Clinical trial NCT03306589: Lipopolysaccharide (LPS) or Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) Challenge Study on Healthy Subjects
Official title: An Open Label Parallel Group Study to Investigate the Optimum Methodology for the Use of LPS or GM-CSF as Challenge Agents on Healthy Participants by Assessing Inflammatory Biomarkers in Cantharidin-induced Skin Blisters, Peripheral Blood, and Urine
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Arthritis, Rheumatoid
Keywords: Inflammation
GM-CSF
LPS
Skin blisters
Healthy subjects
cantharidin
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2017-10-11
Enrollment: 12
Sex: MALE
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Subjects in 2 separate groups will be randomized to receive either LPS or GM-CSF at the same time.
Primary purpose: DIAGNOSTIC

Brief summary: 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.


Eligibility criteria: 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.

Primary outcomes:
measure: Part 1: Change From Baseline Primary Soluble Inflammatory Mediators in Blood: Tumor Necrosis Factor (TNF) Alpha and Interleukin (IL) 6 for LPS Arm
timeFrame: 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
measure: Part 1: Change From Baseline in Primary Soluble Inflammatory Mediators : Urinary Tetranor Prostaglandin D Metabolite (PGDM) LPS Arm
timeFrame: Baseline, Session 2 Day 1
measure: Part 2: Change From Baseline Primary Soluble Inflammatory Mediators in Blood: TNF Alpha and IL 6: LPS Arm
timeFrame: 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
measure: Part 2: Change From Baseline Primary Soluble Inflammatory Mediators : Urinary Tetranor PGDM: LPS Arm
timeFrame: Baseline, Session 2 Day 1
measure: Part 1: Change From Baseline in White Blood Cell Numbers in Blood: GM-CSF
timeFrame: 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
measure: Part 2: Change From Baseline in White Blood Cell Numbers in Blood: GM-CSF
timeFrame: 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:
measure: Part 1: Change From Baseline Soluble Inflammatory Biomarkers in Skin Blister
timeFrame: Baseline; Session1: 48 hours on Day3; Session 2: 24 hours on Day 2 and 48 hours on Day 3
measure: Part 2: Change From Baseline Soluble Inflammatory Biomarkers in Skin Blister
timeFrame: Baseline; Session1: 48 hours Day3; Session 2: 24 hours Day 2 and 48 hours Day 3
measure: Part 1: Absolute Values of Blister Volume
timeFrame: Baseline, Session 1: 48 hours Day 3. Session 2: 24 hours Day 2, 48 hours Day 3
measure: Part 2: Absolute Values of Blister Volume
timeFrame: Baseline, Session 1: 48 hours Day 3. Session 2: 24 hours Day 2, 48 hours Day 3
measure: Part 1: Change From Baseline in Cell Numbers in Blister
timeFrame: Baseline, Session 1: 48 hours Day 3. Session 2: 24 hours Day 2, 48 hours Day 3
measure: Part 2: Change From Baseline in Cell Numbers in Blister
timeFrame: Baseline, Session 1: 48 hours Day 3. Session 2: 24 hours Day 2, 48 hours Day 3
measure: Part 1:Change From Baseline in Cell Activation Markers by Flow Cytometry on Monocytes in Blister
timeFrame: Baseline, Session1: 48 hours Day 3, Session 2: 24 hours Day 2 and 48 hours Day 3
measure: Part 2:Change From Baseline in Cell Activation Markers by Flow Cytometry on Monocytes in Blister
timeFrame: Baseline, Session1: 48 hours Day 3, Session 2: 24 hours Day 2 and 48 hours Day 3
measure: Part 1:Change From Baseline of CD40+/CD80+ by Flow Cytometry on Monocytes in Blister
timeFrame: Baseline, Session1: 48 hours Day 3, Session 2: 24 hours Day 2 and 48 hours Day 3
measure: Part 2:Change From Baseline of CD40+/CD80+ by Flow Cytometry on Monocytes in Blister
timeFrame: Baseline, Session1: 48 hours Day 3, Session 2: 24 hours Day 2 and 48 hours Day 3
measure: Part 1:Change From Baseline in Cell Activation Markers by Flow Cytometry on Dendritic Cells in Blister
timeFrame: Baseline; Session1: 48 hours Day 3, Session 2: 24 hours Day 2 and 48 hours Day 3
measure: Part 2:Change From Baseline in Cell Activation Markers by Flow Cytometry on Dendritic Cells in Blister
timeFrame: Baseline, Session1: 48 hours Day 3, Session 2: 24 hours Day 2 and 48 hours Day 3
measure: Part 1:Change From Baseline of CD40+/CD80+ by Flow Cytometry on Dendritic Cells in Blister
timeFrame: Baseline, Session1: 48 hours Day 3, Session 2: 24 hours Day 2 and 48 hours Day 3
measure: Part 2:Change From Baseline of CD40+/CD80+ by Flow Cytometry on Dendritic Cells in Blister
timeFrame: Baseline, Session1: 48 hours Day 3, Session 2: 24 hours Day 2 and 48 hours Day 3
measure: Part 1:Change From Baseline in Cell Activation Markers by Flow Cytometry on Macrophages in Blister
timeFrame: Baseline, Session1: 48 hours Day 3, Session 2: 24 hours Day 2 and 48 hours Day 3
measure: Part 2:Change From Baseline in Cell Activation Markers by Flow Cytometry on Macrophages in Blister
timeFrame: Baseline, Session1: 48 hours Day 3, Session 2: 24 hours Day 2 and 48 hours Day 3
measure: Part 1:Change From Baseline of CD40+/CD80+ by Flow Cytometry on Macrophages in Blister
timeFrame: Baseline, Session1: 48 hours Day 3, Session 2: 24 hours Day 2 and 48 hours Day 3
measure: Part 2:Change From Baseline of CD40+/CD80+ by Flow Cytometry on Macrophages in Blister
timeFrame: Baseline, Session1: 48 hours Day 3, Session 2: 24 hours Day 2 and 48 hours Day 3
measure: Part 1:Change From Baseline in Soluble Inflammatory Mediators in Blood
timeFrame: 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
measure: Part 2:Change From Baseline in Soluble Inflammatory Mediators in Blood
timeFrame: 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
measure: Part 1: Change From Baseline in Soluble Inflammatory Mediators in Blood: TNF-alpha, IL-6 and GM-CSF: GM-CSF Arm
timeFrame: 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
measure: Part 2: Change From Baseline in Soluble Inflammatory Mediators in Blood: TNF-alpha, IL-6 and GM-CSF for GM-CSF Arm
timeFrame: 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
measure: Part 1: Change From Baseline in Soluble Inflammatory Mediators in Blood: C-reactive Protein (CRP)
timeFrame: Baseline; Session 2: Post challenge Day 1. Pre-fluid sample on Day 2 and Day 3
measure: Part 2: Change From Baseline in Soluble Inflammatory Mediators in Blood: CRP
timeFrame: Baseline; Session 2: Post challenge Day 1; Pre-fluid sample on Day 2 and Day 3
measure: Part 1: Change From Baseline in Cell Activation Markers by Flow Cytometry on Monocytes in Blood
timeFrame: 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
measure: Part 2: Change From Baseline in Cell Activation Markers by Flow Cytometry on Monocytes in Blood
timeFrame: 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
measure: Part 1: Change From Baseline in Cell Activation Markers by Flow Cytometry on Dendritic Cells in Blood
timeFrame: 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
measure: Part 2: Change From Baseline in Cell Activation Markers by Flow Cytometry on Dendritic Cells in Blood
timeFrame: 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
measure: Part 1: Change From Baseline in Circulating Leukocyte Numbers in Blood: LPS Arm
timeFrame: 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
measure: Part 2: Change From Baseline in Circulating Leukocyte Numbers in Blood: LPS Arm
timeFrame: 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
Other outcomes:
Locations:
city: Cambridge
country: United Kingdom
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References: