivo at a dose of 60 mcg/m^2. The administration of LPS or GM-CSF was followed by blister induction on forearm (0.2% cantharidin). Participants received once daily repeat dose of GSK3358699 10 mg on Days 1 to 14. In Cohort 4, on Day 14, participants were administered an IV in vivo LPS challenge at a dose of 0.75 ng/kg or an IV infusion of GM-CSF, in vivo at a dose of 60 mcg/m^2. The administration of LPS or GM-CSF was followed by blister induction on forearm (0.2% cantharidin). Participants in Part C Cohort 6 were planned to receive once daily repeat dose of GSK3358699 or placebo on Days 1 to 14. Participants in Part C Cohort 7 were planned to receive once daily repeat dose of GSK3358699 or placebo on Days 1 to 14. Participants in Part C Cohort 8 were planned to receive once daily repeat dose of GSK3358699 or placebo on Days 1 to 14. On Day 14, participants were planned to receive an IV in vivo LPS challenge at a dose of 0.75 ng/kg or an IV infusion of GM-CSF, in vivo as 60 mcg/m^2. The administration of LPS or GM-CSF was planned to be followed by blister induction on forearm (0.2% cantharidin).
Measure Participants 11 14 0 0 0
AEs
7
700%
8
400%
SAEs
0
0%
1
50%
4. Primary Outcome
Title Part A: Number of Participants With Worst Case Chemistry Results by Potential Clinical Importance (PCI) Criteria Post-Baseline Relative to Baseline
Description Blood samples were collected for analysis of clinical chemistry parameters. PCI ranges were <30 grams per liter (g/L) (albumin), <2 or >2.75 millimoles/L (mmol/L) (calcium), >1.3* upper limit of normal (ULN) mmol/L (creatinine), <3 or >9 mmol/L (glucose), <3 or >5.5 mmol/L (potassium), and <130 or >150 mmol/L (sodium). Participants were counted in worst case category that their value changes to (low, within range or no change or high), unless there is no change in their category. Participants whose laboratory value category was unchanged (e.g., High to High), or whose value became within range, were recorded in To within Range or No Change (NC) category. Participants were counted twice if participant had values that changed To Low and To High, so the percentages may not add to 100%.
Time Frame Up to Day 193

Outcome Measure Data

Analysis Population Description
Safety Population.
Arm/Group Title Part A: Placebo SD Part A: GSK3358699 1 mg SD Part A: GSK3358699 3 mg SD Part A: GSK3358699 10 mg SD Part A: GSK3358699 20 mg SD Part A: GSK3358699 25 mg SD Part A: GSK3358699 30 mg SD Part A: GSK3358699 40 mg SD
Arm/Group Description Participants in Part A received a SD of placebo on Day 1 in either treatment Period 1, 2 and 3. On Day 1 of treatment Period 4, participants were administered a SD of placebo followed by IV administration of in vivo LPS challenge at a dose of 0.75 ng/kg for induction of blisters on the forearm in Cohort 1 and in Cohort 2, participants were administered with IV administration of in vivo GM-CSF challenge at a dose of 60 mcg/m^2 and further treated with 0.2% cantharidin for induction of blisters on the forearm. Placebo were administered via the oral route. Participants in Part A received a SD of GSK3358699 1 mg on Day 1 in treatment Period 1. Participants in Part A received a SD of GSK3358699 3 mg on Day 1 in treatment Period 1. Participants in Part A received a SD of GSK3358699 10 mg on Day 1 in treatment Period 2. Participants in Part A received a SD of GSK3358699 20 mg on Day 1 in treatment Period 2. Participants in Part A received a SD of GSK3358699 25 mg on Day 1 in treatment Period 4. On Day 1, participants were administered a SD of GSK3358699 25 mg followed by IV administration of in vivo LPS challenge at a dose of 0.75 ng/kg for induction of blisters on the forearm in Cohort 1 and in Cohort 2, participants were administered with IV administration of in vivo GM-CSF challenge at a dose of 60 mcg/m^2 and further treated with 0.2% cantharidin for induction of blisters on the forearm. GSK3358699 were administered via the oral route. Participants in Part A received a SD of GSK3358699 30 mg on Day 1 in treatment Period 3. Participants in Part A received a SD of GSK3358699 40 mg on Day 1 in treatment Period 3.
Measure Participants 23 5 3 6 6 12 6 6
Albumin: To Low
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
Albumin: To within Range or No Change
23
2300%
5
250%
3
150%
6
300%
6
300%
12
300%
6
600%
6
200%
Albumin: To High
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
Calcium: To Low
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
Calcium: To within Range or No Change
23
2300%
5
250%
3
150%
6
300%
6
300%
12
300%
6
600%
6
200%
Calcium: To High
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
Creatinine: To Low
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
Creatinine: To within Range or No Change
23
2300%
5
250%
3
150%
6
300%
6
300%
12
300%
6
600%
6
200%
Creatinine: To High
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
Glucose: To Low
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
Glucose: To within Range or No Change
22
2200%
5
250%
3
150%
6
300%
6
300%
12
300%
6
600%
6
200%
Glucose: To High
1
100%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
Potassium: To Low
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
Potassium: To within Range or No Change
23
2300%
5
250%
3
150%
6
300%
6
300%
12
300%
6
600%
6
200%
Potassium: To High
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
Sodium: To Low
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
Sodium: To within Range or No Change
23
2300%
5
250%
3
150%
6
300%
6
300%
12
300%
6
600%
6
200%
Sodium: To High
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
5. Primary Outcome
Title Part A: Number of Participants With Worst Case Chemistry Results Relative to Normal Range Post-Baseline Relative to Baseline
Description Clinical chemistry parameters assessed were alanine aminotransferase(ALT)(<10 or >50 international units per liter[IU/L]),alkaline phosphatase(ALP)(<40 or >129 IU/L),aspartate aminotransferase(AST)(<0 or >37 IU/L),cholesterol(<2.3 or >4.9 mmol/L),direct bilirubin(DB)(<0 or >5 micromoles[mcmol]/L),high density lipoprotein (DL)(<0.9 or >1.5 mmol/L),C-reactive protein(CRP)(<0.0 or >5.0mg/liter),low DL(<0 or >3.0 mmol/L), total bilirubin (<0 or >20 mcmol/L),total protein(<63 or >83 grams/L),triglycerides(<0 or >2.3 mmol/L) and blood urea nitrogen(BUN)(<4.76 or >23.24 mg/deciliter).Participants were counted in worst case category that their value changes to (low, normal or high), unless there is NC in their category.Participants whose laboratory value category was unchanged(e.g.,High to High) or whose value became normal, are recorded in "To Normal or NC" category.Participants were counted twice if participant had values that changed To Low and To High, so percentages may not add to 100%.
Time Frame Up to Day 193

Outcome Measure Data

Analysis Population Description
Safety Population. Only those participants with data available at the specified time points were analyzed (represented by n= X in the category titles).
Arm/Group Title Part A: Placebo SD Part A: GSK3358699 1 mg SD Part A: GSK3358699 3 mg SD Part A: GSK3358699 10 mg SD Part A: GSK3358699 20 mg SD Part A: GSK3358699 25 mg SD Part A: GSK3358699 30 mg SD Part A: GSK3358699 40 mg SD
Arm/Group Description Participants in Part A received a SD of placebo on Day 1 in either treatment Period 1, 2 and 3. On Day 1 of treatment Period 4, participants were administered a SD of placebo followed by IV administration of in vivo LPS challenge at a dose of 0.75 ng/kg for induction of blisters on the forearm in Cohort 1 and in Cohort 2, participants were administered with IV administration of in vivo GM-CSF challenge at a dose of 60 mcg/m^2 and further treated with 0.2% cantharidin for induction of blisters on the forearm. Placebo were administered via the oral route. Participants in Part A received a SD of GSK3358699 1 mg on Day 1 in treatment Period 1. Participants in Part A received a SD of GSK3358699 3 mg on Day 1 in treatment Period 1. Participants in Part A received a SD of GSK3358699 10 mg on Day 1 in treatment Period 2. Participants in Part A received a SD of GSK3358699 20 mg on Day 1 in treatment Period 2. Participants in Part A received a SD of GSK3358699 25 mg on Day 1 in treatment Period 4. On Day 1, participants were administered a SD of GSK3358699 25 mg followed by IV administration of in vivo LPS challenge at a dose of 0.75 ng/kg for induction of blisters on the forearm in Cohort 1 and in Cohort 2, participants were administered with IV administration of in vivo GM-CSF challenge at a dose of 60 mcg/m^2 and further treated with 0.2% cantharidin for induction of blisters on the forearm. GSK3358699 were administered via the oral route. Participants in Part A received a SD of GSK3358699 30 mg on Day 1 in treatment Period 3. Participants in Part A received a SD of GSK3358699 40 mg on Day 1 in treatment Period 3.
Measure Participants 23 5 3 6 6 12 6 6
ALT: To Low,n=23,5,3,6,6,12,6,6
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
ALT: To Normal or NC,n=23,5,3,6,6,12,6,6
22
2200%
5
250%
3
150%
6
300%
6
300%
12
300%
6
600%
6
200%
ALT: To High,n=23,5,3,6,6,12,6,6
1
100%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
ALP: To Low,n=23,5,3,6,6,12,6,6
0
0%
1
50%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
ALP: To Normal or NC,n=23,5,3,6,6,12,6,6
23
2300%
4
200%
3
150%
6
300%
6
300%
12
300%
6
600%
6
200%
ALP: To High,n=23,5,3,6,6,12,6,6
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
AST: To Low,n=23,5,3,6,6,12,6,6
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
AST: To Normal or NC,n=23,5,3,6,6,12,6,6
22
2200%
5
250%
3
150%
6
300%
6
300%
12
300%
6
600%
6
200%
AST: To High,n=23,5,3,6,6,12,6,6
1
100%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
Cholesterol: To Low,n=23,5,3,6,6,12,6,6
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
Cholesterol: To Normal or NC,n=23,5,3,6,6,12,6,6
22
2200%
4
200%
3
150%
5
250%
5
250%
10
250%
5
500%
4
133.3%
Cholesterol: To High,n=23,5,3,6,6,12,6,6
1
100%
1
50%
0
0%
1
50%
1
50%
2
50%
1
100%
2
66.7%
DB: To Low,n=23,5,3,6,6,12,6,6
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
DB:To Normal or NC,n=23,5,3,6,6,12,6,6
22
2200%
5
250%
2
100%
6
300%
6
300%
12
300%
6
600%
6
200%
DB: To High,n=23,5,3,6,6,12,6,6
1
100%
0
0%
1
50%
0
0%
0
0%
0
0%
0
0%
0
0%
High DL: To Low,n=23,5,3,6,6,12,6,6
1
100%
2
100%
0
0%
1
50%
0
0%
0
0%
0
0%
0
0%
High DL:To Normal or NC,n=23,5,3,6,6,12,6,6
22
2200%
2
100%
3
150%
5
250%
6
300%
11
275%
6
600%
6
200%
High DL: To High,n=23,5,3,6,6,12,6,6
0
0%
1
50%
0
0%
0
0%
0
0%
1
25%
0
0%
0
0%
CRP: To Low,n=23,5,3,6,4,12,6,6
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
CRP: To Normal or NC,n=23,5,3,6,4,12,6,6
18
1800%
5
250%
2
100%
6
300%
4
200%
4
100%
6
600%
5
166.7%
CRP: To High,n=23,5,3,6,4,12,6,6
5
500%
0
0%
1
50%
0
0%
0
0%
8
200%
0
0%
1
33.3%
Low DL: To Low,n=23,5,3,6,6,12,6,6
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
Low DL: To Normal or NC,n=23,5,3,6,6,12,6,6
21
2100%
5
250%
2
100%
4
200%
5
250%
11
275%
5
500%
4
133.3%
Low DL: To High,n=23,5,3,6,6,12,6,6
2
200%
0
0%
1
50%
2
100%
1
50%
1
25%
1
100%
2
66.7%
Total bilirubin: To Low,n=23,5,3,6,6,12,6,6
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
Total bilirubin:ToNormal or NC,n=23,5,3,6,6,12,6,6
22
2200%
5
250%
3
150%
6
300%
6
300%
11
275%
6
600%
6
200%
Total bilirubin: To High,n=23,5,3,6,6,12,6,6
1
100%
0
0%
0
0%
0
0%
0
0%
1
25%
0
0%
0
0%
Total protein: To Low,n=23,5,3,6,6,12,6,6
4
400%
0
0%
1
50%
0
0%
2
100%
3
75%
1
100%
1
33.3%
Total protein:To Normal or NC,n=23,5,3,6,6,12,6,6
19
1900%
5
250%
2
100%
6
300%
4
200%
9
225%
5
500%
5
166.7%
Total protein: To High,n=23,5,3,6,6,12,6,6
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
Triglycerides: To Low,n=23,5,3,6,6,12,6,6
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
Triglycerides:To Normal or NC,n=23,5,3,6,6,12,6,6
17
1700%
3
150%
2
100%
4
200%
4
200%
12
300%
3
300%
4
133.3%
Triglycerides: To High,n=23,5,3,6,6,12,6,6
6
600%
2
100%
1
50%
2
100%
2
100%
0
0%
3
300%
2
66.7%
BUN: To Low,n=23,5,3,6,6,12,6,6
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
BUN: To Normal or NC,n=23,5,3,6,6,12,6,6
23
2300%
5
250%
3
150%
6
300%
6
300%
12
300%
6
600%
6
200%
BUN: To High,n=23,5,3,6,6,12,6,6
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
6. Primary Outcome
Title Part B: Number of Participants With Worst Case Chemistry Results by PCI Criteria Post-Baseline Relative to Baseline
Description Blood samples were planned to be collected to analyze the chemistry parameters.
Time Frame Up to Day 30

Outcome Measure Data

Analysis Population Description
Safety Population. Data was not collected as no participants were enrolled in Part B.
Arm/Group Title Part B: Cohort 3- GSK3358699 Fed + GSK3358699 Fasted Part B: Cohort 3- GSK3358699 Fasted + GSK3358699 Fed
Arm/Group Description Participants in Part B Cohort 3 were planned to receive a SD of GSK3358699 under fed conditions on Day 1 in treatment Period 1; followed by a SD of GSK3358699 under fasted conditions on Day 1 in treatment Period 2. There was a planned washout period of 14 days between each treatment period. Participants in Part B Cohort 3 were planned to receive a SD of GSK3358699 under fasted conditions on Day 1 in treatment Period 1; followed by a SD of GSK3358699 under fed conditions on Day 1 in treatment Period 2. There was a planned washout period of 14 days between each treatment period.
Measure Participants 0 0
7. Primary Outcome
Title Part B: Number of Participants With Worst Case Chemistry Results Relative to Normal Range Post-Baseline Relative to Baseline
Description Blood samples were planned to be collected to analyze the chemistry parameters.
Time Frame Up to Day 30

Outcome Measure Data

Analysis Population Description
Safety Population. Data was not collected as no participants were enrolled in Part B.
Arm/Group Title Part B: Cohort 3- GSK3358699 Fed + GSK3358699 Fasted Part B: Cohort 3- GSK3358699 Fasted + GSK3358699 Fed
Arm/Group Description Participants in Part B Cohort 3 were planned to receive a SD of GSK3358699 under fed conditions on Day 1 in treatment Period 1; followed by a SD of GSK3358699 under fasted conditions on Day 1 in treatment Period 2. There was a planned washout period of 14 days between each treatment period. Participants in Part B Cohort 3 were planned to receive a SD of GSK3358699 under fasted conditions on Day 1 in treatment Period 1; followed by a SD of GSK3358699 under fed conditions on Day 1 in treatment Period 2. There was a planned washout period of 14 days between each treatment period.
Measure Participants 0 0
8. Primary Outcome
Title Part C: Number of Participants With Worst Case Chemistry Results by PCI Criteria Post-Baseline Relative to Baseline
Description Blood samples were collected for analysis of chemistry parameters. PCI ranges were <30 g/L (albumin), <2 or >2.75 mmol/L (calcium), >1.3* ULN mmol/L (creatinine), <3 or >9 mmol/L (glucose), <3 or >5.5 mmol/L (potassium), and <130 or >150 mmol/L (sodium). Participants were counted in worst case category that their value changes to (low, within range or no change or high), unless there is no change in their category. Participants whose laboratory value category was unchanged (e.g., High to High), or whose value became within range, were recorded in To within Range or No Change category. Participants were counted twice if participant had values that changed To Low and To High, so the percentages may not add to 100%.
Time Frame Up to Day 28

Outcome Measure Data

Analysis Population Description
Safety Population. Data was not collected for Cohorts 6 to 8 as no participants were enrolled.
Arm/Group Title Part C: Cohort 4 and 5- Placebo RD Part C: Cohort 4 and 5- GSK3358699 10 mg RD Part C: Cohort 6- GSK3358699 or Placebo RD Part C: Cohort 7- GSK3358699 or Placebo RD Part C: Cohort 8- GSK3358699 or Placebo RD
Arm/Group Description Participants received once daily RD of placebo on Days 1 to 14. In Cohort 4, on Day 14, participants were administered an IV in vivo LPS challenge at a dose of 0.75 ng/kg or an IV infusion of GM-CSF, in vivo at a dose of 60 mcg/m^2. The administration of LPS or GM-CSF was followed by blister induction on forearm (0.2% cantharidin). Participants received once daily repeat dose of GSK3358699 10 mg on Days 1 to 14. In Cohort 4, on Day 14, participants were administered an IV in vivo LPS challenge at a dose of 0.75 ng/kg or an IV infusion of GM-CSF, in vivo at a dose of 60 mcg/m^2. The administration of LPS or GM-CSF was followed by blister induction on forearm (0.2% cantharidin). Participants in Part C Cohort 6 were planned to receive once daily repeat dose of GSK3358699 or placebo on Days 1 to 14. Participants in Part C Cohort 7 were planned to receive once daily repeat dose of GSK3358699 or placebo on Days 1 to 14. Participants in Part C Cohort 8 were planned to receive once daily repeat dose of GSK3358699 or placebo on Days 1 to 14. On Day 14, participants were planned to receive an IV in vivo LPS challenge at a dose of 0.75 ng/kg or an IV infusion of GM-CSF, in vivo as 60 mcg/m^2. The administration of LPS or GM-CSF was planned to be followed by blister induction on forearm (0.2% cantharidin).
Measure Participants 11 14 0 0 0
Albumin: To Low
0
0%
0
0%
Albumin: To within Range or No Change
11
1100%
14
700%
Albumin: To High
0
0%
0
0%
Calcium: To Low
0
0%
0
0%
Calcium: To within Range or No Change
11
1100%
14
700%
Calcium: To High
0
0%
0
0%
Creatinine: To Low
0
0%
0
0%
Creatinine: To within Range or No Change
11
1100%
14
700%
Creatinine: To High
0
0%
0
0%
Glucose: To Low
0
0%
0
0%
Glucose: To within Range or No Change
11
1100%
14
700%
Glucose: To High
0
0%
0
0%
Potassium: To Low
0
0%
0
0%
Potassium: To within Range or No Change
11
1100%
14
700%
Potassium: To High
0
0%
0
0%
Sodium: To Low
0
0%
0
0%
Sodium: To within Range or No Change
11
1100%
14
700%
Sodium: To High
0
0%
0
0%
9. Primary Outcome
Title Part C: Number of Participants With Worst Case Chemistry Results Relative to Normal Range Post-Baseline Relative to Baseline
Description Clinical chemistry parameters assessed were ALT (<10 or >50 IU/L), ALP (<40 or >129 IU/L), AST (<0 or >37 IU/L), cholesterol (<2.3 or >4.9 mmol/L), DB (<0 or >5 mcmol/L), high DL (<0.9 or >1.5 mmol/L), CRP (<0.0 or >5.0 mg/liter), low DL (<0 or >3.0 mmol/L), total bilirubin (<0 or >20 mcmol/L), total protein (<63 or >83 grams/L), triglycerides (<0 or >2.3 mmol/L) and BUN (<4.76 or >23.24 mg/deciliter). Participants were counted in worst case category that their value changes to (low, normal or high), unless there is NC in their category. Participants whose laboratory value category was unchanged (e.g., High to High) or whose value became normal, are recorded in "To Normal or NC" category. Participants were counted twice if participant had values that changed To Low and To High, so percentages may not add to 100%.
Time Frame Up to Day 28

Outcome Measure Data

Analysis Population Description
Safety Population. Only those participants with data available at the specified time points were analyzed (represented by n= X in the category titles). Data was not collected for Cohorts 6 to 8 as no participants were enrolled.
Arm/Group Title Part C: Cohort 4 and 5- Placebo RD Part C: Cohort 4 and 5- GSK3358699 10 mg RD Part C: Cohort 6- GSK3358699 or Placebo RD Part C: Cohort 7- GSK3358699 or Placebo RD Part C: Cohort 8- GSK3358699 or Placebo RD
Arm/Group Description Participants received once daily RD of placebo on Days 1 to 14. In Cohort 4, on Day 14, participants were administered an IV in vivo LPS challenge at a dose of 0.75 ng/kg or an IV infusion of GM-CSF, in vivo at a dose of 60 mcg/m^2. The administration of LPS or GM-CSF was followed by blister induction on forearm (0.2% cantharidin). Participants received once daily repeat dose of GSK3358699 10 mg on Days 1 to 14. In Cohort 4, on Day 14, participants were administered an IV in vivo LPS challenge at a dose of 0.75 ng/kg or an IV infusion of GM-CSF, in vivo at a dose of 60 mcg/m^2. The administration of LPS or GM-CSF was followed by blister induction on forearm (0.2% cantharidin). Participants in Part C Cohort 6 were planned to receive once daily repeat dose of GSK3358699 or placebo on Days 1 to 14. Participants in Part C Cohort 7 were planned to receive once daily repeat dose of GSK3358699 or placebo on Days 1 to 14. Participants in Part C Cohort 8 were planned to receive once daily repeat dose of GSK3358699 or placebo on Days 1 to 14. On Day 14, participants were planned to receive an IV in vivo LPS challenge at a dose of 0.75 ng/kg or an IV infusion of GM-CSF, in vivo as 60 mcg/m^2. The administration of LPS or GM-CSF was planned to be followed by blister induction on forearm (0.2% cantharidin).
Measure Participants 11 14 0 0 0
ALT: To Low,n=11,14,0,0,0
0
0%
1
50%
ALT: To Normal or NC,n=11,14,0,0,0
11
1100%
12
600%
ALT: To High,n=11,14,0,0,0
0
0%
1
50%
ALP: To Low,n=11,14,0,0,0
0
0%
0
0%
ALP: To Normal or NC,n=11,14,0,0,0
11
1100%
14
700%
ALP: To High,n=11,14,0,0,0
0
0%
0
0%
AST: To Low,n=11,14,0,0,0
0
0%
0
0%
AST: To Normal or NC,n=11,14,0,0,0
10
1000%
14
700%
AST: To High,n=11,14,0,0,0
1
100%
0
0%
Cholesterol: To Low,n=11,14,0,0,0
0
0%
0
0%
Cholesterol: To Normal or NC,n=11,14,0,0,0
9
900%
13
650%
Cholesterol: To High,n=11,14,0,0,0
2
200%
1
50%
DB: To Low,n=11,14,0,0,0
0
0%
0
0%
DB:To Normal or NC,n=11,14,0,0,0
11
1100%
14
700%
DB: To High,n=11,14,0,0,0
0
0%
0
0%
High DL: To Low,n=11,14,0,0,0
1
100%
1
50%
High DL:To Normal or NC,n=11,14,0,0,0
10
1000%
13
650%
High DL: To High,n=11,14,0,0,0
0
0%
0
0%
CRP: To Low,n=10,13,0,0,0
0
0%
0
0%
CRP: To Normal or NC,n=10,13,0,0,0
9
900%
12
600%
CRP: To High,n=10,13,0,0,0
1
100%
1
50%
Low DL: To Low,n=11,14,0,0,0
0
0%
0
0%
Low DL: To Normal or NC,n=11,14,0,0,0
8
800%
13
650%
Low DL: To High,n=11,14,0,0,0
3
300%
1
50%
Total bilirubin: To Low,n=11,14,0,0,0
0
0%
0
0%
Total bilirubin:ToNormal or NC,n=11,14,0,0,0
11
1100%
14
700%
Total bilirubin: To High,n=11,14,0,0,0
0
0%
0
0%
Total protein: To Low,n=11,14,0,0,0
1
100%
2
100%
Total protein:To Normal or NC,n=11,14,0,0,0
10
1000%
12
600%
Total protein: To High,n=11,14,0,0,0
0
0%
0
0%
Triglycerides: To Low,n=11,14,0,0,0
0
0%
0
0%
Triglycerides:To Normal or NC,n=11,14,0,0,0
10
1000%
13
650%
Triglycerides: To High,n=11,14,0,0,0
1
100%
1
50%
BUN: To Low,n=11,14,0,0,0
0
0%
0
0%
BUN: To Normal or NC,n=11,14,0,0,0
11
1100%
14
700%
BUN: To High,n=11,14,0,0,0
0
0%
0
0%
10. Primary Outcome
Title Part A: Number of Participants With Worst Case Hematology Results by PCI Criteria Post-Baseline Relative to Baseline
Description Blood samples collected for analysis of hematology parameters. PCI ranges were >0.54 proportion of red blood cells in blood (hematocrit), >180 grams/liter (hemoglobin), <0.8 *10^9 cells/L (lymphocyte count), <1.5 *10^9 cells/L (total absolute neutrophil count [ANC]), <100 or >550 *10^9 cells/L (platelet count), and <3 or >20*10^9 cells/L (white blood cell [WBC] count). Participants were counted in worst case category that their value changes to (low, within range or no change or high), unless there is no change in their category. Participants whose laboratory value category was unchanged (e.g., High to High), or whose value became within range, were recorded in To within Range or No Change category. Participants were counted twice if the participant had values that changed To Low and To High, so the percentages may not add to 100%.
Time Frame Up to Day 193

Outcome Measure Data

Analysis Population Description
Safety Population.
Arm/Group Title Part A: Placebo SD Part A: GSK3358699 1 mg SD Part A: GSK3358699 3 mg SD Part A: GSK3358699 10 mg SD Part A: GSK3358699 20 mg SD Part A: GSK3358699 25 mg SD Part A: GSK3358699 30 mg SD Part A: GSK3358699 40 mg SD
Arm/Group Description Participants in Part A received a SD of placebo on Day 1 in either treatment Period 1, 2 and 3. On Day 1 of treatment Period 4, participants were administered a SD of placebo followed by IV administration of in vivo LPS challenge at a dose of 0.75 ng/kg for induction of blisters on the forearm in Cohort 1 and in Cohort 2, participants were administered with IV administration of in vivo GM-CSF challenge at a dose of 60 mcg/m^2 and further treated with 0.2% cantharidin for induction of blisters on the forearm. Placebo were administered via the oral route. Participants in Part A received a SD of GSK3358699 1 mg on Day 1 in treatment Period 1. Participants in Part A received a SD of GSK3358699 3 mg on Day 1 in treatment Period 1. Participants in Part A received a SD of GSK3358699 10 mg on Day 1 in treatment Period 2. Participants in Part A received a SD of GSK3358699 20 mg on Day 1 in treatment Period 2. Participants in Part A received a SD of GSK3358699 25 mg on Day 1 in treatment Period 4. On Day 1, participants were administered a SD of GSK3358699 25 mg followed by IV administration of in vivo LPS challenge at a dose of 0.75 ng/kg for induction of blisters on the forearm in Cohort 1 and in Cohort 2, participants were administered with IV administration of in vivo GM-CSF challenge at a dose of 60 mcg/m^2 and further treated with 0.2% cantharidin for induction of blisters on the forearm. GSK3358699 were administered via the oral route. Participants in Part A received a SD of GSK3358699 30 mg on Day 1 in treatment Period 3. Participants in Part A received a SD of GSK3358699 40 mg on Day 1 in treatment Period 3.
Measure Participants 23 5 3 6 6 12 6 6
Hematocrit: To Low
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
Hematocrit: To within Range or No Change
23
2300%
5
250%
3
150%
6
300%
6
300%
12
300%
6
600%
6
200%
Hematocrit: To High
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
Hemoglobin: To Low
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
Hemoglobin: To within Range or No Change
23
2300%
5
250%
3
150%
6
300%
6
300%
12
300%
6
600%
6
200%
Hemoglobin: To High
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
Lymphocyte count: To Low
2
200%
0
0%
0
0%
0
0%
0
0%
2
50%
0
0%
0
0%
Lymphocyte count: To within Range or No Change
21
2100%
5
250%
3
150%
6
300%
6
300%
10
250%
6
600%
6
200%
Lymphocyte count: To High
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
Platelet count: To Low
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
Platelet count: To within Range or No Change
23
2300%
5
250%
3
150%
6
300%
6
300%
12
300%
6
600%
6
200%
Platelet count: To High
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
Total ANC: To Low
0
0%
1
50%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
Total ANC: To within Range or No Change
23
2300%
4
200%
3
150%
6
300%
6
300%
12
300%
6
600%
6
200%
Total ANC: To High
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
WBC: To Low
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
WBC: To within Range or No Change
23
2300%
5
250%
3
150%
6
300%
6
300%
12
300%
6
600%
6
200%
WBC: To High
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
11. Primary Outcome
Title Part A: Number of Participants With Worst Case Hematology Results Relative to Normal Range Post-Baseline Relative to Baseline
Description Hematology parameters assessed were activated partial thromboplastin time (APTT) (<25 or >37 seconds), basophil count (<0.0 or >0.1*10^9 cells/L), eosinophil count (<0.0 or >0.4*10^9 cells/L), fibrinogen (<1.5 or >4.0 g/L), mean corpuscle hemoglobin (MCH) (<26.0 or >33.5 picogram), mean corpuscle volume (MCV) (<80 or >99 femtoliter), monocyte count (<0.2 or >1.0*10^9 cells/L), prothrombin time (PT) (<10 or >12 seconds), red blood cell (RBC) count (<4.4 or >5.8*10^12 cells/L) and reticulocyte count (<0.38 or >2.64 percentage of reticulocytes). Participants were counted in worst case category that their value changes to (low, normal or high), unless there is NC in their category. Participants whose laboratory value category was unchanged (e.g., High to High) or whose value became normal, are recorded in "To Normal or NC" category. Participants were counted twice if participant had values that changed To Low and To High, so percentages may not add to 100%.
Time Frame Up to Day 193

Outcome Measure Data

Analysis Population Description
Safety Population.
Arm/Group Title Part A: Placebo SD Part A: GSK3358699 1 mg SD Part A: GSK3358699 3 mg SD Part A: GSK3358699 10 mg SD Part A: GSK3358699 20 mg SD Part A: GSK3358699 25 mg SD Part A: GSK3358699 30 mg SD Part A: GSK3358699 40 mg SD
Arm/Group Description Participants in Part A received a SD of placebo on Day 1 in either treatment Period 1, 2 and 3. On Day 1 of treatment Period 4, participants were administered a SD of placebo followed by IV administration of in vivo LPS challenge at a dose of 0.75 ng/kg for induction of blisters on the forearm in Cohort 1 and in Cohort 2, participants were administered with IV administration of in vivo GM-CSF challenge at a dose of 60 mcg/m^2 and further treated with 0.2% cantharidin for induction of blisters on the forearm. Placebo were administered via the oral route. Participants in Part A received a SD of GSK3358699 1 mg on Day 1 in treatment Period 1. Participants in Part A received a SD of GSK3358699 3 mg on Day 1 in treatment Period 1. Participants in Part A received a SD of GSK3358699 10 mg on Day 1 in treatment Period 2. Participants in Part A received a SD of GSK3358699 20 mg on Day 1 in treatment Period 2. Participants in Part A received a SD of GSK3358699 25 mg on Day 1 in treatment Period 4. On Day 1, participants were administered a SD of GSK3358699 25 mg followed by IV administration of in vivo LPS challenge at a dose of 0.75 ng/kg for induction of blisters on the forearm in Cohort 1 and in Cohort 2, participants were administered with IV administration of in vivo GM-CSF challenge at a dose of 60 mcg/m^2 and further treated with 0.2% cantharidin for induction of blisters on the forearm. GSK3358699 were administered via the oral route. Participants in Part A received a SD of GSK3358699 30 mg on Day 1 in treatment Period 3. Participants in Part A received a SD of GSK3358699 40 mg on Day 1 in treatment Period 3.
Measure Participants 23 5 3 6 6 12 6 6
APTT: To Low
0
0%
0
0%
0
0%
0
0%
1
50%
1
25%
0
0%
0
0%
APTT: To Normal or NC
21
2100%
5
250%
2
100%
6
300%
4
200%
11
275%
6
600%
4
133.3%
APTT: To High
2
200%
0
0%
1
50%
0
0%
1
50%
0
0%
0
0%
2
66.7%
Basophil count: To Low
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
Basophil count: To Normal or NC
23
2300%
5
250%
3
150%
6
300%
5
250%
12
300%
6
600%
6
200%
Basophil count: To High
0
0%
0
0%
0
0%
0
0%
1
50%
0
0%
0
0%
0
0%
Eosinophil count: To Low
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
Eosinophil count: To Normal or NC
21
2100%
5
250%
3
150%
6
300%
5
250%
12
300%
6
600%
5
166.7%
Eosinophil count: To High
2
200%
0
0%
0
0%
0
0%
1
50%
0
0%
0
0%
1
33.3%
Fibrinogen: To Low
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
Fibrinogen: To Normal or NC
23
2300%
5
250%
3
150%
6
300%
6
300%
12
300%
6
600%
5
166.7%
Fibrinogen: To High
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
1
33.3%
MCH: To Low
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
MCH: To Normal or NC
23
2300%
4
200%
3
150%
6
300%
6
300%
12
300%
6
600%
6
200%
MCH: To High
0
0%
1
50%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
MCV: To Low
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
MCV: To Normal or NC
23
2300%
5
250%
3
150%
6
300%
6
300%
12
300%
6
600%
6
200%
MCV: To High
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
Monocyte count: To Low
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
Monocyte count: To Normal or NC
19
1900%
5
250%
3
150%
6
300%
6
300%
6
150%
6
600%
6
200%
Monocyte count: To High
4
400%
0
0%
0
0%
0
0%
0
0%
6
150%
0
0%
0
0%
PT: To Low
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
PT: To Normal or NC
23
2300%
5
250%
2
100%
6
300%
6
300%
12
300%
6
600%
5
166.7%
PT: To High
0
0%
0
0%
1
50%
0
0%
0
0%
0
0%
0
0%
1
33.3%
RBC: To Low
1
100%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
RBC: To Normal or NC
22
2200%
5
250%
2
100%
6
300%
6
300%
12
300%
6
600%
6
200%
RBC: To High
0
0%
0
0%
1
50%
0
0%
0
0%
0
0%
0
0%
0
0%
Reticulocyte count: To Low
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
Reticulocyte count: To Normal or NC
23
2300%
4
200%
3
150%
6
300%
6
300%
12
300%
6
600%
6
200%
Reticulocyte count: To High
0
0%
1
50%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
12. Primary Outcome
Title Part B: Number of Participants With Worst Case Hematology Results by PCI Criteria Post-Baseline Relative to Baseline
Description Blood samples were planned to be collected to analyze hematology parameters.
Time Frame Up to Day 30

Outcome Measure Data

Analysis Population Description
Safety Population. Data was not collected as no participants were enrolled in Part B.
Arm/Group Title Part B: Cohort 3- GSK3358699 Fed + GSK3358699 Fasted Part B: Cohort 3- GSK3358699 Fasted + GSK3358699 Fed
Arm/Group Description Participants in Part B Cohort 3 were planned to receive a SD of GSK3358699 under fed conditions on Day 1 in treatment Period 1; followed by a SD of GSK3358699 under fasted conditions on Day 1 in treatment Period 2. There was a planned washout period of 14 days between each treatment period. Participants in Part B Cohort 3 were planned to receive a SD of GSK3358699 under fasted conditions on Day 1 in treatment Period 1; followed by a SD of GSK3358699 under fed conditions on Day 1 in treatment Period 2. There was a planned washout period of 14 days between each treatment period.
Measure Participants 0 0
13. Primary Outcome
Title Part B: Number of Participants With Worst Case Hematology Results Relative to Normal Range Post-Baseline Relative to Baseline
Description Blood samples were planned to be collected to analyze hematology parameters.
Time Frame Up to Day 30

Outcome Measure Data

Analysis Population Description
Safety Population. Data was not collected as no participants were enrolled in Part B.
Arm/Group Title Part B: Cohort 3- GSK3358699 Fed + GSK3358699 Fasted Part B: Cohort 3- GSK3358699 Fasted + GSK3358699 Fed
Arm/Group Description Participants in Part B Cohort 3 were planned to receive a SD of GSK3358699 under fed conditions on Day 1 in treatment Period 1; followed by a SD of GSK3358699 under fasted conditions on Day 1 in treatment Period 2. There was a planned washout period of 14 days between each treatment period. Participants in Part B Cohort 3 were planned to receive a SD of GSK3358699 under fasted conditions on Day 1 in treatment Period 1; followed by a SD of GSK3358699 under fed conditions on Day 1 in treatment Period 2. There was a planned washout period of 14 days between each treatment period.
Measure Participants 0 0
14. Primary Outcome
Title Part C: Number of Participants With Worst Case Hematology Results by PCI Criteria Post-Baseline Relative to Baseline
Description Blood samples were collected for analysis of hematology parameters. PCI ranges were >0.54 proportion of red blood cells in blood (hematocrit), >180 grams/liter (hemoglobin), <0.8*10^9 cells/L (lymphocyte count), <1.5*10^9 cells/L (total ANC), <100 or >550*10^9 cells/L (platelet count), and <3 or >20*10^9 cells/L (WBC count). Participants were counted in worst case category that their value changes to (low, within range or no change or high), unless there is no change in their category. Participants whose laboratory value category was unchanged (e.g., High to High), or whose value became within range, were recorded in To within Range or No Change category. Participants were counted twice if the participant had values that changed To Low and To High, so the percentages may not add to 100%.
Time Frame Up to Day 28

Outcome Measure Data

Analysis Population Description
Safety Population. Data was not collected for Cohorts 6 to 8 as no participants were enrolled.
Arm/Group Title Part C: Cohort 4 and 5- Placebo RD Part C: Cohort 4 and 5- GSK3358699 10 mg RD Part C: Cohort 6- GSK3358699 or Placebo RD Part C: Cohort 7- GSK3358699 or Placebo RD Part C: Cohort 8- GSK3358699 or Placebo RD
Arm/Group Description Participants received once daily RD of placebo on Days 1 to 14. In Cohort 4, on Day 14, participants were administered an IV in vivo LPS challenge at a dose of 0.75 ng/kg or an IV infusion of GM-CSF, in vivo at a dose of 60 mcg/m^2. The administration of LPS or GM-CSF was followed by blister induction on forearm (0.2% cantharidin). Participants received once daily repeat dose of GSK3358699 10 mg on Days 1 to 14. In Cohort 4, on Day 14, participants were administered an IV in vivo LPS challenge at a dose of 0.75 ng/kg or an IV infusion of GM-CSF, in vivo at a dose of 60 mcg/m^2. The administration of LPS or GM-CSF was followed by blister induction on forearm (0.2% cantharidin). Participants in Part C Cohort 6 were planned to receive once daily repeat dose of GSK3358699 or placebo on Days 1 to 14. Participants in Part C Cohort 7 were planned to receive once daily repeat dose of GSK3358699 or placebo on Days 1 to 14. Participants in Part C Cohort 8 were planned to receive once daily repeat dose of GSK3358699 or placebo on Days 1 to 14. On Day 14, participants were planned to receive an IV in vivo LPS challenge at a dose of 0.75 ng/kg or an IV infusion of GM-CSF, in vivo as 60 mcg/m^2. The administration of LPS or GM-CSF was planned to be followed by blister induction on forearm (0.2% cantharidin).
Measure Participants 11 14 0 0 0
Hematocrit: To Low
0
0%
0
0%
Hematocrit: To within Range or No Change
11
1100%
14
700%
Hematocrit: To High
0
0%
0
0%
Hemoglobin: To Low
0
0%
0
0%
Hemoglobin: To within Range or No Change
11
1100%
14
700%
Hemoglobin: To High
0
0%
0
0%
Lymphocyte count: To Low
1
100%
0
0%
Lymphocyte count: To within Range or No Change
10
1000%
14
700%
Lymphocyte count: To High
0
0%
0
0%
Platelet count: To Low
0
0%
0
0%
Platelet count: To within Range or No Change
11
1100%
14
700%
Platelet count: To High
0
0%
0
0%
Total ANC: To Low
1
100%
0
0%
Total ANC: To within Range or No Change
10
1000%
14
700%
Total ANC: To High
0
0%
0
0%
WBC: To Low
1
100%
1
50%
WBC: To within Range or No Change
10
1000%
13
650%
WBC: To High
0
0%
0
0%
15. Primary Outcome
Title Part C: Number of Participants With Worst Case Hematology Results Relative to Normal Range Post-Baseline Relative to Baseline
Description Hematology parameters assessed were APTT (<25 or >37 seconds), basophil count (<0.0 or >0.1*10^9 cells/L), eosinophil count (<0.0 or >0.4*10^9 cells/L), fibrinogen (<1.5 or >4.0 g/L), MCH (<26.0 or >33.5 picogram), MCV (<80 or >99 femtoliter), monocyte count (<0.2 or >1.0*10^9 cells/L), PT (<10 or >12 seconds), RBC count (<4.4 or >5.8*10^12 cells/L) and reticulocyte count (<0.38 or >2.64 percentage of reticulocytes). Participants were counted in worst case category that their value changes to (low, normal or high), unless there is NC in their category. Participants whose laboratory value category was unchanged (e.g., High to High) or whose value became normal, are recorded in "To Normal or NC" category. Participants were counted twice if participant had values that changed To Low and To High, so percentages may not add to 100%.
Time Frame Up to Day 28

Outcome Measure Data

Analysis Population Description
Safety Population. Data was not collected for Cohorts 6 to 8 as no participants were enrolled.
Arm/Group Title Part C: Cohort 4 and 5- Placebo RD Part C: Cohort 4 and 5- GSK3358699 10 mg RD Part C: Cohort 6- GSK3358699 or Placebo RD Part C: Cohort 7- GSK3358699 or Placebo RD Part C: Cohort 8- GSK3358699 or Placebo RD
Arm/Group Description Participants received once daily RD of placebo on Days 1 to 14. In Cohort 4, on Day 14, participants were administered an IV in vivo LPS challenge at a dose of 0.75 ng/kg or an IV infusion of GM-CSF, in vivo at a dose of 60 mcg/m^2. The administration of LPS or GM-CSF was followed by blister induction on forearm (0.2% cantharidin). Participants received once daily repeat dose of GSK3358699 10 mg on Days 1 to 14. In Cohort 4, on Day 14, participants were administered an IV in vivo LPS challenge at a dose of 0.75 ng/kg or an IV infusion of GM-CSF, in vivo at a dose of 60 mcg/m^2. The administration of LPS or GM-CSF was followed by blister induction on forearm (0.2% cantharidin). Participants in Part C Cohort 6 were planned to receive once daily repeat dose of GSK3358699 or placebo on Days 1 to 14. Participants in Part C Cohort 7 were planned to receive once daily repeat dose of GSK3358699 or placebo on Days 1 to 14. Participants in Part C Cohort 8 were planned to receive once daily repeat dose of GSK3358699 or placebo on Days 1 to 14. On Day 14, participants were planned to receive an IV in vivo LPS challenge at a dose of 0.75 ng/kg or an IV infusion of GM-CSF, in vivo as 60 mcg/m^2. The administration of LPS or GM-CSF was planned to be followed by blister induction on forearm (0.2% cantharidin).
Measure Participants 11 14 0 0 0
APTT: To Low
1
100%
0
0%
APTT: To Normal or NC
10
1000%
13
650%
APTT: To High
0
0%
1
50%
Basophil count: To Low
0
0%
0
0%
Basophil count: To Normal or NC
11
1100%
14
700%
Basophil count: To High
0
0%
0
0%
Eosinophil count: To Low
0
0%
0
0%
Eosinophil count: To Normal or NC
11
1100%
14
700%
Eosinophil count: To High
0
0%
0
0%
Fibrinogen: To Low
0
0%
0
0%
Fibrinogen: To Normal or NC
11
1100%
14
700%
Fibrinogen: To High
0
0%
0
0%
MCH: To Low
0
0%
0
0%
MCH: To Normal or NC
11
1100%
14
700%
MCH: To High
0
0%
0
0%
MCV: To Low
0
0%
0
0%
MCV: To Normal or NC
11
1100%
14
700%
MCV: To High
0
0%
0
0%
Monocyte count: To Low
0
0%
0
0%
Monocyte count: To Normal or NC
11
1100%
14
700%
Monocyte count: To High
0
0%
0
0%
PT: To Low
0
0%
0
0%
PT: To Normal or NC
10
1000%
14
700%
PT: To High
1
100%
0
0%
RBC: To Low
0
0%
1
50%
RBC: To Normal or NC
11
1100%
13
650%
RBC: To High
0
0%
0
0%
Reticulocyte count: To Low
0
0%
0
0%
Reticulocyte count: To Normal or NC
11
1100%
14
700%
Reticulocyte count: To High
0
0%
0
0%
16. Primary Outcome
Title Part A: Number of Participants With Abnormal Urinalysis Parameters
Description Urine samples were collected from participants for analyzing the following urine parameters: potential of hydrogen (pH) and glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocytes levels by dipstick. Urine samples showing any abnormality were sent for microscopic examination to detect the presence of RBC, WBC, cellular casts, granular casts, hyaline casts, and were counted as cells per high-power field (cells/HPF). Number of participants with abnormal urinalysis result by microscopic examination have been presented.
Time Frame Up to Day 193

Outcome Measure Data

Analysis Population Description
Safety Population.
Arm/Group Title Part A: Placebo SD Part A: GSK3358699 1 mg SD Part A: GSK3358699 3 mg SD Part A: GSK3358699 10 mg SD Part A: GSK3358699 20 mg SD Part A: GSK3358699 25 mg SD Part A: GSK3358699 30 mg SD Part A: GSK3358699 40 mg SD
Arm/Group Description Participants in Part A received a SD of placebo on Day 1 in either treatment Period 1, 2 and 3. On Day 1 of treatment Period 4, participants were administered a SD of placebo followed by IV administration of in vivo LPS challenge at a dose of 0.75 ng/kg for induction of blisters on the forearm in Cohort 1 and in Cohort 2, participants were administered with IV administration of in vivo GM-CSF challenge at a dose of 60 mcg/m^2 and further treated with 0.2% cantharidin for induction of blisters on the forearm. Placebo were administered via the oral route. Participants in Part A received a SD of GSK3358699 1 mg on Day 1 in treatment Period 1. Participants in Part A received a SD of GSK3358699 3 mg on Day 1 in treatment Period 1. Participants in Part A received a SD of GSK3358699 10 mg on Day 1 in treatment Period 2. Participants in Part A received a SD of GSK3358699 20 mg on Day 1 in treatment Period 2. Participants in Part A received a SD of GSK3358699 25 mg on Day 1 in treatment Period 4. On Day 1, participants were administered a SD of GSK3358699 25 mg followed by IV administration of in vivo LPS challenge at a dose of 0.75 ng/kg for induction of blisters on the forearm in Cohort 1 and in Cohort 2, participants were administered with IV administration of in vivo GM-CSF challenge at a dose of 60 mcg/m^2 and further treated with 0.2% cantharidin for induction of blisters on the forearm. GSK3358699 were administered via the oral route. Participants in Part A received a SD of GSK3358699 30 mg on Day 1 in treatment Period 3. Participants in Part A received a SD of GSK3358699 40 mg on Day 1 in treatment Period 3.
Measure Participants 23 5 3 6 6 12 6 6
RBC
2
200%
0
0%
0
0%
0
0%
0
0%
1
25%
0
0%
0
0%
WBC
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
1
100%
0
0%
Cellular casts
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
Granular casts
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
Hyaline casts
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
17. Primary Outcome
Title Part B: Number of Participants With Abnormal Urinalysis Parameters
Description Urine samples were planned to be collected to analyze urine parameters.
Time Frame Up to Day 30

Outcome Measure Data

Analysis Population Description
Safety Population. Data was not collected as no participants were enrolled in Part B.
Arm/Group Title Part B: Cohort 3- GSK3358699 Fed + GSK3358699 Fasted Part B: Cohort 3- GSK3358699 Fasted + GSK3358699 Fed
Arm/Group Description Participants in Part B Cohort 3 were planned to receive a SD of GSK3358699 under fed conditions on Day 1 in treatment Period 1; followed by a SD of GSK3358699 under fasted conditions on Day 1 in treatment Period 2. There was a planned washout period of 14 days between each treatment period. Participants in Part B Cohort 3 were planned to receive a SD of GSK3358699 under fasted conditions on Day 1 in treatment Period 1; followed by a SD of GSK3358699 under fed conditions on Day 1 in treatment Period 2. There was a planned washout period of 14 days between each treatment period.
Measure Participants 0 0
18. Primary Outcome
Title Part C: Number of Participants With Abnormal Urinalysis Parameters
Description Urine samples were collected from participants for analyzing the following urine parameters: pH and glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocytes levels by dipstick. Urine samples showing any abnormality were sent for microscopic examination to detect the presence of RBC, WBC, cellular casts, granular casts, hyaline casts, and were counted as cells/HPF. Number of participants with abnormal urinalysis result by microscopic examination have been presented.
Time Frame Up to Day 28

Outcome Measure Data

Analysis Population Description
Safety Population. Data was not collected for Cohorts 6 to 8 as no participants were enrolled.
Arm/Group Title Part C: Cohort 4 and 5- Placebo RD Part C: Cohort 4 and 5- GSK3358699 10 mg RD Part C: Cohort 6- GSK3358699 or Placebo RD Part C: Cohort 7- GSK3358699 or Placebo RD Part C: Cohort 8- GSK3358699 or Placebo RD
Arm/Group Description Participants received once daily RD of placebo on Days 1 to 14. In Cohort 4, on Day 14, participants were administered an IV in vivo LPS challenge at a dose of 0.75 ng/kg or an IV infusion of GM-CSF, in vivo at a dose of 60 mcg/m^2. The administration of LPS or GM-CSF was followed by blister induction on forearm (0.2% cantharidin). Participants received once daily repeat dose of GSK3358699 10 mg on Days 1 to 14. In Cohort 4, on Day 14, participants were administered an IV in vivo LPS challenge at a dose of 0.75 ng/kg or an IV infusion of GM-CSF, in vivo at a dose of 60 mcg/m^2. The administration of LPS or GM-CSF was followed by blister induction on forearm (0.2% cantharidin). Participants in Part C Cohort 6 were planned to receive once daily repeat dose of GSK3358699 or placebo on Days 1 to 14. Participants in Part C Cohort 7 were planned to receive once daily repeat dose of GSK3358699 or placebo on Days 1 to 14. Participants in Part C Cohort 8 were planned to receive once daily repeat dose of GSK3358699 or placebo on Days 1 to 14. On Day 14, participants were planned to receive an IV in vivo LPS challenge at a dose of 0.75 ng/kg or an IV infusion of GM-CSF, in vivo as 60 mcg/m^2. The administration of LPS or GM-CSF was planned to be followed by blister induction on forearm (0.2% cantharidin).
Measure Participants 11 14 0 0 0
RBC
0
0%
0
0%
WBC
1
100%
1
50%
Cellular casts
0
0%
0
0%
Granular casts
0
0%
0
0%
Hyaline casts
0
0%
0
0%
19. Primary Outcome
Title Part A: Number of Participants With Worst Case Vital Sign Results by PCI Criteria Post-Baseline Relative to Baseline
Description Vital signs included systolic blood pressure(SBP), diastolic blood pressure(DBP), heart rate, respiratory rate and body temperature and were measured in a semi-supine position after 5 minutes rest. PCI ranges were, SBP (millimeters of mercury [mmHg]): <85 (low) or >160 (high), DBP (mmHg): <45 (low) or >100 (high), heart rate (beats per minute): <40 (low) or >110 (high), respiration rate (breaths per minute): <11(low) or >20(high) and body temperature (degrees Celsius) <35.5 (low) or >38.0 (high). Participants were counted in the worst case category that their value changes to (low, within range or no change, or high), unless there is no change in their category. Participants whose vital signs value category was unchanged (e.g., High to High), or whose value became within range, were recorded in the "To within Range or No Change" category. Participants were counted twice if the participant had values that changed "To Low" and "To High", so the percentages may not add to 100%.
Time Frame Up to Day 193

Outcome Measure Data

Analysis Population Description
Safety Population.
Arm/Group Title Part A: Placebo SD Part A: GSK3358699 1 mg SD Part A: GSK3358699 3 mg SD Part A: GSK3358699 10 mg SD Part A: GSK3358699 20 mg SD Part A: GSK3358699 25 mg SD Part A: GSK3358699 30 mg SD Part A: GSK3358699 40 mg SD
Arm/Group Description Participants in Part A received a SD of placebo on Day 1 in either treatment Period 1, 2 and 3. On Day 1 of treatment Period 4, participants were administered a SD of placebo followed by IV administration of in vivo LPS challenge at a dose of 0.75 ng/kg for induction of blisters on the forearm in Cohort 1 and in Cohort 2, participants were administered with IV administration of in vivo GM-CSF challenge at a dose of 60 mcg/m^2 and further treated with 0.2% cantharidin for induction of blisters on the forearm. Placebo were administered via the oral route. Participants in Part A received a SD of GSK3358699 1 mg on Day 1 in treatment Period 1. Participants in Part A received a SD of GSK3358699 3 mg on Day 1 in treatment Period 1. Participants in Part A received a SD of GSK3358699 10 mg on Day 1 in treatment Period 2. Participants in Part A received a SD of GSK3358699 20 mg on Day 1 in treatment Period 2. Participants in Part A received a SD of GSK3358699 25 mg on Day 1 in treatment Period 4. On Day 1, participants were administered a SD of GSK3358699 25 mg followed by IV administration of in vivo LPS challenge at a dose of 0.75 ng/kg for induction of blisters on the forearm in Cohort 1 and in Cohort 2, participants were administered with IV administration of in vivo GM-CSF challenge at a dose of 60 mcg/m^2 and further treated with 0.2% cantharidin for induction of blisters on the forearm. GSK3358699 were administered via the oral route. Participants in Part A received a SD of GSK3358699 30 mg on Day 1 in treatment Period 3. Participants in Part A received a SD of GSK3358699 40 mg on Day 1 in treatment Period 3.
Measure Participants 23 5 3 6 6 12 6 6
SBP: To Low
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
SBP: To within Range or No Change
23
2300%
5
250%
3
150%
6
300%
6
300%
12
300%
6
600%
6
200%
SBP: To High
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
DBP: To Low
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
DBP: To within Range or No Change
23
2300%
5
250%
3
150%
6
300%
6
300%
12
300%
6
600%
6
200%
DBP: To High
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
Heart rate: To Low
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
Heart rate: To within Range or No Change
23
2300%
5
250%
3
150%
6
300%
6
300%
12
300%
6
600%
6
200%
Heart rate: To High
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
Respiratory rate: To Low
1
100%
0
0%
0
0%
0
0%
0
0%
1
25%
0
0%
0
0%
Respiratory rate: To within Range or No Change
22
2200%
5
250%
3
150%
6
300%
6
300%
11
275%
6
600%
6
200%
Respiratory rate: To High
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
Body temperature: To Low
0
0%
0
0%
0
0%
1
50%
0
0%
0
0%
0
0%
0
0%
Body temperature: To within Range or No Change
22
2200%
5
250%
3
150%
5
250%
6
300%
11
275%
6
600%
6
200%
Body temperature: To High
1
100%
0
0%
0
0%
0
0%
0
0%
1
25%
0
0%
0
0%
20. Primary Outcome
Title Part B: Number of Participants With Worst Case Vital Sign Results by PCI Criteria Post-Baseline Relative to Baseline
Description Vital signs were planned to be measured in a semi-supine position after 5 minutes of rest.
Time Frame Up to Day 30

Outcome Measure Data

Analysis Population Description
Safety Population. Data was not collected as no participants were enrolled in Part B.
Arm/Group Title Part B: Cohort 3- GSK3358699 Fed + GSK3358699 Fasted Part B: Cohort 3- GSK3358699 Fasted + GSK3358699 Fed
Arm/Group Description Participants in Part B Cohort 3 were planned to receive a SD of GSK3358699 under fed conditions on Day 1 in treatment Period 1; followed by a SD of GSK3358699 under fasted conditions on Day 1 in treatment Period 2. There was a planned washout period of 14 days between each treatment period. Participants in Part B Cohort 3 were planned to receive a SD of GSK3358699 under fasted conditions on Day 1 in treatment Period 1; followed by a SD of GSK3358699 under fed conditions on Day 1 in treatment Period 2. There was a planned washout period of 14 days between each treatment period.
Measure Participants 0 0
21. Primary Outcome
Title Part C: Number of Participants With Worst Case Vital Sign Results by PCI Criteria Post-Baseline Relative to Baseline
Description Vital signs included SBP, DBP, heart rate, respiratory rate and body temperature and were measured in a semi-supine position after 5 minutes rest. PCI ranges were, SBP (mmHg): <85 (low) or >160 (high), DBP (mmHg): <45 (low) or >100 (high), heart rate (beats per minute): <40 (low) or >110 (high), respiration rate (breaths per minute): <11 (low) or >20 (high) and body temperature (degrees Celsius) <35.5 (low) or >38.0 (high). Participants were counted in the worst case category that their value changes to (low, within range or no change, or high), unless there is no change in their category. Participants whose vital signs value category was unchanged (e.g., High to High), or whose value became within range, were recorded in the "To within Range or No Change" category. Participants were counted twice if the participant had values that changed "To Low" and "To High", so the percentages may not add to 100%.
Time Frame Up to Day 49

Outcome Measure Data

Analysis Population Description
Safety Population. Data was not collected for Cohorts 6 to 8 as no participants were enrolled.
Arm/Group Title Part C: Cohort 4 and 5- Placebo RD Part C: Cohort 4 and 5- GSK3358699 10 mg RD Part C: Cohort 6- GSK3358699 or Placebo RD Part C: Cohort 7- GSK3358699 or Placebo RD Part C: Cohort 8- GSK3358699 or Placebo RD
Arm/Group Description Participants received once daily RD of placebo on Days 1 to 14. In Cohort 4, on Day 14, participants were administered an IV in vivo LPS challenge at a dose of 0.75 ng/kg or an IV infusion of GM-CSF, in vivo at a dose of 60 mcg/m^2. The administration of LPS or GM-CSF was followed by blister induction on forearm (0.2% cantharidin). Participants received once daily repeat dose of GSK3358699 10 mg on Days 1 to 14. In Cohort 4, on Day 14, participants were administered an IV in vivo LPS challenge at a dose of 0.75 ng/kg or an IV infusion of GM-CSF, in vivo at a dose of 60 mcg/m^2. The administration of LPS or GM-CSF was followed by blister induction on forearm (0.2% cantharidin). Participants in Part C Cohort 6 were planned to receive once daily repeat dose of GSK3358699 or placebo on Days 1 to 14. Participants in Part C Cohort 7 were planned to receive once daily repeat dose of GSK3358699 or placebo on Days 1 to 14. Participants in Part C Cohort 8 were planned to receive once daily repeat dose of GSK3358699 or placebo on Days 1 to 14. On Day 14, participants were planned to receive an IV in vivo LPS challenge at a dose of 0.75 ng/kg or an IV infusion of GM-CSF, in vivo as 60 mcg/m^2. The administration of LPS or GM-CSF was planned to be followed by blister induction on forearm (0.2% cantharidin).
Measure Participants 11 14 0 0 0
SBP: To Low
0
0%
0
0%
SBP: To within Range or No Change
11
1100%
14
700%
SBP: To High
0
0%
0
0%
DBP: To Low
0
0%
0
0%
DBP: To within Range or No Change
11
1100%
14
700%
DBP: To High
0
0%
0
0%
Heart rate: To Low
0
0%
1
50%
Heart rate: To within Range or No Change
10
1000%
13
650%
Heart rate: To High
1
100%
0
0%
Respiratory rate: To Low
1
100%
1
50%
Respiratory rate: To within Range or No Change
9
900%
13
650%
Respiratory rate: To High
1
100%
0
0%
Body temperature: To Low
0
0%
0
0%
Body temperature: To within Range or No Change
11
1100%
14
700%
Body temperature: To High
0
0%
0
0%
22. Primary Outcome
Title Part A: Number of Participants With Worst Case Post-Baseline Abnormal Electrocardiogram (ECG) Findings
Description Twelve lead ECGs were obtained using an ECG machine that automatically calculated the heart rate and measured PR, QRS, QT, and QT interval corrected using the Fridericia's formula (QTcF) intervals. Abnormal findings were categorized as clinically significant (CS) and not clinically significant (NCS). Clinically significant abnormal findings are those which are not associated with the underlying disease, unless judged by the investigator to be more severe than expected for the participant's condition. Data for number of participants with worst case post-Baseline abnormal ECG findings have been presented.
Time Frame Up to Day 193

Outcome Measure Data

Analysis Population Description
Safety Population.
Arm/Group Title Part A: Placebo SD Part A: GSK3358699 1 mg SD Part A: GSK3358699 3 mg SD Part A: GSK3358699 10 mg SD Part A: GSK3358699 20 mg SD Part A: GSK3358699 25 mg SD Part A: GSK3358699 30 mg SD Part A: GSK3358699 40 mg SD
Arm/Group Description Participants in Part A received a SD of placebo on Day 1 in either treatment Period 1, 2 and 3. On Day 1 of treatment Period 4, participants were administered a SD of placebo followed by IV administration of in vivo LPS challenge at a dose of 0.75 ng/kg for induction of blisters on the forearm in Cohort 1 and in Cohort 2, participants were administered with IV administration of in vivo GM-CSF challenge at a dose of 60 mcg/m^2 and further treated with 0.2% cantharidin for induction of blisters on the forearm. Placebo were administered via the oral route. Participants in Part A received a SD of GSK3358699 1 mg on Day 1 in treatment Period 1. Participants in Part A received a SD of GSK3358699 3 mg on Day 1 in treatment Period 1. Participants in Part A received a SD of GSK3358699 10 mg on Day 1 in treatment Period 2. Participants in Part A received a SD of GSK3358699 20 mg on Day 1 in treatment Period 2. Participants in Part A received a SD of GSK3358699 25 mg on Day 1 in treatment Period 4. On Day 1, participants were administered a SD of GSK3358699 25 mg followed by IV administration of in vivo LPS challenge at a dose of 0.75 ng/kg for induction of blisters on the forearm in Cohort 1 and in Cohort 2, participants were administered with IV administration of in vivo GM-CSF challenge at a dose of 60 mcg/m^2 and further treated with 0.2% cantharidin for induction of blisters on the forearm. GSK3358699 were administered via the oral route. Participants in Part A received a SD of GSK3358699 30 mg on Day 1 in treatment Period 3. Participants in Part A received a SD of GSK3358699 40 mg on Day 1 in treatment Period 3.
Measure Participants 23 5 3 6 6 12 6 6
Abnormal - not clinically significant
6
600%
1
50%
0
0%
0
0%
3
150%
2
50%
3
300%
0
0%
Abnormal - clinically significant
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
23. Primary Outcome
Title Part B: Number of Participants With Worst Case Post-Baseline Abnormal ECG Findings
Description Twelve lead ECGs were planned to be performed to measure PR interval, QRS duration, QT interval and QTcF.
Time Frame Up to Day 30

Outcome Measure Data

Analysis Population Description
Safety Population. Data was not collected as no participants were enrolled in Part B.
Arm/Group Title Part B: Cohort 3- GSK3358699 Fed + GSK3358699 Fasted Part B: Cohort 3- GSK3358699 Fasted + GSK3358699 Fed
Arm/Group Description Participants in Part B Cohort 3 were planned to receive a SD of GSK3358699 under fed conditions on Day 1 in treatment Period 1; followed by a SD of GSK3358699 under fasted conditions on Day 1 in treatment Period 2. There was a planned washout period of 14 days between each treatment period. Participants in Part B Cohort 3 were planned to receive a SD of GSK3358699 under fasted conditions on Day 1 in treatment Period 1; followed by a SD of GSK3358699 under fed conditions on Day 1 in treatment Period 2. There was a planned washout period of 14 days between each treatment period.
Measure Participants 0 0
24. Primary Outcome
Title Part C: Number of Participants With Worst Case Post-Baseline Abnormal ECG Findings
Description Twelve lead ECGs were obtained using an ECG machine that automatically calculated the heart rate and measured PR, QRS, QT, and QTcF intervals. Abnormal findings were categorized as clinically significant and not clinically significant. Clinically significant abnormal findings are those which are not associated with the underlying disease, unless judged by the investigator to be more severe than expected for the participant's condition. Data for number of participants with worst case post-Baseline abnormal ECG findings have been presented.
Time Frame Up to Day 28

Outcome Measure Data

Analysis Population Description
Safety Population. Data was not collected for Cohorts 6 to 8 as no participants were enrolled.
Arm/Group Title Part C: Cohort 4 and 5- Placebo RD Part C: Cohort 4 and 5- GSK3358699 10 mg RD Part C: Cohort 6- GSK3358699 or Placebo RD Part C: Cohort 7- GSK3358699 or Placebo RD Part C: Cohort 8- GSK3358699 or Placebo RD
Arm/Group Description Participants received once daily RD of placebo on Days 1 to 14. In Cohort 4, on Day 14, participants were administered an IV in vivo LPS challenge at a dose of 0.75 ng/kg or an IV infusion of GM-CSF, in vivo at a dose of 60 mcg/m^2. The administration of LPS or GM-CSF was followed by blister induction on forearm (0.2% cantharidin). Participants received once daily repeat dose of GSK3358699 10 mg on Days 1 to 14. In Cohort 4, on Day 14, participants were administered an IV in vivo LPS challenge at a dose of 0.75 ng/kg or an IV infusion of GM-CSF, in vivo at a dose of 60 mcg/m^2. The administration of LPS or GM-CSF was followed by blister induction on forearm (0.2% cantharidin). Participants in Part C Cohort 6 were planned to receive once daily repeat dose of GSK3358699 or placebo on Days 1 to 14. Participants in Part C Cohort 7 were planned to receive once daily repeat dose of GSK3358699 or placebo on Days 1 to 14. Participants in Part C Cohort 8 were planned to receive once daily repeat dose of GSK3358699 or placebo on Days 1 to 14. On Day 14, participants were planned to receive an IV in vivo LPS challenge at a dose of 0.75 ng/kg or an IV infusion of GM-CSF, in vivo as 60 mcg/m^2. The administration of LPS or GM-CSF was planned to be followed by blister induction on forearm (0.2% cantharidin).
Measure Participants 11 14 0 0 0
Abnormal - not clinically significant
2
200%
3
150%
Abnormal - clinically significant
0
0%
1
50%
25. Secondary Outcome
Title Part A: Plasma Concentrations of GSK3358699
Description Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3358699. Pharmacokinetic (PK) parameters were calculated using standard non-compartmental analysis. PK Population consisted of all participants in the Safety Population who received an active dose and for whom a PK sample was obtained and analyzed.
Time Frame Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose in each treatment period

Outcome Measure Data

Analysis Population Description
PK Population. Only those participants with data available at the specified time points were analyzed (represented by n= X in the category titles).
Arm/Group Title Part A: GSK3358699 1 mg SD Part A: GSK3358699 3 mg SD Part A: GSK3358699 10 mg SD Part A: GSK3358699 20 mg SD Part A: GSK3358699 25 mg SD Part A: GSK3358699 30 mg SD Part A: GSK3358699 40 mg SD
Arm/Group Description Participants in Part A received a SD of GSK3358699 1 mg on Day 1 in treatment Period 1. Participants in Part A received a SD of GSK3358699 3 mg on Day 1 in treatment Period 1. Participants in Part A received a SD of GSK3358699 10 mg on Day 1 in treatment Period 2. Participants in Part A received a SD of GSK3358699 20 mg on Day 1 in treatment Period 2. Participants in Part A received a SD of GSK3358699 25 mg on Day 1 in treatment Period 4. On Day 1, participants were administered a SD of GSK3358699 25 mg followed by IV administration of in vivo LPS challenge at a dose of 0.75 ng/kg for induction of blisters on the forearm in Cohort 1 and in Cohort 2, participants were administered with IV administration of in vivo GM-CSF challenge at a dose of 60 mcg/m^2 and further treated with 0.2% cantharidin for induction of blisters on the forearm. GSK3358699 were administered via the oral route. Participants in Part A received a SD of GSK3358699 30 mg on Day 1 in treatment Period 3. Participants in Part A received a SD of GSK3358699 40 mg on Day 1 in treatment Period 3.
Measure Participants 5 3 6 6 12 6 6
Pre-dose, n=5,3,6,6,12,6,6
0.0000
0.0000
0.0000
0.0000
0.0000
0.0000
0.0000
15 minutes, n=5,3,6,6,12,6,6
0.4950
0.6470
1.0480
0.5390
0.2620
5.8460
0.9245
30 minutes, n=5,3,6,6,12,6,6
0.6840
1.9510
6.4560
5.1050
5.9130
64.4810
33.2120
1 hour, n=5,3,6,6,12,6,6
0.4210
0.9960
3.5150
9.1840
11.0785
28.4500
28.8380
2 hours, n=5,3,6,6,12,6,6
0.1810
0.4790
1.6930
4.8100
6.9495
10.6550
8.6735
4 hours, n=5,2,6,6,12,6,6
NA
0.1560
0.5265
1.2865
1.9095
3.6390
2.5920
6 hours, n=5,3,6,6,12,6,6
NA
NA
0.3160
0.6720
1.1020
1.4305
1.2515
8 hours, n=5,3,6,6,12,6,6
NA
NA
0.2120
0.3775
0.5915
0.8340
0.6665
12 hours, n=5,3,2,6,12,6,6
NA
NA
0.1390
0.1490
0.2510
0.5195
0.4255
24 hours, n=5,3,6,6,9,4,5
NA
NA
NA
NA
0.1510
0.1250
0.2090
48 hours, n=5,3,6,6,6,6,6
NA
NA
NA
NA
0.0000
NA
NA
26. Secondary Outcome
Title Part B: Plasma Concentrations of GSK3358699
Description Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of GSK3358699.
Time Frame Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose in each treatment period

Outcome Measure Data

Analysis Population Description
PK Population. Data was not collected as no participants were enrolled in Part B.
Arm/Group Title Part B: Cohort 3- GSK3358699 Fed + GSK3358699 Fasted Part B: Cohort 3- GSK3358699 Fasted + GSK3358699 Fed
Arm/Group Description Participants in Part B Cohort 3 were planned to receive a SD of GSK3358699 under fed conditions on Day 1 in treatment Period 1; followed by a SD of GSK3358699 under fasted conditions on Day 1 in treatment Period 2. There was a planned washout period of 14 days between each treatment period. Participants in Part B Cohort 3 were planned to receive a SD of GSK3358699 under fasted conditions on Day 1 in treatment Period 1; followed by a SD of GSK3358699 under fed conditions on Day 1 in treatment Period 2. There was a planned washout period of 14 days between each treatment period.
Measure Participants 0 0
27. Secondary Outcome
Title Part C: Plasma Concentrations of GSK3358699
Description Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3358699. PK parameters were calculated using standard non-compartmental analysis.
Time Frame Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12 and 24 hours; Days 4, 8 and 12: Pre-dose; Day 14: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose

Outcome Measure Data

Analysis Population Description
PK Population. Only those participants with data available at the specified time points were analyzed (represented by n= X in the category titles). Data was not collected for Cohorts 6 to 8 as no participants were enrolled.
Arm/Group Title Part C: Cohort 4 and 5- GSK3358699 10 mg RD Part C: Cohort 6- GSK3358699 RD Part C: Cohort 7- GSK3358699 RD Part C: Cohort 8- GSK3358699 RD
Arm/Group Description Participants received once daily repeat dose of GSK3358699 10 mg on Days 1 to 14. In Cohort 4, on Day 14, participants were administered an IV in vivo LPS challenge at a dose of 0.75 ng/kg or an IV infusion of GM-CSF, in vivo at a dose of 60 mcg/m^2. The administration of LPS or GM-CSF was followed by blister induction on forearm (0.2% cantharidin). Participants in Part C Cohort 6 were planned to receive once daily repeat dose of GSK3358699 on Days 1 to 14. Participants in Part C Cohort 7 were planned to receive once daily repeat dose of GSK3358699 on Days 1 to 14. Participants in Part C Cohort 8 were planned to receive once daily repeat dose of GSK3358699 on Days 1 to 14. On Day 14, participants were planned to receive an IV in vivo LPS challenge at a dose of 0.75 ng/kg or an IV infusion of GM-CSF, in vivo as 60 mcg/m^2. The administration of LPS or GM-CSF was planned to be followed by blister induction on forearm (0.2% cantharidin).
Measure Participants 14 0 0 0
Day 1:Pre-dose,n=14,0,0,0
0.0000
Day 1:15 minutes,n=14,0,0,0
0.2825
Day 1:30 minutes,n=14,0,0,0
5.7430
Day 1:1 hour,n=14,0,0,0
3.8955
Day 1:2 hours,n=14,0,0,0
1.3365
Day 1:4 hours,n=14,0,0,0
0.5730
Day 1:6 hours,n=14,0,0,0
0.2940
Day 1:8 hours,n=10,0,0,0
0.1690
Day 1:12 hours,n=3,0,0,0
0.1390
Day 1:24 hours,n=14,0,0,0
NA
Day 4: Pre-dose,n=1,0,0,0
0.0000
Day 8: Pre-dose,n=2,0,0,0
0.0000
Day 12: Pre-dose,n=4,0,0,0
NA
Day 14:Pre-dose,n=2,0,0,0
NA
Day 14:15 minutes,n=2,0,0,0
4.3390
Day 14:30 minutes,n=2,0,0,0
6.0065
Day 14:1 hour,n=2,0,0,0
3.0170
Day 14:2 hours,n=2,0,0,0
1.4905
Day 14:4 hours,n=2,0,0,0
0.8295
Day 14:6 hours,n=2,0,0,0
0.6360
Day 14:8 hours,n=2,0,0,0
0.3920
Day 14:12 hours,n=1,0,0,0
0.2730
Day 14:24 hours,n=2,0,0,0
NA
Day 14:48 hours,n=2,0,0,0
NA
28. Secondary Outcome
Title Part A: Area Under the Plasma Concentration Curve From Time Zero to Last Time of Quantifiable Concentration (AUC[0-t]) of GSK3358699
Description Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3358699. PK parameters were calculated using standard non-compartmental analysis.
Time Frame Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose in each treatment period

Outcome Measure Data

Analysis Population Description
PK Population.
Arm/Group Title Part A: GSK3358699 1 mg SD Part A: GSK3358699 3 mg SD Part A: GSK3358699 10 mg SD Part A: GSK3358699 20 mg SD Part A: GSK3358699 25 mg SD Part A: GSK3358699 30 mg SD Part A: GSK3358699 40 mg SD
Arm/Group Description Participants in Part A received a SD of GSK3358699 1 mg on Day 1 in treatment Period 1. Participants in Part A received a SD of GSK3358699 3 mg on Day 1 in treatment Period 1. Participants in Part A received a SD of GSK3358699 10 mg on Day 1 in treatment Period 2. Participants in Part A received a SD of GSK3358699 20 mg on Day 1 in treatment Period 2. Participants in Part A received a SD of GSK3358699 25 mg on Day 1 in treatment Period 4. On Day 1, participants were administered a SD of GSK3358699 25 mg followed by IV administration of in vivo LPS challenge at a dose of 0.75 ng/kg for induction of blisters on the forearm in Cohort 1 and in Cohort 2, participants were administered with IV administration of in vivo GM-CSF challenge at a dose of 60 mcg/m^2 and further treated with 0.2% cantharidin for induction of blisters on the forearm. GSK3358699 were administered via the oral route. Participants in Part A received a SD of GSK3358699 30 mg on Day 1 in treatment Period 3. Participants in Part A received a SD of GSK3358699 40 mg on Day 1 in treatment Period 3.
Measure Participants 5 3 6 6 12 6 6
Median (Full Range) [Hours*nanogram per milliliter]
0.74
2.33
10.77
23.40
31.88
66.38
58.09
29. Secondary Outcome
Title Part B: AUC(0-t) of GSK3358699
Description Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of GSK3358699.
Time Frame Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose in each treatment period

Outcome Measure Data

Analysis Population Description
PK Population. Data was not collected as no participants were enrolled in Part B.
Arm/Group Title Part B: Cohort 3- GSK3358699 Fed + GSK3358699 Fasted Part B: Cohort 3- GSK3358699 Fasted + GSK3358699 Fed
Arm/Group Description Participants in Part B Cohort 3 were planned to receive a SD of GSK3358699 under fed conditions on Day 1 in treatment Period 1; followed by a SD of GSK3358699 under fasted conditions on Day 1 in treatment Period 2. There was a planned washout period of 14 days between each treatment period. Participants in Part B Cohort 3 were planned to receive a SD of GSK3358699 under fasted conditions on Day 1 in treatment Period 1; followed by a SD of GSK3358699 under fed conditions on Day 1 in treatment Period 2. There was a planned washout period of 14 days between each treatment period.
Measure Participants 0 0
30. Secondary Outcome
Title Part C: AUC(0-t) of GSK3358699
Description Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3358699. PK parameters were calculated using standard non-compartmental analysis.
Time Frame Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12 and 24 hours; Day 14: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose

Outcome Measure Data

Analysis Population Description
PK Population. Only those participants with data available at the specified time points were analyzed (represented by n= X in the category titles). Data was not collected for Cohorts 6 to 8 as no participants were enrolled.
Arm/Group Title Part C: Cohort 4 and 5- GSK3358699 10 mg RD Part C: Cohort 6- GSK3358699 RD Part C: Cohort 7- GSK3358699 RD Part C: Cohort 8- GSK3358699 RD
Arm/Group Description Participants received once daily repeat dose of GSK3358699 10 mg on Days 1 to 14. In Cohort 4, on Day 14, participants were administered an IV in vivo LPS challenge at a dose of 0.75 ng/kg or an IV infusion of GM-CSF, in vivo at a dose of 60 mcg/m^2. The administration of LPS or GM-CSF was followed by blister induction on forearm (0.2% cantharidin). Participants in Part C Cohort 6 were planned to receive once daily repeat dose of GSK3358699 on Days 1 to 14. Participants in Part C Cohort 7 were planned to receive once daily repeat dose of GSK3358699 on Days 1 to 14. Participants in Part C Cohort 8 were planned to receive once daily repeat dose of GSK3358699 on Days 1 to 14. On Day 14, participants were planned to receive an IV in vivo LPS challenge at a dose of 0.75 ng/kg or an IV infusion of GM-CSF, in vivo as 60 mcg/m^2. The administration of LPS or GM-CSF was planned to be followed by blister induction on forearm (0.2% cantharidin).
Measure Participants 14 0 0 0
Day 1, n=14,0,0,0
9.47
Day 14, n=2,0,0,0
11.70
31. Secondary Outcome
Title Part A: Area Under the Plasma Concentration Curve From Time Zero to Infinity (AUC[0-infinity]) of GSK3358699
Description Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3358699. PK parameters were calculated using standard non-compartmental analysis.
Time Frame Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose in each treatment period

Outcome Measure Data

Analysis Population Description
PK Population. Only those participants with data available at the specified time points were analyzed.
Arm/Group Title Part A: GSK3358699 1 mg SD Part A: GSK3358699 3 mg SD Part A: GSK3358699 10 mg SD Part A: GSK3358699 20 mg SD Part A: GSK3358699 25 mg SD Part A: GSK3358699 30 mg SD Part A: GSK3358699 40 mg SD
Arm/Group Description Participants in Part A received a SD of GSK3358699 1 mg on Day 1 in treatment Period 1. Participants in Part A received a SD of GSK3358699 3 mg on Day 1 in treatment Period 1. Participants in Part A received a SD of GSK3358699 10 mg on Day 1 in treatment Period 2. Participants in Part A received a SD of GSK3358699 20 mg on Day 1 in treatment Period 2. Participants in Part A received a SD of GSK3358699 25 mg on Day 1 in treatment Period 4. On Day 1, participants were administered a SD of GSK3358699 25 mg followed by IV administration of in vivo LPS challenge at a dose of 0.75 ng/kg for induction of blisters on the forearm in Cohort 1 and in Cohort 2, participants were administered with IV administration of in vivo GM-CSF challenge at a dose of 60 mcg/m^2 and further treated with 0.2% cantharidin for induction of blisters on the forearm. GSK3358699 were administered via the oral route. Participants in Part A received a SD of GSK3358699 30 mg on Day 1 in treatment Period 3. Participants in Part A received a SD of GSK3358699 40 mg on Day 1 in treatment Period 3.
Measure Participants 5 3 5 6 9 4 5
Median (Full Range) [Hours*nanogram per milliliter]
NA
NA
13.20
23.89
33.22
69.13
59.68
32. Secondary Outcome
Title Part B: AUC(0-infinity) of GSK3358699
Description Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of GSK3358699.
Time Frame Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose in each treatment period

Outcome Measure Data

Analysis Population Description
PK Population. Data was not collected as no participants were enrolled in Part B.
Arm/Group Title Part B: Cohort 3- GSK3358699 Fed + GSK3358699 Fasted Part B: Cohort 3- GSK3358699 Fasted + GSK3358699 Fed
Arm/Group Description Participants in Part B Cohort 3 were planned to receive a SD of GSK3358699 under fed conditions on Day 1 in treatment Period 1; followed by a SD of GSK3358699 under fasted conditions on Day 1 in treatment Period 2. There was a planned washout period of 14 days between each treatment period. Participants in Part B Cohort 3 were planned to receive a SD of GSK3358699 under fasted conditions on Day 1 in treatment Period 1; followed by a SD of GSK3358699 under fed conditions on Day 1 in treatment Period 2. There was a planned washout period of 14 days between each treatment period.
Measure Participants 0 0
33. Secondary Outcome
Title Part C: AUC(0-infinity) of GSK3358699
Description Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3358699. PK parameters were calculated using standard non-compartmental analysis.
Time Frame Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12 and 24 hours; Day 14: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose

Outcome Measure Data

Analysis Population Description
PK Population. Only those participants with data available at the specified time points were analyzed (represented by n= X in the category titles). Data was not collected for Cohorts 6 to 8 as no participants were enrolled.
Arm/Group Title Part C: Cohort 4 and 5- GSK3358699 10 mg RD Part C: Cohort 6- GSK3358699 RD Part C: Cohort 7- GSK3358699 RD Part C: Cohort 8- GSK3358699 RD
Arm/Group Description Participants received once daily repeat dose of GSK3358699 10 mg on Days 1 to 14. In Cohort 4, on Day 14, participants were administered an IV in vivo LPS challenge at a dose of 0.75 ng/kg or an IV infusion of GM-CSF, in vivo at a dose of 60 mcg/m^2. The administration of LPS or GM-CSF was followed by blister induction on forearm (0.2% cantharidin). Participants in Part C Cohort 6 were planned to receive once daily repeat dose of GSK3358699 on Days 1 to 14. Participants in Part C Cohort 7 were planned to receive once daily repeat dose of GSK3358699 on Days 1 to 14. Participants in Part C Cohort 8 were planned to receive once daily repeat dose of GSK3358699 on Days 1 to 14. On Day 14, participants were planned to receive an IV in vivo LPS challenge at a dose of 0.75 ng/kg or an IV infusion of GM-CSF, in vivo as 60 mcg/m^2. The administration of LPS or GM-CSF was planned to be followed by blister induction on forearm (0.2% cantharidin).
Measure Participants 7 0 0 0
Day 1, n=7,0,0,0
9.07
34. Secondary Outcome
Title Part A: Area Under the Plasma Concentration Curve From Time Zero to 24 Hours (AUC[0-24]) of GSK3358699
Description Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3358699. PK parameters were calculated using standard non-compartmental analysis.
Time Frame Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12 and 24 hours post-dose in each treatment period

Outcome Measure Data

Analysis Population Description
PK Population. Only those participants with data available at the specified time points were analyzed.
Arm/Group Title Part A: GSK3358699 1 mg SD Part A: GSK3358699 3 mg SD Part A: GSK3358699 10 mg SD Part A: GSK3358699 20 mg SD Part A: GSK3358699 25 mg SD Part A: GSK3358699 30 mg SD Part A: GSK3358699 40 mg SD
Arm/Group Description Participants in Part A received a SD of GSK3358699 1 mg on Day 1 in treatment Period 1. Participants in Part A received a SD of GSK3358699 3 mg on Day 1 in treatment Period 1. Participants in Part A received a SD of GSK3358699 10 mg on Day 1 in treatment Period 2. Participants in Part A received a SD of GSK3358699 20 mg on Day 1 in treatment Period 2. Participants in Part A received a SD of GSK3358699 25 mg on Day 1 in treatment Period 4. On Day 1, participants were administered a SD of GSK3358699 25 mg followed by IV administration of in vivo LPS challenge at a dose of 0.75 ng/kg for induction of blisters on the forearm in Cohort 1 and in Cohort 2, participants were administered with IV administration of in vivo GM-CSF challenge at a dose of 60 mcg/m^2 and further treated with 0.2% cantharidin for induction of blisters on the forearm. GSK3358699 were administered via the oral route. Participants in Part A received a SD of GSK3358699 30 mg on Day 1 in treatment Period 3. Participants in Part A received a SD of GSK3358699 40 mg on Day 1 in treatment Period 3.
Measure Participants 5 3 5 6 10 5 6
Median (Full Range) [Hours*nanogram per milliliter]
NA
NA
13.17
23.86
32.69
67.38
59.05
35. Secondary Outcome
Title Part B: AUC(0-24) of GSK3358699
Description Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of GSK3358699.
Time Frame Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12 and 24 hours post-dose in each treatment period

Outcome Measure Data

Analysis Population Description
PK Population. Data was not collected as no participants were enrolled in Part B.
Arm/Group Title Part B: Cohort 3- GSK3358699 Fed + GSK3358699 Fasted Part B: Cohort 3- GSK3358699 Fasted + GSK3358699 Fed
Arm/Group Description Participants in Part B Cohort 3 were planned to receive a SD of GSK3358699 under fed conditions on Day 1 in treatment Period 1; followed by a SD of GSK3358699 under fasted conditions on Day 1 in treatment Period 2. There was a planned washout period of 14 days between each treatment period. Participants in Part B Cohort 3 were planned to receive a SD of GSK3358699 under fasted conditions on Day 1 in treatment Period 1; followed by a SD of GSK3358699 under fed conditions on Day 1 in treatment Period 2. There was a planned washout period of 14 days between each treatment period.
Measure Participants 0 0
36. Secondary Outcome
Title Part C: AUC(0-24) of GSK3358699
Description Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3358699. PK parameters were calculated using standard non-compartmental analysis.
Time Frame Days 1 and 14: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, and 24 hours post-dose

Outcome Measure Data

Analysis Population Description
PK Population. Only those participants with data available at the specified time points were analyzed (represented by n= X in the category titles). Data was not collected for Cohorts 6 to 8 as no participants were enrolled.
Arm/Group Title Part C: Cohort 4 and 5- GSK3358699 10 mg RD Part C: Cohort 6- GSK3358699 RD Part C: Cohort 7- GSK3358699 RD Part C: Cohort 8- GSK3358699 RD
Arm/Group Description Participants received once daily repeat dose of GSK3358699 10 mg on Days 1 to 14. In Cohort 4, on Day 14, participants were administered an IV in vivo LPS challenge at a dose of 0.75 ng/kg or an IV infusion of GM-CSF, in vivo at a dose of 60 mcg/m^2. The administration of LPS or GM-CSF was followed by blister induction on forearm (0.2% cantharidin). Participants in Part C Cohort 6 were planned to receive once daily repeat dose of GSK3358699 on Days 1 to 14. Participants in Part C Cohort 7 were planned to receive once daily repeat dose of GSK3358699 on Days 1 to 14. Participants in Part C Cohort 8 were planned to receive once daily repeat dose of GSK3358699 on Days 1 to 14. On Day 14, participants were planned to receive an IV in vivo LPS challenge at a dose of 0.75 ng/kg or an IV infusion of GM-CSF, in vivo as 60 mcg/m^2. The administration of LPS or GM-CSF was planned to be followed by blister induction on forearm (0.2% cantharidin).
Measure Participants 7 0 0 0
Day 1, n=7,0,0,0
9.07
Day 14, n=1,0,0,0
7.99
37. Secondary Outcome
Title Part A: Maximum Plasma Concentration (Cmax) of GSK3358699
Description Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3358699. PK parameters were calculated using standard non-compartmental analysis.
Time Frame Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose in each treatment period

Outcome Measure Data

Analysis Population Description
PK Population.
Arm/Group Title Part A: GSK3358699 1 mg SD Part A: GSK3358699 3 mg SD Part A: GSK3358699 10 mg SD Part A: GSK3358699 20 mg SD Part A: GSK3358699 25 mg SD Part A: GSK3358699 30 mg SD Part A: GSK3358699 40 mg SD
Arm/Group Description Participants in Part A received a SD of GSK3358699 1 mg on Day 1 in treatment Period 1. Participants in Part A received a SD of GSK3358699 3 mg on Day 1 in treatment Period 1. Participants in Part A received a SD of GSK3358699 10 mg on Day 1 in treatment Period 2. Participants in Part A received a SD of GSK3358699 20 mg on Day 1 in treatment Period 2. Participants in Part A received a SD of GSK3358699 25 mg on Day 1 in treatment Period 4. On Day 1, participants were administered a SD of GSK3358699 25 mg followed by IV administration of in vivo LPS challenge at a dose of 0.75 ng/kg for induction of blisters on the forearm in Cohort 1 and in Cohort 2, participants were administered with IV administration of in vivo GM-CSF challenge at a dose of 60 mcg/m^2 and further treated with 0.2% cantharidin for induction of blisters on the forearm. GSK3358699 were administered via the oral route. Participants in Part A received a SD of GSK3358699 30 mg on Day 1 in treatment Period 3. Participants in Part A received a SD of GSK3358699 40 mg on Day 1 in treatment Period 3.
Measure Participants 5 3 6 6 12 6 6
Median (Full Range) [Nanogram per milliliter]
0.68
1.95
6.46
16.10
17.47
64.48
34.58
38. Secondary Outcome
Title Part B: Cmax of GSK3358699
Description Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of GSK3358699.
Time Frame Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose in each treatment period

Outcome Measure Data

Analysis Population Description
PK Population. Data was not collected as no participants were enrolled in Part B.
Arm/Group Title Part B: Cohort 3- GSK3358699 Fed + GSK3358699 Fasted Part B: Cohort 3- GSK3358699 Fasted + GSK3358699 Fed
Arm/Group Description Participants in Part B Cohort 3 were planned to receive a SD of GSK3358699 under fed conditions on Day 1 in treatment Period 1; followed by a SD of GSK3358699 under fasted conditions on Day 1 in treatment Period 2. There was a planned washout period of 14 days between each treatment period. Participants in Part B Cohort 3 were planned to receive a SD of GSK3358699 under fasted conditions on Day 1 in treatment Period 1; followed by a SD of GSK3358699 under fed conditions on Day 1 in treatment Period 2. There was a planned washout period of 14 days between each treatment period.
Measure Participants 0 0
39. Secondary Outcome
Title Part C: Cmax of GSK3358699
Description Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3358699. PK parameters were calculated using standard non-compartmental analysis.
Time Frame Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12 and 24 hours; Day 14: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose

Outcome Measure Data

Analysis Population Description
PK Population. Only those participants with data available at the specified time points were analyzed (represented by n= X in the category titles). Data was not collected for Cohorts 6 to 8 as no participants were enrolled.
Arm/Group Title Part C: Cohort 4 and 5- GSK3358699 10 mg RD Part C: Cohort 6- GSK3358699 RD Part C: Cohort 7- GSK3358699 RD Part C: Cohort 8- GSK3358699 RD
Arm/Group Description Participants received once daily repeat dose of GSK3358699 10 mg on Days 1 to 14. In Cohort 4, on Day 14, participants were administered an IV in vivo LPS challenge at a dose of 0.75 ng/kg or an IV infusion of GM-CSF, in vivo at a dose of 60 mcg/m^2. The administration of LPS or GM-CSF was followed by blister induction on forearm (0.2% cantharidin). Participants in Part C Cohort 6 were planned to receive once daily repeat dose of GSK3358699 on Days 1 to 14. Participants in Part C Cohort 7 were planned to receive once daily repeat dose of GSK3358699 on Days 1 to 14. Participants in Part C Cohort 8 were planned to receive once daily repeat dose of GSK3358699 on Days 1 to 14. On Day 14, participants were planned to receive an IV in vivo LPS challenge at a dose of 0.75 ng/kg or an IV infusion of GM-CSF, in vivo as 60 mcg/m^2. The administration of LPS or GM CSF was planned to be followed by blister induction on forearm (0.2% cantharidin).
Measure Participants 14 0 0 0
Day 1, n=14,0,0,0
6.19
Day 14, n=2,0,0,0
6.01
40. Secondary Outcome
Title Part A: Time to Cmax (Tmax) of GSK3358699
Description Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3358699. PK parameters were calculated using standard non-compartmental analysis.
Time Frame Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose in each treatment period

Outcome Measure Data

Analysis Population Description
PK Population.
Arm/Group Title Part A: GSK3358699 1 mg SD Part A: GSK3358699 3 mg SD Part A: GSK3358699 10 mg SD Part A: GSK3358699 20 mg SD Part A: GSK3358699 25 mg SD Part A: GSK3358699 30 mg SD Part A: GSK3358699 40 mg SD
Arm/Group Description Participants in Part A received a SD of GSK3358699 1 mg on Day 1 in treatment Period 1. Participants in Part A received a SD of GSK3358699 3 mg on Day 1 in treatment Period 1. Participants in Part A received a SD of GSK3358699 10 mg on Day 1 in treatment Period 2. Participants in Part A received a SD of GSK3358699 20 mg on Day 1 in treatment Period 2. Participants in Part A received a SD of GSK3358699 25 mg on Day 1 in treatment Period 4. On Day 1, participants were administered a SD of GSK3358699 25 mg followed by IV administration of in vivo LPS challenge at a dose of 0.75 ng/kg for induction of blisters on the forearm in Cohort 1 and in Cohort 2, participants were administered with IV administration of in vivo GM-CSF challenge at a dose of 60 mcg/m^2 and further treated with 0.2% cantharidin for induction of blisters on the forearm. GSK3358699 were administered via the oral route. Participants in Part A received a SD of GSK3358699 30 mg on Day 1 in treatment Period 3. Participants in Part A received a SD of GSK3358699 40 mg on Day 1 in treatment Period 3.
Measure Participants 5 3 6 6 12 6 6
Median (Full Range) [Hours]
0.50
0.50
0.50
1.00
1.00
0.76
0.51
41. Secondary Outcome
Title Part B: Tmax of GSK3358699
Description Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of GSK3358699.
Time Frame Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose in each treatment period

Outcome Measure Data

Analysis Population Description
PK Population. Data was not collected as no participants were enrolled in Part B.
Arm/Group Title Part B: Cohort 3- GSK3358699 Fed + GSK3358699 Fasted Part B: Cohort 3- GSK3358699 Fasted + GSK3358699 Fed
Arm/Group Description Participants in Part B Cohort 3 were planned to receive a SD of GSK3358699 under fed conditions on Day 1 in treatment Period 1; followed by a SD of GSK3358699 under fasted conditions on Day 1 in treatment Period 2. There was a planned washout period of 14 days between each treatment period. Participants in Part B Cohort 3 were planned to receive a SD of GSK3358699 under fasted conditions on Day 1 in treatment Period 1; followed by a SD of GSK3358699 under fed conditions on Day 1 in treatment Period 2. There was a planned washout period of 14 days between each treatment period.
Measure Participants 0 0
42. Secondary Outcome
Title Part C: Tmax of GSK3358699
Description Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3358699. PK parameters were calculated using standard non-compartmental analysis.
Time Frame Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12 and 24 hours; Day 14: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose

Outcome Measure Data

Analysis Population Description
PK Population. Only those participants with data available at the specified time points were analyzed (represented by n= X in the category titles). Data was not collected for Cohorts 6 to 8 as no participants were enrolled.
Arm/Group Title Part C: Cohort 4 and 5- GSK3358699 10 mg RD Part C: Cohort 6- GSK3358699 RD Part C: Cohort 7- GSK3358699 RD Part C: Cohort 8- GSK3358699 RD
Arm/Group Description Participants received once daily repeat dose of GSK3358699 10 mg on Days 1 to 14. In Cohort 4, on Day 14, participants were administered an IV in vivo LPS challenge at a dose of 0.75 ng/kg or an IV infusion of GM-CSF, in vivo at a dose of 60 mcg/m^2. The administration of LPS or GM-CSF was followed by blister induction on forearm (0.2% cantharidin). Participants in Part C Cohort 6 were planned to receive once daily repeat dose of GSK3358699 on Days 1 to 14. Participants in Part C Cohort 7 were planned to receive once daily repeat dose of GSK3358699 on Days 1 to 14. Participants in Part C Cohort 8 were planned to receive once daily repeat dose of GSK3358699 on Days 1 to 14. On Day 14, participants were planned to receive an IV in vivo LPS challenge at a dose of 0.75 ng/kg or an IV infusion of GM-CSF, in vivo as 60 mcg/m^2. The administration of LPS or GM-CSF was planned to be followed by blister induction on forearm (0.2% cantharidin).
Measure Participants 14 0 0 0
Day 1, n=14,0,0,0
0.50
Day 14, n=2,0,0,0
0.53
43. Secondary Outcome
Title Part A: Apparent Terminal Phase Half-life (t1/2) of GSK3358699
Description Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3358699. PK parameters were calculated using standard non-compartmental analysis.
Time Frame Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose in each treatment period

Outcome Measure Data

Analysis Population Description
PK Population. Only those participants with data available at the specified time points were analyzed.
Arm/Group Title Part A: GSK3358699 1 mg SD Part A: GSK3358699 3 mg SD Part A: GSK3358699 10 mg SD Part A: GSK3358699 20 mg SD Part A: GSK3358699 25 mg SD Part A: GSK3358699 30 mg SD Part A: GSK3358699 40 mg SD
Arm/Group Description Participants in Part A received a SD of GSK3358699 1 mg on Day 1 in treatment Period 1. Participants in Part A received a SD of GSK3358699 3 mg on Day 1 in treatment Period 1. Participants in Part A received a SD of GSK3358699 10 mg on Day 1 in treatment Period 2. Participants in Part A received a SD of GSK3358699 20 mg on Day 1 in treatment Period 2. Participants in Part A received a SD of GSK3358699 25 mg on Day 1 in treatment Period 4. On Day 1, participants were administered a SD of GSK3358699 25 mg followed by IV administration of in vivo LPS challenge at a dose of 0.75 ng/kg for induction of blisters on the forearm in Cohort 1 and in Cohort 2, participants were administered with IV administration of in vivo GM-CSF challenge at a dose of 60 mcg/m^2 and further treated with 0.2% cantharidin for induction of blisters on the forearm. GSK3358699 were administered via the oral route. Participants in Part A received a SD of GSK3358699 30 mg on Day 1 in treatment Period 3. Participants in Part A received a SD of GSK3358699 40 mg on Day 1 in treatment Period 3.
Measure Participants 5 3 5 6 9 4 5
Median (Full Range) [Hours]
NA
NA
2.44
2.75
6.02
4.77
6.88
44. Secondary Outcome
Title Part B: t1/2 of GSK3358699
Description Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of GSK3358699.
Time Frame Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose in each treatment period

Outcome Measure Data

Analysis Population Description
PK Population. Data was not collected as no participants were enrolled in Part B.
Arm/Group Title Part B: Cohort 3- GSK3358699 Fed + GSK3358699 Fasted Part B: Cohort 3- GSK3358699 Fasted + GSK3358699 Fed
Arm/Group Description Participants in Part B Cohort 3 were planned to receive a SD of GSK3358699 under fed conditions on Day 1 in treatment Period 1; followed by a SD of GSK3358699 under fasted conditions on Day 1 in treatment Period 2. There was a planned washout period of 14 days between each treatment period. Participants in Part B Cohort 3 were planned to receive a SD of GSK3358699 under fasted conditions on Day 1 in treatment Period 1; followed by a SD of GSK3358699 under fed conditions on Day 1 in treatment Period 2. There was a planned washout period of 14 days between each treatment period.
Measure Participants 0 0
45. Secondary Outcome
Title Part C: t1/2 of GSK3358699
Description Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3358699. PK parameters were calculated using standard non-compartmental analysis.
Time Frame Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12 and 24 hours; Day 14: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose

Outcome Measure Data

Analysis Population Description
PK Population. Only those participants with data available at the specified time points were analyzed (represented by n= X in the category titles). Data was not collected for Cohorts 6 to 8 as no participants were enrolled.
Arm/Group Title Part C: Cohort 4 and 5- GSK3358699 10 mg RD Part C: Cohort 6- GSK3358699 RD Part C: Cohort 7- GSK3358699 RD Part C: Cohort 8- GSK3358699 RD
Arm/Group Description Participants received once daily repeat dose of GSK3358699 10 mg on Days 1 to 14. In Cohort 4, on Day 14, participants were administered an IV in vivo LPS challenge at a dose of 0.75 ng/kg or an IV infusion of GM-CSF, in vivo at a dose of 60 mcg/m^2. The administration of LPS or GM-CSF was followed by blister induction on forearm (0.2% cantharidin). Participants in Part C Cohort 6 were planned to receive once daily repeat dose of GSK3358699 on Days 1 to 14. Participants in Part C Cohort 7 were planned to receive once daily repeat dose of GSK3358699 on Days 1 to 14. Participants in Part C Cohort 8 were planned to receive once daily repeat dose of GSK3358699 on Days 1 to 14. On Day 14, participants were planned to receive an IV in vivo LPS challenge at a dose of 0.75 ng/kg or an IV infusion of GM-CSF, in vivo as 60 mcg/m^2. The administration of LPS or GM-CSF was planned to be followed by blister induction on forearm (0.2% cantharidin).
Measure Participants 7 0 0 0
Day 1, n=7,0,0,0
2.47
Day 14, n=1,0,0,0
1.57
46. Secondary Outcome
Title Part A: Plasma Concentrations of GSK3206944
Description Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3206944. PK parameters were calculated using standard non-compartmental analysis. GSK3206944 is a metabolite of GSK3358699.
Time Frame Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose in each treatment period

Outcome Measure Data

Analysis Population Description
PK Population.
Arm/Group Title Part A: GSK3358699 1 mg SD Part A: GSK3358699 3 mg SD Part A: GSK3358699 10 mg SD Part A: GSK3358699 20 mg SD Part A: GSK3358699 25 mg SD Part A: GSK3358699 30 mg SD Part A: GSK3358699 40 mg SD
Arm/Group Description Participants in Part A received a SD of GSK3358699 1 mg on Day 1 in treatment Period 1. Participants in Part A received a SD of GSK3358699 3 mg on Day 1 in treatment Period 1. Participants in Part A received a SD of GSK3358699 10 mg on Day 1 in treatment Period 2. Participants in Part A received a SD of GSK3358699 20 mg on Day 1 in treatment Period 2. Participants in Part A received a SD of GSK3358699 25 mg on Day 1 in treatment Period 4. On Day 1, participants were administered a SD of GSK3358699 25 mg followed by IV administration of in vivo LPS challenge at a dose of 0.75 ng/kg for induction of blisters on the forearm in Cohort 1 and in Cohort 2, participants were administered with IV administration of in vivo GM-CSF challenge at a dose of 60 mcg/m^2 and further treated with 0.2% cantharidin for induction of blisters on the forearm. GSK3358699 were administered via the oral route. Participants in Part A received a SD of GSK3358699 30 mg on Day 1 in treatment Period 3. Participants in Part A received a SD of GSK3358699 40 mg on Day 1 in treatment Period 3.
Measure Participants 5 3 6 6 12 6 6
Pre-dose
0.0000
0.000
0.0000
0.0000
0.0000
0.0000
0.0000
15 minutes
0.2050
0.2070
0.0550
0.0000
0.0000
0.0575
0.0000
30 minutes
1.2090
1.8410
3.1930
1.8370
4.3810
17.2245
6.3350
1 hour
3.0310
4.2200
17.1455
26.1280
33.6145
89.1965
74.5130
2 hours
3.2830
5.5640
17.6535
46.4250
70.4010
102.0865
121.2220
4 hours
1.9110
3.2490
10.6790
22.6925
46.8165
51.7230
69.2315
6 hours
0.9490
1.5760
6.7745
13.7955
23.1275
30.4690
36.8305
8 hours
0.5840
1.0200
4.6515
8.3535
13.7165
16.5795
18.4825
12 hours
0.2540
0.4670
1.8400
3.4535
5.3830
6.7365
8.7280
24 hours
0.0000
0.1050
0.2620
0.4790
1.2020
1.1015
1.5040
48 hours
NA
NA
0.0000
0.0000
0.3440
0.1895
0.2565
47. Secondary Outcome
Title Part B: Plasma Concentrations of GSK3206944
Description Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of GSK3206944. GSK3206944 is a metabolite of GSK3358699.
Time Frame Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose in each treatment period

Outcome Measure Data

Analysis Population Description
PK Population. Data was not collected as no participants were enrolled in Part B.
Arm/Group Title Part B: Cohort 3- GSK3358699 Fed + GSK3358699 Fasted Part B: Cohort 3- GSK3358699 Fasted + GSK3358699 Fed
Arm/Group Description Participants in Part B Cohort 3 were planned to receive a SD of GSK3358699 under fed conditions on Day 1 in treatment Period 1; followed by a SD of GSK3358699 under fasted conditions on Day 1 in treatment Period 2. There was a planned washout period of 14 days between each treatment period. Participants in Part B Cohort 3 were planned to receive a SD of GSK3358699 under fasted conditions on Day 1 in treatment Period 1; followed by a SD of GSK3358699 under fed conditions on Day 1 in treatment Period 2. There was a planned washout period of 14 days between each treatment period.
Measure Participants 0 0
48. Secondary Outcome
Title Part C: Plasma Concentrations of GSK3206944
Description Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3206944. PK parameters were calculated using standard non-compartmental analysis. GSK3206944 is a metabolite of GSK3358699.
Time Frame Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12 and 24 hours; Days 4, 8 and 12: Pre-dose; Day 14: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose

Outcome Measure Data

Analysis Population Description
PK Population. Only those participants with data available at the specified time points were analyzed (represented by n= X in the category titles). Data was not collected for Cohorts 6 to 8 as no participants were enrolled.
Arm/Group Title Part C: Cohort 4 and 5- GSK3358699 10 mg RD Part C: Cohort 6- GSK3358699 RD Part C: Cohort 7- GSK3358699 RD Part C: Cohort 8- GSK3358699 RD
Arm/Group Description Participants received once daily repeat dose of GSK3358699 10 mg on Days 1 to 14. In Cohort 4, on Day 14, participants were administered an IV in vivo LPS challenge at a dose of 0.75 ng/kg or an IV infusion of GM-CSF, in vivo at a dose of 60 mcg/m^2. The administration of LPS or GM-CSF was followed by blister induction on forearm (0.2% cantharidin). Participants in Part C Cohort 6 were planned to receive once daily repeat dose of GSK3358699 on Days 1 to 14. Participants in Part C Cohort 7 were planned to receive once daily repeat dose of GSK3358699 on Days 1 to 14. Participants in Part C Cohort 8 were planned to receive once daily repeat dose of GSK3358699 on Days 1 to 14. On Day 14, participants were planned to receive an IV in vivo LPS challenge at a dose of 0.75 ng/kg or an IV infusion of GM-CSF, in vivo as 60 mcg/m^2. The administration of LPS or GM-CSF was planned to be followed by blister induction on forearm (0.2% cantharidin).
Measure Participants 14 0 0 0
Day 1:Pre-dose,n=14,0,0,0
0.0000
Day 1:15 minutes,n=14,0,0,0
0.0000
Day 1:30 minutes,n=14,0,0,0
3.1310
Day 1:1 hour,n=14,0,0,0
19.9335
Day 1:2 hours,n=14,0,0,0
22.2250
Day 1:4 hours,n=14,0,0,0
12.7730
Day 1:6 hours,n=14,0,0,0
7.2920
Day 1:8 hours,n=14,0,0,0
4.3750
Day 1:12 hours,n=14,0,0,0
2.2070
Day 1:24 hours,n=14,0,0,0
0.3805
Day 4: Pre-dose,n=14,0,0,0
0.5355
Day 8: Pre-dose,n=7,0,0,0
0.6640
Day 12: Pre-dose,n=4,0,0,0
0.4945
Day 14:Pre-dose,n=2,0,0,0
0.5820
Day 14:15 minutes,n=2,0,0,0
0.7430
Day 14:30 minutes,n=2,0,0,0
6.4130
Day 14:1 hour,n=2,0,0,0
15.3355
Day 14:2 hours,n=2,0,0,0
15.0925
Day 14:4 hours,n=2,0,0,0
10.4550
Day 14:6 hours,n=2,0,0,0
6.8500
Day 14:8 hours,n=2,0,0,0
6.0330
Day 14:12 hours,n=2,0,0,0
2.2290
Day 14:24 hours,n=2,0,0,0
0.5275
Day 14:48 hours,n=1,0,0,0
0.1110
49. Secondary Outcome
Title Part A: AUC(0-t) of GSK3206944
Description Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3206944. PK parameters were calculated using standard non-compartmental analysis. GSK3206944 is a metabolite of GSK3358699.
Time Frame Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose in each treatment period

Outcome Measure Data

Analysis Population Description
PK Population.
Arm/Group Title Part A: GSK3358699 1 mg SD Part A: GSK3358699 3 mg SD Part A: GSK3358699 10 mg SD Part A: GSK3358699 20 mg SD Part A: GSK3358699 25 mg SD Part A: GSK3358699 30 mg SD Part A: GSK3358699 40 mg SD
Arm/Group Description Participants in Part A received a SD of GSK3358699 1 mg on Day 1 in treatment Period 1. Participants in Part A received a SD of GSK3358699 3 mg on Day 1 in treatment Period 1. Participants in Part A received a SD of GSK3358699 10 mg on Day 1 in treatment Period 2. Participants in Part A received a SD of GSK3358699 20 mg on Day 1 in treatment Period 2. Participants in Part A received a SD of GSK3358699 25 mg on Day 1 in treatment Period 4. On Day 1, participants were administered a SD of GSK3358699 25 mg followed by IV administration of in vivo LPS challenge at a dose of 0.75 ng/kg for induction of blisters on the forearm in Cohort 1 and in Cohort 2, participants were administered with IV administration of in vivo GM-CSF challenge at a dose of 60 mcg/m^2 and further treated with 0.2% cantharidin for induction of blisters on the forearm. GSK3358699 were administered via the oral route. Participants in Part A received a SD of GSK3358699 30 mg on Day 1 in treatment Period 3. Participants in Part A received a SD of GSK3358699 40 mg on Day 1 in treatment Period 3.
Measure Participants 5 3 6 6 12 6 6
Median (Full Range) [Hours*nanogram per milliliter]
15.16
29.12
106.55
209.98
381.16
470.40
630.63
50. Secondary Outcome
Title Part B: AUC(0-t) of GSK3206944
Description Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of GSK3206944. GSK3206944 is a metabolite of GSK3358699.
Time Frame Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose in each treatment period

Outcome Measure Data

Analysis Population Description
PK Population. Data was not collected as no participants were enrolled in Part B.
Arm/Group Title Part B: Cohort 3- GSK3358699 Fed + GSK3358699 Fasted Part B: Cohort 3- GSK3358699 Fasted + GSK3358699 Fed
Arm/Group Description Participants in Part B Cohort 3 were planned to receive a SD of GSK3358699 under fed conditions on Day 1 in treatment Period 1; followed by a SD of GSK3358699 under fasted conditions on Day 1 in treatment Period 2. There was a planned washout period of 14 days between each treatment period. Participants in Part B Cohort 3 were planned to receive a SD of GSK3358699 under fasted conditions on Day 1 in treatment Period 1; followed by a SD of GSK3358699 under fed conditions on Day 1 in treatment Period 2. There was a planned washout period of 14 days between each treatment period.
Measure Participants 0 0
51. Secondary Outcome
Title Part C: AUC(0-t) of GSK3206944
Description Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3206944. PK parameters were calculated using standard non-compartmental analysis. GSK3206944 is a metabolite of GSK3358699.
Time Frame Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12 and 24 hours; Day 14: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose

Outcome Measure Data

Analysis Population Description
PK Population. Only those participants with data available at the specified time points were analyzed (represented by n= X in the category titles). Data was not collected for Cohorts 6 to 8 as no participants were enrolled.
Arm/Group Title Part C: Cohort 4 and 5- GSK3358699 10 mg RD Part C: Cohort 6- GSK3358699 RD Part C: Cohort 7- GSK3358699 RD Part C: Cohort 8- GSK3358699 RD
Arm/Group Description Participants received once daily repeat dose of GSK3358699 10 mg on Days 1 to 14. In Cohort 4, on Day 14, participants were administered an IV in vivo LPS challenge at a dose of 0.75 ng/kg or an IV infusion of GM-CSF, in vivo at a dose of 60 mcg/m^2. The administration of LPS or GM-CSF was followed by blister induction on forearm (0.2% cantharidin). Participants in Part C Cohort 6 were planned to receive once daily repeat dose of GSK3358699 on Days 1 to 14. Participants in Part C Cohort 7 were planned to receive once daily repeat dose of GSK3358699 on Days 1 to 14. Participants in Part C Cohort 8 were planned to receive once daily repeat dose of GSK3358699 on Days 1 to 14. On Day 14, participants were planned to receive an IV in vivo LPS challenge at a dose of 0.75 ng/kg or an IV infusion of GM-CSF, in vivo as 60 mcg/m^2. The administration of LPS or GM-CSF was planned to be followed by blister induction on forearm (0.2% cantharidin).
Measure Participants 14 0 0 0
Day 1, n=14,0,0,0
115.17
Day 14, n=2,0,0,0
109.71
52. Secondary Outcome
Title Part A: AUC(0-infinity) of GSK3206944
Description Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3206944. PK parameters were calculated using standard non-compartmental analysis. GSK3206944 is a metabolite of GSK3358699.
Time Frame Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose in each treatment period

Outcome Measure Data

Analysis Population Description
PK Population. Only those participants with data available at the specified time points were analyzed.
Arm/Group Title Part A: GSK3358699 1 mg SD Part A: GSK3358699 3 mg SD Part A: GSK3358699 10 mg SD Part A: GSK3358699 20 mg SD Part A: GSK3358699 25 mg SD Part A: GSK3358699 30 mg SD Part A: GSK3358699 40 mg SD
Arm/Group Description Participants in Part A received a SD of GSK3358699 1 mg on Day 1 in treatment Period 1. Participants in Part A received a SD of GSK3358699 3 mg on Day 1 in treatment Period 1. Participants in Part A received a SD of GSK3358699 10 mg on Day 1 in treatment Period 2. Participants in Part A received a SD of GSK3358699 20 mg on Day 1 in treatment Period 2. Participants in Part A received a SD of GSK3358699 25 mg on Day 1 in treatment Period 4. On Day 1, participants were administered a SD of GSK3358699 25 mg followed by IV administration of in vivo LPS challenge at a dose of 0.75 ng/kg for induction of blisters on the forearm in Cohort 1 and in Cohort 2, participants were administered with IV administration of in vivo GM-CSF challenge at a dose of 60 mcg/m^2 and further treated with 0.2% cantharidin for induction of blisters on the forearm. GSK3358699 were administered via the oral route. Participants in Part A received a SD of GSK3358699 30 mg on Day 1 in treatment Period 3. Participants in Part A received a SD of GSK3358699 40 mg on Day 1 in treatment Period 3.
Measure Participants 2 2 6 4 8 4 6
Median (Full Range) [Hours*nanogram per milliliter]
17.08
29.05
108.29
189.02
357.98
492.92
649.74
53. Secondary Outcome
Title Part B: AUC(0-infinity) of GSK3206944
Description Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of GSK3206944. GSK3206944 is a metabolite of GSK3358699.
Time Frame Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose in each treatment period

Outcome Measure Data

Analysis Population Description
PK Population. Data was not collected as no participants were enrolled in Part B.
Arm/Group Title Part B: Cohort 3- GSK3358699 Fed + GSK3358699 Fasted Part B: Cohort 3- GSK3358699 Fasted + GSK3358699 Fed
Arm/Group Description Participants in Part B Cohort 3 were planned to receive a SD of GSK3358699 under fed conditions on Day 1 in treatment Period 1; followed by a SD of GSK3358699 under fasted conditions on Day 1 in treatment Period 2. There was a planned washout period of 14 days between each treatment period. Participants in Part B Cohort 3 were planned to receive a SD of GSK3358699 under fasted conditions on Day 1 in treatment Period 1; followed by a SD of GSK3358699 under fed conditions on Day 1 in treatment Period 2. There was a planned washout period of 14 days between each treatment period.
Measure Participants 0 0
54. Secondary Outcome
Title Part C: AUC(0-infinity) of GSK3206944
Description Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3206944. PK parameters were calculated using standard non-compartmental analysis. GSK3206944 is a metabolite of GSK3358699.
Time Frame Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12 and 24 hours; Day 14: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose

Outcome Measure Data

Analysis Population Description
PK Population. Only those participants with data available at the specified time points were analyzed (represented by n= X in the category titles). Data was not collected for Cohorts 6 to 8 as no participants were enrolled.
Arm/Group Title Part C: Cohort 4 and 5- GSK3358699 10 mg RD Part C: Cohort 6- GSK3358699 RD Part C: Cohort 7- GSK3358699 RD Part C: Cohort 8- GSK3358699 RD
Arm/Group Description Participants received once daily repeat dose of GSK3358699 10 mg on Days 1 to 14. In Cohort 4, on Day 14, participants were administered an IV in vivo LPS challenge at a dose of 0.75 ng/kg or an IV infusion of GM-CSF, in vivo at a dose of 60 mcg/m^2. The administration of LPS or GM-CSF was followed by blister induction on forearm (0.2% cantharidin). Participants in Part C Cohort 6 were planned to receive once daily repeat dose of GSK3358699 on Days 1 to 14. Participants in Part C Cohort 7 were planned to receive once daily repeat dose of GSK3358699 on Days 1 to 14. Participants in Part C Cohort 8 were planned to receive once daily repeat dose of GSK3358699 on Days 1 to 14. On Day 14, participants were planned to receive an IV in vivo LPS challenge at a dose of 0.75 ng/kg or an IV infusion of GM-CSF, in vivo as 60 mcg/m^2. The administration of LPS or GM-CSF was planned to be followed by blister induction on forearm (0.2% cantharidin).
Measure Participants 14 0 0 0
Day 1, n=14,0,0,0
117.25
55. Secondary Outcome
Title Part A: AUC(0-24) of GSK3206944
Description Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3206944. PK parameters were calculated using standard non-compartmental analysis. GSK3206944 is a metabolite of GSK3358699.
Time Frame Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12 and 24 hours post-dose in each treatment period

Outcome Measure Data

Analysis Population Description
PK Population. Only those participants with data available at the specified time points were analyzed.
Arm/Group Title Part A: GSK3358699 1 mg SD Part A: GSK3358699 3 mg SD Part A: GSK3358699 10 mg SD Part A: GSK3358699 20 mg SD Part A: GSK3358699 25 mg SD Part A: GSK3358699 30 mg SD Part A: GSK3358699 40 mg SD
Arm/Group Description Participants in Part A received a SD of GSK3358699 1 mg on Day 1 in treatment Period 1. Participants in Part A received a SD of GSK3358699 3 mg on Day 1 in treatment Period 1. Participants in Part A received a SD of GSK3358699 10 mg on Day 1 in treatment Period 2. Participants in Part A received a SD of GSK3358699 20 mg on Day 1 in treatment Period 2. Participants in Part A received a SD of GSK3358699 25 mg on Day 1 in treatment Period 4. On Day 1, participants were administered a SD of GSK3358699 25 mg followed by IV administration of in vivo LPS challenge at a dose of 0.75 ng/kg for induction of blisters on the forearm in Cohort 1 and in Cohort 2, participants were administered with IV administration of in vivo GM-CSF challenge at a dose of 60 mcg/m^2 and further treated with 0.2% cantharidin for induction of blisters on the forearm. GSK3358699 were administered via the oral route. Participants in Part A received a SD of GSK3358699 30 mg on Day 1 in treatment Period 3. Participants in Part A received a SD of GSK3358699 40 mg on Day 1 in treatment Period 3.
Measure Participants 2 2 6 6 12 6 6
Median (Full Range) [Hours*nanogram per milliliter]
16.44
28.27
106.55
209.96
374.49
452.66
586.70
56. Secondary Outcome
Title Part B: AUC(0-24) of GSK3206944
Description Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of GSK3206944. GSK3206944 is a metabolite of GSK3358699.
Time Frame Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12 and 24 hours post-dose in each treatment period

Outcome Measure Data

Analysis Population Description
PK Population. Data was not collected as no participants were enrolled in Part B.
Arm/Group Title Part B: Cohort 3- GSK3358699 Fed + GSK3358699 Fasted Part B: Cohort 3- GSK3358699 Fasted + GSK3358699 Fed
Arm/Group Description Participants in Part B Cohort 3 were planned to receive a SD of GSK3358699 under fed conditions on Day 1 in treatment Period 1; followed by a SD of GSK3358699 under fasted conditions on Day 1 in treatment Period 2. There was a planned washout period of 14 days between each treatment period. Participants in Part B Cohort 3 were planned to receive a SD of GSK3358699 under fasted conditions on Day 1 in treatment Period 1; followed by a SD of GSK3358699 under fed conditions on Day 1 in treatment Period 2. There was a planned washout period of 14 days between each treatment period.
Measure Participants 0 0
57. Secondary Outcome
Title Part C: AUC(0-24) of GSK3206944
Description Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3206944. PK parameters were calculated using standard non-compartmental analysis. GSK3206944 is a metabolite of GSK3358699.
Time Frame Days 1 and 14: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, and 24 hours post-dose

Outcome Measure Data

Analysis Population Description
PK Population. Only those participants with data available at the specified time points were analyzed (represented by n= X in the category titles). Data was not collected for Cohorts 6 to 8 as no participants were enrolled.
Arm/Group Title Part C: Cohort 4 and 5- GSK3358699 10 mg RD Part C: Cohort 6- GSK3358699 RD Part C: Cohort 7- GSK3358699 RD Part C: Cohort 8- GSK3358699 RD
Arm/Group Description Participants received once daily repeat dose of GSK3358699 10 mg on Days 1 to 14. In Cohort 4, on Day 14, participants were administered an IV in vivo LPS challenge at a dose of 0.75 ng/kg or an IV infusion of GM-CSF, in vivo at a dose of 60 mcg/m^2. The administration of LPS or GM-CSF was followed by blister induction on forearm (0.2% cantharidin). Participants in Part C Cohort 6 were planned to receive once daily repeat dose of GSK3358699 on Days 1 to 14. Participants in Part C Cohort 7 were planned to receive once daily repeat dose of GSK3358699 on Days 1 to 14. Participants in Part C Cohort 8 were planned to receive once daily repeat dose of GSK3358699 on Days 1 to 14. On Day 14, participants were planned to receive an IV in vivo LPS challenge at a dose of 0.75 ng/kg or an IV infusion of GM-CSF, in vivo as 60 mcg/m^2. The administration of LPS or GM-CSF was planned to be followed by blister induction on forearm (0.2% cantharidin).
Measure Participants 14 0 0 0
Day 1, n=14,0,0,0
115.31
Day 14, n=2,0,0,0
106.19
58. Secondary Outcome
Title Part A: Cmax of GSK3206944
Description Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3206944. PK parameters were calculated using standard non-compartmental analysis. GSK3206944 is a metabolite of GSK3358699.
Time Frame Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose in each treatment period

Outcome Measure Data

Analysis Population Description
PK Population.
Arm/Group Title Part A: GSK3358699 1 mg SD Part A: GSK3358699 3 mg SD Part A: GSK3358699 10 mg SD Part A: GSK3358699 20 mg SD Part A: GSK3358699 25 mg SD Part A: GSK3358699 30 mg SD Part A: GSK3358699 40 mg SD
Arm/Group Description Participants in Part A received a SD of GSK3358699 1 mg on Day 1 in treatment Period 1. Participants in Part A received a SD of GSK3358699 3 mg on Day 1 in treatment Period 1. Participants in Part A received a SD of GSK3358699 10 mg on Day 1 in treatment Period 2. Participants in Part A received a SD of GSK3358699 20 mg on Day 1 in treatment Period 2. Participants in Part A received a SD of GSK3358699 25 mg on Day 1 in treatment Period 4. On Day 1, participants were administered a SD of GSK3358699 25 mg followed by IV administration of in vivo LPS challenge at a dose of 0.75 ng/kg for induction of blisters on the forearm in Cohort 1 and in Cohort 2, participants were administered with IV administration of in vivo GM-CSF challenge at a dose of 60 mcg/m^2 and further treated with 0.2% cantharidin for induction of blisters on the forearm. GSK3358699 were administered via the oral route. Participants in Part A received a SD of GSK3358699 30 mg on Day 1 in treatment Period 3. Participants in Part A received a SD of GSK3358699 40 mg on Day 1 in treatment Period 3.
Measure Participants 5 3 6 6 12 6 6
Median (Full Range) [Nanogram per milliliter]
3.28
6.03
19.39
50.13
71.67
102.09
121.22
59. Secondary Outcome
Title Part B: Cmax of GSK3206944
Description Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of GSK3206944. GSK3206944 is a metabolite of GSK3358699.
Time Frame Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose in each treatment period

Outcome Measure Data

Analysis Population Description
PK Population. Data was not collected as no participants were enrolled in Part B.
Arm/Group Title Part B: Cohort 3- GSK3358699 Fed + GSK3358699 Fasted Part B: Cohort 3- GSK3358699 Fasted + GSK3358699 Fed
Arm/Group Description Participants in Part B Cohort 3 were planned to receive a SD of GSK3358699 under fed conditions on Day 1 in treatment Period 1; followed by a SD of GSK3358699 under fasted conditions on Day 1 in treatment Period 2. There was a planned washout period of 14 days between each treatment period. Participants in Part B Cohort 3 were planned to receive a SD of GSK3358699 under fasted conditions on Day 1 in treatment Period 1; followed by a SD of GSK3358699 under fed conditions on Day 1 in treatment Period 2. There was a planned washout period of 14 days between each treatment period.
Measure Participants 0 0
60. Secondary Outcome
Title Part C: Cmax of GSK3206944
Description Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3206944. PK parameters were calculated using standard non-compartmental analysis. GSK3206944 is a metabolite of GSK3358699.
Time Frame Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12 and 24 hours; Day 14: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose

Outcome Measure Data

Analysis Population Description
PK Population. Only those participants with data available at the specified time points were analyzed (represented by n= X in the category titles). Data was not collected for Cohorts 6 to 8 as no participants were enrolled.
Arm/Group Title Part C: Cohort 4 and 5- GSK3358699 10 mg RD Part C: Cohort 6- GSK3358699 RD Part C: Cohort 7- GSK3358699 RD Part C: Cohort 8- GSK3358699 RD
Arm/Group Description Participants received once daily repeat dose of GSK3358699 10 mg on Days 1 to 14. In Cohort 4, on Day 14, participants were administered an IV in vivo LPS challenge at a dose of 0.75 ng/kg or an IV infusion of GM-CSF, in vivo at a dose of 60 mcg/m^2. The administration of LPS or GM-CSF was followed by blister induction on forearm (0.2% cantharidin). Participants in Part C Cohort 6 were planned to receive once daily repeat dose of GSK3358699 on Days 1 to 14. Participants in Part C Cohort 7 were planned to receive once daily repeat dose of GSK3358699 on Days 1 to 14. Participants in Part C Cohort 8 were planned to receive once daily repeat dose of GSK3358699 on Days 1 to 14. On Day 14, participants were planned to receive an IV in vivo LPS challenge at a dose of 0.75 ng/kg or an IV infusion of GM-CSF, in vivo as 60 mcg/m^2. The administration of LPS or GM-CSF was planned to be followed by blister induction on forearm (0.2% cantharidin).
Measure Participants 14 0 0 0
Day 1, n=14,0,0,0
23.02
Day 14, n=2,0,0,0
15.34
61. Secondary Outcome
Title Part A: Tmax of GSK3206944
Description Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3206944. PK parameters were calculated using standard non-compartmental analysis. GSK3206944 is a metabolite of GSK3358699.
Time Frame Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose in each treatment period

Outcome Measure Data

Analysis Population Description
PK Population.
Arm/Group Title Part A: GSK3358699 1 mg SD Part A: GSK3358699 3 mg SD Part A: GSK3358699 10 mg SD Part A: GSK3358699 20 mg SD Part A: GSK3358699 25 mg SD Part A: GSK3358699 30 mg SD Part A: GSK3358699 40 mg SD
Arm/Group Description Participants in Part A received a SD of GSK3358699 1 mg on Day 1 in treatment Period 1. Participants in Part A received a SD of GSK3358699 3 mg on Day 1 in treatment Period 1. Participants in Part A received a SD of GSK3358699 10 mg on Day 1 in treatment Period 2. Participants in Part A received a SD of GSK3358699 20 mg on Day 1 in treatment Period 2. Participants in Part A received a SD of GSK3358699 25 mg on Day 1 in treatment Period 4. On Day 1, participants were administered a SD of GSK3358699 25 mg followed by IV administration of in vivo LPS challenge at a dose of 0.75 ng/kg for induction of blisters on the forearm in Cohort 1 and in Cohort 2, participants were administered with IV administration of in vivo GM-CSF challenge at a dose of 60 mcg/m^2 and further treated with 0.2% cantharidin for induction of blisters on the forearm. GSK3358699 were administered via the oral route. Participants in Part A received a SD of GSK3358699 30 mg on Day 1 in treatment Period 3. Participants in Part A received a SD of GSK3358699 40 mg on Day 1 in treatment Period 3.
Measure Participants 5 3 6 6 12 6 6
Median (Full Range) [Hours]
1.00
2.00
2.00
2.01
2.00
2.00
2.00
62. Secondary Outcome
Title Part B: Tmax of GSK3206944
Description Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of GSK3206944. GSK3206944 is a metabolite of GSK3358699.
Time Frame Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose in each treatment period

Outcome Measure Data

Analysis Population Description
PK Population. Data was not collected as no participants were enrolled in Part B.
Arm/Group Title Part B: Cohort 3- GSK3358699 Fed + GSK3358699 Fasted Part B: Cohort 3- GSK3358699 Fasted + GSK3358699 Fed
Arm/Group Description Participants in Part B Cohort 3 were planned to receive a SD of GSK3358699 under fed conditions on Day 1 in treatment Period 1; followed by a SD of GSK3358699 under fasted conditions on Day 1 in treatment Period 2. There was a planned washout period of 14 days between each treatment period. Participants in Part B Cohort 3 were planned to receive a SD of GSK3358699 under fasted conditions on Day 1 in treatment Period 1; followed by a SD of GSK3358699 under fed conditions on Day 1 in treatment Period 2. There was a planned washout period of 14 days between each treatment period.
Measure Participants 0 0
63. Secondary Outcome
Title Part C: Tmax of GSK3206944
Description Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3206944. PK parameters were calculated using standard non-compartmental analysis. GSK3206944 is a metabolite of GSK3358699.
Time Frame Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12 and 24 hours; Day 14: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose

Outcome Measure Data

Analysis Population Description
PK Population. Only those participants with data available at the specified time points were analyzed (represented by n= X in the category titles). Data was not collected for Cohorts 6 to 8 as no participants were enrolled.
Arm/Group Title Part C: Cohort 4 and 5- GSK3358699 10 mg RD Part C: Cohort 6- GSK3358699 RD Part C: Cohort 7- GSK3358699 RD Part C: Cohort 8- GSK3358699 RD
Arm/Group Description Participants received once daily repeat dose of GSK3358699 10 mg on Days 1 to 14. In Cohort 4, on Day 14, participants were administered an IV in vivo LPS challenge at a dose of 0.75 ng/kg or an IV infusion of GM-CSF, in vivo at a dose of 60 mcg/m^2. The administration of LPS or GM-CSF was followed by blister induction on forearm (0.2% cantharidin). Participants in Part C Cohort 6 were planned to receive once daily repeat dose of GSK3358699 on Days 1 to 14. Participants in Part C Cohort 7 were planned to receive once daily repeat dose of GSK3358699 on Days 1 to 14. Participants in Part C Cohort 8 were planned to receive once daily repeat dose of GSK3358699 on Days 1 to 14. On Day 14, participants were planned to receive an IV in vivo LPS challenge at a dose of 0.75 ng/kg or an IV infusion of GM-CSF, in vivo as 60 mcg/m^2. The administration of LPS or GM-CSF was planned to be followed by blister induction on forearm (0.2% cantharidin).
Measure Participants 14 0 0 0
Day 1, n=14,0,0,0
2.00
Day 14, n=2,0,0,0
0.99
64. Secondary Outcome
Title Part A: t1/2 of GSK3206944
Description Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3206944. PK parameters were calculated using standard non-compartmental analysis. GSK3206944 is a metabolite of GSK3358699.
Time Frame Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose in each treatment period

Outcome Measure Data

Analysis Population Description
PK Population. Only those participants with data available at the specified time points were analyzed.
Arm/Group Title Part A: GSK3358699 1 mg SD Part A: GSK3358699 3 mg SD Part A: GSK3358699 10 mg SD Part A: GSK3358699 20 mg SD Part A: GSK3358699 25 mg SD Part A: GSK3358699 30 mg SD Part A: GSK3358699 40 mg SD
Arm/Group Description Participants in Part A received a SD of GSK3358699 1 mg on Day 1 in treatment Period 1. Participants in Part A received a SD of GSK3358699 3 mg on Day 1 in treatment Period 1. Participants in Part A received a SD of GSK3358699 10 mg on Day 1 in treatment Period 2. Participants in Part A received a SD of GSK3358699 20 mg on Day 1 in treatment Period 2. Participants in Part A received a SD of GSK3358699 25 mg on Day 1 in treatment Period 4. On Day 1, participants were administered a SD of GSK3358699 25 mg followed by IV administration of in vivo LPS challenge at a dose of 0.75 ng/kg for induction of blisters on the forearm in Cohort 1 and in Cohort 2, participants were administered with IV administration of in vivo GM-CSF challenge at a dose of 60 mcg/m^2 and further treated with 0.2% cantharidin for induction of blisters on the forearm. GSK3358699 were administered via the oral route. Participants in Part A received a SD of GSK3358699 30 mg on Day 1 in treatment Period 3. Participants in Part A received a SD of GSK3358699 40 mg on Day 1 in treatment Period 3.
Measure Participants 2 2 6 4 8 4 6
Median (Full Range) [Hours]
4.97
4.91
4.10
3.80
7.81
6.98
6.76
65. Secondary Outcome
Title Part B: t1/2 of GSK3206944
Description Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of GSK3206944. GSK3206944 is a metabolite of GSK3358699.
Time Frame Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose in each treatment period

Outcome Measure Data

Analysis Population Description
PK Population. Data was not collected as no participants were enrolled in Part B.
Arm/Group Title Part B: Cohort 3- GSK3358699 Fed + GSK3358699 Fasted Part B: Cohort 3- GSK3358699 Fasted + GSK3358699 Fed
Arm/Group Description Participants in Part B Cohort 3 were planned to receive a SD of GSK3358699 under fed conditions on Day 1 in treatment Period 1; followed by a SD of GSK3358699 under fasted conditions on Day 1 in treatment Period 2. There was a planned washout period of 14 days between each treatment period. Participants in Part B Cohort 3 were planned to receive a SD of GSK3358699 under fasted conditions on Day 1 in treatment Period 1; followed by a SD of GSK3358699 under fed conditions on Day 1 in treatment Period 2. There was a planned washout period of 14 days between each treatment period.
Measure Participants 0 0
66. Secondary Outcome
Title Part C: t1/2 of GSK3206944
Description Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3206944. PK parameters were calculated using standard non-compartmental analysis. GSK3206944 is a metabolite of GSK3358699.
Time Frame Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12 and 24 hours; Day 14: Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose

Outcome Measure Data

Analysis Population Description
PK Population. Only those participants with data available at the specified time points were analyzed (represented by n= X in the category titles). Data was not collected for Cohorts 6 to 8 as no participants were enrolled.
Arm/Group Title Part C: Cohort 4 and 5- GSK3358699 10 mg RD Part C: Cohort 6- GSK3358699 RD Part C: Cohort 7- GSK3358699 RD Part C: Cohort 8- GSK3358699 RD
Arm/Group Description Participants received once daily repeat dose of GSK3358699 10 mg on Days 1 to 14. In Cohort 4, on Day 14, participants were administered an IV in vivo LPS challenge at a dose of 0.75 ng/kg or an IV infusion of GM-CSF, in vivo at a dose of 60 mcg/m^2. The administration of LPS or GM-CSF was followed by blister induction on forearm (0.2% cantharidin). Participants in Part C Cohort 6 were planned to receive once daily repeat dose of GSK3358699 on Days 1 to 14. Participants in Part C Cohort 7 were planned to receive once daily repeat dose of GSK3358699 on Days 1 to 14. Participants in Part C Cohort 8 were planned to receive once daily repeat dose of GSK3358699 on Days 1 to 14. On Day 14, participants were planned to receive an IV in vivo LPS challenge at a dose of 0.75 ng/kg or an IV infusion of GM-CSF, in vivo as 60 mcg/m^2. The administration of LPS or GM-CSF was planned to be followed by blister induction on forearm (0.2% cantharidin).
Measure Participants 14 0 0 0
Day 1, n=14,0,0,0
5.02
Day 14, n=2,0,0,0
6.15
67. Secondary Outcome
Title Part A: Monocyte Intracellular Concentration of GSK3206944
Description Blood samples were collected into sodium heparin tubes for the isolation of monocytes and for measurement of GSK3206944 concentrations in monocytes. GSK3206944 is a metabolite of GSK3358699.
Time Frame Day 1: 1, 4, 8, 24 and 48 hours post-dose in each treatment period

Outcome Measure Data

Analysis Population Description
PK Population.
Arm/Group Title Part A: GSK3358699 1 mg SD Part A: GSK3358699 3 mg SD Part A: GSK3358699 10 mg SD Part A: GSK3358699 20 mg SD Part A: GSK3358699 25 mg SD Part A: GSK3358699 30 mg SD Part A: GSK3358699 40 mg SD
Arm/Group Description Participants in Part A received a SD of GSK3358699 1 mg on Day 1 in treatment Period 1. Participants in Part A received a SD of GSK3358699 3 mg on Day 1 in treatment Period 1. Participants in Part A received a SD of GSK3358699 10 mg on Day 1 in treatment Period 2. Participants in Part A received a SD of GSK3358699 20 mg on Day 1 in treatment Period 2. Participants in Part A received a SD of GSK3358699 25 mg on Day 1 in treatment Period 4. On Day 1, participants were administered a SD of GSK3358699 25 mg followed by IV administration of in vivo LPS challenge at a dose of 0.75 ng/kg for induction of blisters on the forearm in Cohort 1 and in Cohort 2, participants were administered with IV administration of in vivo GM-CSF challenge at a dose of 60 mcg/m^2 and further treated with 0.2% cantharidin for induction of blisters on the forearm. GSK3358699 were administered via the oral route. Participants in Part A received a SD of GSK3358699 30 mg on Day 1 in treatment Period 3. Participants in Part A received a SD of GSK3358699 40 mg on Day 1 in treatment Period 3.
Measure Participants 5 3 6 6 12 6 6
Day 1: 1 hour
NA
NA
0.177
0.673
NA
1.243
1.410
Day 1: 4 hours
NA
NA
NA
0.105
0.149
0.277
0.297
Day 1: 8 hours
NA
NA
NA
NA
NA
NA
NA
Day 1: 24 hours
NA
NA
NA
NA
NA
NA
NA
Day 1: 48 hours
NA
NA
NA
NA
NA
NA
NA
68. Secondary Outcome
Title Part B: Monocyte Intracellular Concentration of GSK3206944
Description Blood samples were planned to be collected into sodium heparin tubes for the isolation of monocytes and for measurement of GSK3206944 concentrations in monocytes. GSK3206944 is a metabolite of GSK3358699.
Time Frame Day 1: 1, 4, 8, 24 and 48 hours post-dose in each treatment period

Outcome Measure Data

Analysis Population Description
PK Population. Data was not collected as no participants were enrolled in Part B.
Arm/Group Title Part B: Cohort 3- GSK3358699 Fed + GSK3358699 Fasted Part B: Cohort 3- GSK3358699 Fasted + GSK3358699 Fed
Arm/Group Description Participants in Part B Cohort 3 were planned to receive a SD of GSK3358699 under fed conditions on Day 1 in treatment Period 1; followed by a SD of GSK3358699 under fasted conditions on Day 1 in treatment Period 2. There was a planned washout period of 14 days between each treatment period. Participants in Part B Cohort 3 were planned to receive a SD of GSK3358699 under fasted conditions on Day 1 in treatment Period 1; followed by a SD of GSK3358699 under fed conditions on Day 1 in treatment Period 2. There was a planned washout period of 14 days between each treatment period.
Measure Participants 0 0
69. Secondary Outcome
Title Part C: Monocyte Intracellular Concentration of GSK3206944
Description Blood samples were collected into sodium heparin tubes for the isolation of monocytes and for measurement of GSK3206944 concentrations in monocytes. GSK3206944 is a metabolite of GSK3358699.
Time Frame Days 1 and 13: 1, 4 and 8 hour; Days 4, 8 and 12: Pre-dose; Day 14: 1, 4, 8, 24 and 48 hours post-dose

Outcome Measure Data

Analysis Population Description
PK Population. Only those participants with data available at the specified time points were analyzed (represented by n= X in the category titles). Data was not collected for Cohorts 6 to 8 as no participants were enrolled.
Arm/Group Title Part C: Cohort 4 and 5- GSK3358699 10 mg RD Part C: Cohort 6- GSK3358699 RD Part C: Cohort 7- GSK3358699 RD Part C: Cohort 8- GSK3358699 RD
Arm/Group Description Participants received once daily repeat dose of GSK3358699 10 mg on Days 1 to 14. In Cohort 4, on Day 14, participants were administered an IV in vivo LPS challenge at a dose of 0.75 ng/kg or an IV infusion of GM-CSF, in vivo at a dose of 60 mcg/m^2. The administration of LPS or GM-CSF was followed by blister induction on forearm (0.2% cantharidin). Participants in Part C Cohort 6 were planned to receive once daily repeat dose of GSK3358699 on Days 1 to 14. Participants in Part C Cohort 7 were planned to receive once daily repeat dose of GSK3358699 on Days 1 to 14. Participants in Part C Cohort 8 were planned to receive once daily repeat dose of GSK3358699 on Days 1 to 14. On Day 14, participants were planned to receive an IV in vivo LPS challenge at a dose of 0.75 ng/kg or an IV infusion of GM-CSF, in vivo as 60 mcg/m^2. The administration of LPS or GM-CSF was planned to be followed by blister induction on forearm (0.2% cantharidin).
Measure Participants 14 0 0 0
Day 1: 1 hour,n=14,0,0,0
0.313
Day 1: 4 hours,n=14,0,0,0
NA
Day 1: 8 hours,n=14,0,0,0
NA
Day 4: Pre-dose,n=14,0,0,0
NA
Day 8: Pre-dose,n=14,0,0,0
NA
Day 12: Pre-dose,n=14,0,0,0
NA
Day 13: 1 hour,n=1,0,0,0
0.317
Day 13: 4 hours,n=1,0,0,0
NA
Day 13: 8 hours,n=1,0,0,0
NA
Day 14: 1 hour,n=1,0,0,0
0.256
Day 14: 4 hours,n=1,0,0,0
NA
Day 14: 8 hours,n=1,0,0,0
NA
Day 14: 24 hours,n=1,0,0,0
NA
Day 14: 48 hours,n=1,0,0,0
NA
70. Secondary Outcome
Title Part A: Absolute Values of Monocyte Chemotactic Protein (MCP)-1, Interleukin (IL)6, Tumor Necrosis Factor (TNF) Alpha in Blood After Ex-vivo Lipopolysaccharide (LPS) Activation
Description Whole blood samples of 1 milliliter (mL) were collected in TruCulture tubes, containing LPS and incubated for 24 hours, post which the inflammatory mediators (MCP-1, IL-6 and TNF alpha) were analyzed.
Time Frame Day 1: 1, 4, 8, 12, 24 and 48 hours

Outcome Measure Data

Analysis Population Description
Safety Population. Only those participants with data available at the specified time points were analyzed (represented by n= X in the category titles). Data was not collected for GSK3358699 25 mg SD arm.
Arm/Group Title Part A: Placebo SD Part A: GSK3358699 1 mg SD Part A: GSK3358699 3 mg SD Part A: GSK3358699 10 mg SD Part A: GSK3358699 20 mg SD Part A: GSK3358699 25 mg SD Part A: GSK3358699 30 mg SD Part A: GSK3358699 40 mg SD
Arm/Group Description Participants in Part A received a SD of placebo on Day 1 in either treatment Period 1, 2 and 3. On Day 1 of treatment Period 4, participants were administered a SD of placebo followed by IV administration of in vivo LPS challenge at a dose of 0.75 ng/kg for induction of blisters on the forearm in Cohort 1 and in Cohort 2, participants were administered with IV administration of in vivo GM-CSF challenge at a dose of 60 mcg/m^2 and further treated with 0.2% cantharidin for induction of blisters on the forearm. Placebo were administered via the oral route. Participants in Part A received a SD of GSK3358699 1 mg on Day 1 in treatment Period 1. Participants in Part A received a SD of GSK3358699 3 mg on Day 1 in treatment Period 1. Participants in Part A received a SD of GSK3358699 10 mg on Day 1 in treatment Period 2. Participants in Part A received a SD of GSK3358699 20 mg on Day 1 in treatment Period 2. Participants in Part A received a SD of GSK3358699 25 mg on Day 1 in treatment Period 4. On Day 1, participants were administered a SD of GSK3358699 25 mg followed by IV administration of in vivo LPS challenge at a dose of 0.75 ng/kg for induction of blisters on the forearm in Cohort 1 and in Cohort 2, participants were administered with IV administration of in vivo GM-CSF challenge at a dose of 60 mcg/m^2 and further treated with 0.2% cantharidin for induction of blisters on the forearm. GSK3358699 were administered via the oral route. Participants in Part A received a SD of GSK3358699 30 mg on Day 1 in treatment Period 3. Participants in Part A received a SD of GSK3358699 40 mg on Day 1 in treatment Period 3.
Measure Participants 17 5 3 6 6 0 6 6
Day 1: IL6, 1 hour, n=17,5,3,6,6,0,6,6
10352.87
15208.12
20385.25
12820.72
15596.95
10057.64
5728.17
Day 1: IL6, 4 hours, n=17,5,3,6,6,0,6,6
13092.01
13851.61
19431.61
15636.75
12900.07
12074.28
7544.02
Day 1: IL6, 8 hours, n=17,5,3,6,6,0,6,6
12560.83
13629.60
28805.81
16564.79
17019.48
16486.96
8688.63
Day 1: IL6, 12 hour, n=17,5,3,6,6,0,6,6
15125.82
13890.39
28948.13
18712.82
15622.25
12305.88
6754.46
Day 1: IL6, 24 hours, n=17,5,3,6,6,0,6,6
12876.74
16961.79
23634.22
14387.39
12593.53
12894.02
8705.59
Day 1: IL6, 48 hours, n=17,5,3,6,6,0,6,6
13204.84
16209.14
27160.99
14786.71
13685.44
14374.44
8359.81
Day 1: MCP-1, 1 hour, n=17,5,2,6,6,0,6,6
2107.38
2997.62
2539.15
1273.19
1278.42
1604.85
1047.32
Day 1: MCP-1, 4 hours, n=17,5,3,6,6,0,6,6
1748.71
2638.95
3774.02
1410.01
1648.51
2604.00
1643.37
Day 1: MCP-1, 8 hours, n=17,5,3,6,6,0,6,6
1300.34
2911.87
3145.66
1606.85
1533.33
2312.12
1863.25
Day 1: MCP-1, 12 hour, n=17,5,3,6,6,0,6,6
1791.07
2738.20
3048.56
2003.41
1297.53
2062.41
2270.49
Day 1: MCP-1, 24 hours, n=17,5,3,6,6,0,6,6
1662.28
2349.62
2216.41
1691.59
1062.86
2275.17
1988.64
Day 1: MCP-1, 48 hours, n=17,5,3,6,6,0,6,6
1398.36
2306.83
1621.46
1729.87
1200.15
1595.51
1828.23
Day 1: TNF alpha, 1 hour, n=17,5,3,6,6,0,6,6
2525.78
2281.20
4340.00
3455.53
3916.76
1971.77
1552.10
Day 1: TNF alpha, 4 hours, n=17,5,3,6,6,0,6,6
3189.81
3452.27
3381.52
4493.55
2672.58
3618.72
1876.55
Day 1: TNF alpha, 8 hours, n=17,5,3,6,6,0,6,6
3673.78
3630.47
9631.19
4612.79
4908.42
5233.22
2934.21
Day 1: TNF alpha, 12 hour, n=17,5,3,6,6,0,6,6
4206.18
3680.34
8736.93
5139.53
3079.37
2846.57
1729.42
Day 1: TNF alpha, 24 hours, n=17,5,3,5,6,0,6,6
3164.79
4528.14
4694.58
5576.01
3543.62
3649.08
2741.96
Day 1: TNF alpha, 48 hours, n=17,5,3,6,6,0,6,6
3445.95
4077.77
10364.95
4186.10
3963.40
3788.04
2404.11
71. Secondary Outcome
Title Part B: Absolute Values of MCP-1, IL6, TNF Alpha in Blood After Ex-vivo LPS Activation
Description Whole blood samples were planned to be collected in TruCulture tubes, containing LPS and incubated for 24 hours, post which the inflammatory mediators (MCP-1, IL6 and TNF alpha) were planned to be analyzed.
Time Frame Day 1: 1, 4, 8, 12, 24 and 48 hours

Outcome Measure Data

Analysis Population Description
Safety Population. Data was not collected as no participants were enrolled in Part B.
Arm/Group Title Part B: Cohort 3- GSK3358699 Fed + GSK3358699 Fasted Part B: Cohort 3- GSK3358699 Fasted + GSK3358699 Fed
Arm/Group Description Participants in Part B Cohort 3 were planned to receive a SD of GSK3358699 under fed conditions on Day 1 in treatment Period 1; followed by a SD of GSK3358699 under fasted conditions on Day 1 in treatment Period 2. There was a planned washout period of 14 days between each treatment period. Participants in Part B Cohort 3 were planned to receive a SD of GSK3358699 under fasted conditions on Day 1 in treatment Period 1; followed by a SD of GSK3358699 under fed conditions on Day 1 in treatment Period 2. There was a planned washout period of 14 days between each treatment period.
Measure Participants 0 0
72. Secondary Outcome
Title Part C: Absolute Values of MCP-1, IL6, TNF Alpha in Blood After Ex-vivo LPS Activation
Description Whole blood samples of 1 mL were collected in TruCulture tubes, containing LPS and incubated for 24 hours, post which the inflammatory mediators (MCP-1, IL-6 and TNF alpha) were analyzed.
Time Frame Day 1: 1, 4 and 8 hours; Days 2, 4, 8 and 12: Pre-dose; Day 13: Pre-dose, 1, 4 and 8 hours; Day 14: Pre-dose, Pre-LPS challenge, 1, 4, 8, 24 and 48 hours

Outcome Measure Data

Analysis Population Description
Safety Population. Data was not collected for Cohorts 6 to 8 as no participants were enrolled. Only those participants with data available at the specified time points were analyzed (represented by n= X in the category titles).
Arm/Group Title Part C: Cohort 4 and 5- Placebo RD Part C: Cohort 4 and 5- GSK3358699 10 mg RD Part C: Cohort 6- GSK3358699 or Placebo RD Part C: Cohort 7- GSK3358699 or Placebo RD Part C: Cohort 8- GSK3358699 or Placebo RD
Arm/Group Description Participants received once daily RD of placebo on Days 1 to 14. In Cohort 4, on Day 14, participants were administered an IV in vivo LPS challenge at a dose of 0.75 ng/kg or an IV infusion of GM-CSF, in vivo at a dose of 60 mcg/m^2. The administration of LPS or GM CSF was followed by blister induction on forearm (0.2% cantharidin). Participants received once daily repeat dose of GSK3358699 10 mg on Days 1 to 14. In Cohort 4, on Day 14, participants were administered an IV in vivo LPS challenge at a dose of 0.75 ng/kg or an IV infusion of GM-CSF, in vivo at a dose of 60 mcg/m^2. The administration of LPS or GM CSF was followed by blister induction on forearm (0.2% cantharidin). Participants in Part C Cohort 6 were planned to receive once daily repeat dose of GSK3358699 or placebo on Days 1 to 14. Participants in Part C Cohort 7 were planned to receive once daily repeat dose of GSK3358699 or placebo on Days 1 to 14. Participants in Part C Cohort 8 were planned to receive once daily repeat dose of GSK3358699 or placebo on Days 1 to 14. On Day 14, participants were planned to receive an IV in vivo LPS challenge at a dose of 0.75 ng/kg or an IV infusion of GM-CSF, in vivo as 60 mcg/m^2. The administration of LPS or GM CSF was planned to be followed by blister induction on forearm (0.2% cantharidin).
Measure Participants 11 14 0 0 0
IL6:Day 1,1 hour,n=11,13,0,0,0
9488.65
9629.75
IL6:Day 1,4 hours,n=11,14,0,0,0
9121.35
10686.75
IL6:Day 1,8 hours,n=11,14,0,0,0
13079.21
15475.58
IL6:Day 2,Pre-dose,n=11,14,0,0,0
9323.67
12396.71
IL6:Day 4,Pre-dose,n=11,14,0,0,0
11002.47
12558.78
IL6:Day 8,Pre-dose,n=6,7,0,0,0
11305.84
10766.02
IL6:Day 12,Pre-dose,n=5,4,0,0,0
9329.36
10539.82
IL6:Day 13,Pre-dose,n=1,1,0,0,0
9966.64
12743.26
IL6:Day 13,1 hour,n=1,1,0,0,0
11718.40
12508.94
IL6:Day 13,4 hours,n=1,1,0,0,0
7099.42
11616.53
IL6:Day 13,8 hours,n=1,1,0,0,0
10722.24
16723.58
IL6:Day 14,Pre-dose,n=1,1,0,0,0
8918.96
14654.83
IL6:Day 14,Pre LPS challenge,n=1,1,0,0,0
8696.65
11340.79
IL6:Day 14,1 hour,n=1,1,0,0,0
10082.23
13244.20
IL6:Day 14,4 hours,n=1,1,0,0,0
9122.21
11543.08
IL6:Day 14,8 hours,n=1,1,0,0,0
10986.16
12544.55
IL6:Day 14,24 hours,n=1,1,0,0,0
9176.89
9114.15
IL6:Day 14,48 hours,n=1,1,0,0,0
8257.88
10304.01
MCP-1:Day 1,1 hour,n=11,14,0,0,0
1739.49
2216.06
MCP-1:Day 1,4 hours,n=11,14,0,0,0
1825.09
2405.11
MCP-1:Day 1,8 hours,n=11,14,0,0,0
2002.44
2044.64
MCP-1:Day 2,Pre-dose,n=11,14,0,0,0
1939.09
1928.51
MCP-1:Day 4,Pre-dose,n=11,14,0,0,0
1677.88
1939.65
MCP-1:Day 8,Pre-dose,n=6,7,0,0,0
1638.33
1719.26
MCP-1:Day 12,Pre-dose,n=5,4,0,0,0
1799.12
2176.12
MCP-1:Day 13,Pre-dose,n=1,1,0,0,0
1839.00
513.36
MCP-1:Day 13,1 hour,n=1,1,0,0,0
2113.92
294.72
MCP-1:Day 13,4 hours,n=1,1,0,0,0
1872.12
890.77
MCP-1:Day 13,8 hours,n=1,1,0,0,0
1997.87
1412.52
MCP-1:Day 14,Pre-dose,n=1,1,0,0,0
2007.09
4935.03
MCP-1:Day 14,Pre LPS challenge,n=1,1,0,0,0
1876.05
1981.15
MCP-1:Day 14,1 hour,n=1,1,0,0,0
3503.11
3623.79
MCP-1:Day 14,4 hours,n=1,1,0,0,0
2066.72
3293.92
MCP-1:Day 14,8 hours,n=1,1,0,0,0
2593.90
3150.84
MCP-1:Day 14,24 hours,n=1,1,0,0,0
2082.28
3372.94
MCP-1:Day 14,48 hours,n=1,1,0,0,0
1879.53
2715.94
TNF alpha:Day 1,1 hour,n=11,13,0,0,0
1994.72
2078.66
TNF alpha:Day 1,4 hours,n=11,14,0,0,0
1843.08
2297.36
TNF alpha:Day 1,8 hours,n=11,14,0,0,0
3692.36
3854.86
TNF alpha:Day 2,Pre-dose,n=11,14,0,0,0
2711.07
3028.33
TNF alpha:Day 4,Pre-dose,n=11,14,0,0,0
2987.24
3045.05
TNF alpha:Day 8,Pre-dose,n=6,7,0,0,0
2932.72
2849.52
TNF alpha:Day 12,Pre-dose,n=5,4,0,0,0
2482.03
2407.60
TNF alpha:Day 13,Pre-dose,n=1,1,0,0,0
2311.66
2995.36
TNF alpha:Day 13,1 hour,n=1,1,0,0,0
3495.21
2648.27
TNF alpha:Day 13,4 hours,n=1,1,0,0,0
1573.18
2815.39
TNF alpha:Day 13,8 hours,n=1,1,0,0,0
2486.89
4472.25
TNF alpha:Day 14,Pre-dose,n=1,1,0,0,0
2304.40
3327.69
TNF alpha:Day 14,Pre LPS challenge,n=1,1,0,0,0
2092.07
2081.54
TNF alpha:Day 14,1 hour,n=1,1,0,0,0
2103.62
3133.32
TNF alpha:Day 14,4 hours,n=1,1,0,0,0
1771.69
2457.35
TNF alpha:Day 14,8 hours,n=1,1,0,0,0
2560.84
3481.91
TNF alpha:Day 14,24 hours,n=1,1,0,0,0
1482.94
2187.40
TNF alpha:Day 14,48 hours,n=1,1,0,0,0
1909.65
2597.32

Adverse Events

Time Frame Up to Day 193 in Part A and up to Day 49 in Part C (Cohorts 4 and 5)
Adverse Event Reporting Description Safety Population.All-cause mortality,non-SAEs and SAEs were not collected in Part B and Part C(Cohorts 6 to 8) as no participants were enrolled.Data is presented for Part A and Part C(Cohorts4 and 5) only as data was not collected in Part B and Part C(Cohorts6 to 8) due to study termination and Part B and Part C(Cohorts 6 to 8) were not initiated.
Arm/Group Title Part A: Placebo SD Part A: GSK3358699 1 mg SD Part A: GSK3358699 3 mg SD Part A: GSK3358699 10 mg SD Part A: GSK3358699 20 mg SD Part A: GSK3358699 25 mg SD Part A: GSK3358699 30 mg SD Part A: GSK3358699 40 mg SD Part B: Cohort 3- GSK3358699 Fed + GSK3358699 Fasted Part B: Cohort 3- GSK3358699 Fasted + GSK3358699 Fed Part C: Cohort 4 and 5- Placebo RD Part C: Cohort 4 and 5- GSK3358699 10 mg RD Part C: Cohort 6- GSK3358699 or Placebo RD Part C: Cohort 7- GSK3358699 or Placebo RD Part C: Cohort 8- GSK3358699 or Placebo RD
Arm/Group Description Participants in Part A received a SD of placebo on Day 1 in either treatment Period 1, 2 and 3. On Day 1 of treatment Period 4, participants were administered a SD of placebo followed by IV administration of in vivo LPS challenge at a dose of 0.75 ng/kg for induction of blisters on the forearm in Cohort 1 and in Cohort 2, participants were administered with IV administration of in vivo GM-CSF challenge at a dose of 60 mcg/m^2 and further treated with 0.2% cantharidin for induction of blisters on the forearm. Placebo were administered via the oral route. Participants in Part A received a SD of GSK3358699 1 mg on Day 1 in treatment Period 1. Participants in Part A received a SD of GSK3358699 3 mg on Day 1 in treatment Period 1. Participants in Part A received a SD of GSK3358699 10 mg on Day 1 in treatment Period 2. Participants in Part A received a SD of GSK3358699 20 mg on Day 1 in treatment Period 2. Participants in Part A received a SD of GSK3358699 25 mg on Day 1 in treatment Period 4. On Day 1, participants were administered a SD of GSK3358699 25 mg followed by IV administration of in vivo LPS challenge at a dose of 0.75 ng/kg for induction of blisters on the forearm in Cohort 1 and in Cohort 2, participants were administered with IV administration of in vivo GM-CSF challenge at a dose of 60 mcg/m^2 and further treated with 0.2% cantharidin for induction of blisters on the forearm. GSK3358699 were administered via the oral route. Participants in Part A received a SD of GSK3358699 30 mg on Day 1 in treatment Period 3. Participants in Part A received a SD of GSK3358699 40 mg on Day 1 in treatment Period 3. Participants in Part B Cohort 3 were planned to receive a SD of GSK3358699 under fed conditions on Day 1 in treatment Period 1; followed by a SD of GSK3358699 under fasted conditions on Day 1 in treatment Period 2. There was a planned washout period of 14 days between each treatment period. Participants in Part B Cohort 3 were planned to receive a SD of GSK3358699 under fasted conditions on Day 1 in treatment Period 1; followed by a SD of GSK3358699 under fed conditions on Day 1 in treatment Period 2. There was a planned washout period of 14 days between each treatment period. Participants received once daily RD of placebo on Days 1 to 14. In Cohort 4, on Day 14, participants were administered an IV in vivo LPS challenge at a dose of 0.75 ng/kg or an IV infusion of GM-CSF, in vivo at a dose of 60 mcg/m^2. The administration of LPS or GM-CSF was followed by blister induction on forearm (0.2% cantharidin). Participants received once daily repeat dose of GSK3358699 10 mg on Days 1 to 14. In Cohort 4, on Day 14, participants were administered an IV in vivo LPS challenge at a dose of 0.75 ng/kg or an IV infusion of GM-CSF, in vivo at a dose of 60 mcg/m^2. The administration of LPS or GM-CSF was followed by blister induction on forearm (0.2% cantharidin). Participants in Part C Cohort 6 were planned to receive once daily repeat dose of GSK3358699 or placebo on Days 1 to 14. Participants in Part C Cohort 7 were planned to receive once daily repeat dose of GSK3358699 or placebo on Days 1 to 14. Participants in Part C Cohort 8 were planned to receive once daily repeat dose of GSK3358699 or placebo on Days 1 to 14. On Day 14, participants were planned to receive an IV in vivo LPS challenge at a dose of 0.75 ng/kg or an IV infusion of GM-CSF, in vivo as 60 mcg/m^2. The administration of LPS or GM-CSF was planned to be followed by blister induction on forearm (0.2% cantharidin).
All Cause Mortality
Part A: Placebo SD Part A: GSK3358699 1 mg SD Part A: GSK3358699 3 mg SD Part A: GSK3358699 10 mg SD Part A: GSK3358699 20 mg SD Part A: GSK3358699 25 mg SD Part A: GSK3358699 30 mg SD Part A: GSK3358699 40 mg SD Part B: Cohort 3- GSK3358699 Fed + GSK3358699 Fasted Part B: Cohort 3- GSK3358699 Fasted + GSK3358699 Fed Part C: Cohort 4 and 5- Placebo RD Part C: Cohort 4 and 5- GSK3358699 10 mg RD Part C: Cohort 6- GSK3358699 or Placebo RD Part C: Cohort 7- GSK3358699 or Placebo RD Part C: Cohort 8- GSK3358699 or Placebo RD
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 0/23 (0%) 0/5 (0%) 0/3 (0%) 0/6 (0%) 0/6 (0%) 0/12 (0%) 0/6 (0%) 0/6 (0%) 0/0 (NaN) 0/0 (NaN) 0/11 (0%) 0/14 (0%) 0/0 (NaN) 0/0 (NaN) 0/0 (NaN)
Serious Adverse Events
Part A: Placebo SD Part A: GSK3358699 1 mg SD Part A: GSK3358699 3 mg SD Part A: GSK3358699 10 mg SD Part A: GSK3358699 20 mg SD Part A: GSK3358699 25 mg SD Part A: GSK3358699 30 mg SD Part A: GSK3358699 40 mg SD Part B: Cohort 3- GSK3358699 Fed + GSK3358699 Fasted Part B: Cohort 3- GSK3358699 Fasted + GSK3358699 Fed Part C: Cohort 4 and 5- Placebo RD Part C: Cohort 4 and 5- GSK3358699 10 mg RD Part C: Cohort 6- GSK3358699 or Placebo RD Part C: Cohort 7- GSK3358699 or Placebo RD Part C: Cohort 8- GSK3358699 or Placebo RD
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 0/23 (0%) 0/5 (0%) 0/3 (0%) 0/6 (0%) 0/6 (0%) 0/12 (0%) 0/6 (0%) 0/6 (0%) 0/0 (NaN) 0/0 (NaN) 0/11 (0%) 1/14 (7.1%) 0/0 (NaN) 0/0 (NaN) 0/0 (NaN)
Cardiac disorders
Atrial fibrillation 0/23 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/12 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/0 (NaN) 0 0/0 (NaN) 0 0/11 (0%) 0 1/14 (7.1%) 1 0/0 (NaN) 0 0/0 (NaN) 0 0/0 (NaN) 0
Other (Not Including Serious) Adverse Events
Part A: Placebo SD Part A: GSK3358699 1 mg SD Part A: GSK3358699 3 mg SD Part A: GSK3358699 10 mg SD Part A: GSK3358699 20 mg SD Part A: GSK3358699 25 mg SD Part A: GSK3358699 30 mg SD Part A: GSK3358699 40 mg SD Part B: Cohort 3- GSK3358699 Fed + GSK3358699 Fasted Part B: Cohort 3- GSK3358699 Fasted + GSK3358699 Fed Part C: Cohort 4 and 5- Placebo RD Part C: Cohort 4 and 5- GSK3358699 10 mg RD Part C: Cohort 6- GSK3358699 or Placebo RD Part C: Cohort 7- GSK3358699 or Placebo RD Part C: Cohort 8- GSK3358699 or Placebo RD
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 4/23 (17.4%) 2/5 (40%) 3/3 (100%) 2/6 (33.3%) 3/6 (50%) 8/12 (66.7%) 4/6 (66.7%) 3/6 (50%) 0/0 (NaN) 0/0 (NaN) 7/11 (63.6%) 7/14 (50%) 0/0 (NaN) 0/0 (NaN) 0/0 (NaN)
Blood and lymphatic system disorders
Neutropenia 0/23 (0%) 0 1/5 (20%) 1 0/3 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/12 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/0 (NaN) 0 0/0 (NaN) 0 0/11 (0%) 0 0/14 (0%) 0 0/0 (NaN) 0 0/0 (NaN) 0 0/0 (NaN) 0
Cardiac disorders
Palpitations 0/23 (0%) 0 0/5 (0%) 0 1/3 (33.3%) 2 0/6 (0%) 0 0/6 (0%) 0 0/12 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/0 (NaN) 0 0/0 (NaN) 0 1/11 (9.1%) 1 0/14 (0%) 0 0/0 (NaN) 0 0/0 (NaN) 0 0/0 (NaN) 0
Sinus tachycardia 0/23 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/12 (8.3%) 1 0/6 (0%) 0 0/6 (0%) 0 0/0 (NaN) 0 0/0 (NaN) 0 0/11 (0%) 0 0/14 (0%) 0 0/0 (NaN) 0 0/0 (NaN) 0 0/0 (NaN) 0
Tachycardia 0/23 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/12 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/0 (NaN) 0 0/0 (NaN) 0 1/11 (9.1%) 1 2/14 (14.3%) 2 0/0 (NaN) 0 0/0 (NaN) 0 0/0 (NaN) 0
Atrial fibrillation 0/23 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/12 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/0 (NaN) 0 0/0 (NaN) 0 1/11 (9.1%) 1 0/14 (0%) 0 0/0 (NaN) 0 0/0 (NaN) 0 0/0 (NaN) 0
Atrial tachycardia 0/23 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/12 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/0 (NaN) 0 0/0 (NaN) 0 0/11 (0%) 0 1/14 (7.1%) 1 0/0 (NaN) 0 0/0 (NaN) 0 0/0 (NaN) 0
Ventricular extrasystoles 0/23 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/12 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/0 (NaN) 0 0/0 (NaN) 0 0/11 (0%) 0 1/14 (7.1%) 1 0/0 (NaN) 0 0/0 (NaN) 0 0/0 (NaN) 0
Ventricular tachycardia 0/23 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/12 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/0 (NaN) 0 0/0 (NaN) 0 0/11 (0%) 0 1/14 (7.1%) 1 0/0 (NaN) 0 0/0 (NaN) 0 0/0 (NaN) 0
Eye disorders
Ocular hyperaemia 0/23 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/12 (8.3%) 1 0/6 (0%) 0 0/6 (0%) 0 0/0 (NaN) 0 0/0 (NaN) 0 0/11 (0%) 0 0/14 (0%) 0 0/0 (NaN) 0 0/0 (NaN) 0 0/0 (NaN) 0
Keratitis 0/23 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/12 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/0 (NaN) 0 0/0 (NaN) 0 1/11 (9.1%) 1 0/14 (0%) 0 0/0 (NaN) 0 0/0 (NaN) 0 0/0 (NaN) 0
Gastrointestinal disorders
Abdominal pain upper 1/23 (4.3%) 1 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/12 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/0 (NaN) 0 0/0 (NaN) 0 0/11 (0%) 0 0/14 (0%) 0 0/0 (NaN) 0 0/0 (NaN) 0 0/0 (NaN) 0
Diarrhoea 0/23 (0%) 0 0/5 (0%) 0 1/3 (33.3%) 2 0/6 (0%) 0 0/6 (0%) 0 0/12 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/0 (NaN) 0 0/0 (NaN) 0 0/11 (0%) 0 0/14 (0%) 0 0/0 (NaN) 0 0/0 (NaN) 0 0/0 (NaN) 0
Dyspepsia 0/23 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/12 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/0 (NaN) 0 0/0 (NaN) 0 0/11 (0%) 0 0/14 (0%) 0 0/0 (NaN) 0 0/0 (NaN) 0 0/0 (NaN) 0
Nausea 0/23 (0%) 0 0/5 (0%) 0 1/3 (33.3%) 1 0/6 (0%) 0 0/6 (0%) 0 0/12 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/0 (NaN) 0 0/0 (NaN) 0 0/11 (0%) 0 0/14 (0%) 0 0/0 (NaN) 0 0/0 (NaN) 0 0/0 (NaN) 0
General disorders
Feeling cold 1/23 (4.3%) 1 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/12 (8.3%) 1 0/6 (0%) 0 0/6 (0%) 0 0/0 (NaN) 0 0/0 (NaN) 0 1/11 (9.1%) 1 0/14 (0%) 0 0/0 (NaN) 0 0/0 (NaN) 0 0/0 (NaN) 0
Feeling hot 0/23 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 2/12 (16.7%) 2 0/6 (0%) 0 0/6 (0%) 0 0/0 (NaN) 0 0/0 (NaN) 0 0/11 (0%) 0 0/14 (0%) 0 0/0 (NaN) 0 0/0 (NaN) 0 0/0 (NaN) 0
Malaise 0/23 (0%) 0 0/5 (0%) 0 1/3 (33.3%) 1 0/6 (0%) 0 0/6 (0%) 0 0/12 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/0 (NaN) 0 0/0 (NaN) 0 0/11 (0%) 0 0/14 (0%) 0 0/0 (NaN) 0 0/0 (NaN) 0 0/0 (NaN) 0
Pain 0/23 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/12 (8.3%) 1 0/6 (0%) 0 0/6 (0%) 0 0/0 (NaN) 0 0/0 (NaN) 0 0/11 (0%) 0 0/14 (0%) 0 0/0 (NaN) 0 0/0 (NaN) 0 0/0 (NaN) 0
Pyrexia 1/23 (4.3%) 1 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/12 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/0 (NaN) 0 0/0 (NaN) 0 0/11 (0%) 0 0/14 (0%) 0 0/0 (NaN) 0 0/0 (NaN) 0 0/0 (NaN) 0
Infections and infestations
Hordeolum 0/23 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/12 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/0 (NaN) 0 0/0 (NaN) 0 0/11 (0%) 0 0/14 (0%) 0 0/0 (NaN) 0 0/0 (NaN) 0 0/0 (NaN) 0
Nasopharyngitis 0/23 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/12 (8.3%) 1 0/6 (0%) 0 0/6 (0%) 0 0/0 (NaN) 0 0/0 (NaN) 0 0/11 (0%) 0 0/14 (0%) 0 0/0 (NaN) 0 0/0 (NaN) 0 0/0 (NaN) 0
Urinary tract infection 0/23 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/12 (8.3%) 1 0/6 (0%) 0 0/6 (0%) 0 0/0 (NaN) 0 0/0 (NaN) 0 0/11 (0%) 0 0/14 (0%) 0 0/0 (NaN) 0 0/0 (NaN) 0 0/0 (NaN) 0
Folliculitis 0/23 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/12 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/0 (NaN) 0 0/0 (NaN) 0 1/11 (9.1%) 1 0/14 (0%) 0 0/0 (NaN) 0 0/0 (NaN) 0 0/0 (NaN) 0
Injury, poisoning and procedural complications
Arthropod bite 1/23 (4.3%) 2 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/12 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/0 (NaN) 0 0/0 (NaN) 0 0/11 (0%) 0 0/14 (0%) 0 0/0 (NaN) 0 0/0 (NaN) 0 0/0 (NaN) 0
Contusion 0/23 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/12 (8.3%) 1 0/6 (0%) 0 0/6 (0%) 0 0/0 (NaN) 0 0/0 (NaN) 0 1/11 (9.1%) 1 0/14 (0%) 0 0/0 (NaN) 0 0/0 (NaN) 0 0/0 (NaN) 0
Head injury 0/23 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/12 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/0 (NaN) 0 0/0 (NaN) 0 0/11 (0%) 0 0/14 (0%) 0 0/0 (NaN) 0 0/0 (NaN) 0 0/0 (NaN) 0
Investigations
Alanine aminotransferase increased 0/23 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/12 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/0 (NaN) 0 0/0 (NaN) 0 1/11 (9.1%) 1 1/14 (7.1%) 1 0/0 (NaN) 0 0/0 (NaN) 0 0/0 (NaN) 0
Musculoskeletal and connective tissue disorders
Back pain 0/23 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/12 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/0 (NaN) 0 0/0 (NaN) 0 1/11 (9.1%) 1 0/14 (0%) 0 0/0 (NaN) 0 0/0 (NaN) 0 0/0 (NaN) 0
Nervous system disorders
Headache 2/23 (8.7%) 2 1/5 (20%) 3 1/3 (33.3%) 1 1/6 (16.7%) 3 2/6 (33.3%) 2 4/12 (33.3%) 4 1/6 (16.7%) 2 2/6 (33.3%) 2 0/0 (NaN) 0 0/0 (NaN) 0 2/11 (18.2%) 2 2/14 (14.3%) 2 0/0 (NaN) 0 0/0 (NaN) 0 0/0 (NaN) 0
Renal and urinary disorders
Renal atrophy 0/23 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/12 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/0 (NaN) 0 0/0 (NaN) 0 1/11 (9.1%) 1 0/14 (0%) 0 0/0 (NaN) 0 0/0 (NaN) 0 0/0 (NaN) 0
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain 0/23 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/12 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/0 (NaN) 0 0/0 (NaN) 0 0/11 (0%) 0 0/14 (0%) 0 0/0 (NaN) 0 0/0 (NaN) 0 0/0 (NaN) 0
Rhinorrhoea 0/23 (0%) 0 0/5 (0%) 0 1/3 (33.3%) 1 1/6 (16.7%) 1 0/6 (0%) 0 0/12 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/0 (NaN) 0 0/0 (NaN) 0 0/11 (0%) 0 0/14 (0%) 0 0/0 (NaN) 0 0/0 (NaN) 0 0/0 (NaN) 0
Throat irritation 0/23 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/12 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/0 (NaN) 0 0/0 (NaN) 0 0/11 (0%) 0 0/14 (0%) 0 0/0 (NaN) 0 0/0 (NaN) 0 0/0 (NaN) 0
Productive cough 0/23 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/12 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/0 (NaN) 0 0/0 (NaN) 0 0/11 (0%) 0 1/14 (7.1%) 1 0/0 (NaN) 0 0/0 (NaN) 0 0/0 (NaN) 0
Skin and subcutaneous tissue disorders
Dermatitis contact 0/23 (0%) 0 0/5 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/12 (8.3%) 1 0/6 (0%) 0 0/6 (0%) 0 0/0 (NaN) 0 0/0 (NaN) 0 0/11 (0%) 0 1/14 (7.1%) 1 0/0 (NaN) 0 0/0 (NaN) 0 0/0 (NaN) 0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.

Results Point of Contact

Name/Title GSK Response Center
Organization GlaxoSmithKline
Phone 866-435-7343
Email GSKClinicalSupportHD@gsk.com
Responsible Party:
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT03426995
Other Study ID Numbers:
  • 207546
  • 2017-003997-15
First Posted:
Feb 9, 2018
Last Update Posted:
Dec 2, 2020
Last Verified:
Oct 1, 2020