A Phase 1 interventional study of Cantharidin and Lipopolysaccharide in Arthritis, Rheumatoid, sponsored by GlaxoSmithKline. Completed at 1 site in United Kingdom. Open to male participants aged 18 Years to 45 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2019-08-08.
Sponsored by GlaxoSmithKline · Phase 1, Interventional, and Diagnostic
This exploratory study aims to assess exposure of healthy subjects to systemic challenge with either LPS or GM-CSF. This will be done by measuring inflammatory mediators and cellular activation markers both in circulation and in skin blisters induced by exposure to cantharidin (an agent that causes blisters). LPS is often used to induce inflammation whereas GM-CSF is a cytokine and a key mediator in inflammatory diseases. In this 2 parts study, subjects will have 2 sessions in each part. Part I of the study is a dose-exploration phase and part II will be a continuation phase to draw more precise outcomes. In session 1, subjects will be randomized to receive either LPS or GM-CSF and will have 2 blisters induced on each forearm followed by blood draws and a blister harvest on each forearm at 24 and 48 hours post-induction. After a minimum of 14 days blister healing period, subjects will return for session 2. In part I, Up to 6 cohorts will be tested and all cohorts will have 2 sessions. For Part I, initially Cohort 1 will proceed with session 1. After their blister healing period, Cohort 1 will return for their session 2 visit in two groups (Group A and Group B) on different days. Group A will be dosed on the same day (one with LPS and one with GM-CSF) and Group B will be dosed on a different day (one with LPS and one with GM-CSF) after group A. Dose-escalation in Cohort 2-6 will be continued until the well tolerated dose has been determined. The same dose will be administered to an additional Cohort in Part II and the same 2-session design will be used. Approximately 24-30 healthy subjects will be enrolled for the study and the total duration of the study for each subject will be approximately 13 weeks from screening to follow up.
Exclusion criteria:
Eligible subjects will be randomized to receive LPS in a dose-escalation manner ranging from 0.5 nanogram (ng)/kg to 4 ng/kg. Subjects will be hydrated prior to administration of LPS with normal saline at a rate of 250 mL/hour for 4 hours prior to dosing and 8 hours after dosing.
Biological: Cantharidin · Biological: Lipopolysaccharide · Drug: Saline Solution
Eligible subjects will be randomized to receive GM-CSF in a dose-escalation manner ranging from 5 to 15 microgram (µg)/kg.
Biological: Cantharidin · Biological: Granulocyte-Macrophage Colony-Stimulating Factor
5 microliter (µL) of 0.2 percent Cantharidin solution (diluted in acetone) will be applied to all subjects on forearm by topical route.
0.5 to 4 ng/kg body weight of LPS formulated as suspension in normal saline will be administered to randomized subjects via intravenous (IV) route in dose-escalation manner.
5 to 15 µg/kg of GM-CSF will be administered to randomized subjects via subcutaneous (SC) route in the abdominal region in dose-escalation manner.
0.9 percent sodium chloride will be administered via IV route to all subjects at a rate of 250 mL/hour for 4 hours prior to dosing with LPS and 8 hours after dosing with LPS.
Part 1: Change From Baseline Primary Soluble Inflammatory Mediators in Blood: Tumor Necrosis Factor (TNF) Alpha and Interleukin (IL) 6 for LPS Arm
Blood samples were collected at indicated timepoints for the analysis of primary soluble inflammatory mediators like TNF-alpha and IL-6 in blood. Latest pre-challenge LPS assessment with a non-missing value, including those from unscheduled visits was considered as Baseline. Change from Baseline was calculated as the value at specified visit minus the Baseline value. Each session was for three days. NA indicates that data was not available as standard deviation could not be calculated for a single participant. All participants who were randomized to receive the treatment (LPS or GM-CSF challenge) and received one dose of challenge agent were included in Safety Population.
Time frame: Baseline, Session 2: -5, 10, 25, 40 minutes, 1 hour 10 minutes, 1 hour 40 minutes, 2 hours 40 minutes,5 hours 40 minutes on Day 1. Pre-fluid sample on Day 2 and Day 3
Part 1: Change From Baseline in Primary Soluble Inflammatory Mediators : Urinary Tetranor Prostaglandin D Metabolite (PGDM) LPS Arm
The post-challenge urine samples were collected during session 2 after LPS challenge. In session 2, participants were encouraged to pass urine immediately before LPS challenge dose and urine voids were collected from after LPS until 12 hours post-LPS and the time of the urine collection were recorded as post-challenge 1 to 11. These samples were collected for measurement of tetranor-PGDM. Latest pre-challenge LPS assessment with a non-missing value, including those from unscheduled visits was considered as Baseline. Change from Baseline was calculated as the value at specified visit minus the Baseline value. The data for normalized Tetranor PGDM was normalized by (Tetranor PGDM \[pg/mL\] divided by Creatinine \[milligram per deciliter\]) multiplied by 100. NA indicates that data was not available as standard deviation could not be calculated for a single participant.
Time frame: Baseline, Session 2 Day 1
Part 2: Change From Baseline Primary Soluble Inflammatory Mediators in Blood: TNF Alpha and IL 6: LPS Arm
Blood samples were planned to be collected at indicated timepoints for the analysis of primary soluble inflammatory mediators like TNF-alpha and IL-6 in blood. Latest pre-challenge LPS assessment with a non-missing value, including those from unscheduled visits was considered as Baseline. Change from Baseline was calculated as the value at specified visit minus the Baseline value. Part 2 of the study was not conducted as agreed criteria for Interim analysis was achieved.
Time frame: Baseline, Session 2: -5, 10, 25, 40 minutes, 1 hour 10 minutes, 1 hour 40 minutes, 5 hours 40 minutes on Day 1. Pre-fluid sample on Day 2 and Day 3
Part 2: Change From Baseline Primary Soluble Inflammatory Mediators : Urinary Tetranor PGDM: LPS Arm
Urine samples were planned to be collected for analysis. Latest pre-challenge LPS assessment with a non-missing value, including those from unscheduled visits was considered as Baseline. Change from Baseline was calculated as the value at specified visit minus the Baseline value. Part 2 of the study was not conducted as agreed criteria for Interim analysis was achieved.
Time frame: Baseline, Session 2 Day 1
Part 1: Change From Baseline in White Blood Cell Numbers in Blood: GM-CSF
Blood samples were collected at indicated time-points for analysis of white blood cells. Latest pre-challenge GM-CSF assessment with a non-missing value, including those from unscheduled visits was considered as Baseline. Change from Baseline was calculated as the value at specified visit minus the Baseline value.
Time frame: Baseline, Session 2: 40 minutes, 2 hours 40 minutes, 5 hours 40 minutes, 9 hours 40 minutes on Day 1. Pre-fluid sample on Day 2 and Day 3
Part 2: Change From Baseline in White Blood Cell Numbers in Blood: GM-CSF
Blood samples were planned to be collected at indicated time-points for analysis of white blood cells. Baseline value is Session 2 Day 1. Change from Baseline was calculated as the value at specified visit minus the Baseline value. Part 2 of the study was not conducted as agreed criteria for Interim analysis was achieved.
Time frame: Baseline, Session 2: 40 minutes, 2 hours 40 minutes, 5 hours 40 minutes, 9 hours 40 minutes on Day 1. Pre-fluid sample on Day 2 and Day 3
Part 1: Change From Baseline Soluble Inflammatory Biomarkers in Skin Blister
Blister samples were collected at indicated time-points for the analysis of soluble inflammatory mediators like IL-1 beta (b), Interferon-gamma (INFg), IL-6, IL-2, IL-8, Monocyte chemotactic protein-1 (MCP-1) and TNF-alpha. Latest pre-challenge (LPS or GM-CSF) assessment with a non-missing value, including those from unscheduled visits was considered as Baseline. Change from Baseline was calculated as the value at specified visit minus the Baseline value. NA indicates that data was not available as standard deviation could not be calculated for a single participant.
Time frame: Baseline; Session1: 48 hours on Day3; Session 2: 24 hours on Day 2 and 48 hours on Day 3
Part 2: Change From Baseline Soluble Inflammatory Biomarkers in Skin Blister
Blister samples were planned to be collected at indicated time-points for the analysis of soluble inflammatory mediators like IL-1 beta, INFg, IL-6, IL-2, IL-8, MCP-1 and TNF-alpha. Latest pre-challenge (LPS or GM-CSF) assessment with a non-missing value, including those from unscheduled visits was considered as Baseline. Change from Baseline was calculated as the value at specified visit minus the Baseline value. Part 2 of the study was not conducted as agreed criteria for Interim analysis was achieved.
Time frame: Baseline; Session1: 48 hours Day3; Session 2: 24 hours Day 2 and 48 hours Day 3
Part 1: Absolute Values of Blister Volume
Blister samples were collected at indicated time-points for analysis of blister volumes. . Latest pre-challenge (LPS or GM-CSF) assessment with a non-missing value, including those from unscheduled visits was considered as Baseline.
Time frame: Baseline, Session 1: 48 hours Day 3. Session 2: 24 hours Day 2, 48 hours Day 3
Part 2: Absolute Values of Blister Volume
Blister samples were planned to be collected at indicated time-points for analysis of blister volumes. Latest pre-challenge (LPS or GM-CSF) assessment with a non-missing value, including those from unscheduled visits was considered as Baseline. Part 2 of the study was not conducted as agreed criteria for Interim analysis was achieved.
Time frame: Baseline, Session 1: 48 hours Day 3. Session 2: 24 hours Day 2, 48 hours Day 3
Part 1: Change From Baseline in Cell Numbers in Blister
Blister samples were collected at indicated time-points for analysis of white blood cell in blister. Latest pre-challenge LPS assessment with a non-missing value, including those from unscheduled visits was considered as Baseline. Change from Baseline was calculated as the value at specified visit minus the Baseline value.
Time frame: Baseline, Session 1: 48 hours Day 3. Session 2: 24 hours Day 2, 48 hours Day 3
Part 2: Change From Baseline in Cell Numbers in Blister
Blood samples were planned to be collected at indicated time-points for analysis of white blood cell in blister. Latest pre-challenge (LPS or GM-CSF) assessment with a non-missing value, including those from unscheduled visits was considered as Baseline. Change from Baseline was calculated as the value at specified visit minus the Baseline value. Part 2 of the study was not conducted as agreed criteria for Interim analysis was achieved.
Time frame: Baseline, Session 1: 48 hours Day 3. Session 2: 24 hours Day 2, 48 hours Day 3
Part 1:Change From Baseline in Cell Activation Markers by Flow Cytometry on Monocytes in Blister
Blister samples were collected at indicated time-points for the measurement of activation markers by flow cytometry for monocytes in blister. Activation markers included Cluster of Differentiation (CD) 16, CD163, CD206, CD209, CD40, CD80, CD83, CD86 and Human Leukocyte Antigen - antigen D Related (HLA-DR). Latest pre-challenge (LPS or GM-CSF) assessment with a non-missing value, including those from unscheduled visits was considered as Baseline. Change from Baseline was calculated as the value at specified visit minus the Baseline value. NA indicates that data was not available as standard deviation could not be calculated for a single participant.
Time frame: Baseline, Session1: 48 hours Day 3, Session 2: 24 hours Day 2 and 48 hours Day 3
Part 2:Change From Baseline in Cell Activation Markers by Flow Cytometry on Monocytes in Blister
Blister samples were planned to be collected at indicated time-points for the measurement of activation. Latest pre-challenge (LPS or GM-CSF) assessment with a non-missing value, including those from unscheduled visits was considered as Baseline. Change from Baseline was calculated as the value at specified visit minus the Baseline value. Part 2 of the study was not conducted as agreed criteria for Interim analysis was achieved.
Time frame: Baseline, Session1: 48 hours Day 3, Session 2: 24 hours Day 2 and 48 hours Day 3
Part 1:Change From Baseline of CD40+/CD80+ by Flow Cytometry on Monocytes in Blister
Blister samples were collected at indicated time-points for the measurement of activation markers by flow cytometry for monocytes in blister like CD40+/CD80+. Latest pre-challenge (LPS or GM-CSF) assessment with a non-missing value, including those from unscheduled visits was considered as Baseline. Change from Baseline was calculated as the value at specified visit minus the Baseline value. NA indicates that data was not available as standard deviation could not be calculated for a single participant.
Time frame: Baseline, Session1: 48 hours Day 3, Session 2: 24 hours Day 2 and 48 hours Day 3
Part 2:Change From Baseline of CD40+/CD80+ by Flow Cytometry on Monocytes in Blister
Blister samples were planned to be collected at indicated time-points for the measurement of activation. Latest pre-challenge (LPS or GM-CSF) assessment with a non-missing value, including those from unscheduled visits was considered as Baseline. Change from Baseline was calculated as the value at specified visit minus the Baseline value. Part 2 of the study was not conducted as agreed criteria for Interim analysis was achieved.
Time frame: Baseline, Session1: 48 hours Day 3, Session 2: 24 hours Day 2 and 48 hours Day 3
Part 1:Change From Baseline in Cell Activation Markers by Flow Cytometry on Dendritic Cells in Blister
Blister samples were collected at indicated time-points for the measurement of activation markers by flow cytometry for dendritic cells in blister. Activation markers included CD16, CD163, CD206, CD209, CD40, CD80, CD83, CD86 and HLA-DR. Latest pre-challenge (LPS or GM-CSF) assessment with a non-missing value, including those from unscheduled visits was considered as Baseline. Change from Baseline was calculated as the value at specified visit minus the Baseline value. NA indicates that data was not available as standard deviation could not be calculated for a single participant.
Time frame: Baseline; Session1: 48 hours Day 3, Session 2: 24 hours Day 2 and 48 hours Day 3
Part 2:Change From Baseline in Cell Activation Markers by Flow Cytometry on Dendritic Cells in Blister
Blister samples were planned to be collected at indicated time-points for the measurement of activation. Latest pre-challenge (LPS or GM-CSF) assessment with a non-missing value, including those from unscheduled visits was considered as Baseline. Change from Baseline was calculated as the value at specified visit minus the Baseline value. Part 2 of the study was not conducted as agreed criteria for Interim analysis was achieved.
Time frame: Baseline, Session1: 48 hours Day 3, Session 2: 24 hours Day 2 and 48 hours Day 3
Part 1:Change From Baseline of CD40+/CD80+ by Flow Cytometry on Dendritic Cells in Blister
Blister samples were collected at indicated time-points for the measurement of activation markers by flow cytometry for dendritic cells in blister like CD40+/CD80+. Latest pre-challenge (LPS or GM-CSF) assessment with a non-missing value, including those from unscheduled visits was considered as Baseline. Change from Baseline was calculated as the value at specified visit minus the Baseline value. NA indicates that data was not available as standard deviation could not be calculated for a single participant.
Time frame: Baseline, Session1: 48 hours Day 3, Session 2: 24 hours Day 2 and 48 hours Day 3
Part 2:Change From Baseline of CD40+/CD80+ by Flow Cytometry on Dendritic Cells in Blister
Blister samples were planned to be collected at indicated time-points for the measurement of activation. Latest pre-challenge (LPS or GM-CSF) assessment with a non-missing value, including those from unscheduled visits was considered as Baseline. Change from Baseline was calculated as the value at specified visit minus the Baseline value. Part 2 of the study was not conducted as agreed criteria for Interim analysis was achieved.
Time frame: Baseline, Session1: 48 hours Day 3, Session 2: 24 hours Day 2 and 48 hours Day 3
Part 1:Change From Baseline in Cell Activation Markers by Flow Cytometry on Macrophages in Blister
Blister samples were collected at indicated time-points for the measurement of activation markers by flow cytometry for macrophages in blister. Activation markers included CD16, CD163, CD206, CD209, CD40, CD80, CD83, CD86 and HLA-DR. Latest pre-challenge (LPS or GM-CSF) assessment with a non-missing value, including those from unscheduled visits was considered as Baseline. Change from Baseline was calculated as the value at specified visit minus the Baseline value. NA indicates that data was not available as standard deviation could not be calculated for a single participant.
Time frame: Baseline, Session1: 48 hours Day 3, Session 2: 24 hours Day 2 and 48 hours Day 3
Part 2:Change From Baseline in Cell Activation Markers by Flow Cytometry on Macrophages in Blister
Blister samples were planned to be collected at indicated time-points for the measurement of activation. Latest pre-challenge (LPS or GM-CSF) assessment with a non-missing value, including those from unscheduled visits was considered as Baseline. Change from Baseline was calculated as the value at specified visit minus the Baseline value. Part 2 of the study was not conducted as agreed criteria for Interim analysis was achieved.
Time frame: Baseline, Session1: 48 hours Day 3, Session 2: 24 hours Day 2 and 48 hours Day 3
Part 1:Change From Baseline of CD40+/CD80+ by Flow Cytometry on Macrophages in Blister
Blister samples were collected at indicated time-points for the measurement of activation markers by flow cytometry for dendritic cells in blister like CD40+/CD80+. Latest pre-challenge (LPS or GM-CSF) assessment with a non-missing value, including those from unscheduled visits was considered as Baseline. Change from Baseline was calculated as the value at specified visit minus the Baseline value. NA indicates that data was not available as standard deviation could not be calculated for a single participant.
Time frame: Baseline, Session1: 48 hours Day 3, Session 2: 24 hours Day 2 and 48 hours Day 3
Part 2:Change From Baseline of CD40+/CD80+ by Flow Cytometry on Macrophages in Blister
Blister samples were planned to be collected at indicated time-points for the measurement of activation. Latest pre-challenge (LPS or GM-CSF) assessment with a non-missing value, including those from unscheduled visits was considered as Baseline. Change from Baseline was calculated as the value at specified visit minus the Baseline value. Part 2 of the study was not conducted as agreed criteria for Interim analysis was achieved.
Time frame: Baseline, Session1: 48 hours Day 3, Session 2: 24 hours Day 2 and 48 hours Day 3
Part 1:Change From Baseline in Soluble Inflammatory Mediators in Blood
Blood samples were collected at indicated timepoints for the analysis of primary soluble inflammatory mediators like IL-1 beta, INFg, IL-2, IL-8, and MCP-1 in blood. Latest pre-challenge (LPS or GM-CSF) assessment with a non-missing value, including those from unscheduled visits was considered as Baseline. Change from Baseline was calculated as the value at specified visit minus the Baseline value. NA indicates that data was not available as standard deviation could not be calculated for a single participant.
Time frame: Baseline, Session 2: -5, 10, 25, 40 minutes, 1 hour 10 minutes, 1 hour 40 minutes, 2 hours 40 minutes, 5 hours 40 minutes on Day 1. Pre-fluid sample on Day 2 and Day 3
Part 2:Change From Baseline in Soluble Inflammatory Mediators in Blood
Blood samples were planned to be collected at indicated time-points for the measurement of activation. Latest pre-challenge (LPS or GM-CSF) assessment with a non-missing value, including those from unscheduled visits was considered as Baseline. Change from Baseline was calculated as the value at specified visit minus the Baseline value. Part 2 of the study was not conducted as agreed criteria for Interim analysis was achieved.
Time frame: Baseline, Session 2: -5, 10, 25, 40 minutes, 1 hour 10 minutes, 1 hour 40 minutes, 2 hours 40 minutes, 5 hours 40 minutes on Day 1. Pre-fluid sample on Day 2 and Day 3
Part 1: Change From Baseline in Soluble Inflammatory Mediators in Blood: TNF-alpha, IL-6 and GM-CSF: GM-CSF Arm
Blood samples were collected at indicated time-points for the analysis of soluble inflammatory mediators like TNF-alpha, IL-6 and GM-CSF in blood. Latest pre-challenge GM-CSF assessment with a non-missing value, including those from unscheduled visits was considered as Baseline. Change from Baseline was calculated as the value at specified visit minus the Baseline value.
Time frame: Baseline, Session 2: -5, 10, 25, 40 minutes, 1 hour 10 minutes, 1 hour 40 minutes, 2 hours 40 minutes, 5 hours 40 minutes on Day 1. Pre-fluid sample on Day 2 and Day 3
Part 2: Change From Baseline in Soluble Inflammatory Mediators in Blood: TNF-alpha, IL-6 and GM-CSF for GM-CSF Arm
Blood samples were planned to be collected at indicated time-points for the measurement of activation. Latest pre-challenge GM-CSF assessment with a non-missing value, including those from unscheduled visits was considered as Baseline. Change from Baseline was calculated as the value at specified visit minus the Baseline value. Part 2 of the study was not conducted as agreed criteria for Interim analysis was achieved.
Time frame: Baseline, Session 2: -5, 10, 25, 40 minutes, 1 hour 10 minutes, 1 hour 40 minutes, 2 hours 40 minutes, 5 hours 40 minutes on Day 1. Pre-fluid sample on Day 2 and Day 3
Part 1: Change From Baseline in Soluble Inflammatory Mediators in Blood: C-reactive Protein (CRP)
Blood samples were collected at indicated time-points for the analysis of soluble inflammatory mediators like CRP in blood. Latest pre-challenge (LPS or GM-CSF) assessment with a non-missing value, including those from unscheduled visits was considered as Baseline. Change from Baseline was calculated as the value at specified visit minus the Baseline value.
Time frame: Baseline; Session 2: Post challenge Day 1. Pre-fluid sample on Day 2 and Day 3
Part 2: Change From Baseline in Soluble Inflammatory Mediators in Blood: CRP
Blood samples were planned to be collected at indicated time-points for the measurement of activation. Latest pre-challenge (LPS or GM-CSF) assessment with a non-missing value, including those from unscheduled visits was considered as Baseline. Change from Baseline was calculated as the value at specified visit minus the Baseline value. Part 2 of the study was not conducted as agreed criteria for Interim analysis was achieved.
Time frame: Baseline; Session 2: Post challenge Day 1; Pre-fluid sample on Day 2 and Day 3
Part 1: Change From Baseline in Cell Activation Markers by Flow Cytometry on Monocytes in Blood
Blood samples were collected at indicated time-points for the measurement of activation markers by flow cytometry for monocytes in blood. Activation markers included CD16, CD163, CD206, CD209, CD40, CD80, CD83, CD86 and HLA-DR. Latest pre-challenge (LPS or GM-CSF) assessment with a non-missing value, including those from unscheduled visits was considered as Baseline. Change from Baseline was calculated as the value at specified visit minus the Baseline value.
Time frame: Baseline; Session 2: 40 minutes, 2 hours 40 minutes, 5 hours 40 minutes, 9 hours 40 minutes on Day 1. Pre-fluid sample on Day 2 and Day 3
Part 2: Change From Baseline in Cell Activation Markers by Flow Cytometry on Monocytes in Blood
Blood samples were planned to be collected at indicated time-points for the measurement of activation. Latest pre-challenge (LPS or GM-CSF) assessment with a non-missing value, including those from unscheduled visits was considered as Baseline. Change from Baseline was calculated as the value at specified visit minus the Baseline value. Part 2 of the study was not conducted as agreed criteria for Interim analysis was achieved.
Time frame: Baseline, Session 2: 40 minutes, 2 hour 40 minutes, 5 hour 40 minutes,9hours 40 minutes on Day 1; Pre-fluid sample on Day 2 and Day 3
Part 1: Change From Baseline in Cell Activation Markers by Flow Cytometry on Dendritic Cells in Blood
Blood samples were collected at indicated time-points for the measurement of activation markers by flow cytometry for dendritic cells in blood. Activation markers included CD16, CD163, CD206, CD209, CD40, CD80, CD83, CD86 and HLA-DR. Latest pre-challenge (LPS or GM-CSF) assessment with a non-missing value, including those from unscheduled visits was considered as Baseline. Change from Baseline was calculated as the value at specified visit minus the Baseline value.
Time frame: Baseline, Session 2: 40 minutes, 2 hours 40 minutes, 5 hours 40 minutes, 9 hours 40 minutes on Day 1. Pre-fluid sample on Day 2 and Day 3
Part 2: Change From Baseline in Cell Activation Markers by Flow Cytometry on Dendritic Cells in Blood
Blood samples were planned to be collected at indicated time-points for the measurement of activation. Latest pre-challenge (LPS or GM-CSF) assessment with a non-missing value, including those from unscheduled visits was considered as Baseline. Change from Baseline was calculated as the value at specified visit minus the Baseline value. Part 2 of the study was not conducted as agreed criteria for Interim analysis was achieved.
Time frame: Baseline, Session 2: 40 minutes, 2 hours 40 minutes, 5 hours 40 minutes, 9 hours 40 minutes on Day 1. Pre-fluid sample on Day 2 and Day 3
Part 1: Change From Baseline in Circulating Leukocyte Numbers in Blood: LPS Arm
Blood samples were collected at indicated time-points for analysis of leukocyte. Latest pre-challenge assessment with a non-missing value, including those from unscheduled visits was considered as Baseline. Change from Baseline was calculated as the value at specified visit minus the Baseline value.
Time frame: Baseline; Session 2: 40 minutes, 2 hours 40 minutes, 5 hours 40 minutes on Day 1. Pre-fluid sample on Day 2 and Day 3
Part 2: Change From Baseline in Circulating Leukocyte Numbers in Blood: LPS Arm
Blood samples were planned to be collected at indicated time-points for the measurement of activation. Latest pre-challenge assessment with a non-missing value, including those from unscheduled visits was considered as Baseline. Change from Baseline was calculated as the value at specified visit minus the Baseline value. Part 2 of the study was not conducted as agreed criteria for Interim analysis was achieved.
Time frame: Baseline; Session 2: 40 minutes, 2 hours 40 minutes, 5 hours 40 minutes on Day 1. Pre-fluid sample on Day 2 and Day 3
This study aimed to assess 2 models of systemic inflammatory response: exposure of healthy participants to systemic challenge with either Lipopolysaccharide (LPS) or Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF).
| Milestone | Part 1: LPS 0.5 ng/kg | Part 1: LPS 0.75 ng/kg | Part 1: LPS 1 ng/kg | Part 1: GM-CSF 60 µg/m^2 | Part 2: Participants With LPS | Part 2: Participants With GM-CSF |
|---|---|---|---|---|---|---|
| Started | 2 | 4 | 2 | 4 | 0 | 0 |
| Completed | 2 | 4 | 2 | 4 | 0 | 0 |
| Not completed | 0 | 0 | 0 | 0 | 0 | 0 |
| Milestone | Part 1: LPS 0.5 ng/kg | Part 1: LPS 0.75 ng/kg | Part 1: LPS 1 ng/kg | Part 1: GM-CSF 60 µg/m^2 | Part 2: Participants With LPS | Part 2: Participants With GM-CSF |
|---|---|---|---|---|---|---|
| Started | 0 | 0 | 0 | 0 | 0 | 0 |
| Completed | 0 | 0 | 0 | 0 | 0 | 0 |
| Not completed | 0 | 0 | 0 | 0 | 0 | 0 |
Blood samples were collected at indicated timepoints for the analysis of primary soluble inflammatory mediators like TNF-alpha and IL-6 in blood. Latest pre-challenge LPS assessment with a non-missing value, including those from unscheduled visits was considered as Baseline. Change from Baseline was calculated as the value at specified visit minus the Baseline value. Each session was for three days. NA indicates that data was not available as standard deviation could not be calculated for a single participant. All participants who were randomized to receive the treatment (LPS or GM-CSF challenge) and received one dose of challenge agent were included in Safety Population.
| Picograms per milliliter | Part 1: LPS 0.5 ng/kg | Part 1: LPS 0.75 ng/kg | Part 1: LPS 1 ng/kg |
|---|---|---|---|
| IL-6, Session2,Day1, -5 minutes, n=2, 4, 2 | 2.4086 ± 0.09467 | 0.2798 ± 0.12546 | -0.0126 ± 0.01785 |
| IL-6, Session2,Day1, 10 minutes, n=2, 4, 2 | 3.6460 ± 2.68681 | 0.2450 ± 0.16048 | 0.0123 ± 0.01746 |
| IL-6, Session2,Day1, 25 minutes, n=1, 4, 2 | 3.3141 ± NA | 1.3623 ± 0.88290 | 1.8854 ± 0.15615 |
| IL-6, Session2,Day1, 40 minutes, n=2, 4, 2 | 10.8074 ± 9.22779 | 8.7622 ± 8.41234 | 11.8672 ± 3.39867 |
| IL-6, Session2,Day1, 1 hour 10 minutes, n=2, 4, 2 | 30.6395 ± 26.77767 | 81.0629 ± 104.23961 | 51.8232 ± 22.59507 |
| IL-6, Session2,Day1, 1 hour 40 minutes, n=2, 4, 2 | 41.3221 ± 35.42047 | 193.7107 ± 218.97996 | 65.5675 ± 36.08430 |
| IL-6, Session2,Day1, 2 hour 40 minutes, n=2, 4, 2 | 23.9321 ± 21.46574 | 133.2063 ± 92.47028 | 32.3842 ± 25.56374 |
| IL-6, Session2,Day1, 5 hour 40 minutes, n=2, 4, 2 | 5.6991 ± 0.68051 | 2.5645 ± 1.20737 | 4.5141 ± 2.09962 |
| IL-6, Session2,Day2, Pre-fluid sampling, n=2, 4, 2 | 17.8308 ± 16.52950 | 3.2880 ± 2.52703 | 0.3442 ± 0.03336 |
| IL-6, Session2,Day3, Pre-fluid sampling, n=2, 4, 2 | -0.4610 ± 0.08488 | 0.5909 ± 0.96127 | 0.1542 ± 0.21529 |
| TNF alpha, Session2,Day1, -5 minutes, n=2, 4, 2 | -0.2541 ± 0.33782 | -0.0726 ± 0.14769 | 6.4056 ± 8.96887 |
| TNF alpha, Session2,Day1, 10 minutes, n=2, 4, 2 | 6.5720 ± 1.84896 | 2.3784 ± 2.45156 | 12.7647 ± 13.08048 |
| TNF alpha, Session2,Day1, 25 minutes, n=1, 4, 2 | 20.2469 ± NA | 56.6529 ± 51.91815 | 84.6080 ± 33.94449 |
| TNF alpha, Session2,Day1, 40 minutes, n=2, 4, 2 | 52.1665 ± 37.61641 | 157.5403 ± 165.48643 | 152.9415 ± 60.31144 |
| TNF alpha, Session2,Day1, 1hour 10minutes, n=2,4,2 | 43.4949 ± 30.81434 | 202.6136 ± 215.34410 | 115.6693 ± 54.14279 |
| TNF alpha, Session2,Day1, 1hour 40minutes, n=2,4,2 | 34.3031 ± 20.26768 | 147.3472 ± 122.68010 | 78.4734 ± 38.13965 |
| TNF alpha, Session2,Day1, 2hour 40minutes, n=2,4,2 | 22.5571 ± 11.11988 | 68.8879 ± 24.42514 | 44.3372 ± 22.32753 |
| TNF alpha, Session2,Day1, 5hour 40minutes, n=2,4,2 | 5.0087 ± 2.65663 | 15.4828 ± 7.05404 | 11.1378 ± 4.74317 |
| TNF alpha, Session2,Day2,Pre-fluid sample, n=2,4,2 | 12.9279 ± 16.96994 | 1.2532 ± 0.83802 | 0.6475 ± 0.28268 |
| TNF alpha, Session2,Day3,Pre-fluid sample, n=2,4,2 | 0.2453 ± 0.29126 | 0.2951 ± 0.39912 | 0.1391 ± 0.15747 |
The post-challenge urine samples were collected during session 2 after LPS challenge. In session 2, participants were encouraged to pass urine immediately before LPS challenge dose and urine voids were collected from after LPS until 12 hours post-LPS and the time of the urine collection were recorded as post-challenge 1 to 11. These samples were collected for measurement of tetranor-PGDM. Latest pre-challenge LPS assessment with a non-missing value, including those from unscheduled visits was considered as Baseline. Change from Baseline was calculated as the value at specified visit minus the Baseline value. The data for normalized Tetranor PGDM was normalized by (Tetranor PGDM \[pg/mL\] divided by Creatinine \[milligram per deciliter\]) multiplied by 100. NA indicates that data was not available as standard deviation could not be calculated for a single participant.
| Picograms per milligram | Part 1: LPS 0.5 ng/kg | Part 1: LPS 0.75 ng/kg | Part 1: LPS 1 ng/kg |
|---|---|---|---|
| Session2, Day1,Post challenge1, n=2, 4, 2 | 73.846 ± 116.0073 | -85.080 ± 226.4168 | 134.806 ± 166.6716 |
| Session2, Day1,Post challenge 2, n=2, 4, 2 | 99.438 ± 112.5337 | 88.984 ± 155.1855 | 276.788 ± 134.7190 |
| Session2, Day1,Post challenge 3, n=2, 4, 2 | 32.006 ± 88.2367 | 25.390 ± 181.8009 | 200.337 ± 183.9484 |
| Session2, Day1,Post challenge 4, n=2, 4, 2 | -119.091 ± 304.0503 | -68.209 ± 262.6169 | 140.482 ± 108.7880 |
| Session2, Day1,Post challenge 5, n=1, 4, 2 | 112.355 ± NA | -146.294 ± 165.8587 | 184.263 ± 262.9020 |
| Session2, Day1,Post challenge 6, n=0, 4, 1 | — | -202.918 ± 197.6455 | -125.839 ± NA |
| Session2, Day1,Post challenge 7, n=0, 4, 1 | — | -227.544 ± 226.2006 | 6.336 ± NA |
| Session2, Day1,Post challenge 8, n=0, 3, 1 | — | -144.855 ± 53.7768 | -117.672 ± NA |
| Session2, Day1,Post challenge 9, n=0, 2, 1 | — | -147.066 ± 39.8858 | -30.861 ± NA |
| Session2, Day1,Post challenge 10, n=0, 1, 1 | — | -172.982 ± NA | -37.732 ± NA |
| Session2, Day1,Post challenge 11, n=0, 1, 1 | — | -199.316 ± NA | -78.792 ± NA |
Blood samples were planned to be collected at indicated timepoints for the analysis of primary soluble inflammatory mediators like TNF-alpha and IL-6 in blood. Latest pre-challenge LPS assessment with a non-missing value, including those from unscheduled visits was considered as Baseline. Change from Baseline was calculated as the value at specified visit minus the Baseline value. Part 2 of the study was not conducted as agreed criteria for Interim analysis was achieved.
No measurements were reported for this outcome.
Urine samples were planned to be collected for analysis. Latest pre-challenge LPS assessment with a non-missing value, including those from unscheduled visits was considered as Baseline. Change from Baseline was calculated as the value at specified visit minus the Baseline value. Part 2 of the study was not conducted as agreed criteria for Interim analysis was achieved.
No measurements were reported for this outcome.
Blood samples were collected at indicated time-points for analysis of white blood cells. Latest pre-challenge GM-CSF assessment with a non-missing value, including those from unscheduled visits was considered as Baseline. Change from Baseline was calculated as the value at specified visit minus the Baseline value.
| Giga cells per liter | Part 1: GM-CSF 60 µg/m^2 |
|---|---|
| Session2, Day 1, 40 minutes | 0.3754 ± 2.78811 |
| Session2, Day 1, 2 hours 40 minutes | 6.7609 ± 2.94642 |
| Session2, Day 1, 5 hours 40 minutes | 5.8083 ± 1.11242 |
| Session2, Day 1, 9 hours 40 minutes | 3.4558 ± 0.82059 |
| Session2, Day 2, Pre-fluid sample | 0.4224 ± 1.01622 |
| Session2, Day 3, Pre-fluid sample | -0.0136 ± 2.05134 |
Blister samples were collected at indicated time-points for the analysis of soluble inflammatory mediators like IL-1 beta (b), Interferon-gamma (INFg), IL-6, IL-2, IL-8, Monocyte chemotactic protein-1 (MCP-1) and TNF-alpha. Latest pre-challenge (LPS or GM-CSF) assessment with a non-missing value, including those from unscheduled visits was considered as Baseline. Change from Baseline was calculated as the value at specified visit minus the Baseline value. NA indicates that data was not available as standard deviation could not be calculated for a single participant.
| Picograms per milliliter | Part 1: LPS 0.5 ng/kg | Part 1: LPS 0.75 ng/kg | Part 1: LPS 1 ng/kg | Part 1: GM-CSF 60 µg/m^2 |
|---|---|---|---|---|
| IL-1b, Session1, Day 3, 48 hours, n=2, 2, 2,3 | -30.9691 ± 3.58338 | -41.5298 ± 149.67553 | 3.6243 ± 35.28147 | 35.4452 ± 48.42938 |
| IL-1b, Session2,Day2, 24 hours, n=2, 2, 2,1 | -48.4241 ± 69.70779 | -83.1670 ± 108.13325 | 7.9733 ± 19.49142 | -0.3579 ± NA |
| IL-1b, Session2,Day3, 48 hours, n=2, 2, 2,1 | -51.0992 ± 46.78156 | -81.6788 ± 130.42664 | 7.6783 ± 0.42508 | -6.8302 ± NA |
| IFNg, Session1,Day3, 48 hours, n=2, 0, 2, 0 | 32.5244 ± 28.81866 | — | 55.9575 ± 65.86745 | — |
| IFNg, Session2,Day2, 24 hours, n=2, 0, 2, 0 | -3.8191 ± 6.06240 | — | -4.5772 ± 7.20432 | — |
| IFNg, Session2,Day3, 48 hours, n=2, 0, 2, 0 | 0.6652 ± 2.58511 | — | 2.9556 ± 13.15578 | — |
| IL-2, Session1,Day3, 48 hours, n=2, 2, 2, 3 | 1.3470 ± 1.58747 | -0.5699 ± 0.80595 | 0.1623 ± 0.22960 | 1.2444 ± 1.98677 |
| IL-2, Session2,Day2, 24 hours, n=2, 2, 2, 1 | 0.2525 ± 0.66014 | 0.1804 ± 0.58673 | 0.0000 ± 0.0000 | 0.0000 ± NA |
| IL-2, Session2,Day3, 48 hours, n=2, 2, 2, 1 | 0.2451 ± 0.64975 | 2.1377 ± 2.64598 | 0.6968 ± 0.98543 | 2.1293 ± NA |
| IL-6, Session1,Day3,48 hours, n=2, 0, 2, 0 | -1588.01 ± 1379.357 | — | 1535.45 ± 3195.182 | — |
| IL-6, Session2,Day2, 24 hours, n=1, 0, 1, 0 | -0.13 ± NA | — | -349.63 ± NA | — |
| IL-6, Session2,Day3, 48 hours, n=1, 0, 2, 0 | 41.39 ± NA | — | -25.74 ± 864.740 | — |
| IL-8, Session1,Day3,48 hours, n=2, 0, 2, 0 | -127550.93 ± 141294.871 | — | -42387.41 ± 31786.992 | — |
| IL-8, Session2,Day2, 24 hours, n=2, 0, 2, 0 | -31850.03 ± 186366.091 | — | 34295.91 ± 34575.984 | — |
| IL-8, Session2,Day3, 48 hours, n=2, 0, 2, 0 | -126387.78 ± 140485.270 | — | -42836.70 ± 30559.892 | — |
| MCP-1, Session1,Day3, 48 hours, n=2,4,2,4 | -36463.42 ± 4187.967 | -10520.93 ± 5858.889 | -18336.31 ± 9925.681 | -10284.38 ± 10327.369 |
| MCP-1, Session2,Day2, 24 hours, n=2,4,2,4 | -2842.63 ± 19696.319 | 4723.83 ± 11253.334 | 18049.87 ± 1010.158 | 4299.94 ± 11160.896 |
| MCP-1, Session2,Day3, 48 hours, n=2,4,2,4 | -18920.55 ± 2850.508 | 1077.95 ± 10014.723 | -16980.85 ± 11928.656 | -11416.80 ± 9587.163 |
| TNF alpha,Session1,Day3,48 hours, n=2,2,2,3 | -69.1140 ± 31.11083 | -98.8930 ± 55.29269 | -16.0826 ± 17.76133 | -33.5839 ± 62.80430 |
| TNF alpha,Session2,Day2, 24 hours, n=2,2,2,1 | -25.3949 ± 68.42872 | 53.6996 ± 266.29344 | 34.8290 ± 63.07748 | -29.6573 ± NA |
| TNF alpha,Session2,Day3,48 hours, n=2,2,2,1 | -83.6471 ± 72.97148 | -110.6500 ± 52.29742 | -10.5091 ± 18.47463 | -51.9244 ± NA |
Blister samples were planned to be collected at indicated time-points for the analysis of soluble inflammatory mediators like IL-1 beta, INFg, IL-6, IL-2, IL-8, MCP-1 and TNF-alpha. Latest pre-challenge (LPS or GM-CSF) assessment with a non-missing value, including those from unscheduled visits was considered as Baseline. Change from Baseline was calculated as the value at specified visit minus the Baseline value. Part 2 of the study was not conducted as agreed criteria for Interim analysis was achieved.
No measurements were reported for this outcome.
Blister samples were collected at indicated time-points for analysis of blister volumes. . Latest pre-challenge (LPS or GM-CSF) assessment with a non-missing value, including those from unscheduled visits was considered as Baseline.
| Microliter | Part 1: LPS 0.5 ng/kg | Part 1: LPS 0.75 ng/kg | Part 1: LPS 1 ng/kg | Part 1: GM-CSF 60 µg/m^2 |
|---|---|---|---|---|
| Baseline | 361.325 ± 145.9115 | 156.638 ± 112.1876 | 185.550 ± 22.4860 | 230.425 ± 146.2442 |
| Session 1, Day 3, 48 hours | 372.125 ± 105.8892 | 188.625 ± 128.1457 | 232.175 ± 15.0967 | 216.775 ± 141.8914 |
| Session 2, Day 2, 24 hours | 156.225 ± 49.4621 | 102.838 ± 64.6195 | 162.975 ± 26.9054 | 105.363 ± 60.7083 |
| Session 2, Day 3, 48 hours | 274.625 ± 110.4147 | 164.100 ± 104.8817 | 190.650 ± 10.6066 | 108.313 ± 79.5137 |
Blister samples were planned to be collected at indicated time-points for analysis of blister volumes. Latest pre-challenge (LPS or GM-CSF) assessment with a non-missing value, including those from unscheduled visits was considered as Baseline. Part 2 of the study was not conducted as agreed criteria for Interim analysis was achieved.
No measurements were reported for this outcome.
Blister samples were collected at indicated time-points for analysis of white blood cell in blister. Latest pre-challenge LPS assessment with a non-missing value, including those from unscheduled visits was considered as Baseline. Change from Baseline was calculated as the value at specified visit minus the Baseline value.
| Cells per milliliter | Part 1: LPS 0.5 ng/kg | Part 1: LPS 0.75 ng/kg | Part 1: LPS 1 ng/kg |
|---|---|---|---|
| Session 1, Day 3, 48 hours | 841250.0 ± 171473.39 | -1405000.0 ± 6808193.03 | 667500.0 ± 1375322.69 |
| Session 2, Day 2, 24 hours | -298750.0 ± 2137230.25 | -936062.5 ± 3258497.75 | 5447500.0 ± 7124100.82 |
| Session 2, Day 3, 48 hours | 586250.0 ± 786656.29 | -1316000.0 ± 6556133.25 | 3275000.0 ± 1216223.66 |
Blood samples were planned to be collected at indicated time-points for analysis of white blood cell in blister. Latest pre-challenge (LPS or GM-CSF) assessment with a non-missing value, including those from unscheduled visits was considered as Baseline. Change from Baseline was calculated as the value at specified visit minus the Baseline value. Part 2 of the study was not conducted as agreed criteria for Interim analysis was achieved.
No measurements were reported for this outcome.
Blister samples were collected at indicated time-points for the measurement of activation markers by flow cytometry for monocytes in blister. Activation markers included Cluster of Differentiation (CD) 16, CD163, CD206, CD209, CD40, CD80, CD83, CD86 and Human Leukocyte Antigen - antigen D Related (HLA-DR). Latest pre-challenge (LPS or GM-CSF) assessment with a non-missing value, including those from unscheduled visits was considered as Baseline. Change from Baseline was calculated as the value at specified visit minus the Baseline value. NA indicates that data was not available as standard deviation could not be calculated for a single participant.
| Mean fluorescence intensity | Part 1: LPS 0.5 ng/kg | Part 1: LPS 0.75 ng/kg | Part 1: LPS 1 ng/kg | Part 1: GM-CSF 60 µg/m^2 |
|---|---|---|---|---|
| CD16+, Session1,Day3, 48 hours, n=2, 4, 2, 4 | 255.500 ± 343.6539 | 304.409 ± 387.9039 | 314.000 ± 129.4005 | 94.943 ± 140.1057 |
| CD16+, Session2,Day2, 24 hours, n=2, 4, 2, 4 | 512.000 ± 515.4808 | 507.721 ± 375.7470 | 711.250 ± 942.9269 | 174.016 ± 226.3189 |
| CD16+, Session2,Day3, 48 hours, n=2, 4, 2, 4 | 220.750 ± 228.0419 | -26.379 ± 183.4741 | 438.250 ± 329.1582 | 279.814 ± 332.5659 |
| CD163+, Session1,Day3, 48 hours, n=2, 4, 2, 4 | 1022.000 ± 291.3280 | 710.660 ± 645.7405 | 663.750 ± 149.5531 | 367.626 ± 245.5936 |
| CD163+, Session2,Day2, 24 hours, n=2, 4, 2, 4 | 51.750 ± 217.4353 | 247.858 ± 249.5824 | 460.500 ± 120.2082 | 122.859 ± 88.9027 |
| CD163+, Session2,Day3, 48 hours, n=2, 4, 2, 4 | 1173.750 ± 213.1927 | 585.093 ± 238.4787 | 978.750 ± 426.7389 | 713.995 ± 519.2420 |
| CD206+, Session1,Day3, 48 hours, n=2, 2, 2, 4 | 849.00 ± 3251.277 | -562.71 ± 207.541 | 3188.75 ± 5879.946 | 1295.95 ± 1671.924 |
| CD206+, Session2,Day2, 24 hours, n=2, 0, 2, 4 | 119.50 ± 2805.093 | — | -1224.50 ± 1317.340 | 9194.06 ± 4046.382 |
| CD206+, Session2,Day3, 48 hours, n=2, 0, 2, 4 | -1596.50 ± 823.779 | — | -1812.25 ± 1074.449 | 613.37 ± 1127.116 |
| CD209+, Session1,Day3,48 hours, n=2, 4, 2, 4 | 827.000 ± 478.7113 | 1256.721 ± 676.3278 | 377.500 ± 457.4981 | 753.682 ± 482.3904 |
| CD209+, Session2,Day2, 24 hours, n=2, 4, 2, 4 | 166.750 ± 78.8424 | 63.622 ± 309.3805 | 982.250 ± 601.3943 | 1386.776 ± 1523.3802 |
| CD209+, Session2,Day3, 48 hours, n=2, 4, 2, 4 | 577.750 ± 334.8151 | 767.291 ± 469.9624 | 1330.250 ± 491.7928 | 2161.950 ± 1465.6418 |
| CD40, Session1,Day3, 48 hours, n=2, 4, 2, 4 | 124.750 ± 47.7297 | 131.238 ± 104.7629 | 7.500 ± 108.8944 | 76.408 ± 149.4601 |
| CD40, Session2,Day2, 24 hours, n=2, 4, 2, 4 | 200.750 ± 211.7785 | -60.255 ± 174.9309 | 116.500 ± 64.3467 | 436.294 ± 350.2183 |
| CD40, Session2,Day3, 48 hours, n=1, 4, 2, 3 | -167.500 ± NA | -6.274 ± 238.7732 | -8.250 ± 42.0729 | 236.171 ± 304.2282 |
| CD80, Session1,Day3, 48 hours, n=2, 4, 2, 4 | 490.500 ± 236.1737 | 342.798 ± 181.3639 | 404.500 ± 137.8858 | 316.762 ± 145.7658 |
| CD80, Session2,Day2, 24 hours, n=2, 4, 2, 4 | 155.250 ± 284.6105 | 50.962 ± 31.2323 | 44.250 ± 158.0384 | 44.488 ± 94.3934 |
| CD80, Session2,Day3, 48 hours, n=2, 4, 2, 4 | 286.250 ± 14.4957 | 324.662 ± 223.8334 | 254.000 ± 77.7817 | 401.521 ± 43.5362 |
| CD83, Session1,Day3, 48 hours, n=2, 4, 2, 4 | -832.500 ± 89.8026 | -816.619 ± 242.1554 | -373.250 ± 578.7669 | -824.574 ± 521.9010 |
| CD83, Session2,Day2, 24 hours, n=2, 4, 2, 4 | 83.250 ± 361.6851 | 44.949 ± 222.8885 | 791.500 ± 1207.0313 | 280.947 ± 870.1350 |
| CD83, Session2,Day3, 48 hours, n=2, 4, 2, 4 | -978.250 ± 339.0577 | -773.455 ± 383.3063 | -328.250 ± 171.4734 | -529.900 ± 854.9675 |
| CD86+, Session1,Day3, 48 hours, n=2, 4, 2, 4 | -439.750 ± 195.5150 | -51.662 ± 369.1392 | -319.750 ± 71.7713 | -497.468 ± 327.7072 |
| CD86+, Session2,Day2, 24 hours, n=2, 4, 2, 4 | -275.500 ± 30.4056 | -241.591 ± 286.2295 | 103.750 ± 15.9099 | 6.398 ± 418.6691 |
| CD86+, Session2,Day3, 48 hours, n=2, 4, 2, 4 | -723.250 ± 104.2983 | 312.288 ± 458.1399 | -292.250 ± 16.6170 | -97.004 ± 1081.7203 |
| HLA-DR, Session1,Day3, 48 hours, n=2, 4, 2, 4 | -5189.00 ± 2028.689 | -3291.05 ± 4596.102 | -7267.75 ± 11655.595 | -2543.35 ± 3800.276 |
| HLA-DR, Session2,Day2, 24 hours, n=2, 4, 2, 4 | 388.50 ± 3168.545 | -9344.96 ± 2661.368 | -2229.25 ± 4812.922 | 10097.91 ± 12898.982 |
| HLA-DR, Session2,Day3, 48 hours, n=2, 4, 2, 4 | -7846.25 ± 6101.978 | -10329.79 ± 4408.080 | -9340.00 ± 10061.422 | 8884.70 ± 15377.757 |
Blister samples were planned to be collected at indicated time-points for the measurement of activation. Latest pre-challenge (LPS or GM-CSF) assessment with a non-missing value, including those from unscheduled visits was considered as Baseline. Change from Baseline was calculated as the value at specified visit minus the Baseline value. Part 2 of the study was not conducted as agreed criteria for Interim analysis was achieved.
No measurements were reported for this outcome.
Blister samples were collected at indicated time-points for the measurement of activation markers by flow cytometry for monocytes in blister like CD40+/CD80+. Latest pre-challenge (LPS or GM-CSF) assessment with a non-missing value, including those from unscheduled visits was considered as Baseline. Change from Baseline was calculated as the value at specified visit minus the Baseline value. NA indicates that data was not available as standard deviation could not be calculated for a single participant.
| Ratio | Part 1: LPS 0.5 ng/kg | Part 1: LPS 0.75 ng/kg | Part 1: LPS 1 ng/kg | Part 1: GM-CSF 60 µg/m^2 |
|---|---|---|---|---|
| Session1,Day3, 48 hours, n=2, 4, 2, 4 | 0.1475 ± 0.22981 | 0.2764 ± 0.19587 | 0.0610 ± 0.13294 | -0.4060 ± 0.82999 |
| Session2,Day2, 24 hours, n=2, 4, 2, 4 | 0.0925 ± 0.15203 | 0.5062 ± 0.70807 | 0.5108 ± 0.67069 | -0.0994 ± 1.34749 |
| Session2,Day3, 48 hours, n=1, 4, 2, 3 | -0.1210 ± NA | 0.3015 ± 0.39252 | 0.1300 ± 0.03748 | -0.2698 ± 1.09270 |
Blister samples were planned to be collected at indicated time-points for the measurement of activation. Latest pre-challenge (LPS or GM-CSF) assessment with a non-missing value, including those from unscheduled visits was considered as Baseline. Change from Baseline was calculated as the value at specified visit minus the Baseline value. Part 2 of the study was not conducted as agreed criteria for Interim analysis was achieved.
No measurements were reported for this outcome.
Blister samples were collected at indicated time-points for the measurement of activation markers by flow cytometry for dendritic cells in blister. Activation markers included CD16, CD163, CD206, CD209, CD40, CD80, CD83, CD86 and HLA-DR. Latest pre-challenge (LPS or GM-CSF) assessment with a non-missing value, including those from unscheduled visits was considered as Baseline. Change from Baseline was calculated as the value at specified visit minus the Baseline value. NA indicates that data was not available as standard deviation could not be calculated for a single participant.
| Mean fluorescence intensity | Part 1: LPS 0.5 ng/kg | Part 1: LPS 0.75 ng/kg | Part 1: LPS 1 ng/kg | Part 1: GM-CSF 60 µg/m^2 |
|---|---|---|---|---|
| CD16+, Session1,Day3, 48 hours, n=2, 4, 2, 4 | -31.250 ± 48.4368 | 668.512 ± 634.0204 | 44.500 ± 90.5097 | 83.647 ± 119.1684 |
| CD16+, Session2,Day2, 24 hours, n=2, 4, 2, 4 | 284.750 ± 2.4749 | 235.293 ± 200.9269 | 62.750 ± 48.4368 | 225.589 ± 233.9677 |
| CD16+, Session2,Day3, 48 hours, n=2, 4, 2, 4 | 154.000 ± 44.5477 | 208.225 ± 339.7035 | 186.250 ± 254.9120 | 268.838 ± 315.3551 |
| CD163+, Session1,Day3, 48 hours, n=2, 4, 2, 4 | -103.7500 ± 129.04699 | -91.1420 ± 123.34114 | -105.7500 ± 107.83378 | -16.6220 ± 31.79210 |
| CD163+, Session2,Day2, 24 hours, n=2, 4, 2, 4 | -112.7500 ± 143.89623 | -49.4854 ± 72.90224 | 267.2500 ± 66.11448 | 47.1343 ± 60.71649 |
| CD163+, Session2,Day3, 48 hours, n=2, 4, 2, 4 | -132.2500 ± 119.85460 | -124.5144 ± 79.57686 | -70.0000 ± 101.11627 | -32.4464 ± 30.09999 |
| CD206+, Session1,Day3, 48 hours, n=2, 2, 2, 4 | -56.00 ± 601.041 | -1057.04 ± 1641.526 | 1372.75 ± 2325.321 | 2032.27 ± 1708.909 |
| CD206+, Session2,Day2, 24 hours, n=2, 0, 2, 4 | -430.25 ± 1407.496 | — | -665.00 ± 481.540 | 3032.02 ± 3183.213 |
| CD206+, Session2,Day3, 48 hours, n=2, 0, 2, 4 | 4.00 ± 171.120 | — | 198.75 ± 150.260 | 856.32 ± 1654.671 |
| CD209+, Session1,Day3,48 hours, n=2, 4, 2, 4 | 83.250 ± 15.2028 | 765.140 ± 690.4086 | -211.000 ± 17.6777 | 95.101 ± 191.7562 |
| CD209+, Session2,Day2, 24 hours, n=2, 4, 2, 4 | 79.750 ± 37.1231 | 38.604 ± 582.9139 | 743.750 ± 482.6004 | 1834.867 ± 1573.3002 |
| CD209+, Session2,Day3, 48 hours, n=2, 4, 2, 4 | 101.750 ± 341.1790 | 297.936 ± 605.5896 | 835.000 ± 444.7702 | 1822.510 ± 1522.9886 |
| CD40, Session1,Day3, 48 hours, n=2, 4, 2, 4 | 963.750 ± 110.6622 | 1403.000 ± 754.2476 | 776.000 ± 30.4056 | 923.024 ± 560.8252 |
| CD40, Session2,Day2, 24 hours, n=2, 4, 2, 4 | 96.000 ± 266.5793 | 17.354 ± 257.3845 | -10.250 ± 61.1647 | 293.485 ± 249.0144 |
| CD40, Session2,Day3, 48 hours, n=1, 4, 2, 3 | 383.500 ± NA | 1072.416 ± 523.9965 | 783.750 ± 127.6328 | 1389.536 ± 710.1286 |
| CD80, Session1,Day3, 48 hours, n=2, 4, 2, 4 | 2609.000 ± 376.8879 | 4155.674 ± 893.4273 | 2366.000 ± 72.8320 | 4998.865 ± 1326.4663 |
| CD80, Session2,Day2, 24 hours, n=2, 4, 2, 4 | -130.000 ± 523.2590 | -583.016 ± 1305.3774 | -237.250 ± 252.0836 | 407.277 ± 615.0693 |
| CD80, Session2,Day3, 48 hours, n=2, 4, 2, 4 | 1235.000 ± 603.8692 | 3665.666 ± 1565.6126 | 1407.250 ± 331.9866 | 3958.838 ± 803.7564 |
| CD83, Session1,Day3, 48 hours, n=2, 4, 2, 4 | 2342.250 ± 423.2034 | 2806.835 ± 741.9070 | 2624.000 ± 770.7464 | 3834.100 ± 1511.6374 |
| CD83, Session2,Day2, 24 hours, n=2, 4, 2, 4 | -28.000 ± 656.9022 | -409.187 ± 1498.2826 | -343.250 ± 597.1517 | 648.346 ± 685.4282 |
| CD83, Session2,Day3, 48 hours, n=2, 4, 2, 4 | 1199.500 ± 900.8540 | 3368.105 ± 953.2468 | 2924.250 ± 510.1775 | 3264.300 ± 988.2407 |
| CD86+, Session1,Day3, 48 hours, n=2, 4, 2, 4 | 2590.75 ± 1485.278 | 4689.54 ± 1189.323 | 2701.50 ± 65.761 | 3936.29 ± 2537.066 |
| CD86+, Session2,Day2, 24 hours, n=2, 4, 2, 4 | -509.75 ± 345.422 | -696.70 ± 1551.690 | -184.00 ± 373.352 | 94.29 ± 782.682 |
| CD86+, Session2,Day3, 48 hours, n=2, 4, 2, 4 | 1175.25 ± 980.404 | 7229.67 ± 2733.004 | 2750.50 ± 421.436 | 4132.68 ± 2423.146 |
| HLA-DR, Session1,Day3, 48 hours, n=2, 4, 2, 4 | 1020.00 ± 2766.909 | 31657.05 ± 11524.385 | -2661.75 ± 19339.017 | 3242.86 ± 11323.629 |
| HLA-DR, Session2,Day2, 24 hours, n=2, 4, 2, 4 | -494.00 ± 1211.981 | -3470.23 ± 16869.569 | 480.50 ± 11477.050 | 11902.82 ± 17969.677 |
| HLA-DR, Session2,Day3, 48 hours, n=2, 4, 2, 4 | -4386.50 ± 911.461 | 16282.97 ± 22938.047 | 1564.00 ± 12854.494 | 19351.27 ± 16136.948 |
Blister samples were planned to be collected at indicated time-points for the measurement of activation. Latest pre-challenge (LPS or GM-CSF) assessment with a non-missing value, including those from unscheduled visits was considered as Baseline. Change from Baseline was calculated as the value at specified visit minus the Baseline value. Part 2 of the study was not conducted as agreed criteria for Interim analysis was achieved.
No measurements were reported for this outcome.
Blister samples were collected at indicated time-points for the measurement of activation markers by flow cytometry for dendritic cells in blister like CD40+/CD80+. Latest pre-challenge (LPS or GM-CSF) assessment with a non-missing value, including those from unscheduled visits was considered as Baseline. Change from Baseline was calculated as the value at specified visit minus the Baseline value. NA indicates that data was not available as standard deviation could not be calculated for a single participant.
| Ratio | Part 1: LPS 0.5 ng/kg | Part 1: LPS 0.75 ng/kg | Part 1: LPS 1 ng/kg | Part 1: GM-CSF 60 µg/m^2 |
|---|---|---|---|---|
| Session1,Day3, 48 hours, n=2, 4, 2, 4 | 42.7675 ± 5.32805 | 43.2094 ± 6.81783 | 47.8100 ± 4.17193 | 39.8453 ± 6.60325 |
| Session2,Day2, 24 hours, n=2, 4, 2, 4 | 2.7250 ± 14.65125 | 0.0825 ± 18.06488 | 0.0900 ± 1.52735 | 6.7523 ± 9.76233 |
| Session2,Day3, 48 hours, n=1, 4, 2, 3 | 27.7000 ± NA | 42.6493 ± 11.60035 | 42.5100 ± 2.82843 | 38.4313 ± 6.81975 |
Blister samples were planned to be collected at indicated time-points for the measurement of activation. Latest pre-challenge (LPS or GM-CSF) assessment with a non-missing value, including those from unscheduled visits was considered as Baseline. Change from Baseline was calculated as the value at specified visit minus the Baseline value. Part 2 of the study was not conducted as agreed criteria for Interim analysis was achieved.
No measurements were reported for this outcome.
Blister samples were collected at indicated time-points for the measurement of activation markers by flow cytometry for macrophages in blister. Activation markers included CD16, CD163, CD206, CD209, CD40, CD80, CD83, CD86 and HLA-DR. Latest pre-challenge (LPS or GM-CSF) assessment with a non-missing value, including those from unscheduled visits was considered as Baseline. Change from Baseline was calculated as the value at specified visit minus the Baseline value. NA indicates that data was not available as standard deviation could not be calculated for a single participant.
| Mean fluorescence intensity | Part 1: LPS 0.5 ng/kg | Part 1: LPS 0.75 ng/kg | Part 1: LPS 1 ng/kg | Part 1: GM-CSF 60 µg/m^2 |
|---|---|---|---|---|
| CD16+, Session1,Day3, 48 hours, n=2, 4, 2, 4 | -5027.00 ± 5289.866 | 4510.75 ± 7162.125 | -3449.75 ± 1895.400 | -2607.25 ± 6559.210 |
| CD16+, Session2,Day2, 24 hours, n=2, 4, 2, 4 | 13111.25 ± 32672.929 | -2948.25 ± 3659.787 | 5372.75 ± 235.113 | -1010.00 ± 5492.201 |
| CD16+, Session2,Day3, 48 hours, n=2, 4, 2, 4 | -4621.75 ± 8382.397 | -6203.50 ± 13105.657 | -3286.25 ± 947.170 | -3653.63 ± 5345.655 |
| CD163+, Session1,Day3, 48 hours, n=2, 4, 2, 4 | 888.500 ± 292.0351 | 400.500 ± 455.9359 | 270.250 ± 97.9343 | 723.125 ± 717.7969 |
| CD163+, Session2,Day2, 24 hours, n=2, 4, 2, 4 | 49.750 ± 215.3140 | 48.250 ± 163.7506 | 415.250 ± 142.4820 | 169.750 ± 160.7060 |
| CD163+, Session2,Day3, 48 hours, n=2, 4, 2, 4 | 1012.000 ± 501.3387 | 411.000 ± 524.8443 | 719.250 ± 63.9932 | 789.513 ± 825.7539 |
| CD206+, Session1,Day3, 48 hours, n=2, 4, 2, 4 | 81.00 ± 2206.173 | -1275.50 ± 3073.903 | -955.75 ± 1183.343 | -734.88 ± 5799.935 |
| CD206+, Session2,Day2, 24 hours, n=2, 4, 2, 4 | 4503.00 ± 9540.992 | 564.00 ± 2911.625 | -1329.50 ± 1668.065 | 12596.63 ± 16264.004 |
| CD206+, Session2,Day3, 48 hours, n=2, 4, 2, 4 | -1229.25 ± 973.332 | -2542.63 ± 4084.922 | -2193.50 ± 543.765 | -2622.75 ± 3423.992 |
| CD209+, Session1,Day3,48 hours, n=2, 4, 2, 4 | 931.00 ± 505.581 | 458.88 ± 1827.032 | -333.00 ± 416.486 | 890.88 ± 2206.644 |
| CD209+, Session2,Day2, 24 hours, n=2, 4, 2, 4 | 474.75 ± 485.429 | 21.63 ± 1282.820 | 1672.25 ± 1038.386 | 5641.13 ± 4969.374 |
| CD209+, Session2,Day3, 48 hours, n=2, 4, 2, 4 | 565.75 ± 840.396 | -236.13 ± 1413.395 | 1607.75 ± 1283.752 | 2835.13 ± 2917.207 |
| CD40, Session1,Day3, 48 hours, n=2, 4, 2, 4 | 593.25 ± 20.860 | 198.00 ± 1021.994 | 371.75 ± 1282.338 | -59.50 ± 536.615 |
| CD40, Session2,Day2, 24 hours, n=2, 4, 2, 4 | 1007.00 ± 1119.350 | -43.38 ± 837.351 | -691.50 ± 542.351 | 3426.13 ± 4547.393 |
| CD40, Session2,Day3, 48 hours, n=1, 4, 2, 4 | 74.50 ± NA | -166.13 ± 503.207 | -480.25 ± 925.956 | -70.50 ± 1739.426 |
| CD80, Session1,Day3, 48 hours, n=2, 4, 2, 4 | 884.00 ± 9.899 | 1193.63 ± 1486.267 | 1403.75 ± 3760.040 | 304.88 ± 2126.019 |
| CD80, Session2,Day2, 24 hours, n=2, 4, 2, 4 | 1250.50 ± 1339.967 | 353.63 ± 2446.460 | -1136.25 ± 1490.935 | 1215.88 ± 2013.518 |
| CD80, Session2,Day3, 48 hours, n=2, 4, 2, 4 | -84.75 ± 23.688 | -114.50 ± 615.327 | -1686.50 ± 2957.121 | -744.88 ± 3479.863 |
| CD83, Session1,Day3, 48 hours, n=2, 4, 2, 4 | -1139.00 ± 477.297 | -556.88 ± 1063.877 | 2522.00 ± 1359.766 | -842.63 ± 1505.636 |
| CD83, Session2,Day2, 24 hours, n=2, 4, 2, 4 | 420.50 ± 3235.014 | 1243.25 ± 3307.491 | 2690.50 ± 4319.008 | 918.75 ± 1945.597 |
| CD83, Session2,Day3, 48 hours, n=2, 4, 2, 4 | -1703.75 ± 15.203 | -1046.38 ± 561.034 | 745.75 ± 496.743 | -1668.63 ± 2068.363 |
| CD86+, Session1,Day3, 48 hours, n=2, 4, 2, 4 | 792.50 ± 338.704 | 577.50 ± 1141.719 | 2311.50 ± 1262.186 | 28.25 ± 2057.408 |
| CD86+, Session2,Day2, 24 hours, n=2, 4, 2, 4 | 381.25 ± 2896.663 | 674.50 ± 1496.032 | -329.75 ± 197.636 | -570.75 ± 3118.314 |
| CD86+, Session2,Day3, 48 hours, n=2, 4, 2, 4 | 13.75 ± 285.318 | 1692.50 ± 1687.192 | 181.75 ± 506.642 | 517.50 ± 5171.981 |
| HLA-DR, Session1,Day3, 48 hours, n=2, 4, 2, 4 | 3326.25 ± 1854.388 | -7695.38 ± 19317.582 | 6003.75 ± 17276.386 | -5724.25 ± 49407.676 |
| HLA-DR, Session2,Day2, 24 hours, n=2, 4, 2, 4 | 7435.25 ± 35884.608 | 13061.88 ± 29527.416 | 1273.75 ± 3391.638 | 36041.13 ± 33139.756 |
| HLA-DR, Session2,Day3, 48 hours, n=2, 4, 2, 4 | -882.00 ± 1575.434 | -20377.25 ± 25175.815 | -8397.75 ± 19009.505 | 11460.13 ± 56951.939 |
Blister samples were planned to be collected at indicated time-points for the measurement of activation. Latest pre-challenge (LPS or GM-CSF) assessment with a non-missing value, including those from unscheduled visits was considered as Baseline. Change from Baseline was calculated as the value at specified visit minus the Baseline value. Part 2 of the study was not conducted as agreed criteria for Interim analysis was achieved.
No measurements were reported for this outcome.
Blister samples were collected at indicated time-points for the measurement of activation markers by flow cytometry for dendritic cells in blister like CD40+/CD80+. Latest pre-challenge (LPS or GM-CSF) assessment with a non-missing value, including those from unscheduled visits was considered as Baseline. Change from Baseline was calculated as the value at specified visit minus the Baseline value. NA indicates that data was not available as standard deviation could not be calculated for a single participant.
| Ratio | Part 1: LPS 0.5 ng/kg | Part 1: LPS 0.75 ng/kg | Part 1: LPS 1 ng/kg | Part 1: GM-CSF 60 µg/m^2 |
|---|---|---|---|---|
| Session1,Day3, 48 hours, n=2, 4, 2, 4 | 11.0475 ± 9.89596 | -1.2837 ± 17.00275 | 21.8500 ± 26.44579 | -0.8938 ± 20.18664 |
| Session2,Day2, 24 hours, n=2, 4, 2, 4 | 15.1225 ± 35.88213 | 1.3537 ± 22.85581 | -16.0250 ± 3.35876 | 9.1137 ± 15.78332 |
| Session2,Day3, 48 hours, n=1, 4, 2, 4 | 0.3500 ± NA | -2.9838 ± 10.58741 | -8.9750 ± 17.00592 | -3.2238 ± 27.65006 |
Blister samples were planned to be collected at indicated time-points for the measurement of activation. Latest pre-challenge (LPS or GM-CSF) assessment with a non-missing value, including those from unscheduled visits was considered as Baseline. Change from Baseline was calculated as the value at specified visit minus the Baseline value. Part 2 of the study was not conducted as agreed criteria for Interim analysis was achieved.
No measurements were reported for this outcome.
Blood samples were collected at indicated timepoints for the analysis of primary soluble inflammatory mediators like IL-1 beta, INFg, IL-2, IL-8, and MCP-1 in blood. Latest pre-challenge (LPS or GM-CSF) assessment with a non-missing value, including those from unscheduled visits was considered as Baseline. Change from Baseline was calculated as the value at specified visit minus the Baseline value. NA indicates that data was not available as standard deviation could not be calculated for a single participant.
| Picograms per milliliter | Part 1: LPS 0.5 ng/kg | Part 1: LPS 0.75 ng/kg | Part 1: LPS 1 ng/kg | Part 1: GM-CSF 60 µg/m^2 |
|---|---|---|---|---|
| INFg, Session2,Day1, -5 minutes, n=2, 4, 2, 4 | -0.5636 ± 0.24961 | -0.1278 ± 0.23076 | 0.0653 ± 0.80201 | 5.7255 ± 1.85029 |
| INFg, Session2,Day1, 10 minutes, n=2, 4, 2, 4 | -0.4140 ± 0.05250 | -0.3298 ± 0.20362 | -0.2355 ± 0.28729 | 6.0071 ± 1.26842 |
| INFg, Session2,Day1, 25 minutes, n=1, 4, 2, 4 | -0.6996 ± NA | -0.3697 ± 0.19518 | -0.2432 ± 0.30593 | 6.1605 ± 1.77144 |
| INFg, Session2,Day1, 40 minutes, n=2, 4, 2, 4 | -0.6745 ± 0.26829 | -0.4771 ± 0.41990 | 0.1501 ± 0.28816 | 5.4142 ± 2.07138 |
| INFg, Session2,Day1, 1 hour 10 minutes, n=2, 4,2,4 | 1.8597 ± 2.47610 | 1.7673 ± 1.80932 | 6.6083 ± 0.78111 | 4.9508 ± 1.77082 |
| INFg, Session2,Day1, 1 hour 40 minutes, n=2, 4,2,4 | 6.5709 ± 5.72091 | 6.5863 ± 3.69982 | 13.6809 ± 3.56564 | 3.8804 ± 2.00819 |
| INFg, Session2,Day1, 2 hour 40 minutes, n=2, 4,2,4 | 9.1319 ± 7.94104 | 8.7498 ± 2.97730 | 15.7306 ± 3.51048 | 2.7181 ± 2.63053 |
| INFg, Session2,Day1, 5 hour 40 minutes, n=2, 4,2,4 | 3.5927 ± 3.83382 | 3.2672 ± 1.86587 | 5.0294 ± 3.92184 | 1.7041 ± 1.64895 |
| INFg, Session2,Day2, Pre-fluid sampling, n=2,4,2,4 | -3.7611 ± 1.04373 | 0.7630 ± 1.43167 | -0.3514 ± 1.05828 | -3.0755 ± 2.76516 |
| INFg, Session2,Day3, Pre-fluid sampling, n=2,4,2,4 | -4.3628 ± 0.31014 | 1.5962 ± 3.09933 | -2.6600 ± 1.75306 | -3.2817 ± 2.72811 |
| IL-1b, Session2,Day1, -5 minutes, n=2, 4, 2,4 | 0.0000 ± 0.0000 | 0.0000 ± 0.0000 | 0.0000 ± 0.0000 | 0.0000 ± 0.0000 |
| IL-1b, Session2,Day1, 10 minutes, n=2, 4, 2,4 | 0.0000 ± 0.0000 | 0.0008 ± 0.00150 | 0.0000 ± 0.0000 | 0.0000 ± 0.0000 |
| IL-1b, Session2,Day1, 25 minutes, n=1, 4, 2,4 | 0.0000 ± NA | 0.0000 ± 0.00000 | 0.0000 ± 0.00000 | 0.0000 ± 0.00000 |
| IL-1b, Session2,Day1, 40 minutes, n=2, 4, 2,4 | 0.0000 ± 0.00000 | 0.0008 ± 0.00150 | 0.0000 ± 0.00000 | 0.0000 ± 0.00000 |
| IL-1b, Session2,Day1, 1hour 10minutes, n=2,4,2,4 | 0.0000 ± 0.00000 | 0.0008 ± 0.00150 | 0.0000 ± 0.00000 | 0.0000 ± 0.00000 |
| IL-1b, Session2,Day1, 1hour 40minutes, n=2,4,2,4 | 0.0000 ± 0.00000 | 0.1875 ± 0.37303 | 0.0000 ± 0.00000 | 0.0000 ± 0.00000 |
| IL-1b, Session2,Day1, 2hour 40minutes, n=2,4,2,4 | 0.0000 ± 0.00000 | 0.3194 ± 0.41468 | 0.0000 ± 0.00000 | 0.0000 ± 0.00000 |
| IL-1b, Session2,Day1, 5hour 40minutes, n=2,4,2,4 | 0.0000 ± 0.00000 | 0.0008 ± 0.00150 | 0.0000 ± 0.00000 | 0.0000 ± 0.00000 |
| IL-1b, Session2,Day2,Pre-fluid sample, n=2,4,2,4 | 0.2225 ± 0.31897 | 0.0008 ± 0.00150 | -0.0030 ± 0.00000 | 0.0857 ± 0.10517 |
| IL-1b, Session2,Day3,Pre-fluid sample, n=2,4,2,4 | -0.0030 ± 0.00000 | 0.0008 ± 0.00150 | -0.0030 ± 0.00000 | -0.0015 ± 0.00173 |
| IL-2, Session2,Day1, -5 minutes, n=0, 4, 2,4 | — | 0.0000 ± 0.00000 | 0.0000 ± 0.00000 | 0.0000 ± 0.00000 |
| IL-2, Session2,Day1, 10 minutes, n=0, 4, 2,2 | — | 0.0031 ± 0.00625 | 0.0000 ± 0.00000 | 0.0000 ± 0.00000 |
| IL-2, Session2,Day1, 25 minutes, n=0, 4, 2,4 | — | 0.0031 ± 0.00625 | 0.0000 ± 0.00000 | 0.0000 ± 0.00000 |
| IL-2, Session2,Day1, 40 minutes, n=0, 3, 2,2 | — | 0.0000 ± 0.00000 | 0.0000 ± 0.00000 | 0.0000 ± 0.00000 |
| IL-2, Session2,Day1, 1 hour 10 minutes, n=0, 4,2,4 | — | 0.0031 ± 0.00625 | 0.0000 ± 0.00000 | 0.0000 ± 0.00000 |
| IL-2, Session2,Day1, 1 hour 40 minutes, n=0, 4,2,2 | — | 0.0031 ± 0.00625 | 0.0000 ± 0.00000 | 0.0000 ± 0.00000 |
| IL-2, Session2,Day1, 2 hour 40 minutes, n=0, 4,2,2 | — | 0.0031 ± 0.00625 | 0.0000 ± 0.00000 | 0.0000 ± 0.00000 |
| IL-2, Session2,Day1, 5 hour 40 minutes, n=0, 4,2,2 | — | 0.0031 ± 0.00625 | 0.0000 ± 0.00000 | 0.0000 ± 0.00000 |
| IL-2, Session2,Day2, Pre-fluid sampling, n=2,4,2,4 | 0.0000 ± 0.00000 | 0.0031 ± 0.00625 | -0.0160 ± 0.00000 | -0.0018 ± 0.01645 |
| IL-2, Session2,Day3, Pre-fluid sampling, n=2,4,2,4 | 0.0000 ± 0.00000 | 0.0031 ± 0.00625 | -0.0160 ± 0.00000 | -0.0018 ± 0.01645 |
| IL-8, Session2,Day1, -5 minutes, n=2, 4, 2,4 | -1.4835 ± 2.97824 | 0.0761 ± 0.99505 | 0.1849 ± 0.08020 | 83.1531 ± 44.11662 |
| IL-8, Session2,Day1, 10 minutes, n=2, 4, 2,4 | 2.2890 ± 3.42770 | 0.0714 ± 1.30027 | 0.8613 ± 0.83194 | 89.0123 ± 48.41011 |
| IL-8, Session2,Day1, 25 minutes, n=1, 4, 2,4 | 1.7998 ± NA | 0.6814 ± 1.27650 | 3.0142 ± 1.22739 | 86.4178 ± 47.57975 |
| IL-8, Session2,Day1, 40 minutes, n=2, 3, 2,4 | 9.4905 ± 1.93306 | 9.3036 ± 5.86829 | 27.1507 ± 3.96686 | 50.4514 ± 20.49601 |
| IL-8, Session2,Day1, 1 hour 10 minutes, n=2, 3,2,4 | 105.0587 ± 43.02522 | 141.7558 ± 104.21164 | 162.3033 ± 42.93991 | 76.6709 ± 36.79748 |
| IL-8, Session2,Day1, 1 hour 40 minutes, n=2,3, 2,4 | 214.1372 ± 181.31639 | 468.8635 ± 296.06234 | 229.6116 ± 155.88116 | 77.3493 ± 73.83422 |
| IL-8, Session2,Day1, 2 hour 40 minutes, n=2,3, 2,4 | 49.6247 ± 26.76026 | 340.0657 ± 234.74182 | 111.6155 ± 118.63027 | 126.3552 ± 204.81735 |
| IL-8, Session2,Day1, 5 hour 40 minutes, n=2,3, 2,4 | 7.6772 ± 3.55867 | 88.5574 ± 24.09240 | 19.5090 ± 6.86764 | 30.1483 ± 10.71198 |
| IL-8, Session2,Day2, Pre-fluid sampling, n=2,3,2,4 | 3.8330 ± 7.21699 | 8.7544 ± 16.57327 | -1.3116 ± 1.93618 | 33.5296 ± 54.13468 |
| IL-8, Session2,Day3, Pre-fluid sampling, n=2,4,2,4 | -1.3819 ± 2.32148 | 0.6465 ± 2.78896 | -0.8507 ± 0.69264 | -2.0468 ± 1.21979 |
| MCP-1, Session2,Day1, -5 minutes, n=2, 4, 2,4 | -1.984 ± 0.9353 | 7.280 ± 11.0662 | -12.078 ± 6.4316 | 2702.736 ± 1675.5428 |
| MCP-1, Session2,Day1, 10 minutes, n=2, 4, 2,4 | 1.716 ± 33.8987 | 15.335 ± 18.3588 | -6.963 ± 11.3479 | 3692.647 ± 1671.9037 |
| MCP-1, Session2,Day1, 25 minutes, n=1, 4, 2,4 | -25.166 ± NA | 22.679 ± 14.0540 | 9.360 ± 10.2709 | 4354.050 ± 1579.4757 |
| MCP-1, Session2,Day1, 40 minutes, n=2, 4, 2,4 | 53.774 ± 44.7737 | 108.005 ± 54.2180 | 273.261 ± 29.0646 | 4218.511 ± 1850.5204 |
| MCP-1, Session2,Day1, 1 hour 10 minutes, n=2,4,2,4 | 1092.558 ± 576.0879 | 3281.560 ± 2188.7631 | 2993.718 ± 17.3345 | 4119.865 ± 2047.7930 |
| MCP-1, Session2,Day1, 1 hour 40 minutes, n=2,4,2,4 | 2521.255 ± 1886.7927 | 5164.946 ± 25.3073 | 6182.663 ± 13.9688 | 2659.013 ± 1778.3867 |
| MCP-1, Session2,Day1, 2 hour 40 minutes, n=2,4,2,4 | 1449.223 ± 880.4065 | 5189.946 ± 75.0973 | 6824.798 ± 3014.6330 | 1405.284 ± 603.0458 |
| MCP-1, Session2,Day1, 5 hour 40 minutes, n=2,4,2,4 | 126.224 ± 72.8644 | 588.424 ± 384.1274 | 350.071 ± 81.7289 | 365.641 ± 156.6637 |
| MCP-1, Session2,Day2,Pre-fluid sampling, n=2,4,2,4 | -0.963 ± 23.0612 | 38.016 ± 54.7584 | -2.917 ± 42.8500 | -14.427 ± 32.7430 |
| MCP-1, Session2,Day3,Pre-fluid sampling, n=2,4,2,4 | -12.333 ± 0.9485 | 28.822 ± 23.2955 | 8.210 ± 9.0286 | -15.571 ± 25.0756 |
Blood samples were planned to be collected at indicated time-points for the measurement of activation. Latest pre-challenge (LPS or GM-CSF) assessment with a non-missing value, including those from unscheduled visits was considered as Baseline. Change from Baseline was calculated as the value at specified visit minus the Baseline value. Part 2 of the study was not conducted as agreed criteria for Interim analysis was achieved.
No measurements were reported for this outcome.
Blood samples were collected at indicated time-points for the analysis of soluble inflammatory mediators like TNF-alpha, IL-6 and GM-CSF in blood. Latest pre-challenge GM-CSF assessment with a non-missing value, including those from unscheduled visits was considered as Baseline. Change from Baseline was calculated as the value at specified visit minus the Baseline value.
| Picograms per milliliter | Part 1: GM-CSF 60 µg/m^2 |
|---|---|
| GM-CSF, Session2,Day1, -5 minutes | 1674.235 ± 635.9050 |
| GM-CSF, Session2,Day1, 10 minutes | 1260.988 ± 850.1777 |
| GM-CSF, Session2,Day1, 25 minutes | 624.895 ± 287.0075 |
| GM-CSF, Session2,Day1, 40 minutes | 364.045 ± 218.4348 |
| GM-CSF, Session2,Day1,1 hour 10 minutes | 145.793 ± 97.7248 |
| GM-CSF, Session2,Day1,1 hour 40 minutes | 52.158 ± 39.5878 |
| GM-CSF, Session2,Day1,2 hour 40 minutes | 7.486 ± 9.9232 |
| GM-CSF, Session2,Day1,5 hour 40 minutes | 0.000 ± 0.0000 |
| GM-CSF, Session2,Day2,Pre-fluid sampling | 0.000 ± 0.0000 |
| GM-CSF, Session2,Day3,Pre-fluid sampling | 0.000 ± 0.0000 |
| IL-6, Session2,Day1, -5 minutes | 8.8136 ± 3.54771 |
| IL-6, Session2,Day1, 10 minutes | 11.3851 ± 1.98376 |
| IL-6, Session2,Day1, 25 minutes | 13.0699 ± 3.47569 |
| IL-6, Session2,Day1, 40 minutes | 10.9359 ± 5.03738 |
| IL-6, Session2,Day1, 1hour 10minutes | 6.8485 ± 3.17943 |
| IL-6, Session2,Day1, 1hour 40minutes | 5.0334 ± 2.72854 |
| IL-6, Session2,Day1, 2hour 40minutes | 2.6496 ± 1.56258 |
| IL-6, Session2,Day1, 5hour 40minutes | 1.9135 ± 1.60586 |
| IL-6, Session2,Day2,Pre-fluid sample | 1.2598 ± 1.72396 |
| IL-6, Session2,Day3,Pre-fluid sample | -0.0324 ± 0.13824 |
| TNF-alpha, Session2,Day1, -5 minutes | 2.6740 ± 0.39814 |
| TNF-alpha, Session2,Day1, 10 minutes | 2.4860 ± 0.70400 |
| TNF-alpha, Session2,Day1, 25 minutes | 2.5475 ± 0.86898 |
| TNF-alpha, Session2,Day1, 40 minutes | 2.2100 ± 0.99729 |
| TNF-alpha, Session2,Day1, 1 hour 10 minutes | 2.1380 ± 0.90651 |
| TNF-alpha, Session2,Day1, 1 hour 40 minutes | 1.9665 ± 1.19555 |
| TNF-alpha, Session2,Day1, 2 hour 40 minutes | 1.6001 ± 0.80929 |
| TNF-alpha, Session2,Day1, 5 hour 40 minutes | 0.9562 ± 0.63271 |
| TNF-alpha, Session2,Day2, Pre-fluid sampling | 0.5423 ± 0.50847 |
| TNF-alpha, Session2,Day3, Pre-fluid sampling | -0.1194 ± 0.55216 |
Blood samples were planned to be collected at indicated time-points for the measurement of activation. Latest pre-challenge GM-CSF assessment with a non-missing value, including those from unscheduled visits was considered as Baseline. Change from Baseline was calculated as the value at specified visit minus the Baseline value. Part 2 of the study was not conducted as agreed criteria for Interim analysis was achieved.
No measurements were reported for this outcome.
Blood samples were collected at indicated time-points for the analysis of soluble inflammatory mediators like CRP in blood. Latest pre-challenge (LPS or GM-CSF) assessment with a non-missing value, including those from unscheduled visits was considered as Baseline. Change from Baseline was calculated as the value at specified visit minus the Baseline value.
| Milligrams per liter | Part 1: LPS 0.5 ng/kg | Part 1: LPS 0.75 ng/kg | Part 1: LPS 1 ng/kg | Part 1: GM-CSF 60 µg/m^2 |
|---|---|---|---|---|
| Session2,Day1, Post-challenge | 0.20 ± 3.111 | 2.75 ± 0.624 | 2.40 ± 0.990 | 1.53 ± 0.457 |
| Session2,Day 2, Pre-fluid sample | 7.50 ± 4.667 | 21.80 ± 2.380 | 18.55 ± 4.455 | 5.80 ± 1.623 |
| Session2,Day 3, Pre-fluid sample | 1.50 ± 3.111 | 10.65 ± 0.968 | 8.45 ± 0.636 | 2.25 ± 0.451 |
Blood samples were planned to be collected at indicated time-points for the measurement of activation. Latest pre-challenge (LPS or GM-CSF) assessment with a non-missing value, including those from unscheduled visits was considered as Baseline. Change from Baseline was calculated as the value at specified visit minus the Baseline value. Part 2 of the study was not conducted as agreed criteria for Interim analysis was achieved.
No measurements were reported for this outcome.
Blood samples were collected at indicated time-points for the measurement of activation markers by flow cytometry for monocytes in blood. Activation markers included CD16, CD163, CD206, CD209, CD40, CD80, CD83, CD86 and HLA-DR. Latest pre-challenge (LPS or GM-CSF) assessment with a non-missing value, including those from unscheduled visits was considered as Baseline. Change from Baseline was calculated as the value at specified visit minus the Baseline value.
| Mean fluorescence intensity | Part 1: LPS 0.5 ng/kg | Part 1: LPS 0.75 ng/kg | Part 1: LPS 1 ng/kg | Part 1: GM-CSF 60 µg/m^2 |
|---|---|---|---|---|
| CD16+, Session2,Day1, 40 minutes, n=2, 4, 2,4 | -117.5000 ± 55.86144 | -10.5565 ± 50.64061 | -47.0000 ± 39.59798 | -26.3505 ± 10.83082 |
| CD16+, Session2,Day1, 2 hour 40 minutes, n=2,4,2,4 | -128.9500 ± 131.45115 | -31.4965 ± 41.99141 | -76.6000 ± 69.29646 | -26.6015 ± 13.40656 |
| CD16+, Session2,Day1, 5 hour 40 minutes, n=2,4,2,4 | -130.1500 ± 78.98383 | -35.3433 ± 40.19923 | -94.3000 ± 56.85139 | -29.1195 ± 15.07448 |
| CD16+, Session2,Day1,9 hour 40 minutes,n-0,0,0,4 | — | — | — | -24.5510 ± 13.98978 |
| CD16+,Session2,Day2, Pre-fluid sampling, n=2,4,2,4 | 125.5000 ± 47.37615 | 162.8120 ± 171.51836 | 427.5000 ± 132.22897 | 42.9945 ± 58.62985 |
| CD16+,Session2,Day3, Pre-fluid sampling, n=2,4,2,4 | -24.5000 ± 40.30509 | -6.6285 ± 33.04476 | 142.5000 ± 71.41778 | -11.7065 ± 24.07118 |
| CD163+, Session2,Day1, 40 minutes, n=2,4,2,4 | -371.000 ± 199.4041 | -833.203 ± 131.9463 | -721.000 ± 131.5219 | -511.618 ± 152.8883 |
| CD163+, Session2,Day1,2 hour 40 minutes, n=2,4,2,4 | -499.500 ± 147.7853 | -902.203 ± 205.5423 | -790.000 ± 8.4853 | -426.253 ± 144.1939 |
| CD163+, Session2,Day1,5 hour 40 minutes, n=2,4,2,4 | -363.500 ± 112.4300 | -694.390 ± 222.5211 | -522.500 ± 112.4300 | -376.659 ± 156.2613 |
| CD163+, Session2,Day1, 9 hour 40 minutes,n-0,0,0,4 | — | — | — | -314.464 ± 132.3300 |
| CD163+,Session2,Day2, Pre-fluid sampling,n=2,4,2,4 | 4.500 ± 19.0919 | 146.403 ± 737.3912 | 22.500 ± 225.5671 | -73.247 ± 127.0624 |
| CD163+,Session2,Day3, Pre-fluid sampling,n=2,4,2,4 | -66.000 ± 8.4853 | 3.801 ± 244.5535 | -80.000 ± 66.4680 | 63.254 ± 54.8309 |
| CD206+, Session2,Day1, 40 minutes, n=2,3,2,4 | -502.500 ± 171.8269 | -892.543 ± 205.7220 | 86.500 ± 263.7508 | 932.807 ± 829.8233 |
| CD206+, Session2,Day1,2 hour 40 minutes, n=2,2,2,4 | 1011.000 ± 2743.5743 | -583.485 ± 672.1029 | -293.500 ± 102.5305 | 1808.345 ± 1763.3758 |
| CD206+, Session2,Day1,5 hour 40 minutes, n=2,2,2,4 | -388.500 ± 74.2462 | -686.465 ± 521.9367 | 12.000 ± 309.7128 | 2051.872 ± 858.1801 |
| CD206+, Session2,Day1,9 hour 40 minutes,n=0,0,0,4 | — | — | — | 2546.884 ± 2810.2028 |
| CD206+,Session2,Day2, Pre-fluid sampling,n=2,2,2,4 | 423.000 ± 196.5757 | -202.457 ± 181.7519 | 273.000 ± 407.2935 | 1724.197 ± 901.9847 |
| CD206+,Session2,Day3, Pre-fluid sampling,n=2,4,2,4 | -496.500 ± 422.1427 | -469.550 ± 397.5609 | -9.500 ± 504.1671 | 11.054 ± 268.4708 |
| CD209+, Session2,Day1, 40 minutes, n=2,4,2,4 | 15.800 ± 109.6016 | 4.001 ± 37.3132 | -9.700 ± 200.1112 | -16.194 ± 23.7386 |
| CD209+, Session2,Day1,2 hour 40 minutes, n=2,4,2,4 | -78.650 ± 39.1030 | -9.406 ± 15.8402 | -2.650 ± 9.9702 | -10.000 ± 17.4401 |
| CD209+, Session2,Day1,5 hour 40 minutes, n=2,4,2,4 | 17.350 ± 123.2487 | -17.622 ± 25.5632 | -44.250 ± 85.9135 | 10.936 ± 32.9481 |
| CD209+, Session2,Day1,9 hour 40 minutes,n=0,0,0,4 | — | — | — | -7.284 ± 34.7539 |
| CD209+,Session2,Day2,Pre-fluid sampling,n=2,4, 2,4 | 36.450 ± 150.6845 | -3.732 ± 32.4741 | 174.850 ± 143.8962 | 71.592 ± 146.6326 |
| CD209+,Session2,Day3, Pre-fluid sampling,n=2,4,2,4 | -30.630 ± 180.9203 | -7.759 ± 29.9928 | 5.850 ± 122.2588 | 23.752 ± 61.2399 |
| CD40, Session2,Day1, 40 minutes, n=2,4,2,4 | -96.5000 ± 111.01576 | -36.2400 ± 53.43955 | 340.0000 ± 53.74012 | -74.1970 ± 70.63576 |
| CD40, Session2,Day1,2 hour 40 minutes, n=2,4,2,4 | -84.0000 ± 263.04372 | -34.9520 ± 59.47287 | -97.0000 ± 43.84062 | -36.8868 ± 86.92683 |
| CD40, Session2,Day1,5 hour 40 minutes, n=2,4,2,4 | -136.5000 ± 48.79037 | -3.5480 ± 23.88276 | -62.0000 ± 117.37973 | -9.8278 ± 40.48593 |
| CD40, Session2,Day1,9 hour 40 minutes,n=0,0,0,4 | — | — | — | 36.2845 ± 55.24688 |
| CD40, Session2,Day2, Pre-fluid sampling,n=2,4, 2,4 | 29.5000 ± 86.97413 | 76.4310 ± 173.35366 | 1.0000 ± 26.87006 | 87.4498 ± 34.37912 |
| CD40, Session2,Day3, Pre-fluid sampling,n=2, 4,2,4 | -184.5000 ± 20.50610 | -8.5503 ± 56.03828 | 1.5000 ± 218.49600 | -33.4253 ± 54.35736 |
| CD80, Session2,Day1, 40 minutes, n=2, 4,2,4 | -56.0000 ± 15.55635 | 22.5760 ± 29.07877 | 151.5000 ± 36.06245 | -10.8950 ± 7.78157 |
| CD80, Session2,Day1,2 hour 40 minutes, n=2,4,2,4 | -48.5000 ± 85.55992 | -14.4080 ± 34.73965 | -43.0000 ± 4.24264 | -11.1910 ± 6.58469 |
| CD80, Session2,Day1,5 hour 40 minutes, n=2, 4,2,4 | -80.5000 ± 27.57716 | -28.4175 ± 31.59217 | -112.9000 ± 97.43931 | -5.9842 ± 18.30542 |
| CD80, Session2,Day1,9 hour 40 minutes, n=0,0,0,4 | — | — | — | 13.1760 ± 30.88285 |
| CD80,Session2,Day2, Pre-fluid sampling,n=2, 4,2,4 | 46.0000 ± 7.07107 | 33.8863 ± 44.87592 | 48.0000 ± 76.36753 | 51.1900 ± 44.73616 |
| CD80,Session2,Day3, Pre-fluid sampling,n=2, 4,2,4 | 45.5000 ± 78.48885 | 11.4885 ± 25.25635 | -5.5000 ± 21.92031 | 29.5018 ± 31.07571 |
| CD83, Session2,Day1, 40 minutes, n=2, 4,2,4 | -360.500 ± 676.7012 | -509.522 ± 743.2824 | 341.000 ± 1500.4806 | 268.284 ± 705.8063 |
| CD83, Session2,Day1,2 hour 40 minutes, n=2, 4,2,4 | 254.500 ± 866.2058 | -192.732 ± 586.9635 | -157.500 ± 96.8736 | 113.359 ± 989.9087 |
| CD83, Session2,Day1,5 hour 40 minutes, n=2, 4,2,4 | -441.500 ± 844.9926 | 136.272 ± 346.4007 | 56.500 ± 610.2332 | -694.319 ± 570.1803 |
| CD83, Session2,Day1,9 hour 40 minutes,n=0,0,0,4 | — | — | — | 450.242 ± 1654.9166 |
| CD83,Session2,Day2, Pre-fluid sampling,n=2, 4,2,4 | -32.000 ± 394.5656 | 185.975 ± 797.3145 | -312.000 ± 417.1930 | -72.629 ± 223.2647 |
| CD83,Session2,Day3, Pre-fluid sampling,n=2, 4,2,4 | -547.000 ± 687.3078 | -261.969 ± 458.2399 | -618.500 ± 1304.6120 | -461.280 ± 449.4745 |
| CD86+, Session2,Day1, 40 minutes, n=2, 4,2,4 | -93.5000 ± 17.67767 | -51.3590 ± 54.09737 | -35.0000 ± 100.40916 | 22.1330 ± 58.85301 |
| CD86+, Session2,Day1,2 hour 40 minutes, n=2, 4,2,4 | 15.5000 ± 191.62594 | -80.7150 ± 36.89354 | -62.5000 ± 40.30509 | 7.4130 ± 91.99398 |
| CD86+, Session2,Day1,5 hour 40 minutes, n=2, 4,2,4 | -130.0000 ± 65.05382 | -85.0973 ± 32.66115 | -11.5000 ± 183.14066 | -77.6915 ± 70.58944 |
| CD86+, Session2,Day1,9 hour 40 minutes,n=0,0,0,4 | — | — | — | -58.9008 ± 99.84882 |
| CD86+,Session2,Day2, Pre-fluid sampling,n=2, 4,2,4 | 32.5000 ± 88.38835 | 43.1203 ± 47.48816 | 120.5000 ± 44.54773 | 27.5388 ± 55.57075 |
| CD86+,Session2,Day3, Pre-fluid sampling,n=2, 4,2,4 | -60.5000 ± 37.47666 | 20.5612 ± 21.58116 | 35.5000 ± 153.44217 | -17.0975 ± 38.55065 |
| HLA-DR, Session2,Day1, 40 minutes, n=2, 4,2,4 | -1701.500 ± 96.8736 | -3036.438 ± 1102.3399 | -2247.000 ± 1572.6055 | -1240.116 ± 874.3051 |
| HLA-DR, Session2,Day1,2 hour 40 minutes, n=2,4,2,4 | -706.000 ± 1269.9638 | -3133.030 ± 1601.2468 | -1898.000 ± 733.9768 | -764.884 ± 1616.7399 |
| HLA-DR, Session2,Day1,5 hour 40 minutes, n=2,4,2,4 | -1452.000 ± 366.2813 | -2242.108 ± 1155.9978 | -1296.500 ± 352.8463 | -126.436 ± 774.0775 |
| HLA-DR, Session2,Day1,9 hour 40 minutes,n=0,0,0,4 | — | — | — | 798.182 ± 1011.1423 |
| HLA-DR,Session2,Day2, Pre-fluid sampling,n=2,4,2,4 | -171.000 ± 835.8002 | 924.615 ± 1288.5384 | 2717.500 ± 2687.7129 | 904.203 ± 1067.6177 |
| HLA-DR,Session2,Day3, Pre-fluid sampling,n=2,4,2,4 | -957.500 ± 514.0666 | -978.224 ± 661.5084 | -3.000 ± 612.3545 | -549.404 ± 673.4385 |
Blood samples were planned to be collected at indicated time-points for the measurement of activation. Latest pre-challenge (LPS or GM-CSF) assessment with a non-missing value, including those from unscheduled visits was considered as Baseline. Change from Baseline was calculated as the value at specified visit minus the Baseline value. Part 2 of the study was not conducted as agreed criteria for Interim analysis was achieved.
No measurements were reported for this outcome.
Blood samples were collected at indicated time-points for the measurement of activation markers by flow cytometry for dendritic cells in blood. Activation markers included CD16, CD163, CD206, CD209, CD40, CD80, CD83, CD86 and HLA-DR. Latest pre-challenge (LPS or GM-CSF) assessment with a non-missing value, including those from unscheduled visits was considered as Baseline. Change from Baseline was calculated as the value at specified visit minus the Baseline value.
| Mean fluorescence intensity | Part 1: LPS 0.5 ng/kg | Part 1: LPS 0.75 ng/kg | Part 1: LPS 1 ng/kg | Part 1: GM-CSF 60 µg/m^2 |
|---|---|---|---|---|
| CD16+, Session2,Day1, 40 minutes, n=2, 4, 2,4 | -1492.500 ± 1341.3816 | -468.314 ± 270.9419 | -1418.700 ± 1089.3687 | -215.981 ± 31.8638 |
| CD16+, Session2,Day1, 2 hour 40 minutes, n=2,4,2,4 | -1561.000 ± 1359.0592 | -579.984 ± 235.0820 | -1495.500 ± 1535.1288 | -118.536 ± 142.1664 |
| CD16+, Session2,Day1, 5 hour 40 minutes, n=2,4,2,4 | -1061.000 ± 823.0723 | -530.365 ± 208.1743 | -1334.500 ± 1035.9114 | 171.104 ± 275.2637 |
| CD16+, Session2,Day1,9 hour 40 minutes,n-0,0,0,4 | — | — | — | 265.065 ± 334.2355 |
| CD16+,Session2,Day2, Pre-fluid sampling, n=2,4,2,4 | 135.500 ± 446.1844 | 300.333 ± 432.7904 | 309.500 ± 436.2849 | 168.661 ± 115.8827 |
| CD16+,Session2,Day3, Pre-fluid sampling, n=2,4,2,4 | -564.500 ± 536.6940 | 1116.482 ± 840.6096 | 984.000 ± 130.1076 | 4.757 ± 149.9929 |
| CD163+, Session2,Day1, 40 minutes, n=2,4,2,4 | 41.0000 ± 65.05382 | -3.8803 ± 39.59977 | -160.5000 ± 152.02796 | 58.3640 ± 66.82273 |
| CD163+, Session2,Day1,2 hour 40 minutes, n=2,4,2,4 | -53.5000 ± 31.81981 | -28.0153 ± 33.20632 | -187.5500 ± 156.34131 | 47.3110 ± 48.31955 |
| CD163+, Session2,Day1,5 hour 40 minutes, n=2,4,2,4 | 28.0000 ± 87.68124 | 13.7295 ± 38.55623 | -41.5000 ± 101.11627 | -12.9720 ± 77.32898 |
| CD163+, Session2,Day1, 9 hour 40 minutes,n=0,0,0,4 | — | — | — | -24.0198 ± 66.75178 |
| CD163+,Session2,Day2, Pre-fluid sampling,n=2,4,2,4 | -35.0000 ± 35.35534 | 68.9850 ± 76.56191 | 239.0000 ± 11.31371 | -19.7730 ± 57.09070 |
| CD163+,Session2,Day3, Pre-fluid sampling,n=2,4,2,4 | 38.0000 ± 50.91169 | 175.6860 ± 104.35800 | 88.5000 ± 27.57716 | -10.6642 ± 38.84898 |
| CD206+, Session2,Day1, 40 minutes, n=2,2,2,4 | -75.000 ± 130.1076 | -140.156 ± 160.1010 | 241.000 ± 22.6274 | 552.855 ± 259.4200 |
| CD206+, Session2,Day1,2 hour 40 minutes, n=2,2,2,4 | 570.500 ± 164.7559 | -130.065 ± 141.4567 | 124.000 ± 229.1026 | 444.094 ± 454.3525 |
| CD206+, Session2,Day1,5 hour 40 minutes, n=2,2,2,4 | -54.500 ± 106.7731 | -84.217 ± 161.6658 | 0.500 ± 215.6676 | 262.268 ± 126.1299 |
| CD206+, Session2,Day1,9 hour 40 minutes,n=0,0,0,4 | — | — | — | 275.423 ± 163.9991 |
| CD206+,Session2,Day2, Pre-fluid sampling,n=2,2,2,4 | 8.500 ± 57.2756 | 70.416 ± 127.1590 | 193.000 ± 190.9188 | 164.064 ± 33.1212 |
| CD206+,Session2,Day3, Pre-fluid sampling,n=2,2,2,4 | -87.500 ± 89.8026 | -7.138 ± 143.0385 | 120.000 ± 277.1859 | 106.723 ± 28.9729 |
| CD209+, Session2,Day1, 40 minutes, n=2,4,2,4 | -46.5000 ± 82.73149 | 18.4320 ± 55.78181 | -105.6500 ± 125.08719 | -6.6660 ± 43.24876 |
| CD209+, Session2,Day1,2 hour 40 minutes, n=2,4,2,4 | -42.0000 ± 16.97056 | -19.1610 ± 8.85490 | 226.5000 ± 201.52543 | -19.5825 ± 32.92128 |
| CD209+, Session2,Day1,5 hour 40 minutes, n=2,4,2,4 | -53.5000 ± 28.99138 | -3.8503 ± 17.48560 | -42.8500 ± 1.90919 | -15.8723 ± 25.15864 |
| CD209+, Session2,Day1,9 hour 40 minutes,n=0,0,0,4 | — | — | — | -45.1118 ± 38.63888 |
| CD209+,Session2,Day2,Pre-fluid sampling,n=2,4, 2,4 | 6.5000 ± 53.03301 | -4.8983 ± 19.52432 | 158.5000 ± 65.76093 | 46.9815 ± 100.06420 |
| CD209+,Session2,Day3, Pre-fluid sampling,n=2,4,2,4 | -64.5000 ± 68.58936 | -16.7770 ± 8.10389 | -9.5000 ± 58.68986 | -6.7250 ± 35.83716 |
| CD40, Session2,Day1, 40 minutes, n=2,4,2,4 | -77.5000 ± 105.35891 | 24.1702 ± 96.21606 | -17.1500 ± 143.04770 | -37.4720 ± 29.71510 |
| CD40, Session2,Day1,2 hour 40 minutes, n=2,4,2,4 | -248.5000 ± 194.45436 | -37.2498 ± 30.55431 | -74.1500 ± 35.14321 | -11.0400 ± 65.99710 |
| CD40, Session2,Day1,5 hour 40 minutes, n=2,4,2,4 | -191.0000 ± 22.62742 | -35.5593 ± 26.02435 | -55.0500 ± 114.62201 | 78.3045 ± 54.05275 |
| CD40, Session2,Day1,9 hour 40 minutes,n=0,0,0,4 | — | — | — | 102.0438 ± 67.79389 |
| CD40, Session2,Day2, Pre-fluid sampling,n=2,4, 2,4 | -93.0000 ± 70.71068 | 62.5378 ± 130.98543 | 135.5000 ± 51.61880 | 83.1860 ± 92.90385 |
| CD40, Session2,Day3, Pre-fluid sampling,n=2, 4,2,4 | -359.9500 ± 219.13239 | 108.3750 ± 91.11295 | 152.5000 ± 78.48885 | 5.2222 ± 66.38351 |
| CD80, Session2,Day1, 40 minutes, n=2, 4,2,4 | -4.000 ± 72.1249 | -35.839 ± 78.4625 | 666.250 ± 1446.3869 | -11.569 ± 10.9548 |
| CD80, Session2,Day1,2 hour 40 minutes, n=2,4,2,4 | -104.500 ± 2.1213 | -95.364 ± 66.7035 | -138.800 ± 45.5377 | -15.964 ± 41.2839 |
| CD80, Session2,Day1,5 hour 40 minutes, n=2, 4,2,4 | -146.000 ± 7.0711 | -85.528 ± 66.3639 | -139.800 ± 25.7387 | 22.829 ± 39.2596 |
| CD80, Session2,Day1,9 hour 40 minutes, n=0,0,0,4 | — | — | — | 19.214 ± 43.1702 |
| CD80,Session2,Day2, Pre-fluid sampling,n=2, 4,2,4 | 34.000 ± 31.1127 | 11.103 ± 88.5547 | 75.000 ± 26.8701 | 36.587 ± 15.1919 |
| CD80,Session2,Day3, Pre-fluid sampling,n=2, 4,2,4 | -47.500 ± 2.1213 | 82.987 ± 84.8958 | 113.500 ± 16.2635 | 11.929 ± 20.6629 |
| CD83, Session2,Day1, 40 minutes, n=2, 4,2,4 | -225.000 ± 31.1127 | 0.262 ± 93.0741 | 647.500 ± 358.5031 | 8.260 ± 38.7864 |
| CD83, Session2,Day1,2 hour 40 minutes, n=2, 4,2,4 | -26.500 ± 246.7803 | -56.590 ± 73.5714 | -17.500 ± 309.0057 | 4.970 ± 118.6525 |
| CD83, Session2,Day1,5 hour 40 minutes, n=2, 4,2,4 | -127.000 ± 97.5807 | -54.265 ± 56.5138 | -40.000 ± 52.3259 | -11.648 ± 63.0964 |
| CD83, Session2,Day1,9 hour 40 minutes,n=0,0,0,4 | — | — | — | 223.093 ± 184.1060 |
| CD83,Session2,Day2, Pre-fluid sampling,n=2, 4,2,4 | -58.000 ± 134.3503 | 125.239 ± 117.8095 | 243.500 ± 153.4422 | 72.982 ± 123.0727 |
| CD83,Session2,Day3, Pre-fluid sampling,n=2, 4,2,4 | -241.500 ± 103.9447 | 142.101 ± 59.5839 | 38.500 ± 188.7975 | -33.869 ± 79.7178 |
| CD86+, Session2,Day1, 40 minutes, n=2, 4,2,4 | -93.5000 ± 21.92031 | -101.1600 ± 78.03703 | 56.0000 ± 29.69848 | 8.9678 ± 29.25980 |
| CD86+, Session2,Day1,2 hour 40 minutes, n=2, 4,2,4 | 14.0000 ± 250.31580 | -121.3668 ± 68.34453 | -144.5000 ± 28.99138 | 30.0005 ± 101.61342 |
| CD86+, Session2,Day1,5 hour 40 minutes, n=2, 4,2,4 | -54.5000 ± 40.30509 | -94.3938 ± 35.37430 | -44.0000 ± 214.96046 | 106.9465 ± 53.12949 |
| CD86+, Session2,Day1,9 hour 40 minutes,n=0,0,0,4 | — | — | — | 118.6338 ± 49.28502 |
| CD86+,Session2,Day2, Pre-fluid sampling,n=2, 4,2,4 | 41.5000 ± 75.66043 | 126.1853 ± 105.91022 | 194.5000 ± 13.43503 | 83.4098 ± 63.12670 |
| CD86+,Session2,Day3, Pre-fluid sampling,n=2, 4,2,4 | -91.0000 ± 32.52691 | 117.9230 ± 55.75943 | 82.0000 ± 94.75231 | 15.2970 ± 75.45627 |
| HLA-DR, Session2,Day1, 40 minutes, n=2, 4,2,4 | 445.50 ± 434.871 | 896.74 ± 1309.134 | 41096.00 ± 47912.141 | -2795.55 ± 2243.871 |
| HLA-DR, Session2,Day1,2 hour 40 minutes, n=2,4,2,4 | -2457.50 ± 775.696 | -1417.49 ± 1937.407 | -5430.00 ± 5929.797 | -1430.37 ± 2743.193 |
| HLA-DR, Session2,Day1,5 hour 40 minutes, n=2,4,2,4 | -320.00 ± 523.259 | -1744.11 ± 2077.874 | -1604.00 ± 3859.389 | -1347.06 ± 2935.540 |
| HLA-DR, Session2,Day1,9 hour 40 minutes,n=0,0,0,4 | — | — | — | -943.38 ± 4035.982 |
| HLA-DR,Session2,Day2, Pre-fluid sampling,n=2,4,2,4 | -1449.00 ± 1571.191 | 688.02 ± 1710.854 | -2085.00 ± 4775.799 | 800.49 ± 2738.323 |
| HLA-DR,Session2,Day3, Pre-fluid sampling,n=2,4,2,4 | -2292.50 ± 416.486 | -2030.80 ± 2398.091 | -6379.00 ± 9237.643 | 113.79 ± 2769.699 |
Blood samples were planned to be collected at indicated time-points for the measurement of activation. Latest pre-challenge (LPS or GM-CSF) assessment with a non-missing value, including those from unscheduled visits was considered as Baseline. Change from Baseline was calculated as the value at specified visit minus the Baseline value. Part 2 of the study was not conducted as agreed criteria for Interim analysis was achieved.
No measurements were reported for this outcome.
Blood samples were collected at indicated time-points for analysis of leukocyte. Latest pre-challenge assessment with a non-missing value, including those from unscheduled visits was considered as Baseline. Change from Baseline was calculated as the value at specified visit minus the Baseline value.
| Cells per milliliter | Part 1: LPS 0.5 ng/kg | Part 1: LPS 0.75 ng/kg | Part 1: LPS 1 ng/kg |
|---|---|---|---|
| Session2, Day 1, 40 minutes | -358893.71 ± 1002862.023 | -1477705.00 ± 811560.729 | -2065961.83 ± 1083290.576 |
| Session2, Day 1, 2 hours 40 minutes | 3347754.14 ± 1701524.775 | 2423233.00 ± 2047535.993 | 5224467.23 ± 800613.402 |
| Session2, Day 1, 5 hours 40 minutes | 2116748.36 ± 3209541.020 | 4511414.25 ± 3044446.191 | 3641780.22 ± 1458532.473 |
| Session2, Day 2, Pre-fluid sample | -447452.27 ± 101410.586 | 881299.75 ± 1640158.830 | 442226.68 ± 232936.722 |
| Session2, Day 3, Pre-fluid sample | -169328.51 ± 21593.240 | -93685.25 ± 1383413.608 | 75348.31 ± 927892.867 |
Blood samples were planned to be collected at indicated time-points for the measurement of activation. Latest pre-challenge assessment with a non-missing value, including those from unscheduled visits was considered as Baseline. Change from Baseline was calculated as the value at specified visit minus the Baseline value. Part 2 of the study was not conducted as agreed criteria for Interim analysis was achieved.
No measurements were reported for this outcome.
Blood samples were planned to be collected at indicated time-points for analysis of white blood cells. Baseline value is Session 2 Day 1. Change from Baseline was calculated as the value at specified visit minus the Baseline value. Part 2 of the study was not conducted as agreed criteria for Interim analysis was achieved.
No measurements were reported for this outcome.
Collected over Adverse events (AEs) and serious adverse events (SAEs) were collected from the start of study treatment until 69 days in Part 1 of the study.. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Part 1: LPS 0.5 ng/kg | 0/2 (0%) | 0/2 (0%) | 2/2 (100%) |
| Part 1: LPS 0.75 ng/kg | 0/4 (0%) | 0/4 (0%) | 4/4 (100%) |
| Part 1: LPS 1 ng/kg | 0/2 (0%) | 0/2 (0%) | 2/2 (100%) |
| Part 1: GM-CSF 60 µg/m^2 | 0/4 (0%) | 0/4 (0%) | 3/4 (75%) |
| Part 2: Participants With LPS | — | — | — |
| Part 2: Participants With GM-CSF | — | — | — |
| Event | Part 1: LPS 0.5 ng/kg | Part 1: LPS 0.75 ng/kg | Part 1: LPS 1 ng/kg | Part 1: GM-CSF 60 µg/m^2 | Part 2: Participants With LPS | Part 2: Participants With GM-CSF |
|---|---|---|---|---|---|---|
| ChillsGeneral disorders | 0/2 | 4/4 | 2/2 | 0/4 | — | — |
| HeadacheNervous system disorders | 0/2 | 2/4 | 2/2 | 1/4 | — | — |
| NasopharyngitisInfections and infestations | 1/2 | 2/4 | 1/2 | 0/4 | — | — |
| FolliculitisInfections and infestations | 0/2 | 0/4 | 1/2 | 0/4 | — | — |
| MyalgiaMusculoskeletal and connective tissue disorders | 0/2 | 1/4 | 1/2 | 0/4 | — | — |
| Oropharyngeal painRespiratory, thoracic and mediastinal disorders | 1/2 | 1/4 | 0/2 | 0/4 | — | — |
| CoughRespiratory, thoracic and mediastinal disorders | 0/2 | 0/4 | 1/2 | 0/4 | — | — |
| Productive coughRespiratory, thoracic and mediastinal disorders | 0/2 | 0/4 | 1/2 | 0/4 | — | — |
| Abdominal painGastrointestinal disorders | 0/2 | 0/4 | 1/2 | 0/4 | — | — |
| Alanine aminotransferase increasedInvestigations | 1/2 | 0/4 | 0/2 | 0/4 | — | — |
Part 2 of the study was not conducted as agreed criteria for Interim analysis was achieved.
| Age, Continuous(Years) | Part 1: LPS 0.5 ng/kg | Part 1: LPS 0.75 ng/kg | Part 1: LPS 1 ng/kg | Part 1: GM-CSF 60 µg/m^2 | Part 2: Participants With LPS | Part 2: Participants With GM-CSF | Total |
|---|---|---|---|---|---|---|---|
| Mean | 23.5 ± 4.95 | 35.5 ± 7.55 | 31.5 ± 10.61 | 33.5 ± 7.33 | — | — | 32.2 ± 7.81 |
| Sex: Female, Male(Participants) | Part 1: LPS 0.5 ng/kg | Part 1: LPS 0.75 ng/kg | Part 1: LPS 1 ng/kg | Part 1: GM-CSF 60 µg/m^2 | Part 2: Participants With LPS | Part 2: Participants With GM-CSF | Total |
|---|---|---|---|---|---|---|---|
| Female | 0 | 0 | 0 | 0 | — | — | 0 |
| Male | 2 | 4 | 2 | 4 | — | — | 12 |
| Race/Ethnicity, Customized(Count of Participants) | Part 1: LPS 0.5 ng/kg | Part 1: LPS 0.75 ng/kg | Part 1: LPS 1 ng/kg | Part 1: GM-CSF 60 µg/m^2 | Part 2: Participants With LPS | Part 2: Participants With GM-CSF | Total |
|---|---|---|---|---|---|---|---|
| White: WHITE/CAUCASIAN/EUROPEAN HERITAGE | 2 | 4 | 2 | 4 | — | — | 12 |
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GlaxoSmithKline