Lipopolysaccharide (LPS) or Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) Challenge Study on Healthy Subjects

GlaxoSmithKline12 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

DIAGNOSTIC

Masking

NONE

Enrollment

Interventions

CantharidinBIOLOGICAL

5 microliter (µL) of 0.2 percent Cantharidin solution (diluted in acetone) will be applied to all subjects on forearm by topical route.

LipopolysaccharideBIOLOGICAL

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.

Granulocyte-Macrophage Colony-Stimulating FactorBIOLOGICAL

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.

Saline SolutionDRUG

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.

Eligibility

Sex: MALEMin age: 18 YearsMax age: 45 YearsHealthy volunteers:

Medical Language ↔ Plain English

Inclusion Criteria: * Subjects must be 18 to 45 years of age inclusive, at the time of signing the informed consent. * Subjects who are overtly healthy as determined by medical evaluation including: medical history, physical examination, laboratory tests, and electrocardiogram (ECG). * Body mass index (BMI) within the range 19.0-30.0 kilogram per meter square (kg/m\^2) (inclusive). * All male subjects. All subjects must agree to use contraception during session 2 and refrain from donating sperm from session 2 to end of study (follow up 2 visits). * Capable of giving signed informed consent. Exclusion criteria: * A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening. * A positive test for human immuno deficiency virus (HIV) antibody. * Persistent abnormal C-reactive protein/ white cell count (CRP/ WCC) levels at screening. * Abnormal liver function tests at screening. For healthy subjects: Aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase and bilirubin more than or equal to 1.5xupper limit of normal (ULN) (isolated bilirubin more than 1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin less than 35 percent) at screening. * A positive pre-study drug/alcohol screen. * Current, or chronic history of (h/o): liver disease or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones), anaphylaxis, and /or anaphylactoid (resembling anaphylaxis) reactions; Cardiac, respiratory or renal disease (childhood asthma can be included); Sensitivity or severe allergic responses to any of the challenge agents or cantharidin, or components thereof or a history of drug or other allergy that, in the opinion of the Investigator or GlaxoSmithKline (GSK) Medical Monitor, contraindicates their participation; Vasovagal syncope; Surgery or significant trauma in 3 months leading to study enrolment; Relevant skin conditions (for example recent h/o eczema or recurrent eczema, keloid, skin allergies, psoriasis, atopic dermatitis, and vitiligo) which in the opinion of the investigator could pose safety issues or cause interference with study procedures; Sepsis or known coagulation disorders; Peripheral edema, lymphangitis, lymph edema, pleural or pericardial effusion; Respiratory conditions including but not limited to asthma, Chronic obstructive pulmonary disease (COPD), and bronchiectasis and any current respiratory infection. * Presence on either forearm of tattoos, naevi, hypertrophic scars, keloids, hyper or hypo-pigmentation. Subjects with very fair skin, very dark skin, excessive hair or any skin abnormalities that may, in the opinion of the Investigator, interfere with study assessments. * Unable to refrain from the use of prescription drugs taken on an intermittent (as needed) basis or non-prescription drugs; these include non-steroidal anti-inflammatory drugs (NSAIDs), vitamins, herbal and dietary supplements (including St John's Wort) within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to Day 1 of session 1 and continuing until the final follow up visit). * The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 90 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer) or currently in a study of an investigational device. * Previous exposure to LPS in a clinical research setting. Where participation in the study would result in donation of blood or blood products in excess of 500 milliliter (mL) within a 56-day period; Current smoker or former regular smoker within 6 months before the screening visit; Unwillingness or inability to follow the procedures outlined in the protocol.

Locations (1)

GSK Investigational Site

Cambridge, United Kingdom

Outcomes

Primary Outcomes

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

Secondary Outcomes

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

Data from ClinicalTrials.gov

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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.