Lipopolysaccharide (LPS) or Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) Challenge Study on Healthy Subjects
Condition: Arthritis, Rheumatoid
MeSH terms: Arthritis, Rheumatoid
Intervention: Cantharidin; Lipopolysaccharide; Granulocyte-Macrophage Colony-Stimulating Factor; Saline Solution
Intervention description: 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.
Intervention MeSH terms: Molgramostim; Sargramostim; Cantharidin
Phase: Phase 1
Study type: Interventional
Primary purpose: Diagnostic
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Subjects in 2 separate groups will be randomized to receive either LPS or GM-CSF at the same time.
Masking: None (Open Label)
Masking description: This will be an open label study and no masking will be performed.
Enrollment: 12.0
Sex: Male
Minimum age: 18 Years
Maximum age: 45 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: Inflammation; GM-CSF; LPS; Skin blisters; Healthy subjects; cantharidin

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.