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

NCT ID: NCT03306589

Last Updated: 2019-08-08

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 12 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-08-11
• Study Completion Date: 2018-06-20

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.

Conditions

Arthritis, Rheumatoid

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: DIAGNOSTIC
• Blinding Strategy: NONE

Study Groups

Subjects receiving LPS: Part I and Part II

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.

Group Type: EXPERIMENTAL

Cantharidin

Intervention Type: BIOLOGICAL

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

Lipopolysaccharide

Intervention Type: BIOLOGICAL

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.

Saline Solution

Intervention Type: DRUG

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.

Subjects receiving GM-CSF: Part I and Part II

Eligible subjects will be randomized to receive GM-CSF in a dose-escalation manner ranging from 5 to 15 microgram (µg)/kg.

Group Type: EXPERIMENTAL

Cantharidin

Intervention Type: BIOLOGICAL

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

Granulocyte-Macrophage Colony-Stimulating Factor

Intervention Type: BIOLOGICAL

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.

Interventions

Cantharidin

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

Intervention Type: BIOLOGICAL

Lipopolysaccharide

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.

Intervention Type: BIOLOGICAL

Granulocyte-Macrophage Colony-Stimulating Factor

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.

Intervention Type: BIOLOGICAL

Saline Solution

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.

Intervention Type: DRUG

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 45 Years
• Eligible Sex: MALE
• Accepts Healthy Volunteers: Yes

Sponsors

GlaxoSmithKline

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

GSK Clinical Trials

Role: STUDY_DIRECTOR

GlaxoSmithKline

Locations

GSK Investigational Site

Cambridge, , United Kingdom

Countries

United Kingdom

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

207654

Identifier Type: -

Identifier Source: org_study_id